neonatal life support - pediatrics...2020/10/19 · article type: supplement article citation:...

Prepublication Release

©2020 American Academy of Pediatrics and American Heart Association, Inc.

Neonatal Life Support 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment

Recommendations

Myra H. Wyckoff, MD, Chair; Gary M. Weiner, MD; On behalf of the Neonatal Life Support

Collaborators

DOI: 10.1542/peds.2020-038505C

Journal: Pediatrics

Article Type: Supplement Article

Citation: Wyckoff MH, Weiner GM, et al. Neonatal Life Support 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Pediatrics. 2020; doi: 10.1542/peds.2020-038505C

This article has been copublished in Circulation.

This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version.

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Neonatal Life Support 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

Myra H. Wyckoff, MD, Chair; Gary M. Weiner, MD; On behalf of the Neonatal Life Support Collaborators ABSTRACT: This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) for neonatal life support includes evidence from 7 systematic reviews, 3 scoping reviews, and 12 evidence updates. The Neonatal Life Support Task Force generally determined by consensus the type of evidence evaluation to perform; the topics for the evidence updates followed consultation with International Liaison Committee on Resuscitation member resuscitation councils. The 2020 CoSTRs for neonatal life support are published either as new statements or, if appropriate, reiterations of existing statements when the task force found they remained valid.

Evidence review topics of particular interest include the use of suction in the presence of both clear and meconium-stained amniotic fluid, sustained inflations for initiation of positive-pressure ventilation, initial oxygen concentrations for initiation of resuscitation in both preterm and term infants, use of epinephrine (adrenaline) when ventilation and compressions fail to stabilize the newborn infant, appropriate routes of drug delivery during resuscitation, and consideration of when it is appropriate to redirect resuscitation efforts after significant efforts have failed.

All sections of the Neonatal Resuscitation Algorithm are addressed, from preparation through to postresuscitation care. This document now forms the basis for ongoing evidence evaluation and reevaluation, which will be triggered as further evidence is published.

Over 140 million babies are born annually worldwide (https:// ourworldindata.org/grapher/births-and-deaths-projected-to-2100). If up to 5% receive positive-pressure ventilation, this evidence evaluation is relevant to more than 7 million newborn infants every year. However, in terms of early care of the newborn infant, some of the topics addressed are relevant to every single baby born.

The full author list is available on page S214.

Key Words: AHA Scientific Statements ■ cardiopulmonary resuscitation ■ neonatal resuscitation ◼ neonate

© 2020 American Heart Association, Inc., European Resuscitation Council, International Liaison Committee on Resuscitation, and American Academy of Pediatrics

This article has been copublished in Circulation.


https://ourworldindata.org/grapher/births-and-deaths-projected-to-2100

https://ourworldindata.org/grapher/births-and-deaths-projected-to-2100

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CONTENTS Abstract. ................................................................. S185 Evidence Evaluation Process. .................................. S187 Generation of Topics. ................................................. S188 2020 Topics Reviewed… ...................................... S189 Anticipation and Preparation… ............................... S189

Prediction of Need of Respiratory Support in the Delivery Room (NLS 611: EvU… .......... S189 Effect of Briefing/Debriefing Following Neonatal Resuscitation (NLS 1562: ScopRev) …S190

Initial Assessment and Intervention. ....................... S190 Warming Adjuncts (NLS 599: EvUp). ............. S190 Suctioning of Clear Fluid (NLS 596: ScopRev) ...................................................... S191 Tracheal Intubation and Suction of Nonvigorous Meconium-Stained Newborns (NLS 865: SysRev) .......................................... S192

Physiological Monitoring and Feedback Devices… S194 Heart Rate Monitoring During Neonatal Resuscitation (NLS 898: EvUp) ...................... S194

Ventilation and Oxygenation… ............................... S195 Sustained Inflation (NRP 809: SysRev) ............... S195 PEEP Versus No PEEP (NLS 897: EvUp) .............. S199 CPAP Versus Intermittent Positive Pressure Ventilation (NLS 590: EvUp) ............................ S199 T-Piece Resuscitator Versus Self-Inflating Bag for Ventilation (NLS 870: ScopRev) ..................... S200 Oxygen for Preterm Resuscitation (NLS 864: 2019 CoSTR). ............................................. S201 Oxygen for Term Resuscitation (NLS 1554: 2019 CoSTR) ................................................ S201

Circulatory Support. .............................................. S202 CPR Ratios for Neonatal Resuscitation (NLS 895: EvUp) .................................................... S202 2-Thumb Versus 2-Finger Compressions for Neonatal Resuscitation (NLS 605: EvUp) ....... S202

Drug and Fluid Administration. ............................... S203 Epinephrine (Adrenaline) for Neonatal Resuscitation (NLS 593: SysRev) .................... S203 Intraosseous Versus Umbilical Vein for Emergency Access (NLS 616: SysRev) ............ S205 Volume Infusion During Neonatal Resuscitation (NLS 598: EvUp) ....................... S207 Sodium Bicarbonate During Neonatal Resuscitation (NLS: 606 EvUp) ....................... S207

Prognostication During CPR. ................................... S208 Impact of Duration of Intensive Resuscitation

(NLS 896: SysRev) .......................................... S208 Postresuscitation Care. ........................................... S212

Rewarming of Hypothermic Newborns (NLS 858: EvUp) .................................................... S212 Induced Hypothermia in Settings With Limited Resources (NLS 734: EvUp) ................... S213 Postresuscitation Glucose Management (NLS 607: EvUp) ............................................ S213

Topics Not Reviewed in 2020… ............................ S214 Acknowledgments… ............................................ S214 Disclosures ................................................................. S215 References. ................................................................. S216

Transition from intrauterine to extrauterine life at

birth requires several critical interdependent physiological events to occur rapidly to allow successful conversion from placental to pulmonary gas exchange.1 Air breathing leads to significant reductions in pulmonary vascular resistance, which increases pulmonary blood flow and thereby maintains left ventricular filling and output (vital for coronary and cerebral perfusion) when the umbilical cord is clamped.2 When the low-resistance placental circulation is removed, systemic vascular resistance and blood pressure increase and right-to-left shunting across the ductus arteriosus decreases.

The majority (approximately 85%) of babies born at term will initiate breathing within 10 to 30 seconds of birth.3 An additional 10% will do so in response to stimulation and drying.4 Nevertheless, approximately 5% of term infants receive positive-pressure ventilation (PPV) to successfully transition, 2% are intubated, 0.1% receive cardiac compressions, and 0.05% receive compressions with epinephrine.5–8 Although most infants successfully transition without assistance, the large number of births worldwide means that availability of appropriate, timely intervention can prevent morbidity and save millions of newborn lives each year.

Newborn infants who are breathing or crying and have good tone and an adequate heart rate may undergo delayed cord clamping and should be dried and placed skin to skin with their mothers to prevent hypothermia. This does not preclude the need for clinical assessment of the newborn as secondary apnea, persistent cyanosis, or breathing difficulties can still occur. For the approximately 5% of newborn infants who do not initiate adequate respiratory effort after stimulation by drying and warming, providers must deliver effective ventilation with a face mask. This is effective in most cases. If it is not effective, providers should take measures to eliminate mask leaks, check for airway patency, and ensure that adequate inflation pressures are used; if ventilation is still not effective, an alternative airway (endotracheal tube or supraglottic airway) must be considered. Providers must optimize ventilation because it is the most important step for successful transition. If, despite efforts to optimize ventilation, the newborn has a persistent heart rate less than 60/min or asystole, then chest compressions are needed. Epinephrine and administration of fluids for circulatory volume expansion may also be required. The neonatal resuscitation algorithm is shown in Figure 1 and is unchanged from 2015.1,9,10


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Figure 1. Neonatal Resuscitation Algorithm. CPAP indicates continuous positive airway pressure; ECG, electrocardiographic; ET, endotracheal; HR, heart rate; IV, intravenous; and PPV, positive-pressure ventilation.

EVIDENCE EVALUATION PROCESS The 2020 International Consensus on Cardiopulmo- nary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) Science With Treatment Recommendations (CoSTR) is the fourth in a series of annual publications from the International Liaison Committee on

Resuscitation (ILCOR) for neonatal life support (NLS). This 2020 CoSTR for NLS includes new topics addressed by systematic reviews performed within the past 12 months. It also includes updates of NLS treatment recommendations published from 2010 through 2019, based on additional evidence evaluations. The 3 types of evidence evaluation supporting this 2020 document


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are the systematic review (SysRev), the scoping review (ScopRev) and the evidence update (EvUp). The choice of the type of evidence evaluation to perform was determined by consensus of the task force and, in the case of EvUps, recommendations of ILCOR member resuscitation councils.

The SysRev is a rigorous process following strict methodology to answer a specific question. The SysRevs informed NLS Task Force deliberations that are summarized in the NLS Task Force CoSTRs included in this document. The SysRevs were performed by a knowledge synthesis unit, an expert systematic reviewer, or by the NLS Task Force, and many resulted in separately published SysRevs.

To begin the SysRev, the question to be answered was developed using the PICOST (population, intervention, comparator, outcome, study design, time frame) format. The methodology used to identify the evidence was based on the Preferred Reporting Items for System- atic Reviews and Meta-Analyses (PRISMA: http://www. prisma-statement.org). The approach used to evaluate the evidence was based on that proposed by the Grad- ing of Recommendations, Assessment, Development and Evaluation (GRADE) working group (https://gdt. gradepro.org/app/handbook/handbook.html). By using this approach for each of the predefined outcomes, the task force rated as high, moderate, low, or very low the certainty/confidence in the estimates of effect of an intervention or assessment across a body of evidence. Randomized controlled trials (RCTs) generally began the analysis as high-certainty evidence, and observational studies generally began the analysis as low- certainty evidence; examination of the evidence using the GRADE approach could result in downgrading or upgrading the certainty of evidence. For additional information, refer to this supplement’s “Evidence Evalua- tion Process and Management of Potential Conflicts of Interest” section.11,11a Disclosure information for writing group members is listed in Appendix 1. Disclosure information for peer reviewers is listed in Appendix 2.

Draft 2020 CoSTRs for NLS were posted on the IL- COR website (www.ilcor.org) for public comment be-

tween January 15, 2019, and February 20, 2020, with comments accepted through March 4 for the last NLS CoSTR posted. All of the NLS draft CoSTRs were viewed a total of 45 032 times, with 279 comments posted. When online viewing statistics were available for individual CoSTRs, these are included in the topic information.

This summary statement contains the final wording of the CoSTRs as approved by the ILCOR task forces and by the ILCOR member councils after review and consideration of comments posted online in response to the draft CoSTRs. Within this manuscript, each topic includes the PICOST as well as the CoSTR, an ex- panded “Justification and Evidence-to-Decision Frame- work Highlights” section, and a list of knowledge gaps

requiring future research studies. In Appendix A in the Supplemental Materials, an evidence-to-decision table is included for each CoSTR and is based on a new SysRev.

The second type of evidence evaluation performed to support this 2020 CoSTR for NLS is the ScopRev. ScopRevs are designed to identify the extent, range, and nature of evidence on a topic or a question, and they were performed by topic experts in consultation with the NLS Task Force. The task force analyzed the identified evidence and determined its value and implications for resuscitation practice or research. The rationale for the ScopRev, the summary of evidence, and task force insights are all highlighted in the body of this manuscript. The most recent treatment recommendations are included. The NLS Task Force notes whether the ScopRev identified substantive evidence suggesting the need for a future SysRev to support the development of an updated CoSTR. Meanwhile, the current treatment recommendation is reiterated. All ScopRevs are included in their entirety in Appendix B in the Supplemental Materials.

The third type of evidence evaluation supporting this 2020 CoSTR for NLS is an EvUp. EvUps are generally performed to identify new studies published after the most recent NLS evidence evaluation, typically through use of similar search terms and methodologies used in previous reviews. These EvUps were performed by task force members, collaborating experts, or members of ILCOR member resuscitation council writing groups. The EvUps are cited in the body of this document with a note as to whether the evidence identified suggested the need to consider a SysRev; the existing ILCOR treatment recommendation is reiterated. In this document, no change in IL- COR treatment recommendations resulted from an EvUp. If substantial new evidence was identified, the task force recommended consideration of a SysRev. All draft EvUps are included in Appendix C in the Supplemental Materials.

GENERATION OF TOPICS After publication of the 2015 International Consensus on CPR and ECC Science With Treatment Recommenda- tions,1,9,10 the NLS Task Force, together with additional neonatal resuscitation content experts (approximately 50 neonatal medicine and nursing professionals, from 17 countries, with expertise in neonatal resuscitation research, education, and implementation), reviewed the list of prior neonatal resuscitation clinical questions to divide them into 3 categories: those that could be retired, those that remained relevant but required additional clinical studies to better address the PICOST question, and those with sufficient evidence to justify a SysRev in the near future. New questions were also proposed and categorized. The list was posted for public comment in June 2017, and as a result, some amendments were made. Using the new ILCOR process of continuous evidence evaluation (see “Evidence Evaluation Process and Management


http://www.prisma-statement.org/

http://www.prisma-statement.org/

https://gdt.gradepro.org/app/handbook/handbook.html

https://gdt.gradepro.org/app/handbook/handbook.html

http://www.ilcor.org/

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of Potential Conflicts of Interest”11 in this supplement), the active questions were prioritized for SysRevs as ILCOR resources became available. Other topics were slated for ScopRevs or EvUps as noted above. The task force met via webinar at least monthly and in person annually; in addition, the task force met with the larger content expert group semiannually to present the science and debate and discuss treatment recommendations. The task

Postresuscitation Care • Rewarming of hypothermic newborns (NLS 858:

EvUp) • Induced hypothermia in settings with limited

resources (NLS 734: EvUp) • Postresuscitation glucose management (NLS 607:

EvUp)

force and larger group of content experts identified and reviewed the published literature and reached consensus to review the topics included in this manuscript.

ANTICIPATION AND PREPARATION The keys to successful neonatal resuscitation include

assessment of perinatal risk and a system to rapidly 2020 TOPICS REVIEWED Anticipation and Preparation

• Prediction of need of respiratory support in the delivery room (NLS 611: EvUp)

• Effect of briefing/debriefing following neonatal resuscitation (NLS 1562: ScopRev)

Initial Assessment and Intervention • Warming adjuncts (NLS 599: EvUp) • Suctioning of clear fluid (NLS 596: ScopRev) • Tracheal intubation and suction of nonvigorous

meconium-stained newborns (NLS 865: SysRev) Physiological Monitoring and Feedback Devices

• Heart rate monitoring during neonatal resuscitation (NLS 898: EvUp)

Ventilation and Oxygenation • Sustained inflation (NLS 809: SysRev) • Positive end-expiratory pressure (PEEP) versus no

PEEP (NLS 897: EvUp) • Continuous positive airway pressure (CPAP) versus

intermittent PPV (NLS 590: EvUp) • T-piece resuscitator versus self-inflating bag for

ventilation (NLS 870: ScopRev) • Oxygen for preterm resuscitation (NLS 864: 2019

CoSTR publication) • Oxygen for term resuscitation (NLS 1554: 2019

CoSTR publication) Circulatory Support

• CPR ratios for neonatal resuscitation (NLS 895: EvUp)

• 2-thumb versus 2-finger compressions for neonatal resuscitation (NLS 605: EvUp)

Drug and Fluid Administration • Epinephrine (adrenaline) for neonatal resuscitation

(NLS 593: SysRev) • Intraosseous versus umbilical vein for emergency

access (NLS 616: SysRev) • Volume infusion during neonatal resuscitation

(NLS 598: EvUp) • Sodium bicarbonate during neonatal resuscitation

(NLS 606: EvUp) Prognostication During CPR

• Impact of duration of intensive resuscitation (NLS 896: SysRev)

assemble team members with skills that are appropriate to the anticipated need for resuscitation on the basis of that risk. Other critical components of successful resuscitation include an organized resuscitation area that ensures immediate access to all needed supplies and equipment and the standardization of behavioral skills that foster optimal teamwork and communication.

Prediction of Need of Respiratory Support in the Delivery Room (NLS 611: EvUp) One important aspect of anticipating risk (determining if operative delivery conferred increased risk of need for intubation) was reviewed by the NLS Task Force most recently in 2010.12–14 In 2020, The NLS Task Force undertook an EvUp to identify additional evidence published after 2010 that warranted consideration of a new SysRev.

An EvUp (see Supplement Appendix C-1) did not identify any evidence that would suggest the need for a new SysRev or a change in the 2010 treatment recommendation.12–14 Most of the new studies confirmed previously identified risk factors for the need for PPV in the delivery room.

Population, Prognostic Factors, Outcome Population: Newborn infants who are to be delivered

Prognostic factors: Maternal, perinatal, or delivery risk factors beyond age of gestation

Outcome: Prediction of need for PPV in the delivery room/operating suite

Treatment Recommendation These treatment recommendations (below) are unchanged from 2010.12–14

When an infant without antenatally identified risk factors is delivered at term by cesarean delivery under regional anesthesia, a provider capable of performing assisted ventilation should be present at the delivery. It is not necessary for a provider skilled in neonatal intubation to be present at that delivery.


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Effect of Briefing/Debriefing Following Neonatal Resuscitation (NLS 1562: ScopRev) Rationale for Review Although a prior review examined the utility of debriefing after simulation training, the NLS Task Force chose this topic for ScopRev because there is emerging evidence in many fields that briefing before and debriefing after clinical events may lead to improvement in practice and outcomes. There was no previous NLS Task Force treatment recommendation on this application of briefing and debriefing.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

• Population: Among healthcare professionals involved in the resuscitation or simulated resuscitation of a neonate

• Intervention: Does briefing/debriefing • Comparator: In comparison with no briefing/

debriefing • Outcome: Improve outcomes for infants, families,

or clinicians • Study design: RCTs and nonrandomized stud-

ies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Manikin studies were eligible for inclusion; animal studies were excluded. Conference abstracts were included; unpublished studies (eg, trial protocols) were excluded.

• Time frame: All years and all languages were included if there was an English abstract.

Summary of Evidence The ScopRev14a identified 1 RCT15 and 3 observational studies of preintervention and postintervention design.16–18 One study considered video debriefing,16 1 considered the use of a checklist combined with video debriefing,18 and 1 considered the use of a checklist with a team prebrief/debrief as the key el- ement in a quality improvement bundle.17 The RCT determined whether there was benefit to rapid cycle deliberate practice compared with standard simulation debriefing.15 This entire ScopRev14a can be found in Supplement Appendix B-1.

Task Force Insights

The evidence identified in this ScopRev is primarily from quality-improvement studies with preintervention and postintervention comparisons. There were no RCTs comparing briefing or debriefing with no briefing or no debriefing. In addition, many investigators studied briefing or debriefing in the context of bundles of interventions; these studies were not included in this evidence review because it was not possible to isolate

the effects of briefing or debriefing alone on outcomes. A small number of studies were identified that included adjuncts to briefing and debriefing (eg, the

review of video recordings to assist debriefing, the use of checklists); these studies compared the use of

adjuncts with no briefing or no debriefing. There is limited evidence that use of video-assisted debriefing may improve the process of care and adherence

to resuscitation guidelines, but none of the included studies evaluated the effect on clinical outcomes.

The use of checklists during briefings and debriefings may help improve team communication and process,

but the evidence did not report changes in clinical outcomes, and the reported effects on the delivery of care were inconsistent.

We identified limited evidence that rapid-cycle deliberate practice may improve short term performance in a resuscitation simulation but not provider confidence in or retention of skills. These findings were similar to a recent SysRev completed by the ILCOR Education, Implementation, and Teams Task Force (see “Education, Implementation, and Teams: Spaced Versus Massed Learning,” in this supplement [EIT 601: SysRev]), which included neonatal studies and also identified limited evidence that rapid-cycle deliberate practice may improve short-term performance in a resuscitation simulation but not provider confidence in or retention of skills.

We conclude that briefing or debriefing may improve short-term clinical and performance outcomes for infants and staff. The effects of briefing or debriefing on long-term clinical and performance outcomes are uncertain.

This scoping review did not identify sufficient evidence to prompt a SysRev.

Treatment Recommendation There was no previous treatment recommendation on the topic.

Because this is a new PICOST question for the NLS Task Force, the task force elected to perform a ScopRev to assess the extent and type of available studies. Although briefing and debriefing in resuscitation has been previously reviewed by the NLS Task Force12–14 and the Educa- tion, Implementation, and Teams Task Force,19,20 clinical outcomes specific to neonates or neonatal resuscitation were not included in those recommendations.

INITIAL ASSESSMENT AND INTERVENTION Warming Adjuncts (NLS 599: EvUp) Maintenance of normal temperature is a key initial step in stabilization of the newborn at birth. There are multiple strategies to prevent hypothermia of the



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newborn. The NLS Task Force published the most recent CoSTR summarizing the evidence supporting warming adjuncts in 2015.1,9,10 In 2020, the NLS Task Force undertook an EvUp to identify any additional studies that would warrant consideration of a new SysRev.


• Population: Preterm neonates less than 32 weeks’ gestationalagewhoareunderradiantwarmersinthe hospital delivery room

• Intervention: Increased room temperature, thermal mattress, or another warming adjunct

• Comparator: Compared with plastic wraps alone • Outcome21:

– Primary: Hypothermia (less than 36.0ºC) on admission to neonatal intensive care unit (NICU)

– Secondary: ○ Survival (critical) ○ Morbidities associated with hypothermia

(important) ○ Hyperthermia and associated morbidities

(important) The EvUp (see Supplement Appendix C-2) identified 13 studies (5 SysRevs and 8 RCTs) supporting the 2015 CoSTR.1,9,10 Although the 2015 treatment recommendations were limited to very preterm babies born at less than 33 weeks’ gestational age, the recommendations remain relevant. The task force agreed to suggest the need for a SysRev on the topic of warming adjuncts in the near future. The task force also suggests division of the target populations to separately analyze effects and pertinent outcomes for term versus preterm infants.

Treatment Recommendation These treatment recommendations (below) are unchanged from 2015.1,9,10

Among newborn preterm infants of less than 32 weeks’ gestation under radiant warmers in the hospital delivery room, we suggest using a combination of interventions that may include environmental temperature 23°C to 25°C, warm blankets, plastic wrapping without drying, cap, and thermal mattress to reduce hypothermia (temperature less than 36.0°C) on admission to NICU (weak recommendation, very low-certainty evidence).

We suggest that hyperthermia (greater than 38.0°C) be avoided because it introduces potential associated risks (weak recommendation, very low-certainty evidence).

Suctioning of Clear Fluid (NLS 596: ScopRev) Rationale for Review Transition from an intrauterine (fetal) to an extrauterine (newborn) physiology involves the replacement of lung liquid in the airways with air. To support liquid clearance, oropharyngeal/nasopharyngeal suctioning at

birth was traditionally used to remove oral and nasal secretions in vigorous infants at birth. The 2010 CoSTR for NLS suggested against this routine practice for the first time.12–14 Similarly, the 2015 American Heart Asso- ciation Guidelines Update for CPR and ECC for neonatal resuscitation emphasized that “suctioning immediately after birth, whether with a bulb syringe or suction catheter, may be considered only if the airway appears obstructed or if PPV is required.”22 The balance of risks and benefits associated with routine suctioning remain controversial. Because this literature has not been sys- tematically reviewed in over a decade, the task force agreed that a ScopRev would determine if there is sufficient evidence published after 2010 to warrant a new SysRev in the near future.


• Population: Newborns delivered through clear amniotic fluid

• Intervention: Immediate routine suctioning (oropharyngeal or nasopharyngeal)

• Comparator: No suctioning or wiping • Outcome21:

– Survival (critical) – Need for delivery room resuscitation and stabili-

zation interventions (important) – Oxygen supplementation, use of PPV, intubation,

CPR/medications, Apgar scores, time to reach heart rate greater than 100/min (important)

– Complications following procedure (desaturation, delay in initiation of PPV, tissue injury, infection)

– Respiratory complications (respiratory distress, tachypnea) (important)

– Other inpatient morbidities (important) • Study design: RCTs and nonrandomized studies

(non-RCTs, interrupted times series, controlled before-and-after studies, cohort studies) were eligible for inclusion

• Time frame: All years and languages were included if there was an English abstract; unpublished studies (eg, conference abstracts, trial protocols) were excluded. Literature search was updated to November 30, 2019.

Summary of Evidence Evidence supporting potential benefits of oropharyngeal/nasopharyngeal suctioning is limited and the practice remains controversial. Oropharyngeal suctioning does not impact liquid removal from the lung. The procedure can have serious side effects.

• It is possible that nasopharyngeal suctioning may result in vagal-induced bradycardia as well as increased risk of infection.23

• The procedure may take significant time to complete.24



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• Suctioning may delay initiation of ventilation in nonbreathing infants.3

• Newborns who received suctioning compared with a control group had significantly lower oxygen saturation through the first 6 minutes of life and took longer to reach a normal saturation range.24,25

• There is a concern that suctioning may have serious additional consequences, such as irritation to mucous membranes and increased risk of iatrogenic infection,26,27 bradycardia,26,28 apnea,28 hypoxemia and arterial oxygen desaturation,25,27,29 hypercap- nia,30 impaired cerebral blood flow regulation,31,32

increased intracranial pressure,33 and development of subsequent neonatal brain injury.34

The entire ScopRev can be found in Supplement Ap- pendix B-2.

Task Force Insights The NLS Task Force noted several strengths and limitations of the evidence identified by the ScopRev:

• The identified studies were from diverse geographical areas, but the results were similar.

• The literature identified by this ScopRev allowed comparisons in 2 types of subgroups (vaginal versus cesarean delivery and preterm versus term infants).

• Most new studies appear to be consistent with the current recommendation of “no routine suctioning” of the newborns in the delivery room.

• Because of the large number of patients (greater than 1500) reported in studies published since 2015, a new SysRev including these patients is likely to increase the certainty of the evidence through GRADE evaluation.

The NLS Task Force suggests consideration of an updated SysRev for this PICO question: “Among vigorous infants delivered through clear amniotic fluid (P), does immediate routine suctioning (oropharyngeal or nasopharyngeal) (I) compared with no suctioning or wiping C) change outcome (O)?” Until such a SysRev is completed and analyzed, the current 2010 treatment recommendation remains.12–14

Treatment Recommendation This treatment recommendation (below) is unchanged from 2010.12–14

Routine intrapartum oropharyngeal and nasopharyngeal suctioning for newborn infants with clear or meconium-stained amniotic fluid is no longer recommended.

Tracheal Intubation and Suction of Nonvigorous Meconium-Stained Newborns (NLS 865: SysRev) Meconium-stained amniotic fluid is present in 5% to 15% of all deliveries and is more common in neonates who are nonvigorous at birth.35,36 Approximately 3% to 5% of neonates born through meconium-stained amniotic fluid develop meconium aspiration syndrome

(MAS), which remains a significant cause of neonatal morbidity and mortality, particularly in developing countries.37 Optimal management of neonates born through meconium-stained amniotic fluid remains a topic of debate. For decades, routine intubation and endotracheal suctioning for nonvigorous, meconium-exposed neonates was suggested on the basis of extremely low-certainty evidence. In 2015, after publication and analysis of new (although limited) randomized trial data, the NLS Task Force changed the treatment recommendation to eliminate routine tracheal intubation and suctioning for nonvigorous meconium-stained infants.1,9,10

Additional studies have been published since 2015, prompting the NLS Task Force to complete a new SysRev with meta-analysis.37


• Population: Nonvigorous infants born at 34 weeks’ or greater gestation delivered through meconium- stained amniotic fluid (of any consistency) at the start of resuscitation (nonvigorous defined as heart rate less than 100/min, decreased muscle tone, and/or depressed breathing at delivery)

• Intervention: Immediate laryngoscopy with or without intubation and suctioning

• Comparator: Immediate resuscitation without direct laryngoscopy at the start of resuscitation

• Outcome21: – Primary ○ Survival to hospital discharge (critical)

– Secondary ○ Neurodevelopmental impairment (critical) ○ MAS (critical) ○ Other respiratory outcomes (continuous posi-

tive airway pressure or mechanical ventilation, treatment of pulmonary hypertension with inhaled nitric oxide, oral medications or extracorporeal membrane oxygenation) (important)

○ Delivery room interventions (CPR/medications, intubation for PPV) (important)

○ Length of hospitalization (important) • Study design: RCTs and nonrandomized stud-

ies (non-RCTs, interrupted time series, controlled before-and-after studies, and cohort studies) were included in the review.

• Time frame: All years and languages were included if there was an English abstract; unpublished studies (eg, conference abstracts, trial protocols) and animal studies were excluded. The literature search was updated to May 2019.

A Priori Subgroups to Be Examined Consistency of meconium (thin versus thick), gestational age categories (late preterm [34 weeks to 36 weeks and 6 days], term [37 weeks to 41 weeks and 6 days], postterm [42 weeks or greater]), presence or absence




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of fetal bradycardia, route of delivery (spontaneous vaginal, instrumented vaginal, cesarean delivery), direct laryngoscopy with versus without suctioning.

International Prospective Register of Systematic Re- views (PROSPERO) Registration: CRD42019122778

Consensus on Science The SysRev identified 4 eligible studies that included 680 newborn infants.37 Data from 3 RCTs involving 449 newborns38–40 and 1 observational study involving 231 newborn infants41 were included.

A draft CoSTR document based on the SysRev was posted on the ilcor.org website for a 2-week public commenting period. During this period, the draft CoSTR was viewed over 5600 times and 65 comments were provided; most comments were very positive. However, there were concerns about clarity, which the task force subsequently addressed. Suggestions made were used to modify the wording of the treatment recommendations, justification and evidence-to-decision framework highlights, and the knowledge gaps to improve clarity. Although these treatment recommendations do not preclude the use of care- fully considered clinical judgment for individual cases, the NLS Task Force cannot use unpublished, personal observations to inform an international consensus on science or to guide treatment recommendations.

For the critical primary outcome of survival to discharge, we identified low-certainty evidence (downgraded for inconsistency and imprecision) from 3 RCTs38–40 involving 449 nonvigorous newborns delivered through meconium-stained amniotic fluid which showed no benefit from the use of immediate laryngoscopy with or without tracheal suctioning when compared with immediate resuscitation without laryngoscopy (relative risk [RR], 0.99; 95% CI, 0.93–1.06; P=0.87); absolute risk reduction, –0.9%; (95% CI, –6.4% to 5.5%), or 9 fewer patients/1000 survived to discharge with the intervention (95% CI, 64 fewer to 55 more patients per 1000 survived to discharge with the intervention). For complete data, see Table 1.

For the remainder of the outcomes of interest (eg, neurodevelopmental impairment (NDI), hypoxic-ischemic encephalopathy (HIE), MAS, use of mechanical ventilation, use of respiratory support excluding mechanical ventilation, endotracheal intubation for PPV in the delivery room, chest compressions in the delivery room, use of epinephrine in the delivery room, treatment of pulmonary hypertension, and length of hospitalization), evidence of very low certainty (downgraded for risk of bias, indirectness, and imprecision) showed no benefit from the use of immediate laryngoscopy with or without tracheal suctioning compared with immediate resuscitation without laryngoscopy for nonvigorous newborns delivered through meconium-stained amniotic fluid (Table 1).

The neurodevelopmental assessment from the single study that reported this outcome was performed at an early and nonstandard time, hence the results are poorly predictive of longer-term outcomes. Therefore, the task force concluded that the effect on NDI of immediate laryngoscopy with or without suctioning remains uncertain.

In 2015, the treatment recommendation indicated that there was insufficient human evidence to continue to suggest routine suctioning of meconium in nonvigorous babies born through meconium-stained amniotic fluid.1,9,10 This new 2020 recommendation is more direct in its suggestion against this practice.

Treatment Recommendations For nonvigorous newborn infants delivered through meconium-stained amniotic fluid, we suggest against routine immediate direct laryngoscopy with or without tracheal suctioning compared with immediate resuscitation without direct laryngoscopy (weak recommendation, low-certainty evidence).

Meconium-stained amniotic fluid remains a significant risk factor for receiving advanced resuscitation in the delivery room. Rarely, an infant may require intubation and tracheal suctioning to relieve airway obstruction.

Justification and Evidence-to-Decision Framework Highlights The task force recognizes that, although the direction of the treatment recommendation has not changed, several studies published after 2015 provide additional evidence to support the recommendation. These studies contributed new evidence, but the certainty of the findings remains low or very low because it is difficult to perform unbiased studies of this clinical question. Finally, even combining the data from all studies does not provide sufficient power for certainty as the optimal information size is still not achieved.

The NLS Task Force considered that the procedure of laryngoscopy and suctioning with or without tracheal intubation is invasive and has potential to harm, particularly if initiation of ventilation is delayed. This, together with the evidence of no benefit of routine tracheal suctioning, led the task force to suggest against routine practice of these interventions. It is possible that the infant born through meconium-stained fluid will require intubation for resuscitation. Therefore, trained personnel and equipment for intubation should be readily available for births where meconium-stained amniotic fluid is present. If meconium is obstructing the trachea, suctioning by using an endotracheal tube with a meconium aspirator may be effective in relieving the obstruction.42,43

See Supplement Appendix A-1 for the evidence-to- decision table for this SysRev.



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Table 1. Meta-analysis of RCTs of Immediate Laryngoscopy With or Without Tracheal Suctioning Versus Immediate Resuscitation Without Laryngoscopy for Nonvigorous Infants Born at 34 Weeks’ or Greater Gestation and Delivered Through Meconium-Stained Amniotic Fluid

Outcome

Article With Outcome of Interest

Total, n

Certainty of Evidence

RR (95% CI); I2

Absolute Difference (95% CI)

Survival at discharge Chettri, 201538; Nangia, 201639;

Singh, 201840

449 Low 0.99 (0.93–1.06); 29% 9/1000 fewer survived to discharge when laryngoscopy ± suction was used (64 fewer to 55 more per 1000)

Cognitive NDI Chettri, 201538 86 Very low 0.75 (0.37–1.50); NA 80/1000 fewer with cognitive NDI

when laryngoscopy ± suction was used (200 fewer to 159 more per 1000)

Motor NDI Chettri, 201538 86 Very low 0.91 (0.49–1.67); NA 31/1000 fewer with motor NDI when

laryngoscopy ± suction was used (174 fewer to 228 more per 1000)

HIE Nangia, 201639; Singh, 201840

327 Very low 0.85 (0.56–1.30); 0% 52/1000 fewer with HIE when laryngoscopy ± suction was used (152 fewer to 104 more per 1000)

MAS Chettri, 201538; Nangia, 201639;

Singh, 201840

449 Very low 0.94 (0.67–1.33); 49% 23/1000 fewer with MAS when laryngoscopy ± suction was used (126 fewer to 126 more per 1000)

Use of mechanical ventilation

Chettri, 201538; Nangia, 201639;

Singh, 201840

449 Very low 1.00 (0.66–1.53); 0% 0/1000 fewer were mechanically ventilated when laryngoscopy ± suction was used (54 fewer to 84 more per 1000)

Use of respiratory support excluding mechanical ventilation

Nangia 201639; Singh 201840

327 Very low 0.99 (0.81–1.20); 0% 4/1000 fewer received respiratory support excluding mechanical ventilation when laryngoscopy ± suction was used (73 fewer to 76 more per 1000)

Endotracheal intubation for PPV in the DR

Chettri, 201538; Nangia, 201639

297 Very low 1.15 (0.83–1.59); 0% 41/1000 more were intubated for PPV in the DR when laryngoscopy ± suction was used (47 fewer to 162 more per 1000)

Chest compressions in the DR


Singh, 201840

449 Very low 1.13 (0.40–3.20); 0% 4/1000 more received chest compressions in the DR when laryngoscopy ± suction was used (19 fewer to 68 more per 1000)

Epinephrine in the DR


Singh, 201840

449 Very low 1.62 (0.37–7.05); 0% 8/1000 more received epinephrine in the DR when laryngoscopy ± suction was used (from 8 fewer to 80 more per 1000)

Treatment of pulmonary hypertension (iNO, medications, ECMO)

Chiruvolu, 201841 231 Very low 0.52 (0.15–1.79); NA 29/1000 fewer received treatment

of pulmonary hypertension when laryngoscopy ± suction was used (50 fewer to 47 more per 1000)

Length of hospitalization, days

Nangia, 201639; Singh, 201840

327 Very low −0.5 days (–1.76 to 0.75); 80%

DR indicates delivery room; ECMO, extracorporeal membrane oxygenation; HIE, hypoxic-ischemic encephalopathy; iNO, inhaled nitric oxide; MAS, meconium aspiration syndrome; NA, not applicable; NDI, neurodevelopmental impairment; PPV, positive-pressure ventilation; RCT, randomized controlled trial; and RR, relative risk.

Knowledge Gaps Priorities for research include the following:

• Additional RCTs are needed that focus on nonvigorous infants in a variety of populations, such as where the incidence of MAS is low, and in settings with various levels of healthcare resources.

• Do risks or benefits of intubation with tracheal suctioning vary with any subgroup (gestational age, thickness of meconium, operator experience)?

• Long-term outcomes are needed in future studies. These include neurodevelopmental, behavioral, or educational assessment, which for future studies

should be at or beyond 18 months of age and completed with a validated tool.

PHYSIOLOGICAL MONITORING AND FEEDBACK DEVICES Heart Rate Monitoring During Neonatal Resuscitation (NLS 898: EvUp) After birth, the newborn’s heart rate is used to assess the effectiveness of spontaneous breathing and the need for interventions such as PPV, and it’s used as the marker


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of response to resuscitation interventions. Therefore, a rapid and reliable method of measuring the newborn’s heart rate is a critical adjunct for neonatal resuscitation. The most recent review of this topic was included in the 2015 CoSTR for NLS.1,9,10 The NLS Task Force undertook an EvUp to identify additional evidence published after 2015 that would warrant consideration of a new SysRev.


• Population: Newborns requiring resuscitation • Intervention: ECG monitoring • Comparator: Oximetry or auscultation • Outcome: Measurement of heart rate (speed and

reliability) (important)21

The EvUp (Supplement Appendix C-3) identified 7 additional studies published after the 2015 CoSTR Sys- Rev,1,9,10 including 2 SysRevs,44,452 RCTs,46,47 and 3 observational studies.48–50 All 7 studies supported the 2015 treatment recommendation.1,9,10 Thus, the NLS Task Force agreed that no new ILCOR SysRev is warranted at this time, and the current recommendation continues.

Of note, there is a need to develop an additional interventional PICOST to determine if routine use of ECG monitoring during neonatal resuscitation improves clinical outcomes. Also, improved tools and methods to enable detection and measurement of heart rate have been reported in the literature or are under development; as a result, the current PICOST question may be too limited in scope. Such methods include new heart rate monitors, digital stethoscopes, photoplethysmography methods in addition to pulse oximetry, and Dop- pler ultrasonography methods with auditory or visual displays. New interfaces for ECG monitoring include dry electrode technology. Future SysRevs will need to compare these technologies to the current “gold standard” of ECG monitoring with gel electrodes. Until such evidence is available, the NLS Task Force agreed that there is no justification to seek a new SysRev or alter the current (2015) treatment recommendations.

Treatment Recommendation This recommendation (below) has not changed from 2015.1,9,10

In babies requiring resuscitation, we suggest the ECG can be used to provide a rapid and accurate esti- mation of heart rate (weak recommendation, very low- certainty evidence).

VENTILATION AND OXYGENATION Sustained Inflation (NRP 809: SysRev) When a newborn does not breathe spontaneously, establishing functional residual capacity requires clearing the lung fluid and replacing it with air. Debate continues about the most effective method to achieve this. Animal

studies suggest that a longer sustained inflation may be beneficial for short term respiratory outcomes, but most such studies were performed in intubated animal models.51 It is unknown whether the same is true in newborn infants.52,53 In 2015, the NLS Task Force evaluated the evidence supporting use of sustained inflation for initiation of PPV in the delivery room and suggested against its routine use.1,9,10 Multiple clinical trials of sustained inflation have been published after that 2015 recommendation, prompting the NLS Task Force to request a 2020 SysRev.53a


• Population: Newborn infants who receive PPV due to bradycardia or ineffective respirations at birth

• Intervention: Initiation of PPV with sustained inflation(s) more than 1 second

• Comparator: Initiation of PPV with intermittent inflations, lasting 1 second or less per breath

• Outcome21: – Primary: Death before discharge (critical) – Secondary: ○ Death in the delivery room (critical) ○ Death within first 48 hours (critical) ○ Need for mechanical ventilation during hos-

pitalization (critical) ○ Air leaks (pneumothorax, pneumomediastinum,

pneumopericardium, pulmonary interstitial emphysema) reported individually or as a composite outcome at any time during initial hospitalization and also within first 48 hours (critical)

○ Bronchopulmonary dysplasia, any grade,54

defined as need for supplemental oxygen at 28 days of life; need for supplemental oxygen at 36 weeks’ gestational age for infants born at or before 32 weeks of gestation (critical)

○ Intraventricular hemorrhage: Of any grade55

and Grade 3 or above (critical) ○ Retinopathy of prematurity: Of any stage56

and Stage 3 or above (critical) ○ Death by time of latest follow-up (critical) ○ Long-term neurodevelopmental or behav-

ioral or education outcomes (greater than18 months of corrected age; test used to assess neurodevelopmental outcome should be of adequate quality and validated) (critical)

• Study design: RCTs and nonrandomized studies (non- RCTs, interrupted time series, controlled before-and- after studies, cohort studies) were eligible for inclusion.

• Time frame: All years and languages were included if there was an English abstract; unpublished studies (eg, conference abstracts, trial protocols) were excluded. Literature search was updated to October 25, 2019.

PROSPERO Registration: CRD 42020155639



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A Priori Subgroup Analyses Preterm infants at 28+0 weeks or less, 28 weeks and 1 day to 31 weeks and 6 days, 32 weeks to 36 weeks and 6 days, 37 weeks or more (term)

Duration of first sustained inflation: 1 to 5 seconds, 6 to 15 seconds, greater than 15 seconds

Inflation pressure used during first sustained inflation: 20 cm H2O or less, greater than 20 cm H2O

Interface or device used to generate sustained inflation: Nasopharyngeal tube, endotracheal tube, face mask, or T-piece device versus other device

A Priori Sensitivity Analyses Effects of whether or not studies allowed multiple sustained inflations

Effects of the methodological quality of trials (to ascertain whether studies with high risk of bias overesti- mated treatment effects)

Consensus on Science The SysRev identified 10 eligible RCTs including 1502 newborn infants. From analysis of this evidence, the NLS Task Force developed a draft CoSTR that was posted on the ILCOR website for a 2-week public commenting period beginning February 17, 2020. The Justification section was revised to address the public comments.

For the primary outcome of death before discharge, evidence of low certainty (downgraded for risk of bias and inconsistency) from 10 RCTs57–66 enrolling 1502 pre-

term newborns who received PPV for bradycardia or ineffective respirations at birth showed no significant benefit or harm from initiating PPV with sustained inflation greater than 1 second compared with initiating PPV with intermittent inflations lasting 1 second or less. See Table 2.

For the secondary critical long-term neurodevelopmental outcomes and death at latest follow-up, no

studies were identified. The remainder of the secondary outcomes are reported in Table 2.

Subgroup Analysis for Primary Outcome Subgroup Newborns Less Than 28+0 Weeks. For the critical outcome of death before discharge, low-certainty evidence (downgraded for risk of bias and imprecision) from 5 RCTs57,58,61,62,65 enrolling 862 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed evidence of potential harm from initiating PPV with sustained inflation(s) greater than 1 second compared with initiating PPV with intermittent inflations lasting 1 second or less per breath (RR, 1.38; 95% CI, 1.00–1.91; I2, 0%; 46 more patients/1000 died before hospital discharge with sustained inflation(s) [0 fewer to 110 more per 1000]). The number needed to harm is 22 (95% CI, 9–1000 or greater).

Subgroup Newborns 28+1 Weeks to 31+6 Weeks of Age. For the critical outcome of death before discharge, very low-certainty evidence (downgraded for risk

of bias and very serious imprecision) from 4 RCTs57,61,62,66

enrolling 175 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed no significant benefit or harm from initiating PPV with sustained inflation(s) greater than 1 second when compared with initiating PPV with intermittent inflations lasting 1 second or less per breath (RR, 1.33; 95% CI, 0.22–8.20; I2, 5%; 4 more patients/1000 died before hospital discharge with sustained inflation(s) [9 fewer to 86 more per 1000]).

Subgroup Newborns 32+0 to 36+6 Weeks. No published data for this gestational age group were available.

Subgroup Newborns 37+0 Weeks or More (Term). No published data for this gestational age group were available.

Subgroup Analyses: by Duration of First Sustained Inflation or Inflation Pressure of the Sustained Inflation. For the critical outcome of death before discharge, subgroup analyses were conducted for the duration of the first sustained inflation (6–15 seconds versus greater than 15 seconds) and for the inspiratory pressure of the first sustained inflation with inspiratory pressure greater than 20 mm Hg versus 20 mm Hg or less). For each of these subgroup analyses, the evidence was of very low certainty (downgraded for risk of bias in all cases and variously for imprecision, very serious imprecision, and inconsistency). None of the subgroup analyses showed any significant benefit or harm of sustained inflation when compared with initiating PPV with intermittent inflations lasting 1 second or less per breath.

These conclusions were based on 9 RCTs57–61,63–66

enrolling 1300 preterm newborns (sustained inflation 6–15 seconds), 2 RCTs62,64 enrolling 222 preterm newborns (sustained inflation of greater than 15 seconds), 6 RCTs58–62,66 enrolling 803 preterm newborns (inspiratory pressure greater than 20 mm Hg), and 4 RCTs57,63–65

enrolling 699 preterm newborns (inspiratory pressure 20 mm Hg or less).

Sensitivity Analysis for Primary Outcome Excluding Studies With High Risk of Bias. For the critical outcome of death before discharge, low- certainty evidence (downgraded for risk of bias and imprecision) from 9 RCTs57–62,64–66 enrolling 1390 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed no significant benefit or harm from initiating PPV with sustained inflation(s) greater than 1 second compared with initiating PPV with intermittent inflations lasting 1 second or less per breath. (RR, 1.24; 95% CI, 0.92–1.68; I2, 24%; 21 more patients/1000 died before hospital discharge with sustained inflation(s) [95% CI, 7 fewer to 61 more per 1000]).


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Table 2. Meta-analysis of RCTs Comparing Initiation of PPV With Sustained Inflation(s) Greater Than 1 Second Versus Initiation of PPV With Intermittent Inflations, Last 1 Second or Less per Breath

Outcome


Total, n


RR (95% CI); I2


Death before Lindner, 200557; 1502 Low 1.09 (0.83–1.43); 42% 10/1000 more patients died before discharge when discharge Lista, 201558; PPV was initiated with sustained inflation(s) >1 s

Schwaberger, 201559; compared with initiating PPV with intermittent Mercadante, 201660; inflations lasting ≤1 s per breath (18 fewer to 47 more Jiravisitkul, 201761; per 1000) Ngan, 201762; El-Chimi, 201763; El-Fattah, 201764; Kirpalani, 201965; La Verde, 201966

Death in the DR Linder, 200557; 1076 Very low 2.82 (0.45–17.66); 0% 4/1000 more patients died in the DR when PPV was Lista, 201558; initiated with sustained inflation(s) >1 s compared Schwaberger, 201559; with initiating PPV with intermittent inflations lasting Mercadante, 201660; ≤1 s per breath (1 fewer to 33 more per 1000) Jiravisitkul, 201761; Ngan, 201762; El-Chimi, 201763; El-Fattah, 201764; LaVerde, 201966

Death within 48 h Linder, 200557; 1502 Low 2.42 (1.15–5.09); 8% 18/1000 more patients died within 48 h after birth Lista, 201558; when PPV was initiated with sustained inflation(s) Schwaberger, 201559; >1 s compared with initiating PPV with intermittent Mercadante, 201660; inflations lasting ≤1 s per breath (2 more to 51 more Jiravisitkul, 201761; per 1000). The number needed to harm is 55 (95% Ngan, 201762; CI, 20–500). El-Chimi, 201763; El-Fattah, 201764; Kirpalani, 201965; La Verde, 201966

Bronchopulmonary Linder, 200557; 1502 Low 0.93 (0.79–1.10); 8% 19/1000 fewer patients developed bronchopulmonary dysplasia Lista, 201558; dysplasia when PPV was initiated with sustained

Schwaberger, 201559; inflation(s) >1 s compared with initiating PPV with Mercadante, 201660; intermittent inflations lasting ≤1 s per breath (58 Jiravisitkul, 201761; fewer to 27 more per 1000) Ngan, 201762; El-Chimi, 201763; El-Fattah, 201764; Kirpalani, 201965; La Verde, 201966

Intraventricular Linder, 200557; 1390 Low 0.88 (0.63–1.23); 0% 11/1000 fewer developed intraventricular hemorrhage hemorrhage Grade Lista, 201558; Grade 3 or 4 when PPV was initiated with sustained 3 or 4 Schwaberger, 201559; inflation(s) >1 s compared with initiating PPV with

Mercadante, 201660; intermittent inflations lasting ≤1 s per breath (35 Jiravisitkul, 201761; fewer to 22 more per 1000) Ngan, 201762; El-Fattah, 201764; Kirpalani, 201965; La Verde, 201966

Retinopathy of Linder, 200557; 1342 Low 0.83 (0.62–1.11); 19% 22/1000 fewer patients developed retinopathy of prematurity Stage 3 Lista, 201558; prematurity Stage 3 or higher when PPV was initiated or higher Schwaberger, 201559; with sustained inflation(s) >1 s compared with

Mercadante, 201660; initiating PPV with intermittent inflations lasting ≤1 s Jiravisitkul, 201761; per breath (49 fewer to 14 more per 1000) Ngan, 201762; El-Fattah, 201764; Kirpalani, 201965; La Verde, 201966

Use of mechanical Lista, 201558; 813 Low 0.87 (0.74–1.02); 0% 51/1000 fewer patients received mechanical ventilation ventilation during Mercadante, 201660; during their hospitalization when PPV was initiated with hospitalization Jiravisitkul, 201761; sustained inflation(s) >1 s compared with initiating PPV

El-Chimi, 201763; with intermittent inflations lasting ≤1 s per breath (103 El-Fattah, 201764; fewer to 8 more per 1000) La Verde, 201966

(Continued )


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Table 2. Continued

Outcome


Total, n


RR (95% CI); I2


Airleak during Linder, 200557; 1076 Low 1.26 (0.72–2.21); 17% 9/1000 more patients developed airleak during their hospitalization Lista, 201558; hospitalization when PPV was initiated with sustained

Schwaberger, 201559; inflation(s) >1 s compared with initiating PPV with Mercadante, 201660; intermittent inflations lasting ≤1 s per breath (9 fewer Jiravisitkul, 201761; to 41 more per 1000) Ngan, 201762; El-Chimni, 201763; El-Fattah, 201764;

La Verde, 201966

DR indicates delivery room; PPV, positive-pressure ventilation; RCT, randomized controlled trial; and RR, relative risk.

Excluding Studies That Allowed Only a Single Sustained Inflation During Resuscitation. For the critical outcome of death before discharge, low- certainty evidence (downgraded for risk of bias and imprecision) from 9 RCTs57–63,65,66 enrolling 1402 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed no significant benefit or harm from initiating PPV with sustained inflation greater than 1 second compared with initiating PPV with intermittent inflations lasting 1 second or less per breath (RR, 1.17; 95% CI, 0.88–1.55; I2, 22%; 18 more patients/1000 died before hospital discharge with sustained inflation(s) [95% CI, 13 fewer to 58 more per 1000]).

Sustained Inflation With Mask Only. When considering only studies where a face mask was used to deliver initial sustained inflation, for the critical outcome of death before discharge, low-certainty evidence (downgraded for risk of bias and imprecision from 9 RCTs58–66 enrolling 1441 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed no significant benefit or harm from initiating PPV with sustained inflation(s) greater than 1 second compared with initiating PPV with intermittent inflations lasting 1 second or less per breath (RR, 1.06; 95% CI, 0.61–1.39; I2, 42%; 7 more patients/1000 died before hospital discharge with sustained inflations [95% CI, 44 fewer to 44 more per 1000]).

Treatment Recommendations For preterm newborn infants who receive PPV for bradycardia or ineffective respirations at birth, we suggest against the routine use of initial sustained inflation(s) greater than 5 seconds (weak recommendation, low- certainty evidence). A sustained inflation may be considered in research settings.

For term or late preterm infants who receive PPV for bradycardia or ineffective respirations at birth, it is not possible to recommend any specific duration for initial inflations due to the very low confidence in effect estimates.

Justification and Evidence-to-Decision Framework Highlights This topic was prioritized by the NLS Task Force after completion of a large RCT65 published after the 2015 CoSTR.1,9,10 In making these recommendations, the NLS Task Force considered the potential for increased death within 48 hours in preterm infants and increased death before discharge in preterm infants less than 28+0 weeks, a predefined subgroup of the systematic review.53a The task force recognizes that the outcome of death within 48 hours was influenced primarily by 1 study for which death within 48 hours was one of multiple secondary outcomes.65 The NLS Task Force also considered the absence of evidence for either benefit or harm after sustained inflation at birth for all other critical and important outcomes.

The study comparisons were compromised by methodological heterogeneity across studies, including indication, duration, the use of different inspiratory pressures during sustained inflation and different inflation durations. No study was identified comparing short duration sustained inflation (less than 5 seconds) with intermittent inflations by using inspiratory time of 1 second or less. There is no new evidence to support or refute the practice of inflations less than 5 seconds immediately after birth. Hunt et al67 was excluded from this systematic review because the control group received short duration sustained inflations (5 inflations of 2–3 seconds each) and the intervention group received sustained inflations of 15 seconds duration (and thus did not meet predefined inflation duration criteria for the comparator group).

A patent airway is necessary for effective lung inflation or ventilation. A recent study demonstrated that preterm rabbit pups are prone to closure of the larynx (ie, it opens only briefly during a spontaneous breath); this impedes noninvasive PPV after birth.53 Studies in preterm infants have shown that very little gas enters the lungs in the absence of spontaneous breathing, suggesting that the same phenomenon occurs in preterm infants.68,69 This SysRev53a (and most studies it identified) focused on use of sustained inflation in newborns who are not breathing effectively, so inadequate


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laryngeal patency could explain the absence of benefit from sustained inflation immediately after birth in preterm infants. In addition, the NLS Task Force noted that the trials included in the systematic review were pragmatic in design and did not include respiratory function monitors to assess actual pressure and volume delivered or the actual duration of the sustained inflation. It remains unknown if mask leak or airway obstruction influenced the effectiveness of the sustained inflations. This further decreases the confidence in the effect estimates, especially for the subgroup analyses.

See Supplement Appendix A-2 for the evidence-to- decision table for this SysRev.

Knowledge Gaps • How much of a role does glottis closure play in

determining the effectiveness of sustained inflation in newborn infants of different gestational ages?

• What is the optimal duration, optimal inspiratory pressure, and number of sustained inflation maneuvers that allow establishment of functional residual capacity without barotrauma?

• The NLS Task Force recognizes that the total number of infants studied thus far is insufficient to have confidence in the estimate of effect. Larger multicenter trials are needed in both term and preterm newborns to determine whether there are benefits or harms from sustained inflations.

• Studies comparing short duration sustained inflation (less than 5 seconds) with intermittent inflations (inspiratory time 1 second or less) are needed. This is an important knowledge gap as the European Resuscitation Council currently recommends using inflations of a 2- to 3-second duration for the first 5 breaths in infants who are gasping or not breathing.

• Is there a role for sustained inflation for other situations in resuscitation, such as during cardiac compressions? (For more detail, see EvUp for NLS 895 CPR Ratios)

PEEP Versus No PEEP (NLS 897: EvUp) During resuscitation after birth, PPV is provided to inflate and ventilate the lungs. The lungs of sick or preterm newborns tend to collapse as they are not supported by a stiff chest wall and the infant’s breathing efforts may be weak; the lungs may also be immature and surfactant-deficient.70 PEEP provides low positive pressure to the airway, which helps prevent lung collapse at the end of expiration. PEEP maintains lung volume during PPV in animal studies and improves lung function and oxygenation.71,72 PEEP may be beneficial during neonatal resuscitation, but the evidence from human studies is limited. The previously reported evidence for use of PEEP was evaluated as part of the 2015 CoSTR for NLS.1,9,10

In 2020, The NLS Task Force undertook an EvUp to

determine whether additional evidence published after 2015 warranted consideration of a new SysRev.

The evidence update (see Supplement Appendix C-4) identified no evidence that would suggest the need for a new SysRev or a change in the 2015 treatment recommendation.1,9,10 Most of the new studies identified confirm the 2015 recommendation for use of PEEP during PPV in the delivery room.


• Population: Preterm/term newborn infants who do not establish spontaneous respiration at birth

• Intervention: Use of PEEP as part of the initial ventilation strategy

• Comparator: No PEEP • Outcome21:

– Survival to discharge (critical) – 5-minute Apgar scores (important) – Time for heart rate to rise above 100/min

(important) – Intubation rate in the delivery room (important) – Chest compressions in the delivery room

(important) – Incidence of air leaks (important) – Oxygen saturation/oxygenation (important) – Fio2 exposure in the delivery room (important) – Mechanical ventilation in the first 72 hours

(important) – Bronchopulmonary dysplasia (any) (important)

Treatment Recommendation This treatment recommendation has not changed from 2015.1,9,10

We suggest using PEEP for the initial ventilation of premature newborn infants during delivery room resuscitation (weak recommendation, low-quality evidence).

We cannot make any recommendation for term infants because of insufficient data.

CPAP Versus Intermittent Positive Pressure Ventilation (NLS 590: EvUp) Newborn infants who breathe spontaneously need to establish a functional residual capacity after birth.73

Some newborn infants experience respiratory distress, which manifests as labored breathing or persistent cyanosis. Continuous positive airway pressure (CPAP), a form of respiratory support, helps prevent atelectasis in newborns. CPAP is especially helpful for preterm newborn infants with breathing difficulty after birth or after resuscitation.74 CPAP may also reduce the risk of death or bronchopulmonary dysplasia in very preterm infants when compared with endotracheal intubation and PPV.75–79 For the newborn infant, CPAP is a less-invasive form of respiratory support than intubation and PPV.




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• Population: Spontaneously breathing preterm newborn infants with respiratory distress requiring respiratory support in the delivery room

• Intervention: CPAP • Comparator: Intubation and intermittent PPV • Outcome21:

– Death or bronchopulmonary dysplasia (critical) – Death (critical) – Bronchopulmonary dysplasia54 (important) – Air leak (important) – Necrotizing enterocolitis (important) – Severe intraventricular hemorrhage55 (critical) – Severe retinopathy of prematurity56 (critical)

This topic was last reviewed in the 2015 CoSTR.1,9,10 The NLS Task Force sought an EvUp to identify any studies published after the 2015 CoSTR. The EvUp did not identify any new studies that would potentially change the current recommendation. The 2015 CoSTR treatment recommendation remains in effect.1,9,10

The entire EvUp can be reviewed in Supplement Appendix C-5.

Treatment Recommendations This treatment recommendation (below) is unchanged from 2010.1,9,10

For spontaneously breathing preterm newborn infants with respiratory distress requiring respiratory support in the delivery room, we suggest initial use of CPAP rather than intubation and intermittent PPV (weak recommendation, moderate certainly of evidence).

T-Piece Resuscitator Versus Self-Inflating Bag for Ventilation (NLS 870: ScopRev) Rationale for Review In 2015, the ILCOR Neonatal Task Force published a CoSTR summarizing the evidence comparing the use of a T-piece resuscitator with the use of a self-inflating bag for newborns receiving ventilation during resuscitation.1,9,10 The studies reviewed for the 2015 CoSTR noted that the use of T-piece resuscitators demonstrated marginal but not statistically significant benefits for the clinical outcome of achieving spontaneous breathing.

The NLS Task Force decided to reevaluate this topic through a ScopRev79a to determine whether sufficient new evidence had been published after the 2015 CoSTR1,9,10 to justify a new SysRev.


• Population: Newborn infants receiving ventilation (PPV) during resuscitation

• Intervention: T-piece resuscitator • Comparator: Self-inflating bag

• Outcome21: – Survival to hospital discharge (critical) – Air leak (important) – Development of stable spontaneous breath-

ing (no need for intubation in delivery room) (important)

– Bronchopulmonary dysplasia (any) (important) • Study design: RCTs and nonrandomized stud-

ies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion.

• Time frame: All years and languages were included if there was an English abstract; unpublished studies (eg, conference abstracts, trial protocols) were excluded. Literature search was updated to January 3, 2020.

Summary of Evidence Using the 2015 search strategy, this ScopRev79a identified 2 additional studies: 1 RCT80 and 1 observational study81 published after the review for the 2015 CoSTR was completed. When these 2 studies were added to the 2 studies identified in the 2015 CoSTR for NLS,1,9,10

a total of 4 clinical studies could be included in the data analysis, representing a total of 2889 newborns (927 in 3 RCTs and 1962 in 1 observational study).80–83

The 4 studies investigated different populations; 2 studies included term and preterm infants,80,83 and 2 studies

enrolled preterm infants only.81,82 The studies also differed in reported outcomes and were from diverse geographical areas. The large observational study found that use of a T-piece resuscitator increased survival and decreased bron-

chopulmonary dysplasia and intubation in the delivery room.81 The latest RCT also found decreased intubation in the delivery room when T-piece resuscitators were used.80

The ScopRev can be reviewed in its entirety in Sup- plement Appendix B-3.

Task Force Insights Data from a substantial number of additional patients reported in 1 RCT and 1 large observational study suggest improved survival, less need for intubation, and a lower incidence of bronchopulmonary dysplasia when a T-piece resuscitator is used (compared with a self-inflating resuscitator bag) during PPV at birth, particularly in preterm infants. The NLS Task Force concludes that these findings justify a new SysRev of the use of a T-piece resuscitator versus self-inflating bag for administering PPV at birth. The task force anticipates that not only the strength, but the direction of evidence may be changing toward support for using T-piece devices. Until a new SysRev is completed and results are analyzed by the NLS Task Force, the 2015 treatment recommendation remains in effect.1,9,10

Treatment Recommendation This treatment recommendation (below) is unchanged from 2010.1,9,10






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There is insufficient evidence regarding the use of T-piece resuscitator or self-inflating bag for initial PPV at birth, so the recommendation of one device over another would be purely speculative because the confidence in effect estimates is so low.

Oxygen for Preterm Resuscitation (NLS 864: 2019 CoSTR) Preterm newborn infants are vulnerable to oxidative stress as a result of reduced antioxidant defenses and frequent exposure to oxygen during stabilization in the delivery room.84 Many common preterm morbidities, such as bronchopulmonary dysplasia, retinopathy of prematurity and intraventricular hemorrhage are directly associated with oxygen toxicity. In the delivery room, it is imperative that clinicians prevent hypoxia while limiting hyperoxia. In 2019, the NLS Task Force published a SysRev with meta-analysis of the relevant available evidence on this topic,85 and published an ILCOR CoSTR statement.86,87


• Population: Preterm newborn infants (less than 35 weeks’ estimated gestational age) who receive respiratory support at birth

• Intervention: Lower initial oxygen concentration (50% or less O2)

• Comparator: Higher initial oxygen concentration (more than 50% O2)

• Outcome21: – Primary: All-cause short-term mortality (in hos-

pital or 30 days) (critical) – Secondary: ○ All-cause long-term mortality (1–3 years)

(critical) ○ Long-term NDI (1–3 years) (critical) ○ Retinopathy of prematurity (Stages III–V)56

(critical) ○ Necrotizing enterocolitis Stage II (pneumato-

sis) or III (surgical)88

(important) ○ Bronchopulmonary dysplasia (moderate to

severe)54 (critical) ○ Major intraventricular hemorrhage (Grade

III–IV)55 (critical) ○ Time to heart rate more than 100/min

(important) • Study design: RCTs, quasi-RCTs and nonrandom-

ized studies included; animal studies, unpublished studies, and published abstracts (eg, conference abstracts) excluded

• Time frame: Literature search was from 1980 to August 10, 2018.

• PROSPERO Registration: CRD42018084902

Treatment Recommendations This treatment recommendation (below) is unchanged from 2019.86,87

For preterm newborn infants (less than 35 weeks’ gestation) who receive respiratory support at birth, we suggest starting with a lower oxygen concentration (21% to 30%) rather than higher initial oxygen concentration (60% to 100%) (weak recommendation, very low-certainty evidence).

We suggest the range of 21% to 30% oxygen because all trials used this for the low oxygen concentration group. Subsequent titration of oxygen concentration using pulse oximetry is advised (weak recommendation, very low-certainty evidence).

Oxygen for Term Resuscitation (NLS 1554: 2019 CoSTR) Administration of high oxygen concentrations leads to free radical formation and may be toxic to many tissues and organs of the newborn. Questions persist about the risks of hypoxia versus risks of exposure to excess oxygen for late preterm and term newborn infants who receive respiratory support in the delivery room. In 2019, the NLS Task Force published a SysRev with meta-analysis of the relevant available evidence on this topic89 and also published an NLS CoSTR.86,87 For complete review of the consensus on science for the secondary outcomes and subgroup analyses, please see the NLS Task Force section of the recently published 2019 CoSTR summary.86,87


• Population: Newborn infants (35 weeks’ or greater gestation) who receive respiratory support at birth

• Intervention: Lower initial oxygen concentration (50% O2 or less)

• Comparator: Higher initial oxygen concentration (greater than 50% O2)

• Outcome21: – Primary: All-cause short-term mortality (in hos-

pital or 30 days) (critical) – Secondary: All-cause long-term mortality (1–3

years) (critical) – Long-term NDI (1–3 years) (critical) – HIE (Sarnat Stage 2–3)90 (critical)

• Study design: RCTs, quasi-RCTs, and nonrandomized studies included; animal studies, unpublished studies, and published abstracts (eg, conference abstracts) excluded

• Time frame: Literature search was from 1980 to August 10, 2018.


Treatment Recommendations This treatment recommendation (below) is unchanged from 2019.86,87


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For newborn infants at 35 weeks’ or greater gestation receiving respiratory support at birth, we suggest starting with 21% oxygen (air) (weak recommendation, low certainty of evidence). We recommend against starting with 100% oxygen (strong recommendation, low certainty of evidence).

CIRCULATORY SUPPORT For each of the following topics, the EvUps were performed to identify any evidence relevant to the topic that was published after the most recent NLS CoSTR on the topic. The goal was to determine if there was sufficient evidence to suggest a need for a SysRev that might change recommendations about performance of cardiac compressions for the few neonates who require circulatory support at birth.

CPR Ratios for Neonatal Resuscitation (NLS 895: EvUp) Chest compressions administered in a 3:1 compression- to-ventilation ratio are recommended for resuscitation of newborn infants.1,9,10 At birth, the fluid filling the lungs

of the newborn must be absorbed during the initial breaths. Lung aeration triggers an increase in pulmonary blood flow. If a newborn infant has sufficient compromise in gas exchange to cause severe bradycardia or cardiac arrest, successful resuscitation must first achieve adequate lung aeration and ventilation to avoid circulation of blood with progressively lower oxygen saturation.

Many newborn infants, even those who are asphyxiated, will respond to respiratory support alone. As a result, the focus of newborn resuscitation is aimed first at establishing effective ventilation, and support of circulation is provided only for those who have persistent bradycardia or asystole. When circulatory support is needed, it is important that it be as effective as possible. This EvUp was performed to identify the most effective compres-

sion-to-ventilation ratio for neonatal resuscitation. Most studies identified by the EvUp (see Supplement

Appendix C-6) either supported the 2015 treatment recommendations or did not refute it. As a result, the NLS Task Force agreed that no SysRev is needed and there is no change to the 2015 treatment recommendation.1,9,10 The NLS Task Force is aware of an ongoing study of a new neonatal compression technique, with compressions delivered while maintaining a sustained inflation (NCT02858583 at Clinicaltrials.gov). The NLS Task Force agreed that a SysRev may be indicated after publication of the results of that study.


• Population: In newborn infants receiving cardiac compressions

• Intervention: other ratios (5:1. 9:3, 15:2, synchronous, etc)

• Comparator: 3 compressions, 1 ventilation • Outcome21:

– Return of spontaneous circulation (ROSC) (critical) – Survival (critical) – Neurodevelopmental impairment (critical) – Time to ROSC (critical) – Perfusion (important) – Gas exchange (important) – Tissue injury (important) – Compressor fatigue (important)


We suggest continued use of a 3:1 compression-to- ventilation ratio for neonatal CPR (weak recommendation, very low-quality evidence).

2- Thumb Versus 2-Finger Compressions for Neonatal Resuscitation (NLS 605: EvUp) In the past, providers used a variety of techniques to perform chest compressions during resuscitation of newborn infants. The most common techniques used 2 thumbs with the remaining fingers surrounding the lat- eral and posterior chest, or 2 fingers placed vertically on the lower sternum. The most recent review of the topic of chest compressions was included in the 2015 CoSTR for NLS.1,9,10 This EvUp was performed to identify any evidence published after the 2015 CoSTR that would suggest the need for a new SysRev and reevaluation of the treatment recommendation.

The only new evidence identified by the EvUp (see Supplement Appendix C-7) supports the 2015 treatment recommendations.1,9,10 Thus, no new SysRev or change in the 2015 treatment recommendation is warranted.

The task force noted that initial reports of a few alternative compression techniques (vertical thumbs, thumb and index finger, 2 thumbs with fisted hands) have been studied in manikin models. Studies testing any of these in a comparative trial in human infants may prompt a future SysRev.


• Population: In newborn infants receiving cardiac compressions

• Intervention: 2-thumb technique • Comparator: 2-finger technique • Outcome21:

– ROSC (critical) – Survival (critical) – Neurodevelopmental impairment (critical) – Perfusion (important)





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– Gas exchange (important) – Compressor fatigue (important)


We suggest that chest compressions in the newborn infant should be delivered by the 2-thumb, hands- encircling-the-chest method as the preferred option (weak recommendation, very low-certainty evidence).

DRUG AND FLUID ADMINISTRATION Although seldom needed, the short list of medications and fluids used for delivery room resuscitation of the newborn includes epinephrine and volume expanders.

Epinephrine (Adrenaline) for Neonatal Resuscitation (NLS 593: SysRev) When the heart is hypoxic and depleted of energy substrate to the point of cardiac arrest, providers must re- establish effective perfusion of the myocardium with oxygenated blood.91 Epinephrine (adrenaline) causes vasoconstriction, which increases the amount of oxygenated blood entering the coronary arteries and improves myocardial blood flow. Perfusion of the myocardium with oxygenated blood facilitates the synthesis of ATP within myocardial mitochondria, thus enhancing cell viability, contractility, and ROSC.91

In 2010, the NLS CoSTR summarized the evidence comparing the endotracheal route with the intravenous (IV) route for delivery of epinephrine (adrenaline) and concluded that the IV route was preferable.12–14 The NLS Task Force has never conducted a SysRev to evaluate the evidence for epinephrine dose, dose interval, or other routes of delivery. In 2019, the NLS Task Force initiated a new SysRev to identify the evidence addressing these gaps.


• Population: Among neonates (of any gestation) less than 28 days of age who have no detected cardiac output or who have asystole or heart rate less than 60/min despite ventilation and chest compressions

• Intervention: Any nonstandard dose, interval, or route of epinephrine (adrenaline)

• Comparator: Epinephrine (adrenaline) doses of 0.01 to 0.03 mg/kg via IV at intervals of every 3 to 5 minutes

• Outcome21: – Mortality before hospital discharge (critical) – Survival to neonatal unit admission (critical) – ROSC: incidence and time until (critical) – HIE stage moderate to severe (term infants

only)90 (critical)

– Intraventricular hemorrhage Grades 3 to 4 (preterm infants only) (critical)55

– Necrotizing enterocolitis92 (important) – Retinopathy of prematurity56 (important) – Bronchopulmonary dysplasia54 (important) – Periventricular leukomalacia (critical) – Neurodevelopmental outcomes (critical)

• Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Cohort studies may compare different interventions or include only 1 arm receiving 1 intervention. They were eligible for this review if they were considered representative of a defined population (eg, infants born at a hospital between specified dates). Otherwise, they were considered to be (ineligible) case series. All languages were eligible if there was an English abstract. Unpublished studies (eg, conference abstracts, trial protocols) were excluded.

• Time frame: Literature search was from inception of the searched databases to March 6, 2019.


Consensus on Science The SysRev identified 2 eligible studies including 97 newborn infants.92a A draft CoSTR document based on the SysRev was posted on the ilcor.org website for a 2-week public commenting period on February 18, 2020.

Only 2 observational studies were found that addressed any of the comparisons prespecified in the PICOST.7,93 They included both preterm and term infants from the same neonatal unit, although the participants were from different epochs. The overall certainty of evidence was rated as very low for all outcomes, primarily for a very serious risk of bias and very serious imprecision. The individual studies were at a critical risk of bias due to confounding.

For the critical outcome of mortality before hospital discharge, we identified very low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 1 observational study7 of 50 neonates treated with epinephrine (adrenaline). In this study, there was no benefit associated with initial endotracheal versus IV epinephrine (adrenaline) dose. This lack of benefit was observed despite the fact that larger initial doses of epinephrine (adrenaline) were given via the endotracheal route (0.03–0.05 mg endotracheal dose compared with 0.01 mg/kg per IV dose). See Table 3 for statistical data.

In a post hoc analysis, we identified very low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 2 observational stud- ies7,93 of 97 neonates treated with epinephrine (adrenaline). These studies showed no significant association between route of administration of first dose and receipt of a second dose (RR, 1.94; 95% CI, 0.18–20.96;


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Table 3. Meta-Analysis of Outcomes After Initial Endotracheal Versus Intravenous Epinephrine

Outcome

Study With Outcome of

Interest

Total, n

Certainty of

Evidence

RR (95% CI); I2


Neonatal Outcomes

Mortality before hospital discharge

Halling, 20177 50 Very low 1.03 (0.62–1.71); NA 17/1000 more neonates died when initial

endotracheal (0.05–0.1 mg/kg) versus initial IV (0.01–0.03 mg/kg) epinephrine was used (209 fewer–391 more per 1000)

Failure to achieve ROSC Halling, 20177

Barber, 200693

97 Very low 0.97 (0.38–2.48); 0 7/1000 fewer failed to achieve ROSC when initial endotracheal (0.05–0.1 mg/kg) versus initial IV (0.01–0.03 mg/kg) epinephrine was used (135 fewer–322 more per 1000)

Time to ROSC (minutes) Halling, 20177 50 Very low ROSC was 2 min later when initial

endotracheal (0.05–0.1 mg/kg) versus initial IV (0.01–0.03 mg/kg) epinephrine was used (0.6 min earlier–4.6 min later)

IV indicates intravenous; NA, not applicable; ROSC, return of spontaneous circulation; and RR, relative risk.

P=0.59; absolute risk difference, 654 more newborn infants; 95% CI, 570 fewer to 1000 more per 1000 newborn infants would receive additional epinephrine (adrenaline) dose or doses after the first). This occurred despite infants receiving larger doses given via the endotracheal route in one of the studies.7

No studies specifically reported the critical outcome of survival to neonatal unit admission, but this was likely similar to the inverse of the reported outcome “failure to achieve ROSC.” We found only 1 eligible study comparing different doses of IV epinephrine (adrenaline).7 This study of 30 neonates who received initial endotracheal epinephrine (adrenaline) allowed a post hoc comparison of 30 newborn infants who received 2 different doses (0.03 versus 0.05 mg/kg per dose) of endotracheal epinephrine (adrenaline) in different epochs of the study. Although no statistically significant difference was found, there was such serious imprecision as to prevent any conclusion.

We did not find any eligible studies comparing different routes of administration other than the comparisons between IV versus endotracheal epinephrine (adrenaline).

We did not find any eligible studies comparing different intervals of epinephrine (adrenaline) administration.

We did not find any eligible studies that allowed comparison of any other prespecified important outcomes (HIE stage moderate-severe90 [term infants only]; intraventricular hemorrhage Grades 3–455 [preterm infants only]; other morbidities in early infancy [eg, necrotizing enterocolitis,92 retinopathy of prematurity,56 bronchopulmonary dysplasia,54 periventricular leukomalacia] or neurodevelopmental outcomes).

The NLS Task Force agreed that the key 2010 CoSTR recommendations about epinephrine (adrenaline) administration remain valid.12–14 The 2020 treatment recommendations include some minor editorial revi- sions in the indications for epinephrine (adrenaline)

administration and more specific dose information and guidance about repeat doses than were contained in the 2010 treatment recommendations.

Treatment Recommendations If the heart rate has not increased to 60/min or greater after optimizing ventilation and chest compressions, we suggest the administration of intravascular epinephrine (adrenaline) (0.01–0.03 mg/kg) (weak recommendation, very low-certainty evidence).

If intravascular access is not yet available, we suggest administering endotracheal epinephrine (adrenaline) at a larger dose (0.05–0.1 mg/kg) than the dose used for IV administration (weak recommendation, very low- certainty evidence). The administration of endotracheal epinephrine (adrenaline) should not delay attempts to establish vascular access (weak recommendation, very low-certainty evidence).

We suggest the administration of further doses of epinephrine (adrenaline) every 3 to 5 minutes, preferably intravascularly, if the heart rate remains less than 60/min (weak recommendation, very low-certainty evidence).

If the response to endotracheal epinephrine (adrenaline) is inadequate, we suggest that an intravascular dose be given as soon as vascular access is obtained, regardless of the interval after any initial endotracheal dose (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights This topic was prioritized by the NLS Task Force because epinephrine (adrenaline) administration is considered to have a key role for newborns who have not responded to all previous steps in resuscitation. The last of NLS CoSTR addressing epinephrine (adrenaline) administration was conducted a decade ago,12–14

at a time when the ILCOR evidence evaluation did


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not use the GRADE assessment tools. Finally, the NLS Task force was aware of new cohort studies published after 2010.

In making these recommendations, the NLS Task Force considered the fact that the very limited human infant evidence does not demonstrate greater effect of endotracheal versus IV epinephrine (adrenaline). Al- though the population identified for this SysRev was human neonates, the task force reviewed 1 animal study. In a RCT of term lambs undergoing perinatal transition with asphyxia-induced cardiopulmonary arrest,94 peak plasma epinephrine (adrenaline) concentrations were higher and were achieved sooner after central venous epinephrine (adrenaline) (right atrium 470±250 ng/mL or low umbilical venous cord 450±190 ng/mL at 1 minute) than after endotracheal epinephrine (adrenaline) (130±60 ng/mL at 5 minutes; P=0.03), despite lower administered central venous than endotracheal doses (0.03 mg/kg central venous IV dose versus 0.1 mg/kg endotracheal dose). In the same study, central venous compared with endotracheal epinephrine (adrenaline) administration resulted in a shorter median time (interquartile range) to achieve ROSC (2 [95% CI, 1.9–3] versus 4.5 [95% CI, 2.9–7.4] minutes; P=0.02), using a lower dose for central venous than for endotracheal administration. In addition, central venous compared with endotracheal epinephrine (adrenaline) administration resulted in higher rates of ROSC (86% [19/22] versus 54% [12/22]; P=0.02, respectively), using the same lower central venous compared with endotracheal doses.94

Subgroup Considerations There was no evidence to suggest any variation in recommendations for subgroups of infants (eg, term versus preterm).

Implementation Considerations This recommendation is similar to the 2010 treatment recommendation (ie, route and dose of epinephrine [adrenaline] NLS-008A, NLS-008B, NRP-009A, NRP- 009B),12–14 so the task force agreed that there are no new implications for implementation.

Monitoring and Implementation We recommend that health services monitor the use of epinephrine (adrenaline) for newborn resuscitation, together with the outcomes of epinephrine (adrenaline) treatment reported in this review. Wherever possible, this monitoring should include the characteristics of the infants, the resuscitation measures they have received before epinephrine (adrenaline), the dose(s), route(s) and treatment intervals, and any adverse effects of treatment. It is unlikely there will be clinical trials to provide high-certainty evidence on which to base future treatment recommendations about epinephrine (adrenaline) doses, administration

time intervals, and delivery routes. However, collec- tion and publication of clinical observational studies can increase the volume of good-quality data to validate or improve treatment recommendations. Finally, the task force agreed that frequency of epinephrine (adrenaline) administration during resuscitation may reflect the quality of earlier steps in intrapartum management and resuscitation.

See Supplement Appendix A-3 for the evidence-to- decision table associated with this SysRev.

Knowledge Gaps The NLS Task Force identified the following specific gaps in knowledge:

• Optimal (heart rate) thresholds for administration of epinephrine (adrenaline)

• Optimal dose and interval of epinephrine (adrenaline)

• Optimal epinephrine dose and intervals specific to gestational age

• Optimal route and method of epinephrine (adrenaline) administration

• Potential harms of epinephrine (adrenaline) (single or multiple doses)

• Effect of vasoactive drugs other than epinephrine (adrenaline)

• Human factors approach to achieve the timely administration of epinephrine (adrenaline)

• Neurodevelopmental outcomes after epinephrine (adrenaline) use

Providers must make the decision to administer epinephrine (adrenaline) rapidly during newborn resuscitation. In addition, epinephrine (adrenaline) use is uncom- mon and unpredictable. As a result, it may be difficult to perform adequate and ethical randomized trials of human newborn infants with prior parental informed consent. Prospective, multicenter cluster-randomized trials could be a good option.

Newborn animal studies are also needed to address pharmacokinetics and pharmacodynamics to determine the optimal dose and route of epinephrine (adrenaline) to inform the optimal design of human infant studies.

Intraosseous Versus Umbilical Vein for Emergency Access (NLS 616: SysRev) In the rare circumstance where epinephrine (adrenaline) or volume is needed during neonatal resuscitation, vascular access is urgently required. There are questions as to the best route of vascular access to use. The last SysRev about this topic for neonates was in 2010 (NLS-020A intraosseous [IO] versus IV).12–

14 In 2020, the NLS Task Force joined the Ad- vanced Life Support Task Force and the Pediatric Life Support Task Force to complete a joint SysRev with meta-analysis.95



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• Population: Newborn infants in any setting (in- hospital or out-of-hospital) with cardiac arrest (includes severe bradycardia and inadequate perfusion requiring chest compressions)

• Intervention: Placement of an IO cannula with drug administration through this IO site during cardiac arrest

• Comparator: Placement of an IV cannula (umbilical vein in newborn infants) and drug administration through this IV during cardiac arrest

• Outcome21: – Death during event, within 24 hours and before

hospital discharge (critical) – Long-term neurodevelopmental outcomes (critical) – ROSC: any signs of cardiac output with heart rate

60/min or greater, and time to ROSC (critical) – Brain injury (HIE Stage 2–3 Sarnat,90 [term only],

intraventricular hemorrhage Grades 3–4,55 periventricular leukomalacia, preterm only) (critical)

– Time to secure access (important) – Morbidity related to IO (osteomyelitis, fracture,

epiphyseal plate injury, compartment syndrome) or to IV (extravasation, embolic phenomenon, phlebitis) (important)

• Study design: – Inclusion criteria: Randomized trials, non-RCTs,

and observational studies (cohort studies and case-control studies) comparing IO with IV administration of drugs; randomized trials assessing the effect of specific drugs (eg, epinephrine [adrenaline]) in subgroups related to IO versus IV administration; studies assessing cost-effectiveness for a descriptive summary

– Exclusion criteria: Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, or unpublished studies

– Search: All years and languages were included if there was an English abstract. MEDLINE (Ovid interface), Embase (Ovid interface), and Cochrane Central Register of Controlled Trials literature search was conducted from 1946 to September 12, 2019, as well as ongoing trials on International Clinical Trials Registry Platform.

A Priori Subgroups to Be Examined Cardiac and noncardiac causes of circulatory collapse; gestational age (preterm less than 37 weeks and term 37 weeks or greater); delivery room or other site; in- hospital or out-of-hospital; central or peripheral IV access; pediatric trained personnel versus non pediatric

PROSPERO Registration: CRD42020150877

Consensus on Science Although small clinical series and case reports suggest that medications and fluids can be successfully delivered

by the IO route during neonatal resuscitation,96,97 case series also report complications with IO catheter insertion or use.96,98–102 To determine if IO or intravascular access is more effective for neonatal resuscitation, evidence from neonatal literature was sought and considered by the NLS Task Force as part of a joint effort with the Adult Life Support and Pediatric Life Support Task Forces. No studies meeting the a priori inclusion criteria were found for newborn infants, precluding meta-analysis in this population. A draft CoSTR was developed that reflected the lack of data and was posted on the ILCOR website; the draft was viewed more than 2600 times, and more than 50 comments were posted. The majority were supportive of the conclusions.

No evidence was identified for newborn infants comparing use of IO and IV cannulas for drug administration in any setting (in-hospital or out-of-hospital) for any prespecified outcome of the review.

In 2010, the NLS Task Force said that temporary IO access to provide fluids and medications to resuscitate critically ill neonates may be indicated after unsuccessful attempts to establish IV vascular access or when caregivers are skilled at securing IO access.12–14 The 2020 SysRev identified reports of serious complications after use of IO access in neonates.96,98–102 As a result, the 2020 treatment recommendations are stronger in support of the umbilical venous route as the primary route for vascular access during delivery room resuscitation but continue to allow that in some circumstances the IO route is acceptable.

Treatment Recommendations We suggest umbilical venous catheterization as the primary method of vascular access during newborn infant resuscitation in the delivery room. If umbilical venous access is not feasible, the intraosseous route is a reasonable alternative for vascular access during newborn resuscitation (weak recommendation, very low-certainty evidence).

Outside the delivery room setting, we suggest that either umbilical venous access or the IO route may be used to administer fluids and medications during newborn resuscitation (weak recommendation, very low-certainty evidence). The actual route used may depend on local availability of equipment, training, and experience.

Justification and Evidence-to-Decision Framework Highlights In making this recommendation, we recognize the absence of data from human neonatal studies supporting any advantage of IO over umbilical venous access. There are a number of case reports of serious adverse effects of IO access in neonates, including tibial fractures and extravasation of fluid and medications resulting in compartment syndrome and amputation.96,98–102

The rate of adverse effects attributable to emergency umbilical venous catheterization is unknown. How- ever, public feedback emphasized umbilical access as


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the technique most commonly taught to and used by neonatal providers, recognizing that IO access may be helpful in out-of-hospital settings or later in the neonatal intensive care stay when the umbilical vein is no longer patent.

For further information, see the evidence-to-decision table in Supplement Appendix A-4.

Knowledge Gaps The absence of clinical trials, cohort studies, and case- control studies leaves many gaps related to IO versus umbilical vein access during newborn resuscitation. We failed to identify even case series or case reports of IO use in neonatal resuscitation at delivery.

Specific research is required in preterm and term neonates:

• Determination of time from start of CPR to achieving successful IO placement

• Determination time from start of CPR to achieving successful IV placement in umbilical vein

• Optimal IO device suitable for newborn infants • Optimal site (head of humerus, proximal tibia,

other) for successful IO access and drug and fluid administration

• Short- and long-term safety of IO placement during newborn resuscitation

• Complications related to emergency umbilical venous catheterization

• Pharmacokinetics and plasma availability of drugs administered through IO compared with IV routes

• Optimal training for IO placement and IV umbilical vein placement during neonatal resuscitation

• How to best secure and maintain any emergency vascular access devices

• Optimal method to determine correct placement of any emergency vascular access device

• Whether results of studies in animal and simulation models apply to clinical practice

• IO access during neonatal resuscitation outside the delivery room

Volume Infusion During Neonatal Resuscitation (NLS 598: EvUp) In the absence of a history of blood loss, there is limited evidence of benefit from administration of volume during resuscitation of newborns who have not responded to chest compressions and epinephrine (adrenaline). This topic was most recently reviewed by the NLS Task Force in 2010.12–14 In 2020, the NLS Task Force undertook an EvUp to see if additional literature warranted consideration of a request for a new SysRev.

The EvUp identified no human studies and a single animal RCT (see Supplement Appendix C-8); the results of this study supported the 2010 CoSTR for NLS treatment recommendations.12–14 The NLS Task Force agreed that

there is no reason at this time to suggest a new SysRev or a change in the 2010 treatment recommendations.


• Population: Term and preterm newborn infants who receive resuscitation immediately after birth and who have a heart rate less than 60/min after chest compressions and epinephrine (adrenaline) and/or suspected hypovolemia based on history and examination.

• Intervention: Blood volume expansion with blood (red cells or whole blood), colloid (eg, albumin, plasma), crystalloid (eg, 0.9% sodium chloride) or other solution

• Comparator: No blood volume expansion • Outcome21:

– Survival (to any stage) (critical) – Neurodevelopmental outcomes (with age-

appropriate, validated tools) (critical) – Time to ROSC (or heart rate 60/min or greater)

(important) – Subsequent use of vasopressor infusion(s)

(important) – Blood pressure at specified time (important) – Pulmonary edema (important) – Serious neonatal morbidity (including intraven-

tricular hemorrhage, necrotizing enterocolitis, persistent pulmonary hypertension of the newborn, HIE, pulmonary hemorrhage) (critical)

Treatment Recommendation These treatment recommendations are unchanged from 2010.12–14

Early volume replacement with crystalloid or red cells is indicated for newborn infants with blood loss who are not responding to resuscitation.

There is insufficient evidence to support the routine use of volume administration in the newborn infant with no blood loss who is refractory to ventilation, chest compressions, and epinephrine. Because blood loss may be occult, a trial of volume administration may be considered in newborn infants who do not respond to resuscitation.

Sodium Bicarbonate During Neonatal Resuscitation (NLS 606: EvUp) In 2019, a request was made by members of the Eu- ropean Resuscitation Council for the NLS Task Force to consider an EvUp concerning the use of sodium bicarbonate during neonatal resuscitation. Since 2005, inconsistency has developed internationally as to whether sodium bicarbonate is even mentioned in council guidelines. The 2010 CoSTR briefly mentioned that sodium bicarbonate may very rarely be useful after resuscitation.12–14 In 2020, the NLS Task Force undertook




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an EvUp to determine if additional evidence published after 2020 warranted consideration of a new SysRev.

The EvUp (see Supplement Appendix C-9) identified only evidence that supported the 2010 treatment recommendations.12–14

Thus, the task force agreed that no SysRev or change in the 2010 treatment recommendation is warranted.


• Population: Newborn infants who are receiving resuscitation in the hospital

• Intervention: Sodium bicarbonate administration • Comparator: No sodium bicarbonate • Outcome21:

– Survival (to hospital discharge or as defined by authors) (critical)

– ROSC (critical) – HIE stage moderate to severe90 (term infants

only) (critical) – Intraventricular hemorrhage Grades 3 to 455

(preterm only) (critical) – Other morbidities in early infancy (eg, necrotiz-

ing enterocolitis,92 retinopathy of prematurity,56

bronchopulmonary dysplasia,54 periventricular leukomalacia) (important)

– Neurodevelopmental outcomes (critical)


Sodium bicarbonate is discouraged during brief CPR but may be useful during prolonged arrests after adequate ventilation is established and there is no response to other therapies.

PROGNOSTICATION DURING CPR Impact of Duration of Intensive Resuscitation (NLS 896: SysRev) It can be difficult for clinicians to decide how long resuscitative efforts should continue in a newborn infant with no heart rate and/or absent respirations with a very low heart rate after sustained resuscitative efforts.12–14

This critical decision involves knowing when to redirect the care of the newborn infant from resuscitation to the provision of comfort and contact with the parents. If such a decision is made too early, some infants with potential to survive with good neurodevelopmental outcome may die. If the decision is made too late, there is likely to be a diminishing potential for survival, especially without severe neurological injury.

In recent years, long-term outcomes for survivors requiring prolonged resuscitation have improved some- what. In 2015, the CoSTR focused on the following question: “In infants with a gestational age of 36 weeks or

greater and an Apgar score of 0 for 10 minutes or longer, despite ongoing resuscitation, what is the rate of survival to NICU admission and death or neurocognitive impairment at 18 to 22 months?” In 2019, the NLS Task Force revised the question slightly to better reflect the questions clinicians and families ask in such a crisis situation.

The current PICOST attempts to reduce the emphasis on the Apgar score at 10 minutes and puts more focus on the incremental time of resuscitation exposure from birth as related to outcome.


• Population: Newborn infants presenting with at least 10 minutes of asystole, bradycardia (heart rate less than 60/min), or pulseless electric activity after birth for which CPR is indicated

• Intervention: Ongoing CPR for incremental time intervals beyond 10 minutes after birth

• Comparator: CPR discontinued at 10 minutes after birth

• Outcome21: – Survival (to any age) (critical) – Neurodevelopmental outcomes (critical) – Composite of survival to any age without mod-

erate or severe neurodisability (critical) • Study design: Cross-sectional or cohort studies

were eligible for inclusion. Ancillary analyses of RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies, case series) were eligible for inclusion. All years and languages were included if there was an English abstract. Conference abstracts and trial protocols were excluded.

• Time frame: All years were included from inception of the searched databases to October 17, 2019.

A Priori Subgroups to Be Examined Hypothermia postresuscitative care among newborn infants 36 weeks’ or greater gestational age; 36 weeks’ or greater gestational age versus less than 36 weeks’; birthweight 2500 g or greater; infants enrolled in population-level cohort studies

PROSPERO Registration: CRD42020157370

Consensus on Science The SysRev102a identified 15 studies that included 470 infants (see Figure 2).

For the critical outcome of survival until last follow up, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 15 studies103–117 reporting outcomes of 470 newborns to last known follow- up (range: 4 months–8 years of age). The number of enrolled newborns ranged from 3 to 177 per study. Across studies, reported survival rates to last follow up ranged from 1.7% to 100%. Among all 470 newborns reported in the literature, including studies that required survival



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Figure 2. Modified flow diagram of number of studies and infants included for each specified outcome for infants experiencing resuscitation that exceeded 10 minutes. Moderate to severe NDI was defined by each study.

to NICU admission or enrollment in a cooling protocol for inclusion, 187 (39.8%) survived to last follow-up. The decision was made not to calculate confidence intervals as a result of heterogeneity across included studies.

For the critical outcome of neurodevelopmental outcomes among survivors, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies including 277 infants.103,104,106–112,114–117

Neurodevelopmental outcomes were assessed in 80 survivors. Thirty infants among 80 survivors (37.5%) did not have moderate or severe NDI (range: 0% to 100%). There was important heterogeneity across studies (and in some cases within studies) about the timing and tools used to assess neurodevelopmental outcomes that precluded calculation of confidence intervals.

For the composite critical outcome of survival without NDI, we identified very low-certainty evidence (down-

graded for risk of bias and inconsistency) from 13 studies of 277 infants103,104,106–112,114–117 reporting neurodevel-

opmental outcomes. Among all 277 infants reported in these studies, 69% died before last follow up, 18% sur-

vived with moderate to severe impairment, and 11% survived without moderate to severe impairment (2% lost to

follow up). There was important heterogeneity across studies (and in some cases, within studies) about the tim-

ing and tools used to assess neurodevelopmental outcomes that precluded calculation of confidence intervals.

Note: Neurodevelopmental outcomes in postdischarge follow-up were reported in 13 studies using

structured exams.103,104,106–112,114–117 In 11 studies, these assessments used validated developmental assessment


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tools.106–112,114–117 These tools included developmental assessment tools such as the Bayley Scales of Infant and Toddler Development (any version) or a Japanese version of the Bayley Scales (Kyoto Scale of Psychological Development); motor assessment tools such as Gross Motor Function Classification System or Peabody Devel- opmental Motor Scales; and cognitive evaluation tools such as Stanford-Binet Test, Griffiths Scales of Child Development (any version), or Wechsler Preschool and Primary Scale of Intelligence (any version). Two stud- ies103,104 reported only a formal neurological evaluation of the survivors. Auditory and visual assessment varied among studies. Of note, children assessed only by screening tools (such as Denver Developmental Screen- ing Test) in any study were analyzed as lost to follow- up. Time of follow-up for the 80 survivors assessed for NDI was 12 months or greater in 83% (66/80) of the infants (range: 12 months–8 years) and less than 12 months in 6% (5/80) of the infants. Time of assessment was not reported in 1 study114 with 11% (9/80) survivors. Moderate and severe NDI were defined by each study.

Subgroup Considerations Prespecified subgroup analyses for the specified critical outcomes of survival to last follow-up, survival without NDI, and the composite of survival without moderate to severe NDI are depicted in Table 4. Insufficient details about birthweight precluded the planned subgroup analysis based on birthweight.

Given the small sample sizes and heterogeneity of study characteristics, there is no strong evidence on which to base recommendations for specific subgroups of infants.

Treatment Recommendations Failure to achieve return of spontaneous circulation in newborn infants despite 10 to 20 minutes of intensive resuscitation is associated with a high risk of mortality and a high risk of moderate-to-severe neurodevelopmental impairment among survivors. However, there is no evidence that any specific duration of resuscitation consistently predicts mortality or moderate-to-severe neurodevelopmental impairment. If, despite provision of all the recommended steps of resuscitation and excluding reversible causes, a newborn infant requires ongoing cardiopulmonary resuscitation (CPR) after birth, we suggest discussion of discontinuing resuscitative efforts with the clinical team and family. A reasonable time frame to consider this change in goals of care is around 20 minutes after birth. (Weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights In making this recommendation, we recognize the need to balance the risk of ceasing resuscitation too

early, when ROSC and long-term survival may still be achievable, and continuing resuscitation for too long, when ROSC may occur but survival is associated with a high risk of severe neurological injury. The appreciable number of survivors without moderate or severe NDI after 10 minutes or greater of resuscitation suggests that early cessation of resuscitation may preclude survival of some infants who may have a good outcome.

While an Apgar score of 0 or 1 at 10 minutes is a strong predictor of mortality and morbidity, recent case reports and series have reported favorable outcomes among newborn infants with Apgar scores of 0 or 1 at 10 minutes after birth who achieved ROSC and received therapeutic hypothermia. In this subgroup of newborns with severe depression at birth, both survival and survival without moderate-to-severe impairment have been reported. Among 105 such infants reported in the literature with Apgar scores 0 or 1 who were successfully resuscitated, were treated with therapeutic hypothermia, and were assessed after discharge, 20% of all infants survived without moderate-to-severe NDI, and 37% of the survivors did not have moderate or severe NDI.107,109–112,116,117

The evidence supporting this recommendation is of very low certainty. However, we value the possibility of survival and intact survival after ongoing resuscitation. In a large multisite cohort of 659 newborn infants who survived to discharge after more than 1 minute of chest compressions in the delivery room, 25% of survivors received 10 minutes or more of resuscitation.118 This study did not specifically report on infants with 10-minute Apgar scores of 0 or 1. While these data indicate that survival to discharge is possible after a lengthy duration of CPR, neurodevelopmental outcomes among survivors in this study were not reported.

Extremely limited data are available about outcomes of newborn infants who received 20 or more minutes of CPR after birth. Five studies included in this systematic review110–112,116,117 reported results for 39 newborn infants in whom first detectable heart rate or heart rate 100/min or greater occurred at or beyond 20 minutes after birth. Of these, 38% (15/39) survived until last follow up and 40% (6/15) of survivors did not have moderate or severe neuroimpairment.

The task force agreed that in addition to considering duration of resuscitation, it was important to consider whether all recommended resuscitation interventions were provided. Studies suggest that the time taken to accomplish steps of a resuscitation up to the point of administration of 1 or more doses of epinephrine varies widely across studies but may take as long as 20 minutes.7,93,111,119 The variation in the interval from birth to completion of these steps may depend on the characteristics and time to attendance of the resuscitation team. Thus, using a single time interval after birth to discontinue intensive resuscitation for all newborns might mean in some cases that the full repertoire of


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Table 4. Subgroup Analyses for Specified Outcomes for Infants Who Had Resuscitation That Exceeded 10 Minutes

Subgroup

Studies Contributing

Infants, n

Survival to Last Follow-up

Assessed for NDI

Survivors Assessed Without

Moderate or Severe NDI

Composite: Survival Without

Moderate or Severe NDI

Population level studies

Casalaz, 1998104

Harrington, 2007103

Jain, 1991106

Sproat, 2017111

Zhang, 2019117

131 13% (17/131) 88% (15/17) 60% (9/15) 7% (9/131)

Therapeutic hypothermia

Ayerapetyan, 2019116

Kasdorf, 2015107

Natarajan, 2013108

Sarkar, 2010109

Shah, 2015110

Shibasaki, 2020112

Sproat, 2017111

Zhang, 2019117

Zhong, 2019113

206 60% (122/206) 47% (57/122) 37% (21/57) 20% (21/105)*

Gestational age ≥36 wk

Ayerapetyan, 2019116

Casalaz, 1998104

Harrington, 2007103

Kasdorf, 2015107

Natarajan, 2013108

Patel, 2004114

Sarkar, 2010109

Shah, 2015110

Shibasaki, 2020112

Sproat, 2017111

Zhang, 2019117

Zhong, 2019113

286 51% (146/286) 50% (73/146) 32% (23/73) 14% (23/166)†

Gestational age <36 wk

Casalaz, 1998104

Harrington, 2007103

Shah, 2015110

Sproat, 2017111

Zhang, 2019117

Zhong, 2019113

99 34% (34/99) 24% (8/34) 63% (5/8) 12% (5/42)‡

*Eight studies with 105 infants reported postdischarge outcomes. †Eleven studies with 166 infants reported postdischarge outcomes. ‡Five studies with 42 infants reported postdischarge outcomes. NDI indicates neurodevelopmental impairment.

recommended resuscitation interventions were not provided before cessation of resuscitation.

Another issue considered by the task force was the potential impact on infants and their families. Among the included studies, most deaths occurred either in the delivery room/birth suite or during the initial hospitalization. In this systematic review, rates of survival to discharge were similar to rates of survival to last follow up (see Figure 2). For those infants who ultimately die in early infancy, achieving even this short- term survival may provide the family the time and opportunity to participate in decision-making and care of their infant. Moreover, intact survival is possible among surviving infants. In this systematic review, 38% of surviving infants did not have moderate or severe impairment.

Given these considerations, we do not recommend a specific duration of resuscitation after which point resuscitative efforts should cease. Instead, we suggest that providers consider changing the goals of care if a newborn infant has not responded to all recommended steps

of resuscitation that are appropriate to the given setting. We acknowledge that cultural and religious differences, including different perceptions of the value of extending life, the quality of life, and the acceptance of comfort care as an option, may influence the decision.120–122

Ultimately, the decision to initiate and continue resuscitative efforts should be individualized and informed by factors such as gestational age, the presence of congenital anomalies, the timing of perinatal insult (if known), the perceived adequacy of resuscitative interventions, the family’s stated preferences and values, and the availability of postresuscitative resources, such as neonatal intensive care, and neuroprotective strategies, such as therapeutic hypothermia. Finally, in low- resource settings, where emphasis is given to face-mask ventilation with 21% oxygen for nonbreathing neonates,123 advanced resuscitation procedures and prolonging resuscitation may not be an option. Therefore, caution must be taken in the global adoption of this treatment recommendation as local/regional discussion and customization are necessary.


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Implementation Considerations Acceptability of the intervention should be thoroughly discussed in the different settings according to cultural, ethical, and moral standards that prevail in each country or region. High-quality resuscitation should be available for infants in need, and training of skills and team performance are critical to achieve it. Communication with families should be optimized, and whenever possible, parents’ wishes and values must be considered, even in urgent and stressful situations. Availability of neonatal intensive care and neuroprotective strategies for postresuscitation care is another aspect that may be considered in the decision-making process.

Monitoring and Implementation It is important to monitor both short- and long-term outcomes for infants who had a prolonged interval between birth and ROSC. In addition, although health equity was not objectively reported for prolonged neonatal resuscitation, it is possible that prolonged resuscitation may be offered to a higher proportion of infants in higher-resource settings; outcomes may also be better in settings with full availability of intensive care and neuroprotective strategies.

Prolonged CPR after birth is relatively rare, so an international registry of events, with detailed description of procedures and their timing in the delivery room, postresuscitation care, and neurological outcomes assessed in follow-up, would provide essential evidence to inform the discussion of how long is too long. Such a registry would also provide valuable information about variability in practice regarding duration of resuscitation in different settings.

For more information, refer to the evidence-to-decision table in Supplement Appendix A-5.

Knowledge Gaps Many studies reported only outcomes of infants who survived resuscitation and met a specific study eligibility criterion, such as NICU admission or initiation of therapeutic hypothermia. Therefore, estimates of mortality after prolonged resuscitation are likely to underestimate the true rate of death after prolonged resuscitation because this would need to also include infants for whom resuscitation had failed. Studies that account for the full population of newborn infants who receive CPR after birth by using consistent definitions of stillbirths and resuscitation failures are needed to identify the incidence of death and NDI after prolonged resuscitation of term and preterm infants.

In addition, the extent and timing of resuscitation interventions were not reported in most studies; therefore, prognosis of newborn infants after prolonged resuscitation at birth is inferred from the available data. Further, most available studies characterized the infant’s response to resuscitation using the Apgar score at 10 minutes, which is prone to subjective assessment and does not provide information about ongoing assessments or responses

to resuscitation beyond 10 minutes. More granular information about the interval from birth to detectable heart rate that uses objective measures such as ECG and time to ROSC is needed to inform more precise recommendations about the duration of intensive resuscitation after birth. Additionally, as the ECG is used more frequently in the delivery room environment, additional information about the presenting rhythm (bradycardia, asystole, pulseless electric activity) preceding chest compressions will be helpful to identify outcomes after these varied presentations.

Therefore, studies that report outcomes on the full population of infants who present without signs of life and receive intensive resuscitation are needed with the following:

• A priori definitions of stillbirths and completeness of resuscitation attempts

• Complete description of cointerventions (resuscitation procedures), timing of procedures at birth, and interventions in postresuscitative care

• Description of methods to assess the heart rate during resuscitation by using objective measures, such as ECG, and report of timing for detection of heart rate and heart rate 60/min or greater and 100/min or greater

• Complete follow-up of survivors with accurate and consistent methods of assessment of neurodevelopment, comparable across studies and population

POSTRESUSCITATION CARE Rewarming of Hypothermic Newborns (NLS 858: EvUp) The most recent review of this topic was published in the 2015 CoSTR for NLS.1,9,10 In 2020, the NLS Task Force undertook an EvUp to determine if any additional evidence was published after 2015 that would necessitate consideration of a new SysRev.

An EvUp (see Supplement Appendix C-10) identified 133 studies; of these, 2 were considered eligible for inclu-

sion. Although the EvUp identified no new prospective trials of rates of rewarming, the 2 new retrospective stud-

ies124,125 increased the number of infants in observational trials nearly 4-fold to 379 infants. Both studies found that the rate of rewarming (after adjustment for confounders) was not associated with the critical outcomes identified in

each study. However, 1 study125 suggested that rapid rewarming reduces the risk for respiratory distress syndrome.

The NLS Task Force agreed that a SysRev that includes the new studies analyzed by using GRADE criteria will likely allow the development of a weak recommendation in relation to the rate of rewarming of hypothermic infants, as opposed to the “no recommendation” that was made in 2015. As a result, the task force will consider prioritization of a SysRev in the near future. Until




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the completion of a new SysRev, the 2015 recommendation remains in effect.1,9,10


• Population: Newborn infants who are hypothermic (less than 36.0°C) on admission

• Intervention: Rapid rewarming • Comparator: Slow rewarming • Outcome21:


– Convulsions/seizures (critical) – Hemorrhage/pulmonary hemorrhage (critical) – Need for respiratory support (important) – Hypoglycemia (important) – Episodes of apnea (important)


The confidence in effect estimates is so low that a recommendation for either rapid rewarming (0.5°C/h or greater) or slow rewarming (0.5°C/h or less) of unintentionally hypothermic newborn infants (temperature less than 36°C) at hospital admission would be speculative.

Induced Hypothermia in Settings With Limited Resources (NLS 734: EvUp) This topic was most recently reviewed in 2015.1,9,10 In 2020, the NLS Task Force undertook an EvUp to identify any studies published after 2015.


• Population: Newborn infants with HIE managed in limited-resource settings

• Intervention: Therapeutic hypothermia delivered by passive hypothermia and/or ice packs

• Comparator: Standard care • Outcome21:

– Survival (critical) – Neurodevelopmental impairment (any) (important)

The EvUp (see Supplement Appendix C-11) identified 142 studies; 13 of these were thought worthy of inclusion.126–138 The NLS Task Force agreed that these 13 studies did not identify sufficient new evidence to consider a new SysRev and, even if added to previous studies, would not likely add to the level of certainty of the evidence summarized in 2015.1,9,10

It is becoming increasingly difficult (as a result of clinician and parent preferences) to perform large, multicenter randomized trials with a “no-therapeutic hypothermia” control group. However, a protocol was published for 1 such study in hospitals in India, Bangladesh, or Sri Lanka; a multicenter RCT of therapeutic hypothermia using a

servo-controlled cooling device compared with standard care without therapeutic hypothermia has a planned enrollment of 418 infants.139 When completed, such a study

(NCT02387385) could provide valuable additional information. Accumulation of data from such a study or from a

group of smaller studies might warrant an updated SysRev. Future studies of this subject should ideally try to exam-

ine the contributions of population characteristics, cooling method, and availability of concomitant intensive care to outcomes. Interestingly, a survey of hospitals in Califor- nia identified a range of practices and opinions about the

additional services (specialized nurses, video electroen- cephalogram monitoring, pediatric neurology and neu-

roradiology services, developmental follow-up services, etc) that should be required of centers providing neonatal therapeutic hypothermia.140 In addition to wide variation in opinions about necessary resources such as electroen-

cephalogram monitoring, only 92% of centers reported using an evidence-based protocol, and there was a lack of

universal agreement that therapeutic hypothermia centers should treat a minimum volume of patients annually. Con-

sidering this variation across high-resource locations, it is not surprising that there is lack of certainty supporting rec-

ommendations for when and how to provide therapeutic hypothermia for low- and middle-income countries.

Treatment Recommendation This recommendation (below) is unchanged from 2015.1,9,10

We suggest that newborn infants at term or near-term with evolving moderate-to-severe hypoxic-ischemic encephalopathy in low-income countries and/or other settings with limited resources may be treated with therapeutic hypothermia (weak recommendation, low-quality evidence).

Cooling should only be considered, initiated, and conducted under clearly defined protocols with treatment in neonatal care facilities with the capabilities for multidisciplinary care and availability of adequate resources to offer intravenous therapy, respiratory support, pulse oximetry, antibiotics, anticonvulsants, and pathology testing. Treatment should be consistent with the protocols used in the randomized clinical trials in developed countries, ie, cooling to commence within 6 hours, strict temperature control at 33°C to 34°C for 72 hours and rewarming over at least 4 hours.

Postresuscitation Glucose Management (NLS 607: EvUp) The most recent review of this topic was published in the 2010 CoSTR.12–14 In 2020, the NLS Task Force undertook an EvUp to determine if any additional studies were published after 2015 that would necessitate an update to the prior SysRev.

The EvUp (see Supplement Appendix C-12) identified 648 studies; 52 were reviewed and, of those, 13




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were worthy of inclusion. Overall, this EvUp suggests the need to maintain vigilance for neonatal hypoglycemia and hyperglycemia in the aftermath of resuscitation, that the use of protocols for blood glucose management may avoid both hypoglycemia and hyperglycemia, and that these protocols may also avoid large swings in blood glucose concentration that have also been associated with harm. The NLS Task Force agreed that the EvUp highlights the fact that research is needed to determine the optimal protocols for glycemic management for preterm and term infants in the aftermath of resuscitation, and identifying the optimal target glucose range should be a high priority. Because the most recent review of the topic was published in 2010, the NLS Task Force agreed that there has been sufficient new evidence published about glucose management after newborn resuscitation to consider prioritizing a SysRev on the topic of blood glucose management.


• Population: Newborn infants who have received drugs for resuscitation

• Intervention: Glucose infusion • Comparator: No glucose infusion • Outcome21:


– Convulsions/seizures (critical) – Hemorrhage/pulmonary hemorrhage (critical) – Need for respiratory support (important) – Hypoglycemia (important) – Episodes of apnea (important)


Intravenous glucose infusion should be considered as soon as practical after resuscitation, with the goal of avoiding hypoglycemia.

• Laryngeal mask for neonatal resuscitation (NLS 618)

• Less-invasive surfactant administration (New) • CPAP versus increased oxygen for term infants in

the delivery room (NLS 1579) • Optimal peak inspiratory pressure (NLS New) • Oxygen saturation target percentiles (NLS 1580) • Use of feedback CPR devices for neonatal cardiac

arrest (NLS 862) • Oxygen use post-ROSC for newborns (NLS 1569) • Oxygen delivery during CPR (Neonatal) (NLS 738) • Hypovolemia (risk factors for newborns) (NLS

1555) • Effect of monitoring technology on team function

(NLS 1559)

ARTICLE INFORMATION The American Heart Association requests that this document be cited as follows: Wyckoff MH, Wyllie J, Aziz K, de Almeida MF, Fabres J, Fawke J, Guinsburg R, Hosono S, Isayama T, Kapadia VS, Kim H-S, Liley HG, McKinlay CJD, Mildenhall L, Perlman JM, Rabi Y, Roehr CC, Schmölzer GM, Szyld E, Trevisanuto D, Velaphi S, Weiner GM; on behalf of the Neonatal Life Support Collaborators. Neonatal life support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(suppl 1):S185–S221. doi: 10.1161/ CIR.0000000000000895

Supplemental materials are available with this article at https://www. ahajournals.org/doi/suppl/10.1161/CIR.0000000000000895

This article has been copublished in Resuscitation. Published by Elsevier Ire- land Ltd. All rights reserved.

This article has been copublished in Pediatrics.

Authors Myra H. Wyckoff, MD, Chair; Jonathan Wyllie, MBChB, Vice Chair; Khalid Aziz, MBBS, MA, MEd(IT); Maria Fernanda de Almeida, MD, PhD; Jorge Fabres, MD, MSPH; Joe Fawke, MBChB; Ruth Guinsburg, MD, PhD; Shigeharu Hosono, MD, PhD; Tetsuya Isayama, MD, MSc, PhD; Vishal S. Kapadia, MD, MSCS; Han-Suk Kim, MD, PhD; Helen G. Liley, MBChB; Christopher J.D. McKinlay, PhD, MBChB DipProfEth; Lindsay Mildenhall, MBChB; Jeffrey M. Perlman, MBChB; Yacov Rabi, MD; Charles C. Roehr, MD, PhD; Georg M. Schmölzer, MD, PhD; Edgardo Szyld, MD, MSc; Daniele Trevisanuto, MD; Sithembiso Velaphi, MBChB, PhD; Gary M. Weiner, MD; on behalf of the Neonatal Life Support Collaborators

Acknowledgments The authors thank the following individuals (the Neonatal Life Support Collabora- tors) for their contributions: Peter G. Davis, MD; Jennifer Dawson, RN, PhD; Hege

Ersdal, MD, PhD; Elizabeth E. Foglia, MD, MA, MSCE; Mandira Kawakami, MD,

TOPICS NOT REVIEWED IN 2020 • Term umbilical cord management (NLS 1551-SysRev

in process) • Preterm umbilical cord management (NLS 787-Sys

Rev in process) • Babies born to mothers who are hypothermic or

hyperthermic (NLS 804) • Stimulation for apneic newborns (NLS 1558) • Respiratory function monitoring in the delivery

room (NLS 806)

PhD; Henry C. Lee, MD; Mario Rüdiger, MD, PhD; Taylor Sawyer, DO; Amuchou Soraisham, MD; Marya Strand, MD, MS; Enrique Udaeta, MD; Berndt Urlesberger, MD; Nicole K. Yamada, MD, MS; John Madar, MBChB; Marilyn B. Escobedo, MD; Abhrajit Ganguly, MBBS; Callum Gately, MBChB; Beena Kamath-Rayne, MD, MPH; Richard Mausling, MBChB, MClinEpi; Jocelyn Domingo-Bates, MD; Firdose Nakwa, MBBCh, MMed(Peds); Shalini Ramachandran, MD; Jenny Ring, PhD; Birju Shah, MD; Christopher Stave, MLS; Masanori Tamura, MD, PhD; and Arjan te Pas, MD, PhD.

In addition, the task force acknowledges and appreciates the participation of the following in debate and discussion: Catherine Cheng, MD; Walid El-Naggar, MD; Emer Finan, MBBCh; Janene Fuerch, MD; Lou Halamek, MD; Omar Kamlin, MBBS; Satyan Lakshminrusimha, MD; Jane McGowan, MD; Susan Niermeyer, MD, MPH; Bin Huey Quek, M Med, MBBS; Nalini Singhal, MD; and Daniela Testoni, MD, MHS.




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Disclosures

Appendix 1. Writing Group Disclosures

Writing Group Member

Employment

Research Grant

Other Research Support

Speakers’ Bureau/

Honoraria

Expert

Witness

Ownership

Interest

Consultant/ Advisory

Board

Other

Myra H. Wyckoff UT Southwestern None None None None None None None

Jonathan Wyllie James Cook University Hospital (United Kingdom)

None None None None None None None

Khalid Aziz University of Alberta (Canada) None None None None None None None

Maria Fernanda de Almeida

Universidade Federal de Sao Paulo (Brazil)


Jorge Fabres Pontificia Universidad Catolica de Chile (Chile)


Joe Fawke University Hospitals Leicester NHS Trust (United Kingdom)


Ruth Guinsburg Federal University of Sao Paulo (Brazil)


Shigeharu Hosono

Jichi Medical University, Saitama Medical Center (Japan)

Japanese Government research grants†

None None None None None None

Tetsuya Isayama National Center for Child Health and Development (Japan)


Vishal S. Kapadia

UT Southwestern NIH, NICHD research grant† None None None None None None

Han-Suk Kim Seoul National University College of Medicine (Republic of Korea)


Helen G. Liley University of Queensland (Australia)


Christopher J.D. McKinlay

University of Auckland (New Zealand)


Lindsay Mildenhall

Middlemore Hospital (New Zealand)


Jeffrey M. Perlman

Weill Cornell Medical College None None None None None None None

Yacov Rabi University of Calgary (Canada) None None None None Masimo Corp* None None

Charles C. Roehr University of Oxford (United Kingdom)

NIHR UK (publicly (gov.) funded RCT)†

None ABBVIE*; CHIESI*

None None None None

Georg M. Schmölzer

Royal Alexandra Hospital (Canada)

Heart and Stroke Foundation Canada (PI of a grant to

examine chest compression during neonatal resuscitation)*;

Canadian Institute of Health Research (e PI of a grant

examining 30% versus 60% oxygen at birth - the HiLoTrial)*; THRASHER Foundation (PI of a

grant to examine different chest compression during neonatal

resuscitation at birth - the SURV1VE-trial)*; Canadian

Institute of Health Research (PI of a grant to examine different

chest compression during neonatal resuscitation at birth -

the SURV1VE-trial)*

None None None RETAIN LABS Medical

Inc (https:// retainlabsmedical. com/index.html,

which designs educational

serious neonatal resuscitation

games for sale)*

None None

Edgardo Szyld University of Oklahoma None None None None None None None

Daniele Trevisanuto

University of Padova (Italy) None None None None None None None

(Continued )


https://retainlabsmedical.com/index.html



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Appendix 1. Continued

Writing Group Member

Employment

Research Grant


Speakers’ Bureau/

Honoraria

Expert

Witness

Ownership

Interest


Board

Other

Sithembiso Velaphi

Resuscitation Council of Southern Africa (South Africa)


Gary M. Weiner University of Michigan None None None None None None None

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

*Modest. †Significant.

Appendix 2. Reviewer Disclosures

Reviewer

Employment

Research

Grant


Speakers’ Bureau/

Honoraria

Expert

Witness

Ownership

Interest


Board

Other

Christoph Bührer Charité University (Germany)

None None University of Tübingen*;

Marien- Krankenhaus

Hamburg*

None None None None

Praveen Chandrasekharan

SUNY Buffalo None None None None None None None

Krithika Lingappan Baylor College of Medicine


Taylor Sawyer Seattle Children’s Hospital/University

of Washington


Birju A. Shah University of Oklahoma


This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

*Modest.

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APPENDIX A-1 QUESTION Should ETT suction vs. No ETT suction be used for non-vigorous infants born through meconium stained amniotic fluid? POPULATION:

INTERVENTION:

COMPARISON:

MAIN OUTCOMES:

SETTING:

PERSPECTIVE:

BACKGROUND:

CONFLICT OF INTERESTS:

Non-vigorous infants delivered through meconium-stained amniotic fluid :a systematic review and meta-analysis

ETT suction

No ETT suction

Survival at discharge; Survival at discharge (obs); Mental neurodevelopmental impairment; Motor neurodevelopmental impairment; Hypoxic ischemic encephalopathy; Hypoxic ischemic encephalopathy (obs) ; Meconium aspiration syndrome; Meconium aspiration syndrome (obs); Mechanical ventilation; Mechanical ventilation (obs); Respiratory support (excluded mechanical ventilation); DR interventions - ETT for PPV; Delivery room interventions (chest compressions); Delivery room interventions (chest compressions) (obs); Delivery room interventions (epinephrine); Treatment of pulmonary hypertension (iNO, oral medications, ECMO); Length of hospitalization; Length of hospitalization (obs);

Delivery suites

Up to 20% of all births are affected by meconium stained amniotic fluid. About 5% of those exposed to meconium stained amniotic fluid aspirate the fluid into their lungs resulting in significant illness after birth called Meconium Aspiration Syndrome (Wis well 1993, 955; Singh 2009, 497). Infants born through MSAF who are nonvigorous represent 1.5% to 3% of all births. When contemplating the worldwide number of births, this question impacts significant number of babies annually (Almeida 2017, 576; Qian 2008, 1115; Bhat 2008, 199). The controversy around the 2015 recommendation for abandoning routine endotracheal suctioning continues to rage, as evidenced by recent randomized trials (Chettri 2015, 1208, Nangia 2016, 79, Singh 2018) and one retrospective study (Chirovolu 2018). Current practice in caring for newborns delivered through meconium-stained amniotic fluid includes immediate resuscitation without laryngoscopy, immediate laryngoscopy with subjective determination of need for tracheal suctioning and immediate laryngoscopy with tracheal suctioning.

Authors declare they have not conflicts of interest.

ASSESSMENT Problem Is the problem a priority?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know

Up to 20% of all births are affected by meconium stained amniotic fluid. About 5% of those exposed to meconium stained amniotic fluid aspirate the fluid into their lungs resulting in significant illness after birth called Meconium Aspiration Syndrome (Wis well 1993, 955; Singh 2009, 497). Infants born through MSAF who are non-vigorous represent 1.5% to 3% of all births. When contemplating the worldwide number of births, this question impacts significant number of babies annually (Almeida 2017, 576; Qian 2008, 1115; Bhat 2008, 199). The controversy around the 2015 recommendation for abandoning routine endotracheal suctioning continues to rage, as evidenced by recent randomized


trials (Chettri 2015, 1208, Nangia 2016, 79, Singh 2018) and one retrospective study (Chirovolu 2018). Current practice in caring for newborns delivered through meconium-stained amniotic fluid includes immediate resuscitation without laryngoscopy, immediate laryngoscopy with subjective determination of need for tracheal suctioning and immediate laryngoscopy with tracheal suctioning.

Desirable Effects How substantial are the desirable anticipated effects?


● Trivial ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know

Severe asphyxia is a common condition in non-vigorous infants delivered through meconium-stained amniotic fluid. Initiating ventilation within the first minute of life in non-breathing or ineffectively breathing infants is strongly recommended. Delay in initiating ventilation, especially where the provider is unable to promptly intubate the infant or suction attempts are repeated, may negatively impact critical outcomes (i.e. survival, long-term neurodevelopmental outcomes). On the other hand, elective suctioning of the upper airways could reduce incidence and severity of the respiratory disease (MAS). If there was a finding of benefit of the intervention, this could be a large benefit for the individual, family, and population. However, our review of the evidence found no significant benefit. If there was a finding of harm of the intervention, this could lead to large degree of harm for the individual, family, and population. However, our review of the evidence found no significant concern for harm of the intervention.

Undesirable Effects How substantial are the undesirable anticipated effects?


○ Large ○ Moderate ○ Small ● Trivial ○ Varies ○ Don't know

Severe asphyxia is a common condition in non-vigorous infants delivered through meconium-stained amniotic fluid. Initiating ventilation within the first minute of life in non-breathing or ineffectively breathing infants is strongly recommended. Delay in initiating ventilation, especially where the provider is unable to promptly intubate the infant or suction attempts are repeated, may negatively impact critical outcomes (i.e. survival, long-term neurodevelopmental outcomes). On the other hand, elective suctioning of the upper airways could reduce incidence and severity of the respiratory disease (MAS). If there was a finding of benefit of the intervention, this could be a large benefit for the individual, family, and population. However, our review of the evidence found no significant benefit. If there was a finding of harm of the intervention, this could lead to large degree of harm for the individual, family, and population. However, our review of the evidence found no significant concern for harm of the intervention.

Certainty of evidence What is the overall certainty of the evidence of effects?



○ Very low ● Low ○ Moderate ○ High ○ No included studies

The certainty of evidence was low for the primary outcome (survival at discharge) and ranged from very low to low for secondary outcomes (neurodevelopmental impairment, incidence of MAS, need for intubation, chest compressions and medications in delivery room, duration of hospital stay, etc...).

Values Is there important uncertainty about or variability in how much people value the main outcomes?


○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability

Despite available studies that were considered to have a high risk of bias, and the certainty of evidence ranged from low to very low for the considered outcomes, the taskforce considers that there is probably no important uncertainty or variability in how much people value the main outcomes.

Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?


○ Favors the comparison ● Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know

The taskforce places value on both harm avoidance (delays in providing bag- mask ventilation, potential harm of the procedure) and the unknown benefit of the intervention of routine laryngoscopy with or without tracheal intubation and suctioning. Routine practice of this intervention for non-vigorous infants is more likely to result in delays in initiating ventilation, especially where the provider is unable to promptly intubate the infant or suction attempts are repeated. In the absence of evidence of benefit for suctioning, the emphasis should be on initiating ventilation within the first minute of life in non-breathing or ineffectively breathing infants.

Resources required How large are the resource requirements (costs)?



○ Large costs ○ Moderate costs ○ Negligible costs and savings ● Moderate savings ○ Large savings ○ Varies ○ Don't know

Routine practice of laryngoscopy with or without tracheal intubation and suctioning would require increased personnel, training, and equipment. Therefore, there would be potentially moderate savings in costs for not routinely performing the intervention. On the other hand, equipment for suctioning and intubation and trained personnel should be available at every delivery (independently from the presence of meconium stained amniotic fluid).

Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?


○ Very low ○ Low ● Moderate ○ High ○ No included studies

The costs were not reported in the included studies. However, as the critical outcomes (survival at discharge, NDI, MAS) and the important outcomes (i.e. need for ventilation, treatment of pulmonary hypertension, duration of hospitalization) were similar between intervention and comparison group, the certainty of the evidence of the required resources seems to be moderate.

Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?


○ Favors the comparison ● Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ No included studies

The critical outcomes (survival at discharge, NDI, MAS) and the important outcomes (i.e. need for ventilation, treatment of pulmonary hypertension, duration of hospitalization) were similar between the intervention and comparison group. As the intervention group would require more equipment use, the cost-effectiveness probably favors the comparison group.


Equity What would be the impact on health equity?


○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ● Increased ○ Varies ○ Don't know

In low-resource settings, equipment and adequately trained personnel to perform the intervention are not always available. An intervention that does not include direct laryngoscopy with or without tracheal intubation and suctioning is more likely to increase health equity globally, including in low- resource settings where the largest incidence of non-vigorous infants delivered through meconium-stained amniotic fluid occurs.

Acceptability Is the intervention acceptable to key stakeholders?


○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know

The intervention is acceptable to key stakeholders.

Feasibility Is the intervention feasible to implement?


○ No ○ Probably no ● Probably yes ○ Yes ○ Varies ○ Don't know

From a practical point of view, avoiding routine laryngoscopy with or without tracheal intubation and suctioning is feasible and easy to implement. Despite new studies that have become available after the 2015 recommendation, this review shows that the certainty of evidence remains low or very low. However, the uncertainty of these results could limit the implementation of the recommendation among clinicians.

SUMMARY OF JUDGEMENTS JUDGEMENT

PROBLEM No Probably no Probably yes Yes Varies Don't know

DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know

UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know


CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies

VALUES

Important uncertainty or

variability

Possibly important uncertainty or

variability

Probably no important

uncertainty or variability

No important uncertainty or

variability

BALANCE OF EFFECTS

Favors the comparison

Probably favors the comparison

Does not favor either the

intervention or the comparison

Probably favors the intervention

Favors the intervention

Varies

Don't know

RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings

Moderate savings Large savings Varies Don't know

CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES

Very low

Low

Moderate

High

No included

studies

COST EFFECTIVENESS






Favors the intervention

Varies

No included

studies

EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know

FEASIBILITY No Probably no Probably yes Yes Varies Don't know

TYPE OF RECOMMENDATION

Strong recommendation against the intervention

○

Conditional recommendation against the intervention

●

Conditional recommendation for either the intervention or the

comparison ○

Conditional recommendation for the intervention

○

Strong recommendation for the intervention

○

CONCLUSIONS Recommendation For non-vigorous newborns delivered through meconium-stained amniotic fluid, we suggest against routine immediate direct laryngoscopy after delivery with or without


tracheal suctioning when compared to immediate resuscitation without direct laryngoscopy. Meconium-stained amniotic fluid remains a significant risk factor for receiving advanced resuscitation in the delivery room. Rarely, an infant may require intubation and tracheal suctioning to relieve airway obstruction.

Justification Overall justification The Task Force recognizes that, while the Treatment Recommendation has not changed, several studies have been added to the literature since the last recommendation

was made. While these studies contribute new evidence regarding this topic, the certainty of the findings remains low or very low due to the difficulty of performing unbiased studies of this clinical question as well as failure of the data to reach optimal information size. In making this suggestion, we place value on both harm avoidance (delays in providing bag-mask ventilation, potential harm of the procedure) and the unknown benefit of routine tracheal intubation and suctioning. Routine suctioning of non-vigorous infants is more likely to result in delays in initiating ventilation, especially where the provider is unable to promptly intubate the infant or suction attempts are repeated. In the absence of evidence of benefit for routine suctioning, the emphasis should be on initiating ventilation within the first minute of life in non-breathing or ineffectively breathing infants born through meconium-stained amniotic fluid. Some newly born infants may receive tracheal intubation in order to clear a blocked airway or for subsequent ventilation (Edwards 2019 E68, Kalra 2019). Detailed justification Undesirable Effects The Taskforce considered the potential for harm in the procedure of endotracheal intubation and the delay of positive pressure ventilation with the intervention, for which there was no evidence of benefit. Certainty of evidence The certainty of evidence for benefit of the intervention remained low to very low. Values The Taskforce considered that the procedure of laryngoscopy with or without tracheal intubation and suctioning is invasive and has potential for harm. The context of no evidence for benefit led to the suggestion against routine practice of the intervention. While immediate intubation and tracheal suctioning after birth is not routinely suggested, the likelihood of intubation for resuscitation remains a strong possibility. Therefore, trained personnel and equipment for intubation should be readily available for deliveries where meconium stained amniotic fluid is present. This includes the potential use of a meconium aspirator after intubation, as in cases of airway obstruction, where the only means of relieving the obstruction could be tracheal suctioning.

Subgroup considerations The criteria for subgroup analyses were not met.

Implementation considerations Implementation will not require further equipment or resources compared to current practice. There may be a decrease in use of equipment due to reduced use of supplies for laryngoscopy, intubation, and suctioning. However, there will not be reduced need for personnel or training. Meconium stained amniotic fluid is a risk factor for receiving advanced neonatal resuscitation. Therefore, appropriate personnel and equipment should always be available.

Monitoring and evaluation As practice recommendations have changed over the past two decades, and there are no current large clinical trials to inform this question for which there is no evidence of benefit, continued monitoring and evaluation is highly recommended.


Research priorities Despite the addition of several randomized trials focused on this clinical question, the optimal information size is not achieved even with all of the studies taken together. The difficulties of performing a study while minimizing the risks of bias due to difficulty with blinding and assessment of outcome make accrual of evidence a significant challenge. The priorities for study remain similar to previous versions of the CoSTR:

• Does the potential for harm (i.e. delay in starting positive pressure ventilation or transient bradycardia/hypoxia, mortality, NDI) outweight the potential for benefit (i.e. reduction of MAS, need for mechanical ventilation or treatment of pulmonary hypertension)?

• Do risks or benefits of intubation with tracheal suctioning vary with any subgroup (gestational age, thickness of meconium, operator experience)?

• Long-term outcomes should be included in future studies. The neurodevelopmental, behavioral, or educational assessment for future studies should be at or after 18 months of age and completed with a validated tool.


APPENDIX A-2 QUESTION

Should Sustained inflation vs. Standard PPV be used for newborn infants who receive positive pressure ventilation due to ineffective breathing or bradycardia at birth?? POPULATION: Newborn infants who receive positive pressure ventilation for ineffective breathing or bradycardia at birth?

INTERVENTION: Sustained inflation

COMPARISON: Standard PPV

MAIN OUTCOMES: Short term mortality ( Death during initial hospitalization); Death in the delivery room; Death within first 48 hours; Death at latest follow up; Long term neurodevelopmental or behavioral or education outcomes ( > 18 months of corrected age, Test used to assess ND outcome should be of adequate quality and validated); Use of mechanical ventilation during hospitalization; Air leaks (pneumothorax, pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema) reported individually or as a composite outcome: at anytime during initial hospitalization ; Air Leaks within first 48 hours; Bronchopulmonary dysplasia, any grade ; Intraventricular hemorrhage: Of any grade ; Intraventricular hemorrhage: grade 3 or above; Retinopathy of prematurity: Of any stage ; Retinopathy of prematurity: stage 3 and above;

SETTING: Delivery room

PERSPECTIVE:

BACKGROUND: The physiologic basis for sustained inflation: Infants at birth have fluid filled lungs. For successful transition, this fluid needs to be replaced with air. { Boon 1979 1031 ,Hooper 2016 266 } Lung aeration is impaired in some infants. These infants present with absent or ineffective breathing at birth, which may be accompanied by bradycardia . { Foglia 2017 360, Lista 2017 360, McCall 2016 175 } Effective ventilation is the key to successful neonatal resuscitation. Current guidelines recommend starting positive pressure ventilation in these infants. { Wyllie 2015 169.} Sustained inflation (SI) breaths at the beginning of positive pressure ventilation may adequately expand the lungs quickly and aid in successful transition. { Bruschettini 2017 4953 .} It can be hypothesized that, by allowing optimal respiratory transition, such maneuvers may improve respiratory outcomes, including improving early cardiorespiratory stability and reducing risk of bronchopulmonary dysplasia. { Foglia 2017 360. Bruschettini 2017 4953, Kirpalani 2019 1165} Evidence for or against sustained inflation: Most newborns are able to clear the fluid in the lungs by generating significant negative pressure (up to -50 cm H2O) during their first few breaths.{ Karlberg 1962 121, Milner 1977 918} However, some infants are unable to clear the fluid and establish optimal lung volume during the first few minutes of life. Preterm infants with weak respiratory muscles and surfactant deficient lungs are more likely to struggle with this transition. { Foglia 2017 360, McCall 2016 175} Boon et al. described that during resuscitation at birth, gas continued to flow and passive inflation occurred in term infants at the end of a 1 second inflation. { Boon 1979 1031 } Based on these observations, when term infants were given an initial inflation of 5 seconds, inflation volume increased 2 fold and facilitated spontaneous respirations.{ Vyas 1981 635} Since then, multiple animal and clinical studies have been conducted. Animal studies have shown SI to be beneficial.{ Crossley 2007 62. Hillman 2013 446. Klingenberg 2013 222. Sobotka 2011 56. Te Pas AB 2016 85. te Pas AB 2009 37. te Pas AB 2009 295} While individual studies have shown reduction in delivery room intubations, improved heart rate and cerebral oxygenation and reduced duration of mechanical ventilation, some observational studies have questioned the effectiveness of SI in infants without spontaneous breaths. { Foglia 2017 360. Lista 2017 360 , McCall 2016 175. Wyllie 2015 169, Fuchs 2011 176. Hunt 2019 17. van Vonderen 2014 903} The recently published SAIL trial, which studied the effect of SI in extreme preterm infants was stopped early due to an increase in 48 hour mortality in sustained inflation arm. {Kirpalani 2019 1165} Potential implications of this systematic review: Guidelines across the world have differing recommendations regarding inflation time and pressure for the first few breaths. For example, ERC guidelines recommend first five breaths that maintain inflation for 2-3 seconds in infants who are gasping or not breathing while ILCOR, AHA and ANZCOR guidelines maintain that there is insufficient evidence to recommend an optimal inflation time. { Wyllie 2015 169, Wyckoff 2015 543. Wyllie 2015 249} SI has become routine practice in some hospitals internationally, but it remains unclear if there is sufficient evidence for this practice. { Foglia 2017 360. McCall 2016 175. Wyckoff 2015 543. Wyllie 2015 249. O'Donnell 2004 583} ILCOR conducted a systematic review and in its 2015 Consensus on Science with Treatment Recommendations (CoSTR), { Wyllie 2015 169} it suggested against routine use of initial SI ( greater than 5s duration) for preterm infants but it did allow for consideration of SI in individual clinical circumstances or research settings. (Weak recommendation, low-quality of evidence) The CoSTR statement stressed that there was heterogeneity of methods and absence of long term outcomes in the studies included in the review. The latest Cochrane systemic review (2017)concluded that “SLI followed by nCPAP in the delivery room decreased the need for MV in the first 72 hours of life in preterm infants at high risk of respiratory distress syndrome compared with nCPAP alone but did not decrease the need for respiratory support and the occurrence of BPD”. { Bruschettini 2017 4953.} Amongst various secondary outcomes, only the duration of mechanical ventilation was decreased in SI group. Since this review, further randomized controlled trials including the SAIL trial have been published. {Kirpalani 2019 1165} Given the availability of new studies, it is essential to determine if SI at birth is beneficial or harmful in preterm and term infants. This systemic review has potential to impact ILCOR recommendations regarding SI in newborn infants, the guidelines generated by ILCOR member organizations and worldwide practice.



The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: The following CoSTR authors were co-authors of cited studies; Aziz K, Liley H, Roehr CC, Schmölzer GM, Trevisanuto D, Urlesberger B

ASSESSMENT Problem Is the problem a priority? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS


Clearance of lung liquid (aeration of the lungs) immediately after birth is a crucial step in establishing gas exchange via the lungs. Research in preterm rabbit pups indicates that an initial sustained inflation results in more rapid and stable aeration of the lungs. {te Pas 2009 537} This has led to studies in newborn infants to determine whether a sustained inflation or inflations improves improves outcomes.

• te Pas AB, Siew M, Wallace MJ, Kitchen MJ, Fouras A, Lewis RA, Yagi N, Uesugi K, Donath S, Davis PG, Morley CJ, Hooper SB. Establishing functional residual capacity at birth: the effect of sustained inflation and positive end-expiratory pressure in a preterm rabbit model. Pediatr Res. 2009 May;65(5):537-41.

• Kirpalani H, Ratcliffe SJ, Keszler M, Davis PG, Foglia EE, Te Pas A, et al. Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial. JAMA. 2019;321(12):1165-75

• Abd El-Fattah N, Nasef N, Al-Harrass MF, Khashaba M. Sustained lung inflation at birth for preterm infants at risk of respiratory distress syndrome: The proper pressure and duration. J Neonatal Perinatal Med. 2017;10(4):409-17.

• Hunt KA, Ling R, White M, Ali KK, Dassios T, Milner AD, et al. Sustained inflations during delivery suite stabilisation in prematurely-born infants - A randomised trial. Early Hum Dev. 2019;130:17-21.

• La Verde A, Franchini S, Lapergola G, Lista G, Barbagallo I, Livolti G, Gazzolo D. Effects of Sustained Inflation or Positive Pressure Ventilation on the Release of Adrenomedullin in Preterm Infants with Respiratory Failure at Birth. Am J Perinatol. 2019;36(S 02):S110-S4. doi: 10.1055/s-0039-1692133. PubMed PMID: 31238370

• Bruschettini M, O'Donnell CP, Davis PG, Morley CJ, Moja L, Zappettini S, et al. Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes. Cochrane Database Syst Rev. 2017;7(7):CD004953-CD

• Guidelines across the world have differing recommendations regarding inflation time and pressure for the first few breaths

• Since last ILCOR Systematic review, new large randomized controlled trials have been published.

• Given the availability of new studies, it is essential to determine if sustained lung inflation (SLI) at birth is beneficial or harmful in preterm and term infants

Desirable Effects How substantial are the desirable anticipated effects? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS


○ Trivial ○ Small ○ Moderate ○ Large ○ Varies ● Don't know

• For the critical outcome of death within 48 hours, low certainty evidence (downgraded for risk of bias and imprecision) from 10 RCTs {Linder 2005 303; Lista 2015 e457; Schwaberger 2015 e0138964; Mecadante 2016 443; Jiravisitkul 2017 68; Ngan 2017 525; El-Chimi 2017 1273; El-Fattah 2017 409; Kirpalani 2019 1165; La Verde 2019 110} enrolling 1502 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed evidence of harm when initiating PPV with SI >1 s compared to initiating PPV with intermittent inflations lasting ≤1 s per breath (RR = 2.42; 95% CI 1.15-5.09; I2 = 10%; 18 more patients/1000 died within 48 hours with SI [95% CI, 2 more to 51 more per 1000]) The number needed to harm is 55 [95% CI, 20 - 500].

• When analyzed in subgroup of newborns < 28 + 0 weeks, For the critical outcome

of death before discharge, low certainty evidence (downgraded for risk of bias and imprecision) from 5 RCTs {Linder 2005 303; Lista 2015 e457; Jiravisitkul 2017 68; Ngan 2017 525; Kirpalani 2019 1165} enrolling 862 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed evidence of potential harm from initiating PPV with SI >1 s compared to initiating PPV with intermittent inflations lasting ≤1 s per breath (RR = 1.38; 95% CI 1.00-1.91; I2 = 0%; 46 more patients/1000 died before discharge with the SI [95% CI, 0 fewer to 110 more per 1000]) The number needed to harm is 22[95% CI, 9 - >1000].

• For the all critical and important outcomes except Death w ithin 48 hours assessed in the metaanalyses of RCTs, the 95% confidence intervals of relative risks (RR) were wide enough to include both potential harm as well as potential benefit. Therefore, it is unclear whether the intervention of interest (sustained inflation) has desirable effects.

See Appendix 1

Undesirable Effects How substantial are the undesirable anticipated effects? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Large ● Moderate ○ Small ○ Trivial ○ Varies ○ Don't know

• For the critical outcome of death within 48 hours, low certainty evidence (downgraded for risk of bias and imprecision) from 10 RCTs {Linder 2005 303; Lista 2015 e457; Schwaberger 2015 e0138964; Mecadante 2016 443; Jiravisitkul 2017 68; Ngan 2017 525; El-Chimi 2017 1273; El-Fattah 2017 409; Kirpalani 2019 1165; La Verde 2019 110} enrolling 1502 preterm newborns who received PPV for bradycardia or ineffective respirations at birth showed evidence of harm when initiating PPV with SI >1 s compared to initiating PPV with intermittent inflations lasting ≤1 s per breath (RR = 2.42; 95% CI 1.15-5.09; I2 = 10%; RD 0.02 (0.00 to 0.03). The number needed to harm is 50 [95% CI, 33 - >1000].

• When analyzed in subgroup of newborns < 28 + 0 weeks, For the critical outcome

of death before discharge, low certainty evidence (downgraded for risk of bias and imprecision) from 5 RCTs {Linder 2005 303; Lista 2015 e457; Jiravisitkul 2017 68; Ngan 2017 525; Kirpalani 2019 1165} enrolling 862 preterm newborns who received PPV for bradycardia or


ineffective respirations at birth showed evidence of potential harm from initiating PPV with SI >1 s compared to initiating PPV with intermittent inflations lasting ≤1 s per breath (RR = 1.38; 95% CI 1.00-1.91; I2 = 0%; RD 0.05 (0.00 to 0.09). The number needed to harm is 20 [95% CI, 11 - >1000].

• For the all critical and important outcomes except Death w ithin 48 hours assessed in the metaanalyses of RCTs, the 95% confidence intervals of relative risks (RR) were wide enough to include both potential harm as well as potential benefit. Therefore, it is unclear whether the intervention of interest (sustained inflation) has undesirable effects.

See Appendix 1

Certainty of evidence What is the overall certainty of the evidence of effects? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Very low ● Low ○ Moderate ○ High ○ No included studies

Please see the same GRADE table in the box for the "desirable effect" in the above. We considered the overall certainty of evidence as low because, for the all the critical and important outcomes assessed in the metaanalyses of RCTs, there was serious risk of bias and serious imprecision with wide 95% confidence intervals for relative risks (RR).

Values Is there important uncertainty about or variability in how much people value the main outcomes? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Important uncertainty or variability ● Possibly important uncertainty or

variability ○ Probably no important uncertainty or variability ○ No important uncertainty or variability

Mortality and neurodevelopmental impairment were deemed critical by the neonatal task force and a larger group of neonatal resuscitation experts who ranked the importance of the outcomes (see abstract). In addition, parents emphasize the importance of these outcomes. Strand M, Simon W, Wyllie J, Wyckoff M, Weiner G. Consensus outcome rating for international neonatal resuscitation guidelines. Arch Dis Child Fetal Neonatal Ed. January 2019.

Although, death within 48 hours is likely to also be an outcomes that parents and clinicians value highly, it may be of lower importance given that for the outcome of death during the entire hospital stay the systematic review could not exclude benefit or harm associated with use of SLI.


Webbe J, et al. Parent, patient and clinician perceptions of outcomes during and following neonatal care: a systematic review of qualitative research BMJ Paediatrics Open 2018;2:e000343. doi:10.1136/bmjpo-2018-000343

Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

● Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know

Although for almost all critical and important outcomes, the systematic review could not exclude either benefit or harm resulting from use of SLI. For the outcome of death within 48 hours of life, showed harm associated with the use of SLI. In subgroup of preterm newborns < 28 +0 weeks, the systematic review showed evidence of potential harm .

Resources required How large are the resource requirements (costs)? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ● Varies ○ Don't know

No data available. Because the outcome of the review did not find a benefit of SI, no additional resources should be required. Had it demonstrated benefit, although there are no published cost data, it is likely that use of SI would require additional resources in resource limited settings. The majority of included RCTs delivered sustained inflation with T-piece resuscitator. Although it can be delivered with flow inflating bag, it cannot be delivered with self-inflating bag. It also requires a compressed gas source.

Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS


○ Very low ○ Low ○ Moderate ○ High ● No included studies

No data available

Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● No included studies

No data available As above, if SI was recommended, it would be likely to result in increased costs in some health care services and hospitals.

Equity What would be the impact on health equity? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ○ Increased ○ Varies ● Don't know

No data available Because none of these studies have been done in low resourced settings we cannot determine the impact of SLI on health equity.




○ No ● Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know

No studies have examined acceptability of the intervention, taking into account the results of the systematic review.

Given the increased risk of death within the first 48 hours and absence of proven benefit for other critical and important outcomes, we believe that routine use of SLI for preterm resuscitation will remain unacceptable to many stakeholders. We found no studies comparing sustained inflation </= 5 seconds with standard resuscitation using inspiratory times of < 1 second, but a series of 5short (2-3 second) inflations is recommended routinely in some resuscitation guidelines, implying acceptability in some regions of the world. The acceptability of SLI of other specific durations for SLI remains unknown.

Feasibility Is the intervention feasible to implement? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS


The included studies, conducted in several countries and several of which were multicenter, demonstrates feasibility of the intervention.

Use of sustained inflation is feasible.

SUMMARY OF JUDGEMENTS JUDGEME

NT PROBLEM No Probably no Probably yes Yes Varies Don't know


UNDESIRABLE EFFECTS

Large Moderate Small Trivial Varies Don't know

CERTAINTY OF EVIDENCE

Very low Low Moderate High No included studies

VALUES

Important


Possibly important




No important


BALANCE OF EFFECTS


Probably favors

the comparison



Probably favors

the intervention

Favors the

intervention

Varies

Don't know

RESOURCES REQUIRED

Large costs

Moderate costs

Negligible costs and savings

Moderate savings

Large savings

Varie

s

Don't know by guest on August 4, 2021www.aappublications.org/newsDownloaded from

JUDGEMENT


Very low

Low

Moderate

High

No included

studies

COST EFFECTIVENESS


Probably favors

the comparison



Probably favors

the intervention

Favors the

intervention

Varies

No included

studies




TYPE OF RECOMMENDATION Strong recommendation against

the intervention Conditional recommendation

against the intervention

Conditional recommendation for either the intervention or the comparison



○ ● ○ ○ ○

CONCLUSIONS

Recommendation For preterm newborn infants who receive positive pressure ventilation due to bradycardia or ineffective respirations at birth, we suggest against the routine use of initial sustained inflation(s) greater than 5 seconds. (weak recommendation, low-quality evidence).

For term or late preterm infants who receive positive pressure ventilation due to bradycardia or ineffective respirations at birth, it is not possible to recommend any specific duration for initial inflations due to the very low confidence in effect estimates.

Justification This topic was prioritized by the NLS Task Force following completion of a large RCT {Kirpalani 2019 1165} published after the previous CoSTR in 2015.{Perlman 2015 S204}

• In making these recommendations, the NLS Task Force considered the potential for increased death within 48 hours in preterm infants and increased death before discharge in preterm infants <28+0 weeks, a predefined subgroup of the systematic review. The Task Force recognizes that the outcome of death within 48 hours was mainly influenced by one study for which it was one of multiple secondary outcomes. {Kirpalani 2019 1165} The NLS Task Force also considered the absence of evidence for either benefit or harm following sustained inflation at birth for all other critical and important outcomes.


• The comparison of studies was compromised by methodological heterogeneity among studies, including indication, duration, and use of different inspiratory pressure during sustained inflation and the duration for which it was applied.

• No study was identified comparing short duration sustained inflation ( < 5 seconds) with intermittent inflations with inspiratory time ≤ 1 second. There is no new evidence to support or refute the practice of inflations < 5 seconds immediately after birth.

• Hunt et al {Hunt 2019 17} was excluded from this systematic review because the control group received short duration sustained inflations (5 inflations of 2-3 s each) and the intervention group, sustained inflations of 15 s duration (ineligible as wrong comparator)

• A patent airway is necessary for effective lung inflation or ventilation. A recent study demonstrated that preterm rabbit pups are prone to closure of the larynx which opens only briefly during a spontaneous breath, and which impedes noninvasive positive pressure ventilation after birth. {Crawshaw 2017 112}. Studies in preterm infants have shown that very little gas enters the lungs in the absence of spontaneous breathing suggesting that the same phenomenon occurs in preterm infants. {Van Vonderen 2014 903, Van Vonderen 2015 514} This PICOST (and most studies) focused on use of sustained inflation on newborns who are not breathing effectively, so inadequate patency of the larynx could explain the absence of benefit from sustained inflation immediately after birth in preterm infants. In addition, the NLS Task Force noted that mask leak or airway obstruction was not measured in the included studies and therefore, whether or not these factors influenced the effectiveness of sustained inflation as applied to the newborns in each study is unknown.

Subgroup considerations The data for preterm infants suggests possible harm from SI. There were no studies available that examined use of SI in term infants.

No data was available to compare short duration SI (<5 seconds) to intermittent inflations lasting ≤1 s per breath

Implementation considerations Since no change in current practice is recommended, there are no implications for implementation.

Monitoring and evaluation

No change in current practice is recommended.

Research priorities

• How much of a role does glottis closure play in determining the effectiveness of sustained inflation in newborn infants of different gestations?

• What is the optimal duration, optimal inspiratory pressure and number of sustained inflation maneuvers that allow establishment of functional residual capacity without barotrauma?

• The NLS Task Force recognizes that the total number of infants studied thus far is insufficient to have confidence in the estimate of effect. Larger multi-center trials are needed in both term

and preterm newborns to determine whether there are benefits or harms from sustained inflations .

• Studies comparing short duration sustained inflation (< 5 seconds) with intermittent inflations with inspiratory time ≤ 1 seconds are needed. This is an important knowledge gap as the European Resuscitation Council currently recommends maintaining inflation for 2-3 seconds for the first five breaths in infants who are gasping or not breathing.

• Is there a role for sustained inflation for other situations in resuscitation such as cardiac compressions? (For more detail see evidence update for NLS 895


Extra APPENDICES for A-2: NLS #809 Sustained Inflation

Outcomes

With Standard PPV

With Sustained inflation

Difference

Relative

effect (95% CI)

Short term mortality ( Death during initial hospitalization)

109 per 1,000 119 per 1,000

(90 to 156)

10 more per 1,000

(18 fewer to 47 more)

RR 1.09 (0.83 to 1.43)

Death in the delivery room 2 per 1,000 6 per 1,000 (1 to 35)

4 more per 1,000 (1 fewer to 33

more)

RR 2.82 (0.45 to 17.66)

Death within first 48 hours 13 per 1,000 30 per 1,000

(14 to 64)

18 more per 1,000 (2 more to 51 more)

RR 2.42 (1.15 to 5.09)

Death at latest follow up 0 per 1,000 0 per 1,000 (0 to 0)

0 fewer per 1,000 (0 fewer to 0 fewer)

not estimable

Long term neurodevelopmental or behavioral or education outcomes ( > 18 months of corrected age, Test used to assess ND outcome should be

of adequate quality and validated)

0 per 1,000 0 per 1,000 (0 to 0)

0 fewer per 1,000 (0 fewer to 0 fewer)

not estimable

Use of mechanical ventilation during hospitalization

395 per 1,000 343 per 1,000

(292 to 402)

51 fewer per 1,000 (103 fewer to 8 more)

RR 0.87 (0.74 to 1.02)

Air leaks (pneumothorax, pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema) reported individually or as a

composite outcome: at anytime during initial hospitalization

34 per 1,000 42 per 1,000

(24 to 74)

9 more per 1,000 (9 fewer to 41

more)

RR 1.26 (0.72 to 2.21)

Bronchopulmonary dysplasia, any grade 274 per 1,000 255 per 1,000

(216 to 301)


RR 0.93 (0.79 to 1.10)

Intraventricular hemorrhage: grade 3 or above 94 per 1,000 82 per 1,000

(59 to 115)


RR 0.88 (0.63 to 1.23)

Retinopathy of prematurity: stage 3 and above 128 per 1,000 106 per 1,000

(79 to 142)


RR 0.83 (0.62 to 1.11)


APPENDIX A-3 QUESTION Should any non-standard dose, interval or route (e.g. IO or ETT etc.) of epinephrine (adrenaline) vs. to standard dose intravenous epinephrine (adrenaline) (0.01-0.03 mg/kg) at intervals of every 3-5 minutes be used for neonates (of any gestation) ≤ 28 days of age who have no detectable cardiac output or who have asystole or heart rate < 60 bpm despite ventilation and chest compressions? POPULATION: Neonates (of any gestation) ≤ 28 days of age who have no detectable cardiac output or who have asystole or heart rate < 60 bpm despite ventilation and chest

compressions

INTERVENTION: Any non-standard dose, interval or route (e.g. IO or ETT etc.) of epinephrine (adrenaline)

COMPARISON: Standard dose intravenous epinephrine (adrenaline) (0.01-0.03 mg/kg) at intervals of every 3-5 minutes

MAIN OUTCOMES: Death at hospital discharge; Failure to achieve ROSC; Time to ROSC; Receiving additional dose(s) of epinephrine

SETTING:

PERSPECTIVE:

BACKGROUND: When the heart is hypoxic and depleted of energy substrate to the point that it actually stops pumping, myocardial perfusion with oxygenated blood must be re-established. {Kapadia 2013 357} Epinephrine (adrenaline) stimulates α-adrenergic vasoconstriction, which increases the amount of oxygenated blood entering the coronary arteries and improves myocardial blood flow. Myocardial blood flow facilitates the synthesis of ATP within myocardial mitochondria, thus enhancing cell viability, contractility and return of spontaneous circulation. {Kapadia 2013 357} In 2010, the Neonatal Task Force completed a SysRev comparing the endotracheal route to the intravenous route for delivery of epinephrine (adrenaline) and concluded that the intravenous route was preferable. {Perlman 2010 S516; Wyllie 2010 e260; Perlman 2010 e1319}. As there had never been a SysRev to evaluate the evidence for dose, interval or other routes of delivery, in 2019 the Task Force initiated a new SysRev for the following question.

CONFLICT OF INTERESTS: MH Wyckoff was co-author on 2 papers included in the review. She was excluded from any decision making regarding selection of articles or analysis or interpretation of the results.

ASSESSMENT Problem

Is the problem a priority?



Large, teaching hospital-based studies indicate that 0.5 to 0.6 per 1000 babies remain asystolic or severely bradycardic despite assisted ventilation {Halling 2017 232; Barber 2006 1028}. Eighty percent of these infants achieved return of spontaneous circulation after administration of epinephrine. There is a need to determine the effects of route of administration, dose, or interval of administration (when multiple doses are required) on efficacy.



○ Trivial ○ Small

If ET epinephrine is effective, ET administration, when compared with the IV route, could result in a shorter time


○ Moderate ○ Large ○ Varies ● Don't know

to provide epinephrine, with the potential for greater efficacy.




Endotracheal administration of epinephrine could result in a team's decision to delay establishing IV access. If the endotracheal route of administration is ineffective, this could result in lower likelihood of an effective dose of epinephrine being provided in a timely way. Animal studies suggest that IV epinephrine has a greater efficacy and a better pharmacokinetic profile than ET epinephrine. In asphyxiated term lambs undergoing perinatal transition with asphyxia-induced cardiac arrest, peak plasma epinephrine concentrations were both higher and were achieved earlier after IV epinephrine (right atrium 470±250ng/mL or low umbilical venous cord 450±190ng/mL by 1 minute) when compared to the ET epinephrine peak level of 130±60 ng/mL at 5 minutes (p=0.03), despite a lower IV (0.03 mg/kg) than ET dose (0.1 mg/kg). {Valli 2017 004402} In the same asphyxiated term lambs undergoing perinatal transition with asphyxia-induced cardiac arrest, using the same doses, IV epinephrine resulted in a shorter median time (interquartile range) to achieve ROSC (2 (1.9-3) than ET epinephrine 4.5 (2.9-7.4) minutes, p=0.02). In addition, IV epinephrine resulted in higher rates of ROSC (19/22 (86%)) than ET epinephrine 12/22 (54%)).



● Very low ○ Low ○ Moderate ○ High ○ No included studies

Comparison between initial ET vs. initial IV epinephrine For the critical outcome of death before discharge (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one observational study {Halling 2017 232} in which 50 neonates were treated with epinephrine (P), that showed no significant benefit or harm of the initial administration of epinephrine via ET (I) when compared with administration via IV (C) (RR, 1.03; 95%CI, 0.62, 1.71; Absolute risk reduction [ARR]; 17 more per 1000 neonates died when epinephrine was administered via ET compared to via IV [95%CI, 209 fewer to 391 more neonates per 1000 neonates died with ET epinephrine]). For the critical outcome of failure to achieve ROSC (which equates to death before neonatal unit admission) (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from two observational studies {Barber 2006 1028; Halling 2017 232} in which 97 neonates were treated with epinephrine (P), that showed no significant benefit or harm of the initial administration of epinephrine via ET (I) when compared to administration via IV (C) (RR, 0.97; 95%CI, 0.38, 2.48; P=0.96; Absolute risk reduction [ARR]; Seven fewer per 1000 neonates died when the epinephrine was administered via ET compared to via IV [95%CI, 135 fewer to 322 more neonates per 1000 neonates died with ET epinephrine]). For the important outcome of time to ROSC (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one observational study {Halling 2017 232}


which compared in 38 neonates time to ROSC after the treatment with epinephrine (P), which showed no significant difference in the time to ROSC after the administration of epinephrine via ET (I) when compared to administration via IV (C) (mean difference 2.00 minutes later when the epinephrine was administered via ET compared to via IV [95%CI, 0.60 minutes earlier to 4.60 minutes later when epinephrine was administered via ET]). For the important outcome of receiving an additional dose after the initial epinephrine administration (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from two observational studies {Barber 2006 1028; Halling 2017 232} in which 97 neonates were treated with epinephrine (P), that showed no significant difference in the receipt of an additional dose after the initial administration of epinephrine via ET (I) when compared with that via IV (C) (RR, 1.94; 95%CI, 0.18, 20.96; P=0.59; Absolute risk reduction [ARR], 654 more neonates per 1000 would receive additional epinephrine dose or doses after the initial epinephrine via ET compared to via IV [95%CI, 570 fewer to 1000 more neonates per 1000 neonates would receive an additional dose or doses after initial epinephrine administration via ET than if the epinephrine was given via IV]). Comparison the outcomes of infants receiving initial ET epinephrine at 0.03 versus 0.05mg/kg/dose (post hoc analysis) For the critical outcome of survival at discharge (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one observational study {Halling 2017 232} in which 30 neonates were treated with ET epinephrine (P), that showed no significant benefit or harm of ET epinephrine at 0.03mg/kg/dose (I) when compared with 0.05mg/kg/dose (C) (RR, 1.12; 95%CI, 0.50, 2.54; Absolute risk difference [ARD]; 49 more per 1000 neonates survived when the initial dose of epinephrine was administered at 0.03mg/kg compared to 0.05mg/kg [95%CI, 206 fewer to 634 more per 1000 neonates). For the critical outcome of No ROSC (O), we have identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one observational study {Halling 2017 232} in which 30 neonates were treated with ET epinephrine (P), that showed no significant benefit or harm of ET epinephrine at a 0.03mg/kg/dose (I) when compared with a 0.05mg/kg/dose (C) (RR, 0.52; 95%CI, 0.12, 2.28; Absolute risk difference [ARD]; 149 fewer per 1000 neonates at 0.03mg/kg compared to 0.05mg/kg [95%CI, 259 fewer to 376 more per 1000 neonates). Except for the comparison between IV vs. ET epinephrine, we did not find any eligible studies comparing different routes of administration. We did not find any eligible studies comparing different intervals of epinephrine administration. We did not find any eligible studies comparing different doses of IV epinephrine.



○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability

A recent study finds agreement on the value of the main outcomes {Strand 2019 316942}




○ Favors the comparison ● Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know

The current evidence from newborn infants is insufficient, but does not favour initial ET over initial IV epinephrine for any important or critical outcome.

The established recommendation is favoured because it is not challenged by available animal evidence which in fact supports present practice. In asphyxiated term lambs undergoing perinatal transition with asphyxia-induced cardiac arrest IV epinephrine compared to ET epinephrine resulted in a shorter median time (interquartile range) of time to achieve ROSC with 2 (1.9-3) versus 4.5 (2.9-7.4) minutes, p=0.02. In addition, IV epinephrine compared to ET epinephrine resulted in higher rates of ROSC with 19/22 (86%) versus 12/22 (54%), respectively. {Valli 2017 004402}



○ Large costs ○ Moderate costs ● Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ○ Don't know

No studies have measured the difference in resources required for ET vs IV epinephrine, or any different dose or interval of epinephrine in newborn infants.

Most infants who require epinephrine will require endotracheal intubation and at some point, establishment of intravenous access. Therefore, in terms of disposable equipment, the resources are similar for ET and IV epinephrine. This recommendation is similar to the previous ILCOR treatment recommendation in 2010. Therefore, there are no new resource implications for implementation.




Based on expert opinion, at least one additional resuscitation team member is required to establish IV access.

Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? by guest on August 4, 2021www.aappublications.org/newsDownloaded from



There are no studies that examine cost effectiveness of different routes, doses or intervals of administration of epinephrine.



○ Reduced ○ Probably reduced ● Probably no impact ○ Probably increased ○ Increased ○ Varies ○ Don't know

There are no studies that examine the impacts of route, dose or interval of administration of epinephrine for newborn infants on health equity.

Because epinephrine is not currently available in low healthcare resourced settings, equity is not promoted by a recommendation for either the intervention of the comparator.




Either IV or ET administration of epinephrine is acceptable to clinicians.




Either the administration of I V or ET epinephrine is feasible, in well-resourced healthcare settings. {Halling 2017 232; Barber 2006 1028}

The administration of either ET or IV epinephrine is likely only to be feasible in locations with moderate or high healthcare resources.

SUMMARY OF JUDGEMENTS by guest on August 4, 2021www.aappublications.org/newsDownloaded from

JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know



CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies

VALUES Important uncertainty

or variability Possibly important


Probably no important uncertainty or

variability


variability

BALANCE OF EFFECTS Favors the comparison


Does not favor either the intervention or the

comparison Probably favors the

intervention Favors the

intervention Varies Don't know

RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know



COST EFFECTIVENESS Favors the comparison


Does not favor either the intervention or the

comparison Probably favors the

intervention Favors the

intervention Varies No included studies




TYPE OF RECOMMENDATION Strong recommendation against the

intervention Conditional recommendation against the

intervention Conditional recommendation for

either the intervention or the comparison



○ ○ ● ○ ○

CONCLUSIONS Recommendation

If the heart rate has not increased to > 60 beats per minute after optimizing ventilation and chest compressions, we suggest the administration of intravascular epinephrine (0.01 to 0.03 mg/kg). (Weak recommendation, very low certainty of evidence). If intravascular access is not yet available, we suggest administering endotracheal epinephrine at a larger dose (0.05 to 0.1 mg/kg). The administration of endotracheal epinephrine should not delay attempts to establish vascular access. (Weak recommendation, very low certainty of evidence). We suggest the administration of further doses of epinephrine every 3-5 minutes, preferably intravascularly, if the heart rate remains less than 60 beats per minute. (Weak recommendation, very low certainty of evidence). If the response to endotracheal epinephrine is inadequate, we suggest that an intravascular dose be given as soon as vascular access is obtained, regardless of the interval. (Weak recommendation, very


low certainty of evidence).

Justification The very limited human infant evidence does not demonstrate greater efficacy of IV vs ET epinephrine. In term lambs undergoing perinatal transition with asphyxia-induced cardiopulmonary arrest: · peak plasma epinephrine concentrations were achieved higher and sooner after central venous epinephrine [right atrium 470±250ng/mL or low umbilical venous cord 450±190ng/mL at one minute] than after endotracheal epinephrine of 130±60 ng/mL at 5 minutes (p=0.03), despite lower central venous doses (0.03 mg/kg IV vs. 0.1 mg/kg ET). · Central venous epinephrine compared to ET epinephrine resulted in a shorter median time (interquartile range) to achieve ROSC with 2 (1.9-3) versus 4.5 (2.9-7.4) minutes, p=0.02, using the same lower central venous doses. · In addition, central venous epinephrine compared to ET epinephrine resulted in higher rates of ROSC with 19/22 (86%) versus 12/22 (54%) p=0.02, respectively, using the same lower central venous doses.

Subgroup considerations There is no evidence on which to differentiate effects on subgroups of infants.

Implementation considerations This recommendation is similar to the previous ILCOR treatment recommendation in 2010 (Route and Dose of Epinephrine NRP-008A, NRP-008B, NRP-009A, NRP-009B);“If adequate ventilation and chest compressions have failed to increase the heart rate to > 60 beats per minute, then it is reasonable to use epinephrine despite the lack of human neonatal data. If epinephrine is indicated, a dose of 0.01 to 0.03 mg/kg should be administered intravenously as soon as possible. If adequate ventilation and chest compressions have failed to increase the heart rate to 60 beats per minute and intravenous access is not available, then it is reasonable to administer endotracheal epinephrine. If epinephrine is administered by the endotracheal route, it is likely that a larger dose (0.05 mg/kg to 0.1 mg/kg) will be required to achieve an effect similar to that of the 0.01 mg/kg intravenous dose. Higher intravenous doses cannot be recommended and may be harmful.” Therefore, there are no new implications for implementation.

Monitoring and evaluation We recommend that health services should monitor the rate of use of epinephrine for newborn resuscitation, together with the outcomes of epinephrine treatment reported in this review. Wherever possible, this monitoring should include the characteristics of the infants, the resuscitation measures they have received before epinephrine, the dose(s), route(s) and treatment intervals and any adverse effects of treatment. The reasons are that there is unlikely to be high certainty evidence from clinical trials on which to base treatment recommendations about epinephrine doses, administration time intervals and delivery routes in the near future. Meanwhile, increasing the number of good quality, published observational studies could offer the best opportunity to validate or improve treatment recommendations. Also, rates of epinephrine administration may reflect the quality of earlier steps in resuscitation and could therefore be a valuable benchmark.

Research priorities The following specific gaps in knowledge were identified: • Optimal (heart rate) thresholds for administration of epinephrine • Potential harms of epinephrine (single or multiple doses) • Optimal dose and interval of epinephrine. • Optimal route and method of administration of epinephrine. • Effect of vasoactive drugs other than epinephrine. Since the decision to administer epinephrine needs to be rapid in newborn resuscitation, and the event is rare and unpredictable, adequate ethical randomized trials of human infants with prior parental informed consent may be difficult. Prospective, multicentre cluster-randomised trials could be a good option. Newborn animal studies that address pharmacokinetics and pharmacodynamics are needed to determine the optimal dose and route of epinephrine are also needed, in order to inform the optimal design of human infant studies.


REFERENCES SUMMARY 1. Halling C, Sparks JE, Christie L, Wyckoff MH. Efficacy of Intravenous and Endotracheal Epinephrine during Neonatal Cardiopulmonary Resuscitation in the Delivery Room. J Pediatr. 2017 Jun;185:232-236. doi: 10.1016/j.jpeds.2017.02.024. Epub 2017 Mar 10. PubMed PMID: 28285754.

2. Barber CA, Wyckoff MH. Use and efficacy of endotracheal versus intravenous epinephrine during neonatal cardiopulmonary resuscitation in the delivery room. Pediatrics. 2006 Sep;118(3):1028-34. PubMed PMID: 16950994.

3. Vali P, Chandrasekharan P, Rawat M, Gugino S, Koenigsknecht C, Helman J, Jusko WJ, Mathew B, Berkelhamer S, Nair J, Wyckoff MH, Lakshminrusimha S. Evaluation of Timing and Route of Epinephrine in a Neonatal Model of Asphyxial Arrest. J Am Heart Assoc. 2017 Feb 18;6(2). pii: e004402. doi: 10.1161/JAHA.116.004402. PubMed PMID: 28214793; PubMed Central PMCID: PMC5523751.

4. Strand ML, Simon WM, Wyllie J, Wyckoff MH, Weiner G. Consensus outcome rating for international neonatal resuscitation guidelines. Arch Dis Child Fetal Neonatal Ed. 2019 Mar 29. pii: fetalneonatal-2019-316942. doi:10.1136/archdischild-2019-316942. [Epub ahead of print] PubMed PMID: 30926715.


APPENDIX A-4 QUESTION IV VS. IO ADMINISTRATION OF DRUGS DURING CARDIAC ARREST - NEONATES

POPULATION: Neonates in any setting (in-hospital or out-of-hospital) with cardiac arrest (includes severe bradycardia and inadequate perfusion requiring chest compressions).

INTERVENTION:

Placement of an intraosseous (IO) cannula and drug administration through this IO during cardiac arrest

COMPARISON:

Placement of an intravenous (IV) cannula (umbilical vein in newly born infants) and drug administration through this IV during cardiac arrest.

MAIN OUTCOMES:

− Death during event, within 24 hours and before hospital discharge − Long term neurodevelopmental outcomes − Return of spontaneous circulation (ROSC): any signs of cardiac output with HR > 60bpm, and time to ROSC − Brain Injury [HIE stage 2-3 Sarnat (term only), IVH Grades III-IV, PVL (preterm only)]; − Time to secure access − Morbidity related to IO (osteomyelitis, fracture, epiphyseal plate injury, compartment syndrome, amputation) or to IV (extravasation, embolic phenomenon, phlebitis)

SETTING: In-hospital (delivery room and neonatal unit) or out-of-hospital

PERSPECTIVE:

Population

BACKGROUND:

When severe bradycardia (< 60bpm) persists at birth, once ongoing aeration of the lungs is established and chest compressions are coordinated with ventilation, adrenaline and/or volume expansion should be given rapidly to increase myocardial blood flow and ensure the best possible chance of return of spontaneous circulation (ROSC).

Approximately 1/1000 newly born infants receive medications in the delivery room {Perlman 1995 20}, and about 75% of the patients achieve ROSC after intravenous adrenaline via the umbilical vein at birth {Barber 2006 1028; Halling 2017 232}. In addition, sick newborns presenting in extremis due to sepsis or congenital heart disease pose a challenge for healthcare practitioners to secure a reliable site to provide life-saving medications and fluids.

In 2010, ILCOR recommended that temporary intraosseous access to provide fluids and medications to resuscitate critically ill neonates may be indicated following unsuccessful attempts to establish intravenous vascular access or when caregivers are more skilled at securing intraosseous access {Perlman 2010, S516}. In 2015, the use of IV route for newborn resuscitation was not reviewed by ILCOR Neonatal Taskforce {Perlman 2015 S204}.

IO administration of drugs, fluids or blood may be the only option in intensive care neonatal units, when peripheral IV access in emergencies is not possible, or the umbilical vein is closed, as published in one case series with 27 neonates {Ellemunter 1999 F74}, and 15 neonatal case reports {Ghirga 1992 377; Kelsall 1993 324; Martino Alba 1994 529; Kakhandki 1997 748; Nasimi 1998 414; Ramet 1998 327; Ellemunter 1999 F74; Lake 2003 F409; Singh Tomar 2006 202; Heyder-Musolf 2011 654}, but with morbidity related to IO access {Vidal 1993 1201; Katz 1994 258; Carreras-Gonzales 2012 233; Oesterlie 2014 413; Suominen 2015 1389].

In the neonatal simulation setting, IO access is easier and faster than IV access by umbilical vein [Abe 2000,126; Rajani 2011 e954; Schwindt 2018 468}.


None

ASSESSEMENT Problem


Is the problem a priority? JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS


Drugs are rarely indicated in resuscitation of the newly born infant. Drug administration varies from approximately 1/1000 {Perlman 1995 20} to 5-6/10000 newly born infants in the delivery room {Barber 2006 1028; Halling 2017 232}. About 75% of patients achieve return of spontaneous circulation after adrenaline by umbilical vein at birth {Barber 2006 1028; Halling 2017 232}.

Regarding very low birth weight infants, 3.9 % receive delivery room cardiopulmonary resuscitation with adrenaline {Finer 1999 428}.

In addition, sick newborns presenting in extremis due to sepsis or congenital heart disease pose a challenge for healthcare practitioners to secure a reliable site to provide life-saving medications and fluids.

Desirable Effects

How substantial are the desirable anticipated effects?


○ Trivial ○ Small ● Moderate ○ Large ○ Varies ○ Don't know

When severe bradycardia (< 60bpm) persists at birth, once ongoing aeration of the lungs is established and chest compressions are coordinated with ventilation, adrenaline and/or volume expansion should be given rapidly to increase myocardial blood flow and ensure the best possible chance of return of spontaneous circulation (ROSC). IO administration of drugs, fluids or blood may be the only option, when peripheral IV access in emergencies is not possible, umbilical vein is closed or the cord stump is dry, making IV administration by umbilical vein almost impossible.

Delay in initiating administration of drugs by umbilical vein, especially when the provider is unable to rapidly reach the central venous circulation, may negatively impact critical outcome (i.e. death). If there is a finding of benefit of the IO administration, this could be a benefit for the individual, family, and population.

Undesirable Effects

How substantial are the undesirable anticipated effects?



IO access in neonates is associated with adverse effects.

Pharmacokinetics and pharmacodynamics of neonatal resuscitation drugs delivered by IO access have not been established.

IO access in neonates is associated with severe complications, including tibial fractures, extravasation of fluid and medications resulting in compartment syndrome and amputation {Vidal 1993 1201; Katz 1994 258; Ellemunter 1999 F74; Carreras-Gonzales 2012 233; Oesterlie 2014 413; Suominen 2015 1389}.

IO pharmacokinetics and plasma availability of drugs might be not as effective as IV administration.





The certainty of evidence cannot be established due to the absence of clinical trials or cohort studies with neonates during resuscitation that received IO vs IV administration regarding any outcome.

No published studies are available on IO administration in neonatal resuscitation in the delivery room or in emergency department or out of hospital deliveries.


JUDGEMENT ADDITIONAL CONSIDERATIONS


Parents and providers are likely to value the outcomes included in this systematic review {Strand 2019 F1}



○ Favors the comparison ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● Don't know

The balance between desirable and undesirable effects could not be ascertained due to the absence of clinical trials or cohort studies with neonates during resuscitation that received IO vs IV administration regarding any outcome.

Case reports suggest that intraosseous lines have the potential for serious complications which include amputation and frequent misplacement {Fuchs 2018 79; Maxien 2019 1}




○ Large costs ○ Moderate costs ○ Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ● Don't know

We did not identify any studies specifically comparing resources including costs between the two interventions.




We did not identify any studies comparing resources including costs between the two interventions.




We did not identify any studies comparing cost-effectiveness between the two interventions.



○ Reduced ○ Probably reduced ○ Probably no impact ○ Probably increased ○ Increased ○ Varies ● Don't know

We did not identify any studies addressing health equity.




○ No ○ Probably no ○ Probably yes ○ Yes ● Varies ○ Don't know

Emergency umbilical vein access has been accepted as standard of care for many years in neonatal resuscitation. In a variety of neonatal simulation settings, IO placement was faster than umbilical venous access {Abe 2000126; Rajani 2011 e954; Schwindt 2018 468}, but there was no assessment of training level in these settings. The relevance to the clinical setting is unknown.



○ No ○ Probably no ○ Probably yes ○ Yes ● Varies ○ Don't know

We did not identify any studies comparing feasibility between IO and IV in neonatal resuscitation. However, there are case reports of successful emergent IO placement in neonates.

SUMMARY OF JUDGEMENTS JUDGEMENT

PROBLEM No Probably no Probably yes Yes Varies Don't know



CERTAINTY OF EVIDENCE Very low Low Moderate High No included

studies

VALUES Important


Possibly important





variability

BALANCE OF EFFECTS Favors the comparison





Favors the intervention Varies Don't know

RESOURCES REQUIRED Large costs Moderate costs Negligible costs

and savings Moderate savings Large savings Varies Don't know


JUDGEMENT CERTAINTY OF EVIDENCE OF

REQUIRED RESOURCES


COST EFFECTIVENESS Favors the comparison





Favors the intervention Varies No included

studies

EQUITY Reduced Probably reduced

Probably no impact

Probably increased Increased Varies Don't know




intervention Conditional recommendation against the

intervention Conditional recommendation for either

the intervention or the comparison Conditional recommendation for the

intervention Strong recommendation for the

intervention ○ ● ○ ○ ○


We suggest umbilical venous catheterization as the primary method of vascular access during newborn resuscitation in the delivery room. If umbilical venous access is not feasible, the intraosseous route as vascular access during newborn resuscitation is a reasonable alternative (weak recommendation, very low certainty of evidence).

Outside the delivery room setting, we suggest that either umbilical venous access or the intraosseous route may be used to administer fluids and medications during newborn resuscitation (weak recommendation, very low certainty of evidence). The actual route used may depend on local availability of equipment, training and experience.

Justification

In making this recommendation we recognize the absence of data from human neonatal studies supporting any advantage of intraosseous over umbilical venous access. There are a number of case reports of serious adverse effects of intraosseous access in neonates, including tibial fractures, extravasation of fluid and medications resulting in compartment syndrome and amputation {Vidal 1993 1201; Katz 1994 258; Ellemunter 1999 F74; Carreras-Gonzales 2012 233; Oesterlie 2014 413; Suominen 2015 1389}.

The rate of adverse effects attributable to emergency umbilical venous catheterization is unknown. However, public feedback from >2500 public viewings emphasized umbilical access as the technique most commonly taught and used whilst recognizing that intraosseous access may be helpful in out of hospital deliveries or in neonatal intensive care units.

Subgroup considerations No data available in neonatal resuscitation.

Implementation considerations by guest on August 4, 2021www.aappublications.org/newsDownloaded from

Although rarely used, training and maintenance of skills for both emergency umbilical venous catheter and intraosseous placement are important.

Monitoring and evaluation Adverse events should be monitored and reported.

Research priorities KNOWLEDGE GAPS There are many knowledge gaps related to IO access and umbilical vein access in newborn during resuscitation due to the absence of clinical trials, cohort studies and case-control studies. Even case series or case reports are not available on IO administration in neonatal resuscitation in the delivery room or in emergency department or out of hospital deliveries.

Specific research is required in preterm and term neonates: o Time from the start of CPR to achieve successful IO placement; o Time from the start of CPR to achieve successful IV umbilical vein placement; o Optimal IO device suitable for newly born infants; o Optimal position of IO device (head of humerus, proximal tibia, other) for successful IO access; o Short and long-term safety of IO placement during newborn resuscitation; o Complications related to emergency umbilical venous catheterization; o Pharmacokinetics and plasma availability of drugs following IO compared to IV administration; o Training for IO placement and IV umbilical vein placement during neonatal resuscitation; o How to best secure and maintain any emergency vascular access devices; o Optimal method to determine correct placement of any emergency vascular access device; o Do animal and simulation models of IO and umbilical venous catheters placement translate to clinical practice? o Success of IO access during neonatal resuscitation outside the delivery room.

References: Abe KK, Blum GT, Yamamoto LG. Intraosseous is faster and easier than umbilical venous catheterization in newborn emergency vascular access models. Am J Emerg Med. 2000 Mar;18(2):126-9.

Barber CA, Wyckoff MH. Use and efficacy of endotracheal versus intravenous epinephrine during neonatal cardiopulmonary resuscitation in the delivery room. Pediatrics. 2006 Sep;118(3):1028-34.

Carreras-González E, Brió-Sanagustín S, Guimerá I, Crespo C. [Complication of the intraosseous route in a newborn infant]. Med Intensiva. 2012 Apr;36(3):233-4.

Ellemunter H, Simma B, Trawöger R, Maurer H. Intraosseous lines in preterm and full term neonates. Arch Dis Child Fetal Neonatal Ed. 1999 Jan;80(1):F74-5.

Finer NN, Horbar JD, Carpenter JH. Cardiopulmonary resuscitation in the very low birth weight infant: the Vermont Oxford Network experience. Pediatrics. 1999 Sep;104(3 Pt 1):428-34.

Fuchs Z, Scaal M, Haverkamp H, Koerber F, Persigehl T, Eifinger F. Anatomical investigations on intraosseous access in stillborns - Comparison of different devices and techniques. Resuscitation. 2018 Jun;127:79-82.

Ghirga G, Ghirga P, Palazzi C, Befani P, Presti A. [Intraosseous route in pediatric emergencies. Description of 2 clinical cases and review of the literature]. Minerva Pediatr. 1992 Jul-Aug;44(7-8):377-84.

Glaeser PW, Hellmich TR, Szewczuga D, Losek JD, Smith DS. Five-year experience in prehospital intraosseous infusions in children and adults. Ann Emerg Med. 1993 Jul;22(7):1119-24.

Heyder-Musolf J, Giest J, Straub J. [Intraosseous access on a 1300 g septical premature infant]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2011 Oct;46(10):654-7.

Halling C, Sparks JE, Christie L, Wyckoff MH. Efficacy of Intravenous and endotracheal epinephrine during neonatal cardiopulmonary resuscitation in the delivery room. J Pediatr. 2017 Jun;185:232-236.

Kakhandki SK. Intraosseous infusion in a LBW neonate. Indian Pediatr. 1997 Aug;34(8):748-9.

Katz DS, Wojtowycz AR. Tibial fracture: a complication of intraosseous infusion. Am J Emerg Med. 1994 Mar;12(2):258-9.

Kelsall AW. Resuscitation with intraosseous lines in neonatal units. Arch Dis Child. 1993 Mar;68(3 Spec No):324-5.

Lake W, Emmerson AJ. Use of a butterfly as an intraosseous needle in an oedematous preterm infant. Arch Dis Child Fetal Neonatal Ed. 2003 Sep;88(5):F409.

Martino Alba R, Ruiz Lopez MJ, Casado Flores J. Use of the intraosseous route in resuscitation in a neonate. Intensive Care Med. 1994 Aug;20(7):529.

Maxien D, Wirth S, Peschel O, Sterzik A, Kirchhoff S, Kreimeier U, Reiser MF, Mück FG. Intraosseous needles in pediatric cadavers: Rate of malposition. Resuscitation. 2019 Dec;145:1-7

Nasimi A, Gorin P, Berthier M, Boussemart T, Follet-Bouhamed C, Oriot D. [Use of the intraosseous route in a premature infant]. Arch Pediatr. 1998 Apr;5(4):414-7.


Oesterlie GE, Petersen KK, Knudsen L, Henriksen TB. Crural amputation of a newborn as a consequence of intraosseous needle insertion and calcium infusion. Pediatr Emerg Care. 2014 Jun;30(6):413-4.

Perlman JM, Risser R. Cardiopulmonary resuscitation in the delivery room. Associated clinical events. Arch Pediatr Adolesc Med. 1995 Jan;149(1):20-5.

Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N, Szyld E, Tamura M, Velaphi S; Neonatal Resuscitation Chapter Collaborators. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010 Oct 19;122(16 Suppl 2):S516-38.

Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, Kim HS, Liley HG, Mildenhall L, Simon WM, Szyld E, Tamura M, Velaphi S; Neonatal Resuscitation Chapter Collaborators. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015 Oct 20;132(16 Suppl 1):S204-41.

Rajani AK, Chitkara R, Oehlert J, Halamek LP. Comparison of umbilical venous and intraosseous access during simulated neonatal resuscitation. Pediatrics. 2011 Oct;128(4):e954-8.

Ramet J, Clybouw C, Benatar A, Hachimi-Idrissi S, Corne L. Successful use of an intraosseous infusion in an 800 grams preterm infant. Eur J Emerg Med. 1998 Sep;5(3):327-8.

Schwindt EM, Hoffmann F, Deindl P, Waldhoer TJ, Schwindt JC. Duration to establish an emergency vascular access and how to accelerate it: a simulation-based study performed in real-life neonatal resuscitation rooms. Pediatr Crit Care Med. 2018 May;19(5):468-476.

Singh Tomar RP, Gupta A. Resuscitation by intraosseous infusion in newborn. Med J Armed Forces India. 2006 Apr;62(2):202-3.

Strand ML, Simon WM, Wyllie J, Wyckoff MH, Weiner G. Consensus outcome rating for international neonatal resuscitation guidelines. Arch Dis Child Fetal Neonatal Ed. 2019;0:F1-F3

Suominen PK, Nurmi E, Lauerma K. Intraosseous access in neonates and infants: risk of severe complications - a case report. Acta Anaesthesiol Scand. 2015 Nov;59(10):1389-93.

Vidal R, Kissoon N, Gayle M. Compartment syndrome following intraosseous infusion. Pediatrics. 1993 Jun;91(6):1201-2.


APPENDIX A-5 QUESTION IMPACT OF DURATION OF INTENSIVE RESUSCITATION - NEONATES

POPULATION: INTERVENTI

ON:

COMPARISO

N:

MAIN OUTCOMES: SETTING:

PERSPECTIV

E:

BACKGROU

ND:

Newly born infants presenting with at least 10 minutes of asystole, bradycardia (heart rate <60 beats per minute), or pulseless electrical activity after birth for which cardiopulmonary resuscitation is indicated.

Ongoing cardiopulmonary resuscitation for incremental time intervals beyond 10 minutes after birth.

Cardiopulmonary resuscitation discontinued at 10 minutes after birth.

− Survival to any age − Long term neurodevelopmental outcomes − Composite of survival to any age without moderate or severe neurodisability

In-hospital (delivery room)

Population

There has been an ongoing controversy as to how long after attempted cardiopulmonary resuscitation after birth for asystole, profound bradycardia (heart rate <60), or pulseless electrical activity, resuscitation should be continued in the face of poor or no response. The balance must be between ceasing too early, when return of spontaneous circulation (ROSC) and long-term survival may still be achievable, and continuing too long, when ROSC may occur, but at the risk of limiting parents’ opportunity to have contact with and provide comfort to their dying infant, or when survival occurs but with an unacceptable degree of neurologic injury. Lack of detectable heart rate or other signs of life, typically reflected by an Apgar Score of zero, have classically a criterion for cessation of resuscitation. However, experience shows that ROSC and survival can occur after an Apgar Score of 0, either because of inadequacy of clinical detection of heart rate or due to the potential for neonatal organs to survive a prolonged pulseless, apneic state. Ongoing cardiopulmonary resuscitation is also indicated for profound bradycardia and pulseless electrical activity, states associated with both acidosis and impaired cardiac output from which recovery is sometimes, but not always, possible. The recommended duration of resuscitative efforts for newborns in the delivery room has variously been 10 or more minutes. According to the 2015 ILCOR CoSTR: “An Apgar score of 0 at 10 minutes is a strong predictor of mortality and morbidity in late-preterm and term infants. We suggest that, in babies with an Apgar score of 0 after 10 minutes of resuscitation, if the heart rate remains undetectable, it may be reasonable to stop resuscitation; however, the decision to continue or discontinue resuscitative efforts should be individualized (weak recommendation, very-low-quality evidence).” {Perlman 2015 S204}. The controversy has been generated from the following uncertainties: (1) It is often not clear whether resuscitation efforts have taken place or been optimal throughout the 10-minute period, (2) There may be questions about whether the infant has been pulseless or profoundly bradycardic throughout the 10 minutes and not just at 10 minutes, and (3) The timing of the onset of fetal bradycardia before birth is often unknown. (4) The 10-minute threshold has been subjected to further controversy, with published reports from therapeutic hypothermia by guest on August 4, 2021www.aappublications.org/newsDownloaded from

trials of an increasing number of intact survivors after 10 minutes of an Apgar score of 0 {Laptook 2009 1619; Natarajan 2013, F473}.


ASSESSEMENT Problem - Is the problem a priority?


○ No Previous ILCOR recommendations {Perlman 2015 S204}, as stated above, were based on 6 studies published between 1998 and 2015 {Casalaz 1998 112; Harrington 2007 463.e1; Kasdorf 2015 F102; Laptook 2009 1619; Patel 2004 136; Sarkar 2010 F423} that showed that 75 of 129 infants (58%) with an estimated gestational age of 36 weeks or greater and an Apgar score of zero at 10 minutes of life died before 22 months of age. After this review, some important issues continue to bring controversy to the question of timing of discontinuing resuscitation efforts: 1) most studies reported case series. Population- based studies were not available; 2) the adequacy of resuscitation procedures and whether prognosis differed after prolonged adequate resuscitation were not reported; 3) several of these studies were done prior to availability of therapeutic hypothermia and therefore they may not be representative of contemporary clinical care and advice regarding continuation of life support given to families; 4) the discussion in most was limited to late preterm and term infants, without any consideration of whether different recommendations were needed for more preterm infants {Perlman 2015 S204; McGrath 2016 102; Haines 2016 1305; Wilkinson 2020 Jan24}. New studies published since 2015, address some of these concerns. {Shah 2015 492; Ayrapetian 2017 545; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77; Shibasaki 2020 64}

○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know



○ Trivial For the critical outcome of survival until last follow up, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 15 studies {Ayrapetian 2017 545; Casalaz 1998 112; Haddad 2000 1210; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015

Widening the time frame for continuation of resuscitative interventions after birth (despite a poor response) may have very important desirable effects, the most important being the possibility of survival without severe neurodevelopmental

○ Small ○ Moderate ● Large ○ Varies ○ Don't know

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Elizabeth E. Foglia and Myra H. Wyckoff authored studies cited in the CoSTR that were not included in the systematic review.



492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77} reporting outcomes of 470 newborns to last known follow up (which ranged

impairment for neonates


from 4 months to 8 years of age). The number of enrolled newborns ranged from 3 to 177 per study. Across studies, reported survival rates to last follow up ranged from 1.7% to 100%. Among all 470 newborns reported in the literature, including studies that required survival to NICU admission or enrolment in a cooling protocol for inclusion, 187 (39.8%) survived to last follow up. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies. For the critical outcome of neurodevelopmental outcomes among survivors, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies including 277 infants {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15}. Neurodevelopmental outcomes were assessed in 80 survivors. Thirty (37.5%) did not have moderate or severe neurodevelopmental impairment (range 0-100%). There was important heterogeneity between studies (and in some cases- within studies) regarding the timing and tools used to assess neurodevelopmental outcomes. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies. For the composite critical outcome of survival w ithout neurodevelopmental impairment, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies of 277 infants {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15} reporting neurodevelopmental outcomes. Among all 277 infants reported in these studies, 69% died before last follow up, 18% survived with moderate to severe impairment, and 11% survived without moderate to severe impairment (2% lost to follow up). There was important heterogeneity between studies (and in some cases, within studies) regarding the timing and tools used to assess neurodevelopmental outcomes. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies.

who otherwise would die. Because there is sometimes uncertainty about whether all resuscitation measures have been performed adequately, longer time intervals afford greater opportunity to summon additional team members or telephone advice, and for rechecking the adequacy of ventilation and drug delivery and that no reversible conditions have been missed. A longer duration may also allow greater communication among resuscitation team members and inclusion of the baby’s parent(s) in the decision.


JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS by guest on August 4, 2021www.aappublications.org/newsDownloaded from

● Large ○ Moderate

Same as above. Extending the duration of intensive resuscitation after birth may also have very important undesirable effects. Ongoing intervention may be futile and still result in

○ Small

○ Trivial

○ Varies


○ Don't know failure to achieve return of circulation. This has the potential to increase moral distress for clinicians or parents without changing the outcome for the infant. More importantly, ongoing resuscitation may result in neonatal survival but with increased risk of moderate or severe neurodevelopmental impairment, increasing the burden on the affected infants and their families.



● Very low ○ Low ○ Moderate ○ High ○ No included studies

The studies included in this systematic review are 14 case series and one cohort nested in an RCT with clinical heterogeneity in population (gestational age), setting, cointerventions and time period. All the studies have a high risk of bias: selection bias, confounding bias, bias in exposure measurement, in outcome measurement and in reporting results, and missing data. The methodological quality of the studies makes the certainty of evidence very low.


JUDGEMENT ADDITIONAL CONSIDERATIONS


Providers value the outcomes included in this systematic review {Strand 2019 F1}. Parents have not been extensively surveyed but are considered likely to have similar views about the importance of survival and of moderate to severe neurodevelopmental disability.

Individual parents and providers may hold different values regarding the relative importance of survival and neurologic impairment.




○ Favors the comparison The balance between desirable and undesirable effects probably favors the intervention since there is a possibility of survival and survival without moderate to severe neurodevelopmental impairment after prolonged resuscitation. Overall 11% (30/277) of infants with an Apgar zero or one at 10 minutes survive without moderate or severe neurodevelopmental impairment. Moreover, if the infant survives resuscitation, 35% will not develop moderate or severe neurodevelopmental impairment. However, how long cardiopulmonary resuscitation should be provided is still unanswered. The small group of reported infants who have a detectable HR only at or after 20 minutes from birth shows that intact survival is still possible (survival 15/38 = 38%; survival without moderate or severe neurodevelopment impairment 6/39 =15%). However, selection bias of the reported case series and cohorts markedly limits the external validity of these findings.

○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know



● Large costs ○ Moderate costs

We did not identify any studies specifically reporting costs of prolonged resuscitation after birth.

Although costs are not objectively reported, it inherently costs more to care for a survivor than a non-survivor. All neonates that survive prolonged resuscitation will need intensive post-resuscitation care, which may include neuroprotective strategies, for a variable duration. Neonatal intensive care is expensive and the additional resources may include a wide range of diagnostic and therapeutic interventions, such as ventilation, EEG monitoring, eventually NIRS monitoring, image resources, with emphasis on MRI imaging, and therapeutic interventions (hypothermia and adjuncts, such as seizure control medication), as well as ongoing resources after hospital discharge. Therefore, the cost of treatment of neonates who survive aggressive and prolonged resuscitation is expected to be higher than the cost of a non-survivor, even if the outcome is good. An adverse outcome can have lifelong costs to the family and to society. Nevertheless, the absolute number of affected infants is small.

○ Negligible costs and

savings

○ Moderate savings

○ Large savings

○ Varies

○ Don't know

Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? by guest on August 4, 2021www.aappublications.org/newsDownloaded from


We did not identify any studies specifically reporting costs of prolonged resuscitation after birth.



○ Favors the comparison ○ Probably favors the comparison

We did not identify any studies specifically assessing the cost effectiveness of prolonged resuscitation after birth.

○ Does not favor either

the intervention or the

comparison

○ Probably favors the

intervention

○ Favors the intervention

○ Varies

● No included studies



○ Reduced ○ Probably reduced

We did not identify studies addressing health equity. Health equity was not objectively reported for prolonged neonatal resuscitation; however, one should consider that a possibility of reduced equity exists. In the first place, extensive neonatal resuscitation is generally not recommended in low resource settings, where face mask ventilation with 21% oxygen for non-breathing neonates is the focus of the intervention {Kamath-Rayne 2018 538}. Secondly, availability of intensive care resources for post-resuscitation care differs between high and low resource settings. Finally, availability of neuroprotective strategies also differs among high, medium

○ Probably no impact

○ Probably increased

○ Increased

○ Varies

● Don't know


and low resource settings. Therefore, it is likely that


prolonged resuscitation would be offered to a higher proportion of infants in higher-resource settings; outcomes may also be better in settings with full availability of neuroprotective strategies.



○ No We did not identify studies addressing acceptability of recommendations on prolonged resuscitation of newly born infants.

The inability to predict the individual outcome of an infant who receives prolonged resuscitation leads to uncertainty on the decision-making process in the delivery room. Cultural and religious differences, including different perceptions on the value of extending life, the quality of life, and the acceptance of comfort care as an option, also influence medical decisions. {Cuttini 2000 212; Fanaroff 2014 701; Schijvers 2018 1710}. Therefore, we expect that acceptability of the treatment recommendation on a matter that ultimately deals with the limits of life and death will be modulated by cultural differences, which includes individual moral and ethical beliefs.

○ Probably no ○ Probably yes ○ Yes ● Varies ○ Don't know



○ No All reported studies show that prolonged resuscitation is feasible, although the success assessed by survival or by survival without moderate or severe neurodevelopmental impairment varies according to several factors that include patient characteristics (such as gestational age, timing and cause of arrest), timing and procedures performed during resuscitation, availability of post-resuscitation care and neuroprotective strategies.{Ayrapetian 2017 545; Casalaz 1998 112; Haddad 2000 1210; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Laptook 2009 1619; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994

○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know


991; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}


SUMMARY OF JUDGEMENTS

JUDGEMENT

PROBLEM No Probably no Probably yes

Yes Varies

Don't know

DESIRABLE EFFECTS Trivial Small Moderate Large Varies

Don't know

UNDESIRABLE EFFECTS

Large Moderate Small Trivial Varies

Don't know

CERTAINTY OF EVIDENCE

Very low Low Moderate High

VALUES

Important uncertainty

or variability

Possibly important


Probably no

important uncertainty

or variability

No important

uncertainty or

variability

BALANCE OF

EFFECTS






Favors

the intervention

Varie

s

Don't know

RESOURCES REQUIRED

Large costs Moderate costs Negligible costs and savings

Moderate savings

Large savings

Varies

Don't know


Very low Low Moderate High No

included studies

COST

EFFECTIVENESS






Favors

the intervention

Varie

s

No

included studies

EQUITY Reduced Probably reduced

Probably no impact

Probably increased

Increased Varies

Don't know

ACCEPTABILITY No Probably no Probably yes

Yes Varies

Don't know by guest on August 4, 2021www.aappublications.org/newsDownloaded from

FEASIBILITY No Probably no Probably yes

Yes Varies

Don't know


intervention ○

Conditional recommendation against the intervention

○

Conditional recommendation for either the intervention or the comparison

○


•


○



Failure to achieve return of spontaneous circulation in newborn infants after 10-20 minutes of intensive resuscitation is associated with a high risk of mortality and a high risk of moderate to severe neuroimpairment among survivors. However, there is no evidence that any specific duration of resuscitation consistently predicts mortality or moderate or severe neurodevelopmental impairment. If a newborn infant requires ongoing cardiopulmonary resuscitation (CPR) despite completing all the recommended steps of resuscitation and excluding reversible causes, we suggest initiating discussion of discontinuing resuscitative efforts with the clinical team and family. A reasonable timeframe for this change in goals of care is around 20 minutes after birth. (Weak recommendation, very low certainty of evidence).

Justification In making this recommendation, we recognize the need to balance the risk of ceasing resuscitation too early, when return of spontaneous circulation and long- term survival may still be achievable, and continuing resuscitation for too long, when return of spontaneous circulation may occur but survival is associated with a high risk of severe neurologic injury. The appreciable number of survivors who do not have moderate or severe neurodevelopmental impairment after ≥10 minutes of resuscitation suggests that early cessation of resuscitation may preclude survival of some infants who may have had a good prognosis.

While an Apgar score of 0 or 1 at 10 minutes is a strong predictor of mortality and morbidity, recent case reports and series have reported favorable outcomes among newborn infants with Apgar scores of 0 or 1 at 10 minutes after birth who achieved return of spontaneous circulation and received therapeutic hypothermia. In this subgroup of newborns with severe depression at birth, both survival and survival without moderate to severe impairment have been reported. Among 105 such infants reported in the literature with Apgar scores 0 or 1 who were successfully resuscitated, were treated with therapeutic hypothermia, and assessed after discharge, 20% survived without moderate to severe impairment and 37% of survivors did not have moderate or severe neurodisability {Ayrapetian 2017 545; Kasdorf 2015 F102; Natajaran 2013 F473; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15}.

The evidence supporting this recommendation is of very low certainty. However, we value the possibility of survival and intact survival following ongoing resuscitation. In a large multisite cohort of 659 newborn infants who survived to discharge following >1 minute chest compressions in the delivery room, 25% of survivors received 10 minutes or more of CPR {Foglia 2020 pii: S0300-9572(20)30031-9}. This study did not specifically report on infants with 10-minute Apgar scores of zero or one. While these data indicate that survival to discharge is possible following a prolonged duration of CPR, neurodevelopmental outcomes among survivors in this study were not reported. Extremely limited data are available regarding outcomes of infants who received 20 or more minutes of CPR after birth. Six studies included in this systematic review {Ayrapetian 2017 545; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15} reported results for 39 patients in which first detectable heart rate or heart rate ≥100 beats per minute occurred at or beyond 20 minutes after birth. Of these patients, 15/39 (38%) survived until last follow up and 6/15 (40%) survivors did not have moderate or severe neuroimpairment.

The Task Force considered that as well as duration of resuscitation, it was important to consider whether all recommended resuscitation interventions had been provided. Studies suggest that the time taken to accomplish steps of a resuscitation up to the point of administration of one or more doses of epinephrine varies widely across studies but may take as long as 20 minutes {Barber 2006 1028; McKinsey 2016 F244; Halling 2017 232; Sprout 2017 F262}. The variation in the interval from birth to completion of these steps may depend on the characteristics and time to attendance of the resuscitation team. Thus,


using a single time interval after birth to discontinue intensive resuscitation for all newborns implies might mean that in some cases, the full repertoire of recommended resuscitation interventions had not yet been provided before cessation of resuscitation.

Another issue considered by the Task Force is the potential impact for infants and their families. Among the included studies, most deaths occurred either in the delivery room/birth suite or during the initial hospitalization. In this systematic review, rates of survival to discharge were similar to rates of survival to last follow up. For those infants who ultimately die in early infancy, achieving even this short-term survival may provide the family the time and opportunity to participate in decision making and care of their infant. Moreover, intact survival is possible among surviving infants. In this systematic review, 38% of surviving infants did not have moderate or severe impairment. Given these considerations, we do not recommend a specific duration of resuscitation after which point resuscitative efforts should be ceased. Instead, we suggest that providers consider changing the goals of care if a newborn infant has not responded to all recommended steps of resuscitation that are appropriate to the given setting. We acknowledge that cultural and religious differences, including different perceptions on the value of extending life, the quality of life, and the acceptance of comfort care as an option, may influence the decision {Cuttini 2000 212; Fanaroff 2014 701; Schijvers 2018 1710}. Ultimately, the decision to initiate and continue resuscitative efforts should be individualized and informed by factors such as gestational age, the presence of congenital anomalies, the timing of perinatal insult (if known), the perceived adequacy of resuscitative interventions performed, the family’s stated preferences and values, and the availability of post-resuscitative resources such as neonatal intensive care and neuroprotective strategies, such as therapeutic hypothermia. Finally, in low resource settings, where emphasis is given to face mask ventilation with 21% oxygen for non-breathing neonates {Kamath-Rayne 2018 538}, advanced resuscitation procedures and prolonging resuscitation may not be an option. Therefore, caution must be taken to globally adopt this treatment recommendation, and local/regional discussion and customization are necessary. Subgroup Analyses for Specified Outcomes

Subgroup Studies contributing

Infants Survival to last follow up

Assessed for NDI

No moderate or severe NDI

Survivors assessed without moderate or severe NDI

Composite: Survival without Moderate or Severe NDI

Population level studies 5 131 17/131 (13%) 15 9 9/15 (60%) 9/131 (7%) Therapeutic hypothermia 9 206 122/206 (60%) 57 21 21/57 (37%) 21/105 (20%)* Gestational Age ≥36 weeks 12 286 146/286 (51%) 73 23 23/73 (32%) 23/166 (14%)** Gestational Age <36 weeks 6 99 34/99 (34%) 8 5 5/8 (63%) 5/42 (12%)***

* 8 studies with 105 infants reported post-discharge outcomes; **11 studies with 166 infants reported post-discharge outcomes; ***5 studies with 42 infants reported post-discharge outcomes

Population-level studies: { Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Sproat 2017 F262; Zhang 2019 Jun15} Studies with any infants treated with therapeutic hypothermia: {Ayrapetian 2017 545; Kasdorf 2015 F102; Natajaran 2013 F473;

Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77} Studies with any infants born at gestational age >=36 weeks: {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1;

Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}

Studies with any infants born at gestational age < 36 weeks {Casalaz 1998 112; Harrington 2007 463.e1; Shah 2015 492; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}.

Subgroup considerations


Insufficient details about birthweight precluded the planned subgroup analysis based on birthweight. Given the small sample sizes and heterogeneity of study characteristics, there is no strong evidence on which to base any variation in recommendations for specific subgroups of infants.

Implementation considerations Acceptability of the intervention should be thoroughly discussed in the different settings according to cultural, ethical and moral standards that prevail in each country or region. Optimal resuscitation should be available for infants in need, and training of skills and team performance is critical to achieve it. Communication with families should be optimized, and whenever possible, parents’ wishes and values must be considered even in urgent and stressful situations. Availability of neonatal intensive care and neuroprotective strategies for post-resuscitation care is another aspect that may be considered in the decision process.

Monitoring and evaluation

Monitoring and evaluation of prognosis of infants that receive prolonged resuscitation at birth is extremely important. In addition, although health equity was not objectively reported for prolonged neonatal resuscitation, it is possible that prolonged resuscitation may be offered to a higher proportion of infants in higher-resource settings; outcomes may also be better in settings with full availability of intensive care and neuroprotective strategies. Since prolonged CPR after birth is relatively rare, an international registry of events, with detailed description of procedures and their timing in the delivery room, post-resuscitation care and neurologic outcomes assessed in follow-up would provide essential evidence to inform the discussion of “how long is too long.” Such a registry would also provide valuable information on variations in practice regarding duration of resuscitation in different settings. Research priorities Many studies only reported outcomes of infants who survived resuscitation and met a specific study eligibility criterion, such as neonatal intensive care unit admission or initiation of therapeutic hypothermia. Therefore, estimates of mortality following prolonged resuscitation likely underestimate the actual incidence of death when failed resuscitations are considered. Studies accounting for the full population of newborn infants who receive CPR after birth, using consistent definitions of stillbirths and resuscitation failures, are needed to identify the incidence of mortality and neurodevelopmental impairment after prolonged resuscitation of term and preterm infants. In addition, the extent and timing of resuscitation procedures were not reported in most studies; therefore, prognosis of newborn infants after prolonged resuscitation at birth is inferred from the available data. Further, most available studies characterized the infant’s response to resuscitation using the Apgar score at 10 minutes, which is prone to subjective assessment and does not provide information about ongoing assessments or response to resuscitation beyond 10 minutes. More granular information about the interval from birth to detectable heart rate using objective measures such as electrocardiogram (ECG) and time to return of circulation is needed to inform more precise recommendations regarding the duration of intensive resuscitation after birth. Additionally, as ECG has become more frequently used in the delivery room environment, additional information about the presenting rhythm (bradycardia, asystole, pulseless electrical activity) preceding chest compressions will be helpful to identify outcomes following these varied presentations. Therefore, studies that report outcomes on the full population of infants who present without signs of life and receive intensive resuscitation are needed with:

− A priori definitions of stillbirths and complete resuscitation attempts − Complete description of co-interventions (resuscitation procedures), timing of procedures at birth, and interventions in post-resuscitative care − Description of methods to assess the heart rate during resuscitation using objective measures, such as ECG, and report of timing for

detection of heart rate and heart rate >60 and >100 beats per minute − Complete follow up of survivors with accurate and consistent methods of assessment of neurodevelopment, comparable across studies and

population


Background References: Ayrapetyan M, Talekar K, Schwabenbauer K, Carola D, Solarin K, McElwee D, Adeniyi-Jones S, Greenspan J, Aghai ZH. Apgar scores at 10 minutes and outcomes in term and late preterm neonates with hypoxic-ischemic encephalopathy in the cooling era. Am J Perinatol. 2019 Apr;36(5):545-54. Barber CA, Wyckoff MH. Use and efficacy of endotracheal versus intravenous epinephrine during neonatal cardiopulmonary resuscitation in the delivery room. Pediatrics. 2006 Sep;118(3):1028-34.

Casalaz DM, Marlow N, Speidel BD. Outcome of resuscitation following unexpected apparent stillbirth. Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F112-15.

Cuttini M, Nadai M, Kaminski M, Hansen G, de Leeuw R, Lenoir S, Persson J, Rebagliato M, Reid M, de Vonderweid U, Lenard HG, Orzalesi M, Saracci R. End-of- life decisions in neonatal intensive care: physicians' self-reported practices in seven European countries. EURONIC Study Group. Lancet. 2000 Jun 17;355(9221):2112-8. Fanaroff JM, Hascoët JM, Hansen TW, Levene M, Norman M, Papageorgiou A, Shinwell E, van de Bor M, Stevenson DK; International Perinatal Collegium (IPC). The ethics and practice of neonatal resuscitation at the limits of viability: an international perspective. Acta Paediatr. 2014 Jul;103(7):701-8. Foglia EE, Jensen EA, Wyckoff MH, Sawyer T, Topjian A, Ratcliffe SJ; American Heart Association’s Get With The Guidelines-Resuscitation Investigators. Survival after delivery room cardiopulmonary resuscitation: A national registry study. Resuscitation. 2020, pii: S0300-9572(20)30031-9.

Haddad B, Mercer BM, Livingston JC, Talati A, Sibai BM. Outcome after successful resuscitation of babies born with Apgar scores of 0 at both 1 and 5 minutes. Am J Obstet Gynecol. 2000 May;182(5):1210-14. Haines M, Wright IM, Bajuk B, Abdel-Latif ME, Hilder L, Challis D, Guaran R, Oei JL. Population-based study shows that resuscitating apparently stillborn extremely preterm babies is associated with poor outcomes. Acta Paediatr. 2016 Nov;105(11):1305-11.

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Appendix B-1

NLS 1562 Effect of Briefing/Debriefing Following Neonatal Resuscitation on Patient/Clinician/Parent Outcomes: A Scoping Review

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable Task Force Scoping Review Citation Yamada N, Stave C, Fawke J. Use of Briefing and Debriefing in Neonatal Resuscitation (NLS 1562 Briefing/Debriefing). [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, 2020 Feb 5. Available from: http://ilcor.org

Methodological Preamble and Link to Published Scoping Review

The continuous evidence evaluation process started with a scoping review conducted by the ILCOR NLS Task Force Scoping Review team. Evidence was obtained using a structured search strategy carried out by an information specialist. Studies identified were evaluated using Covidence. This allowed independent title and abstract review by two authors (JF,NY) to see if full text review was warranted. Studies put forward by both authors were included, conflicting opinions were reviewed, discussed and resolved.

Studies identified for full text review were independently reviewed by two authors (JF,NY) to see if they matched the agreed PICOST and included if agreed by both reviewers. Conflicting opinions were reviewed, discussed and resolved. The authors agreed that psychomotor skill feedback device studies would only be included if supported by a briefing or debriefing component.

The PICOST was agreed with the ILCOR Neonatal Life Support Task Force prior to undertaking the literature search. The final scoping review was considered by the Neonatal Life Support Task Force.

Studies screened by title / abstract, those undergoing full text review and those extracted for data analysis are shown in the PRISMA diagram.

PRISMA Flow Chart


https://costr.ilcor.org/document/=

Scoping Review This question has not previously been reviewed in the ILCOR 2010 or 2015 datasets.

NLS 1562 Briefing/Debriefing PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Among health care professionals involved in the resuscitation or simulated resuscitation of a neonate (P) Intervention: does briefing/debriefing (I)

Comparators: in comparison to no briefing/debriefing (C)

Outcomes: improve outcomes for infants, families or staff (O)?

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Manikin studies are eligible for inclusion, animal studies are excluded. Conference abstracts and unpublished studies (e.g. trial protocols) are excluded.


Timeframe: All years and all languages are included as long as there is an English abstract. Literature search updated to January 27, 2020. Definitions of terms used in this PICOST Neonates: a newborn baby up to 28 days of age Resuscitation: a newborn baby who requires support at birth to consist of a minimum of positive pressure support of breathing (PEEP or breaths given via mask, supraglottic airway device or tracheal tube). Briefing: an act or instance of giving precise instructions or essential information (source: Merriam-Webster medical dictionary) Debriefing: discussions of actions and thought processes after an event to promote reflective learning and improve clinical performance. Sawyer, Loren, Halamek. Post-event debriefings during neonatal care: why are we not doing them, and how can we start? Journal of Perinatology (2016), 1-5 Simulation: an artificial representation of a real-world process to achieve educational goals through experiential learning. Healthcare professionals: staff employed by a healthcare organization, who deliver resuscitative care (as defined above) to neonates. Search Strategies PUBMED: (“infant, newborn” [mesh] OR infant* [tw] OR preterm [tw] OR preemie* [tw] OR newborn* [tw] OR neonat* [tw]) AND (“resuscitation” [mesh] OR resuscitat* [tw] OR cpr [tw]) AND (“critical reflection” [tw] OR reflection [tw] OR “post simulation” [tw] OR “pre briefing” [tw] OR prebrief* [tw] OR debrie* [tw] OR brief [tw] OR briefing [tw] OR “after action review” [tw] OR feedback [tw] OR “communication” [mesh]) AND (English [lang] OR English Abstract[ptyp]) EMBASE: ('newborn'/exp OR 'newborn' OR infant*:ti,kw,ab OR preterm:ti,kw,ab OR preemie*:ti,kw,ab OR newborn*:ti,kw,ab OR neonat*:ti,kw,ab) AND ('resuscitation'/exp OR 'resuscitation' OR resuscitat*:ti,kw,ab OR cpr:ti,kw,ab) AND ('interpersonal communication'/exp OR 'interpersonal communication' OR 'debriefing'/exp OR 'debriefing' OR 'critical reflection':ti,kw,ab OR 'reflection'/exp OR 'reflection' OR reflection:ti,kw,ab OR 'post simulation':ti,kw,ab OR 'pre briefing':ti,kw,ab OR prebrief*:ti,kw,ab OR debrie*:ti,kw,ab OR brief:ti,kw,ab OR briefing:ti,kw,ab OR 'after action review':ti,kw,ab OR feedback:ti,kw,ab) AND ([embase]/lim OR [embase classic]/lim) WEB OF SCIENCE: (infant* OR preterm OR preemie* OR newborn* OR neonat*) AND (resuscitat* OR cpr) AND (“critical reflection” OR reflection OR “post simulation” OR “pre briefing” OR prebrief* OR debrie* OR brief OR briefing OR “after action review” OR feedback) COCHRANE LIBRARY:


(infant* OR preterm OR preemie* OR newborn* OR neonat*) AND (resuscitat* OR cpr) AND (communicat* OR “critical reflection” OR reflection OR “post simulation” OR “pre briefing” OR prebrief* OR debrie* OR brief OR briefing OR “after action review” OR feedback) Inclusion and Exclusion criteria Inclusion Studies needed to match the PICOST Studies of checklists were included if the checklists were specifically used for the purposes of conducting a team briefing or debriefing Manikin or human studies were included Studies of briefing or debriefing in the context of real or simulated neonatal resuscitation Psychomotor skills testing was only included if it was accompanied by debriefing Exclusions Conference abstracts Published protocols without a subsequent published study as a full paper Studies that only have an abstract Papers without an English abstract Bundles of care where the impact of briefing / debriefing could not be separated from the rest of the bundle Studies of briefing or debriefing in the context of pediatric or adult resuscitation Evaluation of Included Studies

Reference Methods Participants Interventions Comparisons Outcomes Notes Skare

2018 394

Prospective, pre/post interventional study. Initial phase of a multi-faceted quality improvement initiative. Skill performance and process of care evaluation before, during and after introducing video debriefing of resuscitation events. Evaluation used a modified Neonatal Resuscitation Evaluation Performance (NRPE) tool.

Midwives and physicians involved in resuscitation of compromised infants at a Norwegian teaching hospital in 2014. 73 resuscitation events pre- implementation were compared to 45 events post- implementation

Introduction of weekly video assisted debriefing (3rd April to 23rd June 2014) Followed by monthly video assisted debriefing in a post implementation period (24th June to 24th August 2014)

NRPE scores in the pre, peri and post intervention period. Baseline evaluations were performed 15th January to 2nd April 2014.

Pre vs post implementation Total NRPE scores (77% vs 89%, p<0.001) Improved preparation & adherence to the initial steps of a neonatal resuscitation algorithm (75% vs 90%, p<0.001) Improved PPV (70% vs 100%, p<0.001) Improved group function,

PPV intervention ran alongside video debriefing intervention


NRPE scores by single investigator but intra-rater reliability and inter-rater reliability checked by a 2nd investigator.

communication – 88% vs 100%, p<0.001)

Sauer 2016

37397

Single centre pre- post quality improvement initiative. Data on 548 infants representing every admission to the Palomar Rady Children’s Hospital NICU during a 35 month period (1st Jan 2010 to 30th November 2012). It aimed to achieve: • Placement of a

functioning pulse oximeter by two minutes after birth

• Delayed intubation in favour of CPAP use

• Normothermia at NICU admission

• Use of a team prebrief, debrief and delivery room checklist to promote teamwork and communication between the obstetrician, labour and delivery room staff and the neonatal resuscitation team

High risk delivery team (not further specified)

Described as a bundle of delivery room interventions. Individual interventions are not clearly described. The delivery room checklist is shown in the paper and appears to be the main intervention. Briefing / debriefing is included within the checklist.

Pre vs post intervention: Data for 249 infants prior to the intervention were compared to data for 299 born after the intervention.

Functioning pulse oximeter by 2 minutes (26% to 55%, p value unclear – see NOTES) % intubated (14% vs 5%, p<0.001) Surfactant use (2.8 vs 1.0%, p=0.198) Normothermia on NICU admission (78% vs 86%, p=0.017) % using checklist (25% to 92%, p<0.001) Outcome data collected for RDS, BPD, death, PDA, pneumothorax, NEC, ROP, post haemorrhagic hydrocephalus (PHH), IVH, length of stay. Univariable & multivariable logistic regression done. (MV regression not for BPD, death, ROP, PHH) No significant differences except for reduced ROP in univariable logistic regression for post

Pre & post % of infants with a functioning pulse oximeter is not clear. Pre is reported both as ‘data not collected’ and approximately 26%. Post is variably reported as 38% (Table 2) and ‘almost 55%’ (Results text). Authors advise caution in interpreting the reduced ROP rates.


intervention group (OR 0,0.696; p=0.008).

Katheria 2013 1552

Pre/post study to evaluate the implementation of a checklist that included pre-brief and debrief components. Outcomes were measured at video resuscitation quality assurance meetings. The completed pre-brief checklist was reviewed prior to seeing each video to see if planned preparation happened. The completed debrief findings were reviewed after watching each video to see if team conclusions matched video review conclusions. The components of the checklist were informed by crew resource management training previously undertaken by NICU staff and ongoing video reviews of neonatal resuscitations.

Neonatal faculty, neonatal fellows, pediatric residents in training, nurses, respiratory therapists.

Pre-brief: Introduction of team members, role assignments, specific considerations, team empowered to voice concerns and to call back orders. Equipment checklist with duty specific sub lists and required setup with the requirement to acknowledge completion. Debrief: Free form questions on what went well, what didn’t go well and what needed to be improved. Debrief completed soon after resuscitation with all team members involved. Members responded in order of seniority, most junior first. QA review: Completed checklists were reviewed with special emphasis on the debrief section at twice monthly video resuscitation quality assurance meetings.

First two years of using the delivery room checklist (March 2009 to November 2011, 260 completed checklists) were compared with the 3rd year of using the delivery room checklist (185 completed checklists).

Most common problems: Communication (n=58) Equipment preparation and use (n=56) Inappropriate decisions (n=87) Leadership (n=56) Procedures (n=25) During the 3rd year of use (Nov 2011 to May 2012), 185 checklists were reviewed. Communication problems decreased from 22% to 4% (p<0.001). This finding was reported on the checklists and validated in audio & video recordings. Non-significant changes: • Lack of

equipment preparation & use (21% vs 23%)

• Inappropriate decisions (33% vs 27%)

• Leadership (21% vs 18%)

• Procedures -sequence, timing, technique (10% vs 6%)

Unclear how often the resuscitation team members were involved in the video review meeting for each resuscitation.

Magee 2018 192

Prospective, randomised

38 pediatric interns in a

Instructional simulation

Instructional simulation

34 interns included in the

Clinical scenarios used


control study of Rapid Cycle Deliberate Practice (RCDP) vs. traditional simulation debriefing methods for neonatal resuscitation training. Study occurred over 1.5 years with 3-4 interns enrolled each month. Randomisation occurred in blocks of 4 interns to account for variations in abilities in the first year of academic training. Pre-survey looking at confidence in neonatal resuscitation and previous experience completed. Primary outcome was the interns’ score on the megacode assessment form (MCAF) on immediate testing. Secondary outcomes measured at a 4 month follow-up were: confidence level in neonatal resuscitation, recall MCAF scores and time to perform critical interventions.

large academic training programme. All the interns held a current NRP certification and were on a neonatology or newborn nursery rotation when enrolled.

session with RCDP Immediate simulation retest

session with standard debriefing that occurred at the conclusion of the simulation scenario Immediate simulation retest

analysis. 4 were excluded due to changes in study protocol and technical issues. Interns in the RCDP group compared to those in the simulation debriefing group: Had higher MCAF scores than those in (89% vs 84%, p<0.026) Initiated PPV ventilation within 1 minute (100% vs 71%, p<0.05) More consistently provided PPV for the appropriate duration of time before starting CC (17 vs 12, p<0.05) Administered epinephrine earlier (152s vs 180s, p=0.039) Self-reported confidence levels increased in both groups but were not different between the two groups. MCAF scores and time to perform critical interventions at 4 months were not different between the two groups.

for the instructional simulation sessions and immediate retests were the same in both arms. Pre-written scripts, set up checklists and teaching point checklists were used for consistency in instruction. A senior neonatologist NRP instructor trained in simulation monitored for inconsistencies.


Task Force Insights

1. Why this topic was reviewed An ILCOR systematic review on Debriefing of Resuscitation Performance (EIT #645) considered debriefing following in hospital and out of hospital cardiac arrest in adults and children. They recommended data-driven, performance focused debriefing of rescuers acknowledging it as a weak recommendation based on very low certainty of evidence. No review has been carried out looking at the impact of briefing or debriefing on outcomes in neonatal resuscitation. Prior systematic review of briefing/debriefing by the NLS Task Force in 2010, primarily focused on use of these techniques in the context of training rather than clinical care.

2. Narrative summary of evidence identified 1789 studies were identified using the structured search strategy. 493 were removed as duplicates leaving 1296 studies that underwent title and abstract screening. Of these 1296 studies, 48 were identified for full text review and from this 44 were excluded. The reasons for exclusion were abstract only (15), wrong intervention (10), wrong study design (8), wrong comparator (7), study protocol (2) and wrong outcomes (2). This left 4 studies to be included in the scoping review. This is summarised in the PRISMA flow chart. The four studies included are listed in the included studies evaluation table. One study considered video debriefing {Skare 2018 394}, one considered the use of a checklist along with video debriefing {Katheria 2013 1552}, one considered the use of a checklist with a team prebrief / debrief as the main part of a quality improvement bundle {Sauer 2016 37397} and one looked at rapid cycle deliberate practice compared to standard simulation debriefing {Magee 2018 192}.

a) Video debriefing Skare et al installed motion activated video cameras in every neonatal resuscitation bay in a Norwegian teaching hospital. Using footage from resuscitations of compromised infants they conducted baseline skill performance and process of care assessments on 74 resuscitation events using the Neonatal Resuscitation Evaluation Performance Tool (NRPE). They implemented weekly video assisted debriefing using this footage. The debriefing was led by two experienced facilitators and focused on guideline adherence and non-technical skills. Video assisted debriefing was reviewed in departmental meeting and by the end of the study period 78% of the pediatric residents had attended. The study period was 7 months and the team evaluations were carried out pre, peri and post implementation. The number of events evaluation was pre (74), peri (69) and post (45). Subcategories of group function / communication, preparation and initial steps, communication of heart rate, administration of oxygen, positive pressure ventilation, endotracheal intubation, chest compressions, administration of medicines and intravenous access were considered. Pre – / post –implementation of video assisted debriefing evaluation showed that overall NRPE score improved from 77% (75, 81) to 89% (86,93) p<0.001. Improvements in were seen in the following subcategories:

• Group function / communication 88% (75,90) to 100% (92,100) p=0.001 • preparation and initial steps 75% (70, 80) to 90% (80, 100) p<0.001 • positive pressure ventilation 70% (67, 75) to 100% (80, 100) p<0.001


No significant differences were reported for communication of heart rate, administration of oxygen, endotracheal intubation or administration of medicines. Limitations of the study are the before after design and the authors acknowledge that an RCT would not have been possible. Improvements could have been due to a “Hawthorne effect” i.e. the candidates were aware they were being videoed and changed their behavior. The study was not able to blind the video reviewer as to the phase of the trial as videos had to be deleted immediately after review at their institutional review board’s request. The authors acknowledge that whilst they have shown improvements in the process of care and adherence to guidelines the study was not powered to detect changes in clinically relevant outcomes.

b) Checklists Two studies were identified that utilized checklists specifically for the purposes of briefing or debriefing in neonatal resuscitation. Sauer et al implemented a quality improvement bundle that included a pre-brief, debrief and delivery room checklist. Other aspects of the quality improvement bundle were placement of a functioning pulse oximeter, normothermia on NICU admission and avoiding intubation by using CPAP. Prompts related to pulse oximeters and thermal care were included on the checklist. This was a single centre, pre / post quality improvement study and involved all deliveries attended by the high risk delivery team at the Palomar Rady Children’s hospital over a 35 month period. The intervention was the use of a delivery room checklist that included pre-brief and debrief components. The comparison was 249 infants studied prior to introducing the checklist with 299 infants afterwards. Data was collected retrospectively from 1st January 2010 to the start of the intervention on 1st May 2011 and prospectively until 30th November 2012. Outcomes were

1. % using checklist 2. % intubated 3. Surfactant use (%) 4. Normothermia on NICU admission (%) 5. % with a functioning pulse oximeter by 2 minutes of age.

Results:

• Use of prebrief, debrief and completion of the checklist increased from an initial 25% to 92% (p<0.001).

• % of babies intubated dropped from 14.1 to 5.4% OR 0.35 (0.17, 0.66) p<0.001. • Surfactant use dropped from 2.8% to 1.0% OR 0.35 (0.06, 1.55) p =0.198. • % with normothermia on admission to NICU increased from 78.3% to 86.3% OR 1.74 (1.09, 2.8)

p=0.017. • The % with a functioning pulse oximeter at 2 minutes was not recorded pre-intervention but

increased from approximately 26% to 55% during the period the checklist was implemented. Outcome data on RDS, death, BPD, PDA, pneumothorax, NEC, ROP, post-haemorrhagic hydrocephalus, IVH and length of stay was also collected. No differences were shown except for decrease in ROP on univariable logistic regression that the authors advised caution in interpreting. Katheria et al conducted a pre/post study evaluating the implementation of a checklist including pre-brief and debrief components. The components of the checklist were informed by crew resource management training previously undertaken by NICU staff and ongoing video reviews of neonatal resuscitations.


Outcomes were measured at video resuscitation quality assurance meetings where the completed pre-brief checklist was reviewed, prior to seeing each video, to see if planned preparation happened. The completed debrief findings were reviewed after watching each video to see if team conclusions matched video review conclusions. The first two years of using the delivery room checklist (March 2009 to November 2011, 260 completed checklists) were compared with the 3rd year of using the delivery room checklist (185 completed checklists). The most common problems seen were communication (n=58), equipment preparation and use (n=56), inappropriate decisions (n=87), leadership (n=56) and procedures (n=25). Communication problems decreased from 22% to 4% (p<0.001). This finding was reported on the checklists and validated in audio & video recordings. Other changes were not statistically significant.

c) Rapid cycle deliberate practice vs. standard debriefing Magee et al performed a prospective, randomized controlled trial to compare rapid cycle deliberate practice (RCDP) to standard simulation debriefing for teaching neonatal resuscitation on learners’ technical abilities as measured by the NRP Megacode Assessment Form (MCAF), confidence level as measured via survey, and recall in neonatal resuscitation as measured using the MCAF at a follow-up session four months later. The study was conducted at a large academic center and enrolled 38 pediatric interns. All subjects underwent a 45-minute teaching session on neonatal resuscitation. Efforts were made to ensure standardization and consistency in teaching by facilitating all sessions by the same neonatology fellow, using the same instructional simulation scenario, and using prewritten scripts, setup checklists, and teaching point checklists. A senior neonatologist NRP instructor who was trained in simulation also observed the teaching in order to monitor for inconsistencies. Outcomes were measured via 15-minute simulation test with a similar clinical scenario that occurred immediately after the instructional simulation, a post-instructional survey of confidence, and a 2nd simulation test at 4 months after the initial session. On immediate testing, subjects in the intervention (RCDP) group had better scores on the NRP Megacode Assessment Form (MCAF), more frequently initiated positive pressure ventilation within one minute, ventilated the patient for at least 25 seconds prior to starting chest compressions, and administered epinephrine earlier. Learners in both groups reported increased confidence in neonatal resuscitation. At the 4-month follow up test, there was no difference in MCAF scores or timing of performing critical interventions.

3. Narrative reporting of the Task Force discussions Given that this is a new PICOST question for the Neonatal Life Support Task Force, the Task Force elected to perform a Scoping Review in order to make an initial assessment of the available literature. Although briefing and debriefing in resuscitation has been previously reviewed by the EIT Task Force, outcomes specific to neonates or neonatal resuscitation were not included in those recommendations. This scoping review has not identified sufficient evidence to prompt a systematic review. The evidence reviewed in this scoping review comes primarily from quality improvement studies with pre/post comparisons. There were no randomized controlled trials that compared briefing or debriefing to no briefing or debriefing. In addition, many investigators have studied briefing or debriefing in the context of bundles of interventions, but these studies were not included in this evidence review as the effects of briefing or debriefing alone were not possible to isolate in the outcomes. We reviewed a small of number studies that included adjuncts to briefing and debriefing (e.g., the use of video and the use of checklists) as these were the only studies that compared these interventions to no


briefing or debriefing rather than other interventions. The use of video-assisted debriefing may help improve the process of care and adherence to resuscitation guidelines, but evidence was not available on the effect on clinical outcomes. The use of checklists during briefings and debriefings may help improve team communication and process, but the evidence identified did not report changes in clinical outcomes and was inconsistent in the effects reported on the delivery of care. We identified limited evidence that rapid cycle deliberate practice (RCDP) may improve short term performance in a resuscitation simulation but not confidence or retention of skills. Briefing or debriefing may improve short-term clinical and performance outcomes for infants and staff. The effects of briefing or debriefing on long-term clinical and performance outcomes are uncertain. Recommendation At this time there does not appear to be enough new evidence to justify a new systematic review on the use of briefing/debriefing. Knowledge Gaps Although this scoping review has not identified sufficient evidence to prompt a systematic review, it highlights significant knowledge gaps in neonatal resuscitation science regarding the effects of briefing and debriefing on outcomes. Identified knowledge gaps include:

• Effects of briefing and debriefing in isolation from other interventions. • Effects of briefing and debriefing on short- and long-term clinical outcomes of neonatal

resuscitation. • Effects of rapid cycle deliberate practice in neonatal resuscitation training.

References 1. Katheria A, Rich W, Finer N. Development of a strategic process using checklists to facilitate team

preparation and improve communication during neonatal resuscitation. Resuscitation. 2013;84(11):1552-1557. doi:10.1016/j.resuscitation.2013.06.012

2. Magee MJ, Farkouh-Karoleski C, Rosen TS. Improvement of Immediate Performance in Neonatal Resuscitation Through Rapid Cycle Deliberate Practice Training. J Grad Med Educ. 2018;10(2):192-197. doi:10.4300/JGME-D-17-00467.1

3. Sauer CW, Boutin MA, Fatayerji AN, Proudfoot JA, Fatayerji NI, Golembeski DJ. Delivery Room Quality Improvement Project Improved Compliance with Best Practices for a Community NICU. Sci Rep. 2016;6:37397. doi:10.1038/srep37397

4. Skåre C, Calisch TE, Saeter E, et al. Implementation and effectiveness of a video-based debriefing programme for neonatal resuscitation. Acta Anaesthesiol Scand. 2018;62(3):394-403. doi:10.1111/aas.13050


Scoping Review Template v1.0 SAC Approved 17 Nov. 2019

12

Appendix B-2 Suctioning Clear Amniotic Fluid During Neonatal Resuscitation in the Delivery Room (NLS #596): Scoping Review and Task Force Insights Conflict of Interest Declaration The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None applicable. The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: None applicable

Task Force Scoping Review Citation Udaeta E, Rudeger M, Ersdal H on behalf of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2020 February 5. Available from: http://ilcor.org Methodological Preamble and Link to Published Scoping Review The continuous evidence evaluation process started with a scoping review of suctioning of clear fluid during delivery room resuscitation conducted by 3 content experts working with the ILCOR NLS Task Force Scoping Review team. Evidence for neonatal literature was sought and considered by the NLS Task Force. The NLS task force discussed the evidence and provided insights.

Scoping Review We expect to submit this Scoping Review for publication in Spring of 2020.

PICOST The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe) was defined as follows:

• Population: Among newborns delivered through clear amniotic fluid

• Intervention: does immediate routine suctioning (oropharyngeal or nasopharyngeal)

• Comparators: compared with no suctioning or no wiping

• Outcomes:

o survival (critical)

o need for delivery room resuscitation and stabilization interventions (important) (i.e. use of oxygen supplementation, initiation of positive pressure ventilation, intubation, use of CPR/medications, Apgar scores);

o Respiratory complications (important) (i.e. respiratory distress, tachypnea),

o Side effects (important): (oxygen desaturation, injury or infection)

o (Time to reach heart rate > 100 (Important)

• Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to November 30, 2019.


http://ilcor.org/


13

Search Strategies Data sources: The following databases were searched on November 21st 2019: MEDLINE complete, Embase, Cochrane using the OVID search engine. The search of the “grey literature” was done manually in Scholar Google, Clinical trials gob, WHO International/ICTRP/ search and NDLTD Global ETD search. The searches that informed the 2010 and 2015 NLS CoSTR {Perlman 2010 S516; Perlman 2015 e169} were conducted on the following dates: Suction clear amniotic fluid August 7, 2009 and Suction meconium stained amniotic fluid February 20, 2014. The new search included published studies from 1997 until November 2019.

"infant, newborn"[MeSH Terms] OR "infant"[All Fields] AND "newborn"[All Fields] OR "newborn infant"[All Fields] OR "newborn"[All Fields] AND "infants"[All Fields] OR "newborn infants"[All Fields]) AND ("suction"[MeSH Terms] OR "suction"[All Fields]) AND ("mouth"[MeSH Terms] OR "mouth"[All Fields]) AND ("nose"[MeSH Terms] OR "nose"[All Fields]) oropharynx" [All Fields] OR "AND ("parturition"[MeSH Terms] OR "parturition"[All Fields] OR "birth"[All Fields]) AND ("amniotic fluid"[MeSH Terms] OR ("amniotic"[All Fields] AND "fluid"[All Fields]) OR "amniotic fluid"[All Fields])

For detailed search results please see Appendix. Inclusion and Exclusion criteria

Studies are considered eligible for inclusion if they were randomized controlled trials (RCTs), non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) peer-reviewed human studies that prospectively or retrospectively compared the effects of interventions listed below on physiological outcomes (e.g. time to reach normal oxygen saturation and heart rate) or clinical outcomes (e.g. resuscitation and stabilization interventions: CPR/meds in delivery room; Apgar scores, oxygen supplementation, intubation); Delay in providing respiratory support; Inpatient morbidities: respiratory complications (respiratory distress, tachypnoea); Side effects (oxygen desaturation, injury or infection)

All years and all languages were included as long as there was an English abstract. Unpublished studies (e.g., conference abstracts, trial protocols) or studies published in abstract form only, manikin studies, animal studies, and studies that did not specifically address the PICO question were excluded.



14



15

Data tables

Critical Outcomes

Survival After the procedure n=0; Hospital discharge n=0

Resuscitation and stabilization interventions in Delivery Room a. Cardiopulmonary resuscitation n= 2 {Kelleher 2013 382; Bancalari 2019 271} ; Medications =0 Reference

Methods Participants

Interventions Comparisons Outcomes Notes

Kelleher 2013

{Kelleher 2013 382}

RCT Alabama, USA

488 infants Born at or after 35 weeks of GA Vaginal 326 Cesarean 162

n= 242 suction mouth and nostrils with bulb syringe Vaginal 154 Cesarean 88

n= 246 Gentle wiping externally over face, mouth and nose with towel Vaginal 172 Cesarean 74

Secondary: Advanced resuscitation 17 (7%) vs. 24 (10%) RR 95% CI: 1.40 (0.76-2.50) (p=0.28)

No definition on “advanced resuscitation required”

Bancalari 2019

{Bancalari 2019 271}

RCT Concepcion, Chile

84 term infants born by C-section

n= 42 Catheter tube 8 F introduced 6 cm Negative pressure <30cmH2O Procedure 15 sec

n=42 No suction Routine care; cleaning

Resuscitation maneuvers 0/42 vs. 0/42

None required resuscitation maneuvers during and for 48 h

Resuscitation and stabilization interventions b. Apgar score less than 7 at 1 minute, 5 and 10 minutes n=0 ; Apgar score at 1, 5, and 10 min n= 7 {Carrasco 1997 832; Waltman 2004 32; Gungor 2005 453; Gungor 2006 9, Kelleher 2013 382; Nejad 2014 400; Bancalari 2019 271) Reference Methods Participants Interventions Comparisons Outcomes Notes Carrasco

1997 {Carrasco 1997 832}

RCT Montevideo, Uruguay

30 term infants, vaginal delivery

n= 15 After birth suction with catheter tube 3R polyethylene, first nasopharynx and then nose no more 6 cm during 8 to 10 sec, negative pressure < 30cmH2O

n= 15 No suction

Secondary: Apgar score at 1 and 5 min At 1 min 7 or more At 5 min 7 or more

No numbers reported

Waltman 2994

{Waltman 2004 32

RCT pilot study Mississippi, USA


n= 10 Suction mouth and nose one time each with 2-ounce soft rubber bulb syringe or ear/ulcer syringe 1.5 inches deep,

n= 10 No suction, all the mouth and nose wiped with a towel if any visible matter

Secondary: Apgar score at 1, 5 and 10 min 1 min: mean 8.95 ± 0.22 5 min: mean 9 ± 0 10 min: 9.40 ± 0.44

Infants were placed under radiant warmer, dried thoroughly, and received standard care



16

and finger pressure, when the head was delivered and mouth and nose wiped with a towel if any visible matter

Range Apgar: < 9 at 1 min 1 vs. 1 < 9 at 5 min 0 vs. 0 < 9 at 10 min 0 vs. 0

according to the NRP guidelines None of both groups had Apgar less than 8 at 1, 5 or 10 min

Gungor 2005

{Gungor 2005 453}

RCT (Ankara Turkey)


n=70 Catheter tube 8 Ch., polyethylene, negative pressure <30cmH2O procedure 15 sec

n=70 No suction or wipe away any visible matter

Secondary: Apgar score at 1, 5 min 1 min: > 7 (8 to 9) n= 70/70 vs. 70/70 5 min Apgar 10 32/70 vs. 70/70 (0.001)

Newborns dried thoroughly under radiant heat next room. SaO2 monitor on right hand from 1st min At 1 and 5 min both groups had Apgar > 7

Gungor 2006

{Gungor 2006 9}

RCT (Ankara Turkey)




Secondary: Apgar score at 1, 5 and 10 min 1 min: 8.17 ± 0.38 vs. 8.26 ± 0.50 (NS) 5 min: 9.34 ± 0.48 vs. 10±0.0 (<0.001) Apgar 10 at 5min 24/70 vs. 70/70 (<0.001)

All mothers received general anesthesia protocol. Newborns dried thoroughly under radiant heat next room. SaO2 monitor on right hand from 1st min At 1 and 5 min both groups had Apgar > 7

Kelleher 2014

{Kelleher 2013 382}

RCT Alabama, USA

488 infants Born or after 35 weeks of GE Vaginal 326 Cesarean 162

n= 242 suction mouth and nostrils with bulb syringe

n= 246 Gentle wiping externally over face, mouth and nose with towel

Secondary: Apgar score at 1 and 5 min Median (IQR) 1 min 8 (7-8) vs. 8 (7-8) 5 min 9 (9-9) vs. 9 (9-9)

After umbilical cord was cut, and long as a neonate remained in resuscitation area 2010 NPR guidelines

Nejad 2014

{Nejad 2014 400}

RCT Kerman, Iran

170 term infants vaginal delivery

n= 85 Suction: < 15 sec after birth Catheter polyethylene

n= 85 No suction: was only to remove any visible material.

Secondary Apgar score at 1 and 5 min: 1 min: all 8 or 9

Under radiant heat “standard care”



17

Negative pressure <30cmH2O

5 min: all 10 Mean 8.96 ± 0.19 vs 8.99 ± 0-11

Bancalari 2019






Secondary: Apgar score 1 min: 9 (8-9) vs. 9 (7-9) NS 5 min 9 (9-10) vs. 9 (9-10) NS

Routine care (cleaning, drying, stimulation), not mentioned how

Resuscitation and stabilization interventions Respiratory rate: n= 1 {Kelleher 2013 382}; Respiratory mechanics n= 1 {Estol 1992 297} Reference Methods Participants Interventions Comparisons Outcomes Notes

Kelleher 2013

{Kelleher 2013 382}

RCT Alabama, USA

488 infants Born or after 35 weeks of GE Vaginal 326 Cesarean 162



Primary mean respiratory rate in first 24 h after birth Respiratory rate 50 ±6 vs. 51 ± 8

Respiratory rates were similar at every time point

Estol 1992 {Estol

1992 297}

RCT Montevideo, Uruguay

40 term infants Vaginal delivery

n= 20 After birth nares and mouth suction with electric aspirator Catheter polyethylene 5F negative pressure < 30cmH2O

n= 20 No suction

Primary: pulmonary mechanics Inspiratory C Dyn.: no differences at 10, 30 and 120 min Expiratory C Dyn: no differences at 10, 30 and 120 min Inspiratory R: no differences at 10, 30 and 120 min no differences at 10, 30 and 120 min Expiratory R: no differences at 10, 30 and 120 min

Newborns after intervention were wrapped in a dry napkin and put on mother´s breast At 10 min after birth 1st spyrometric assessment

Resuscitation and stabilization interventions Time to reach SaO2 > 90% n= ; Time to reach > 92% n= 4 {Waltman 2004 32; Gungor 2005 453; Gungor 2006 9; Nejad 2014 400} ; Time to reach > 86% n= 2 { Gungor 2005 453; Gungor 2006 9} Effect or differences on SaO2 n= 4 {Carrasco 1997 832; Waltman 2004 32; Bancalari 2019 271; Konstantelos 2015 777}



18

Reference Methods Participants

Interventions Comparisons

Outcomes Notes

Carrasco 1997

{Carrasco 1997 832}

RCT 30 term infants, vaginal delivery

n= 15 After birth suction with catheter tube 3R polyethylene, first nasopharynx and then nose no more 6 cm during 8 to 10 sec, negative pressure < 30cmH2O

n= 15 No suction

Differences in SaO2 first 20 min SaO2 lower in suction between 1 to 6 min (0.05) Time to reach 86%: 8.2 ± 3.3 vs 5.0 ± 1.2 (0.05) Time to reach 92%: 10.2 ± 3.3 vs 6.8 ±1.8 s (0.05)

SaO2 sensor in right hand, reading between 20 and 30 sec, 1st reading al 1 minute

Waltman 2004

{Waltman 2004 32}

RCT pilot study Mississippi, USA


n= 10 When the head was delivered the mouth and nose wiped with a towel if any visible matter Suction mouth and nose one time each with 2-ounce soft rubber bulb syringe or ear/ulcer syringe 1.5 inches deep, and finger pressure

n= 10 No suction: all mouth and nose wiped with a towel if any visible matter

Differences in SaO2 first 20 min Average changes over time (5–20 minutes) at 5 min Suction: 3% ± 2.3% less than No (NS) at 10 min Suction: 3% ± 2.3% more (NS) At 15 min Suction: 4.8% ± 1.7% (.005) At 20 min: 92% vs. 97% Time to reach >92% 8 min (48s) vs. 5 min (30s) (model)

Reusable neonatal saturation sensor applied to the hand Only SaO2 measurements recorded from 5 to 20 minutes were used in the analysis

Gungor 2005 {Gungor

2005 453}

RCT Ankara Turkey




Primary; time to reach 92% SaO2: SaO2: 83.37 ± 1.69 vs. 92.06 ± 0.23 (at 6 min. < 0.001); n= 0/70 vs. 70/70 at 6 min) Secondary: Time to reach 86% SaO2: 77.60 ± 1.30 vs. 86.89 ± 2.72 (4 min, < 0.001) n= 10/70 vs. 70/70 (<0.001)

Newborn dried thoroughly under radiant heat next room SaO2 monitor on right hand from 1st min



19

Gungor 2006 {Gungor 2006 9}

RCT Ankara Turkey




Primary; time to reach 92% SaO2: 80.60 ± 1.84 vs. 92.04 ± 0.20 (<0.001); n= 0/70 vs. 70/70 at 6min Secondary: Time to reach 86% SaO2: 77.64 ±1.39 vs. 87.43 ± 3.09 (<0.001) n= 2/70 vs. 70/70 (<0.001)

All mothers received general anesthesia protocol. Newborns dried thoroughly under radiant heat next room SaO2 monitor on right hand from 1st min

Nejad 2014 {Nejad 2014

400}

RCT Kerman, Iran


n= 85 Suction: < 15 sec after birth Catheter polyethylene Negative pressure <30cmH2O


Primary: time to reach 92% SaO2 At 9 min (54s) 89.23 ± 5.17 vs. 92.0 ± 5.119 (0.002) Sao2 at 1 min: 75.91 ± 6.95 vs. 75.46 ± 7.51 (0.7) NS SaO2 at 5 min 85.02 ± 4.85 vs. 85.51 ± 6.64 (0.6) NS

SaO2 monitor attached to middle fingers right hand at 1st min

Konstantelos 2015

{Konstantelos 2015 777}

Observational cohort study Dresden, Germany

n= 346 Born by elective C-section 261 term infants 86 preterm infants

n= 58 term infants n= 57 preterm Suction

n= 202 term infants n= 29 No suction

Primary: Effects on SaO2 In term without respiratory support lower oxygen saturation in suctioning group (p<0.05 at 3 and 5-10 minutes after suctioning). No effect in preterm infants.

One infant with severe desaturation after suctioning.

Bancalari 2019 {Bancalari 2019 271}




n=42 No suction Routine care (cleaning, drying, stimulation)

Primary: Effect on SaO2 during 60 min 1 min: 52.0 ± 8 vs. 56.0 ± 10 (0.2) NS 5 min: 80.7 ± 9 vs. 81.2 ± 8 (0.8) NS 10 min 93.7 ± 2 vs. 93.8 ± 3 NS Need of oxygen supplementation: 0/0 vs.=/0

Pulse oximeter first 10 min and at 15, 30 and 60 min, in one lower extremities There are a difference between the table in SaO2 (52.0 ± 8 vs. 56.0 ± 10) and the authors



20

discussion (1 min: 52.6 ± 7.6 vs. 56.1 ±10.8) This was reported but no was an outcome

Resuscitation and stabilization interventions d. Need endotracheal tube n= 0 Reference Methods Participants Interventions Comparisons Outcomes Notes

Important Outcomes

Delay in providing respiratory support Time needed for intervention (suction) n= 1 {Konstantelos 2015 777} Reference Method

s Participants

Interventions Comparisons

Outcomes Notes

Konstantelos 2015 {Konstantelos 2015 777}



n= 58 term infants n= 57 preterm Suction

n= 202 term infants n= 29 No suction

Primary: Median duration of total suctioning Term: 22 (IQR 11-35) or 36 (12-56) sec for infants without or with respiratory support respectively. Preterm: 35 or 23 (14-61) sec for infants without or with respiratory support respectively. time in suction Median time single suctioning 9 s approx. Median total time 30 s. approx.

Suctioning was performed in 74% oropharyngeal, 8% nasal, 7% oral/nasal,11% other combinations; In median 2.5 suctioning episodes / infant

Morbidities: Respiratory complications (respiratory distress, tachypnea) n= 1 {Kelleher 2013 382} Reference Methods Participants Interventions Comparisons Outcomes Notes Kelleher 2013 {Kelleher 2013 382}

RCT Alabama, USA

488 infants born or after 35 weeks of GE



Secondary any respiratory rate value >60 bpm in first 24 h 112 (46%) vs. 113 (46%)

No specific pathology reported

Side effects:



21

Arrhythmia n= 1 {Cordero 1971 441}; Apnea n=1x {Cordero 1971 441}; Need Oxygen supplementation (desaturation) n= 1 {Bancalari 2019 271}; Injury n= 0 ; Infection n= 0 Reference

Methods Participants

Interventions Comparisons Outcomes Notes

Cordero 1971

{Cordero 1971 441}

Case report Connecticut, USA

n= 87 Apparently term infants Delivery vaginally or by C-section

n= 46 After delivery another suction with introduction through nose or mouth nasogastric Catheter tube 5 or 8 connected to glass de Lee trap

n= 41 After delivery another suction with bulb syringe

Primary: cardiac arrhythmias of vagal origin 7/46 vs. 0/41 Secondary: vagal Apnea 5/46 vs. 0/41

All patients as the head of an infant were delivered, oral and nasal suction is applied with a bulb syringe. Recorded HR and ECG were obtained from one minute of life to 1st hour. All neonates had a HR of 120 to 180 bpm and an identifiable ECG before suction

Bancalari 2019






Oxygen during 48h 0/0 vs. 0/0

None required oxygen for 48 h

Time to reach heart rate > 100 HR at 1 min: n= 1 {Nejad 2014 400}; HR over 5 to 20 min: n=4 {Waltman 2004 32; Gungor 2005 453; Gungor 2006 9; Konstantelos 2015 777}; HR during 60 min: 1 {Bancalari 2019 271} Reference Methods Participant

s Interventions Comparisons Outcomes Notes

Waltman 2004

{Waltman 2004 32}

RCT pilot study Mississippi ,USA


n= 10 When the head was delivered the mouth and nose wiped with a towel if any visible matter Suction mouth and nose one time each with 2-ounce soft rubber bulb syringe or

n= 10 No suction, all the mouth and nose wiped with a towel if any visible matter

HR first 20 min HR mean 160.84 (SD 7.65) for both groups range 150–166 vs. 166–173 bpm HR suction group 11 ± 5.2 bpm less (.042)

Electrodes for simultaneous heart rate recording were also applied to verify the accuracy of measurements obtained by the saturation sensor.



22

ear/ulcer syringe 1.5 inches deep, and finger pressure

HR in both groups never was under 100 bpm

Gungor 2005

{Gungor 2005 453}

RCT Ankara Turkey




Secondary: HR: At 1 min: 136.60 ± 4.09 vs. 133.91 ± 7.87 (NS)

HR in both groups never was under 100 lpm

Gungor 2006

{Gungor 2006 9}

RCT Ankara Turkey




Secondary HR: At 1 min: 137.3683.38 vs. 132.84±10.71 (<0.031)

All mothers received general anesthesia protocol. Newborns dried thoroughly under radiant heat next room SaO2 monitor on right hand from 1st min HR in both groups never was under 100 lpm

Nejad 2014

(Nejad 2014 400}

RCT Kerman, Iran


n= 85 Suction: < 15 sec after birth Catheter polyethylene Negative pressure <30cmH2O


Secondary HR at 1 min: 146.29 ± 8.73 vs 146.67 ± 9.74 (0.8) NS

Under radiant heat “standard care”

Konstantelos 2015

{Konstantelos 2015

777}



n= 58 term infants n= 57 preterm

n= 202 term infants n= 29

Primary: Effect of suctioning on HR In term with respiratory support: higher HR (p<0.05 at 5, 7, 9 and 10 minutes) No difference in preterm infants.

Suctioning did not cause severe bradycardia,

Bancalari

2019 RCT Concepcion, Chile


n= 42 n=42 No suction

Primary: Effect on HR during 60 min

Pulse oximeter first 10 min



23


Catheter tube 8 F introduced 6 cm Negative pressure <30cmH2O Procedure 15 sec

Routine care (cleaning, drying, stimulation)

1 min: 137 ± 25 vs. 148 ± 13 (0.02) 5 min: 162 ± 19 vs. 161 ± 13 (0.35) NS 10 min: 154 ± 16 vs. 151 ± 143 (0.44) NS

and at 15, 30 and 60 min, in one lower extremities In the discussion the authors inverse the results compared with the table HR in both groups never was under 100 lpm

NICU admission required n= 1 {Kelleher 2013 382} Reference Methods Participants Interventions Comparisons Outcomes Notes

Kelleher 2013

{Kelleher 2013,382}

RCT Alabama, USA

488 infants At or after 35 weeks of GE



Secondary NICU admission 30 (12%) vs. 45 (18%) RR (95%CI: 1.5 (0.96-2.30) (0.07)

No special pathology reported

Note: all comparisons are Suctioning vs. NO-suctioning or wiping Further data description This scoping review identified 10 articles with the predefined inclusion criteria. They were reviewed by year of publication, type of study, and by intervention (suction versus no suction or wipe). If available, data were presented separately for premature and term or near-term infants and for different type of delivery; vaginal or C-section (Table ). Most of the available data was from infants at term or near-term. The proportion of delivery mode was similar for vaginal or C-section. The total number of newborn infants included in the suction group was 802 (bulb plus catheter) versus 579 in the no suction or wipe group.

Author year Study type

Preterm (n)

Term or

near term (n)

Vaginal Delivery

(n)

Cesarean Delivery

(n)

Suction bulb (n)

Suction catheter

(n)

No suction or wipe

(n)

Cordero 1971

Case Report

--- 87 Not reported

Not reported

87 +46 de Lee trap

+ 41 another bulb suction

Carrasco 1997

RCT --- 30 30 --- --- 15 15

Estol 1992 RCT --- 40 40 --- --- 20 20



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Task Force Insights 1. Why this topic was reviewed. Successful transition from the intra-uterine fetal to the extra-uterine newborn state requires the replacement of lung liquid within the airways with air. In order to support liquid clearance, oro/nasopharyngeal suctioning at birth, there was a long-standing practice of routine suctioning to remove secretions in vigorous infants at birth. The 2010 International Liaison Committee on Resuscitation Consensus on Science suggested against this practice for the first time {Perlman 2010 S516; Wyllie 2010 e260; Perlman 2010 e1319}. The 2015 American Heart Association Guidelines update emphasized “Suctioning immediately after birth, whether with a bulb syringe or suction catheter, may be considered only if the airway appears obstructed or if PPV is required” {Wyckoff 2015 S963}. The purpose of this scoping review was to identify the available evidence related to suctioning /clearing of the oropharynx immediately after birth in vigorous infants. This scoping review includes the available literature and studies of suctioning clear amniotic fluid at birth, and the outcomes examined to date. 2. Narrative summary of evidence identified Evidence supporting potential benefits of oro/nasopharyngeal suctioning is limited and the benefit of removing liquid from the oropharynx remains controversial.

• Three randomized controlled studies and one observational study were identified that were published since 2010. They compare the use of “suction clear amniotic fluid” with “no suction or wipe” in “premature, near term and term infant population” in 1545 patients

• The identified studies were from diverse geographical areas, and there were similar results in the interventions used.

• The published literature identified by this scoping review fell into two subgroups (route of delivery: vaginal or C-section, and gestational age at birth: preterm or term).

• The procedure can have serious side effects including bradycardia and apnea. {Cordero 1977 4471}. • It is possible that nasopharyngeal suction may result in vagal-induced bradycardia as well as increase

the risk of infection {McCartney 2000 46}. • The procedure may take a significant time to complete {Konstantelos 2015 7777} • It may delay initiation of ventilation in non-breathing infants {Ersdal 2012 8699}.

Gungor 2005 RCT --- 140 140 --- --- 70 70 wiped

Gungor 2006 RCT --- 140 --- 140 --- 70 70 wiped

Waltman 2004

RCT pilot

--- 20 20 --- 10 wiped

--- 10 wiped

Kelleher 2013

RCT --- 488 > 35 w

326 162 242 --- 246 wiped

Nejad 2014 RCT --- 170 170 --- --- 85 85 wiped

Konstantelos 2015

Cohort videos

86 260 --- 346

115 231

Bancalari 2019

RCT --- 84 --- 84 --- 42 42

Total

86 1459 726 732 339 463 579



25

• Newborns who received suctioning compared to a control group had significantly lower oxygen saturation levels through the first 6 minutes of life and took longer to reach a normal range {Carrasco 1997 8328; Konstantelos 2015 7777).

• There is a concern that the procedure may have serious additional consequences such as irritation to mucous membranes and increased risk for iatrogenic infection {Gungor 2005 45310; Gungor 2006 911}, bradycardia {Cordero 1971 4411; Gungor 2006 911}, apnea {Cordero 1971 4411}, hypoxemia and arterial oxygen desaturation {Carrasco 1997 8328; Gungor 2005, 45310; Kohlhauser 2000, 27012}, hypercapnea {Skov 1992 38913}, impaired cerebral blood flow regulation {Van Bel 1988 2714; Perlman 1983 32915}, increased intracranial pressure {Fisher 1982 41616}, and development of subsequent neonatal brain injury {Kaiser 2008 3417}. Fluctuations in cerebral blood flow have been shown to cause intraventricular haemorrhage in premature infants and neonatal animals.

3. Narrative Reporting of the task force discussions

• The identified studies were from diverse geographical areas, and there were similar results in the interventions used.

• The published literature identified by this scoping review fell into two subgroups (delivered by vaginal or C-section and premature and term infants).

• The majority of the new literature does not appear to refute the current recommendation of no routine suctioning of the newborns in the delivery room

• However, because of the large number of patients (>1500) reported since 2015, a new systematic review including these patients may increase the certainty of the evidence through GRADE evaluation

• We suggest based on this Scoping Review to proceed to an update of the Systematic Review for this PICO question: “Among vigorous infants delivered through clear amniotic fluid (P) does immediate routine suctioning (oropharyngeal or nasopharyngeal) (I) compared with no suctioning or wiping C) change outcome (O)”

Knowledge Gaps • There is extremely limited data on suctioning of preterm infants • There is very limited data from RCTs with vigorous infants delivered through clear amniotic fluid

References

Carrasco M, Martell M, Estol PC, et al. Oronasopharyngeal suction at birth: effects on arterial oxygen saturation. J Pediatr. 1997;130:832–834.

Cordero L, Hon EH. Neonatal bradycardia following nasopharyngeal stimulation. J Pediatr. 1971;78(3):441-447. Ersdal HL, Mduma E, Svensen E, Perlman JM. Early initiation of basic resuscitation interventions including facemask ventilation may reduce birth asphyxia related mortality in low-income countries. Resuscitation. 2012; 83:869-73.

Fisher DM, Frewen T, Swedlow DB. Increase in intracranial pressure during suctioning-stimulation vs. rise in PaCO2. Anesthesiology 1982;57(5):416–7.

Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J. 2009;26:91–108.

Gungor S, Teksoz E, Ceyhan T, et al. Oronasopharyngeal suction versus no suction in normal, term and vaginally born infants: a prospective randomized controlled trial. Aust N Z J Obstet Gynaecol. 2005; 45:453–456.

Gungor S, Kurt E, Teksoz E, Goktolga U, Ceyhan T, Baser İ. Oronasopharyngeal Suction versus No Suction in Normal and Term Infants Delivered by Elective Cesarean Section: A Prospective Randomized Controlled Trial. Gynecol Obstet Invest 2006; 61:9-14.



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Kaiser JR, Gauss CH, Williams DK. Tracheal suctioning is associated with prolonged disturbances of cerebral hemodynamics in very low birth weight infants. Journal of Perinatology. 2008;28(1):34–41.

Kelleher J, Bhat R, Salas AA, Addis D, Mills EC, Mallick H, et al. Oronasopharyngeal suction versus wiping of the mouth and nose at birth: a randomised equivalency trial. Lancet. 2013;382(9889):326-30.

Kohlhauser C, Bernert G, Hermon M, Popow C, Seidl R, Pollak A: Effects of endotracheal suctioning in high-frequency oscillatory and conventionally ventilated low birth weight neonates on cerebral hemodynamics observed by near infrared spectroscopy (NIRS). Pediatric Pulmonology 200;29: 270-275.

Konstantelos D, Ifflaender S, Dinger J, Rüdiger M. Suctioning habits in the delivery room and the influence on postnatal adaptation - a video analysis. J Perinat Med. 2015;43(6):777-82.

McCartney. Bulb Syringes in Newborn Care. The American Journal of Maternal/Child Nursing. 2000;25 (4):217.

Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol. 2018;18:143.

Perlman JM, Volpe JJ. Suctioning in the preterm infant: effects on cerebral blood flow velocity, intracranial pressure, and arterial blood pressure. Pediatrics. 1983;72:329–334. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N, Szyld E, Tamura M, Velaphi S; on behalf of the Neonatal Resuscitation Chapter Collaborators. Part 11: neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation. 2010;122(suppl 2):S516 –S538. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Pediatrics. 2010;126(5):e1319-44. Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015;132(16 Suppl 1):S204-41. Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (Reprint). Pediatrics. 2015;136 Suppl 2:S120-66. Skov L, Ryding J, Pryds O, Greisen G. Changes in cerebral oxygenation and cerebral blood volume during endotracheal suctioning in ventilated neonates. Acta Paediatrica 1992;81(5):389–93.

Van Bel F, Van de Bor M, Baan J, Ruys JH. The influence of abnormal blood gases on cerebral blood flow velocity in the preterm newborn. Neuropediatrics. 1988;19(1):27–32.

Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, Simon WM, Weiner GM, Zaichkin, JG. Part 13: Neonatal resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(suppl 2):S543–S560.

Wyllie J, Perlman JM, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2010;81 Suppl 1:e260-87.

Wyllie J, Perlman JM, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, Kim H-S, Liley HG, Mildenhall L, Simon WM, Szyld E, Tamura M, Velaphi S, on behalf of the Neonatal Resuscitation Chapter Collaborators.



27

Part 7: Neonatal resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation.2015;95:e169–e201.

Appendix for Appendix B-2

Database/source Embase <1974 to 2019 November 20>

Date of search 21.11.2019

Search history or search string 1 newborn/ (512125)

2 (newborn or infant* or neonat* or newly born or delivery room).ti,ab,kw. (757818)

3 1 or 2 (977748)

4 exp amnion fluid/ (20354)

5 (((allantoi* or amnion* or amniot*) adj (fluid* or liquid*)) or liquor amnii).ti,ab,kw. (25278)

6 4 or 5 (30050)

7 suction/ (10391)

8 (suction* or mechanical aspiration).ti,ab,kw. (24175)

9 7 or 8 (27578)

10 3 and 6 and 9 (156)

Number 156 (before removal of duplicates)

Comments

Database/source Ovid MEDLINE(R) ALL <1946 to November 19, 2019>


Search history or search string 1 exp Infant, Newborn/ (594199)

2 (newborn or infant* or neonat* or newly born or delivery room).ti,ab,kw. (660992)

3 1 or 2 (962931)

4 Amniotic Fluid/ (18633)

5 (((allantoi* or amnion* or amniot*) adj (fluid* or liquid*)) or liquor amnii).ti,ab,kw. (22026)

6 4 or 5 (27768)

7 Suction/ (12262)

8 (suction* or mechanical aspiration).ti,ab,kw. (18285)



28

9 7 or 8 (26066)

10 3 and 6 and 9 (129)

Numbers 129 (before removal of duplicates)

Comments

Database/source Cochrane Library


Search history or search string

#1 MeSH descriptor: [Infant, Newborn] explode all trees 15370

#2 (newborn or infant* or neonat* or "newly born" or "delivery room"):ti,ab,kw 68896

#3 #1 or #2 68896

#4 MeSH descriptor: [Amniotic Fluid] explode all trees 208

#5 ((((allantoi* or amnion* or amniot*) NEXT (fluid* or liquid*)) or liquor amnii)):ti,ab,kw 877

#6 #4 or #5 877

#7 MeSH descriptor: [Suction] explode all trees 886

#8 (suction* or "mechanical aspiration"):ti,ab,kw 3677

#9 #7 or #8 3677

#10 #3 and #6 and #9 36


Comments

Database/source Scholar Google



#1 Newborn or infant or newly born or delivery room 41,000

#2 Newborn or infant or newly born or delivery room or amniotic fluid 22,700

#3 Newborn or infant or newly born or delivery room or suction amniotic fluid 11,100

#4 Newborn or infant or newly born or delivery room or suction clear amniotic fluid 8,660

#5 Newborn or infant or newly born or delivery room or oropharyngeal suction amniotic 1040

#6 Newborn oropharyngeal suction or wiping amniotic fluid 206


Comments

Database/source WHO Int/ICTRP/search/en



#1 MeSH descriptor:newborn OR infant OR newly born

#2 AND MeSH descriptor [delivery room]

#2 AND MeSH descriptor: [Amniotic Fluid]

#3 AND MeSH descriptor: [Suction]



29

#4 AND MeSH descriptor: [Clear amniotic fluid]

#5 AND MeSH descriptor: [Oropharyngeal] suction amniotic

#6 MeSH descriptor: [Wiping] amniotic fluid 247


Comments

Database/source NALTD Global ETD search



#1 Newborn OR infant

#2 AND delivery room

#2 AND Amniotic Fluid

#3 AND Suction

#4 OR Wiping 18


Comments

Database/source CADTH evidence driver



#1 Newborn OR infant

#2 AND delivery room

#2 AND Amniotic Fluid

#3 AND Suction

#4 OR Wiping 4


Comments



30

Appendix B-3 Scoping Review and Task Force Insights for www.ilcor.org posting T-piece resuscitator or self-inflating bag during neonatal resuscitation (NLS #870): A Scoping Review Conflict of Interest Declaration The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable.

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: GM Schmöelzer was co-author on one included paper, Task Force Member Ruth Guinsburg was co-author on one included paper

Task Force Scoping Review Citation Roehr CC, Weiner GM, Davis PG, Schmöelzer GM, Wyckoff MH, Wyllie J, Trevisanuto D. T-piece resuscitator or self-inflating bag during neonatal resuscitation: A scoping review and Task Force Insights [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, 2020 Feb 14, 2020. Available from: http://ilcor.org

Methodological Preamble and Link to Published Scoping Review The continuous evidence evaluation process started with a systematic review on the devices (T-piece resuscitator or self-inflating bag) for newborns receiving ventilation during resuscitation conducted by the ILCOR NLS Task Force in 2015. In order to investigate whether there was sufficient new evidence published since 2015 to justify a new systematic review, the TF aimed to perform a scoping review. Additional reasons for choosing the format of a scoping review were to identify and analyse remaining knowledge gaps since the last systematic review as a potential precursor to a new systematic review on this topic. Scoping Review This scoping review will be submitted for publication in February 2020. PICOST The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Newborns receiving ventilation (PPV) during resuscitation

Intervention: T-piece resuscitator

Comparators: Self-inflating bag

Outcomes: Survival to hospital discharge, air leak, development of stable spontaneous breathing (no need for intubation in DR), bronchopulmonary dysplasia

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion.

Timeframe: All years and all languages were included if there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to January 3, 2020.


http://www.ilcor.org/


31

Search Strategies

The databases searched were OVID Medline, PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). The search that informed the 2015 NLS CoSTR was conducted on 24 April 2014. This subsequent search was date limited from 1 January 2014 to 3 January 2020 to identify studies published since the 2015 ILCOR NLS CoSTR. Database: Medline (Ovid MEDLINE® Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid

MEDLINE® Daily and Ovid MEDLINE®)

"2014 - 2020" (3rd January 2020)

Search Strategy:

--------------------------------------------------------------------------------

1 Masks/ (4174)

2 Insufflation/ (3324)

3 self-inflating bag*.ti,ab. (175)

4 bag valve mask*.ti,ab. (411)

5 ambu bag*.ti,ab. (66)

6 manual resuscitator*.ti,ab. (61)

7 (t-piece resuscitator* or tpiece resuscitator*).ti,ab. (67)

8 Ventilators, Mechanical/ (8609)

9 or/1-8 (16461)

10 Positive-Pressure Respiration/ (16930)

11 positive end expiratory pressure*.ti,ab. (5714)

12 PEEP.ti,ab. (5208)

13 positive pressure respiration.ti,ab. (234)

14 positive pressure ventilation.ti,ab. (5421)

15 or/10-14 (23267)

16 Respiratory Distress Syndrome, Newborn/ (12756)

17 Bronchopulmonary Dysplasia/ (4519)

18 Infant, Newborn/ (593133)

19 Delivery Rooms/ (1549)

20 Gestational Age/ (79576)

21 Premature Birth/ (13042)

22 Infant, Premature, Diseases/ (20146)

23 Term Birth/ (2869)

24 Live Birth/ (3375)

25 Birth Injuries/ (5008)

26 Birthing Centers/ (757)

27 Neonatal Nursing/ (3940)

28 Neonatal Screening/ (9902)

29 Intensive Care, Neonatal/ (5528)

30 Intensive Care Units, Neonatal/ (14111)

31 Animals, Newborn/ (112411)

32 "Transient Tachypnea of the Newborn"/ (101)

33 Persistent Fetal Circulation Syndrome/ (1148)

34 (newborn or neonatal or neonate or neonates or low birth weight or small for gestational age or prematur* or preterm or infant or infants or birth or delivery

room).ti,ab. (870598)

35 or/16-34 (1237790)

36 9 and 15 and 35 (394)

37 exp animals/ not humans.sh. (4660155)

38 36 not 37 (380)

39 limit 38 to yr="2014 - 2020" (77)

***************************

Database: Embase

"2014 - 2020" (3rd January 2020)

Search Strategy:

--------------------------------------------------------------------------------

1 exp face mask/ (6291)

2 mechanical ventilator/ (3071)



32

3 manual ventilation/ (630)

4 self inflating bag*.ti,ab. (244)

5 bag valve mask*.ti,ab. (674)

6 ambu bag*.ti,ab. (132)

7 (manual adj1 resuscitator*).ti,ab. (68)

8 ((t-piece or tpiece or t piece) adj1 resuscitator*).ti,ab. (113)

9 or/1-8 (10860)

10 positive end expiratory pressure/ (52612)

11 positive end expiratory pressure*.ti,ab. (7257)

12 PEEP.ti,ab. (8858)

13 positive pressure respiration.ti,ab. (125)

14 positive pressure ventilation.ti,ab. (7601)

15 or/10-14 (57385)

16 exp neonatal respiratory distress syndrome/ (7314)

17 exp newborn hypoxia/ (4976)

18 exp prematurity/ (98370)

19 exp newborn apnea attack/ (13)

20 newborn disease/ (20588)

21 exp neonatal stress/ (265)

22 exp lung dysplasia/ (11410)

23 exp newborn/ (513718)

24 exp low birth weight/ (59838)

25 exp newborn screening/ (18326)

26 exp newborn monitoring/ (1011)

27 exp newborn care/ (42311)

28 exp newborn period/ (10796)

29 exp birth weight/ (115493)

30 exp newborn morbidity/ (8641)

31 exp live birth/ (21765)

32 exp newborn death/ (9277)

33 exp newborn mortality/ (13384)

34 exp delivery room/ (3144)

35 (newborn* or low birth weight or small for gestational age or prematur* or preterm or postmature or post mature).ti,ab. (435569)

36 exp macrosomia/ (6528)

37 or/16-36 (872388)

38 9 and 15 and 37 (419)

39 limit 38 to yr="2014 - 2020" (259)

***************************

PubMed ("2014/01/01"[PDAT] : "2019/12/31"[PDAT])

((((((((((((("Masks"[Mesh:NoExp]) OR Insufflation[MeSH Terms]) OR self-inflating bag[Title/Abstract]) OR bag valve mask[Title/Abstract]) OR Ambu bag

[Title/Abstract]) OR manual resuscitator*[Title/Abstract]) OR t-piece resuscitator*[Title/Abstract]) OR "Ventilators, Mechanical"[Mesh:NoExp])) AND

(((((Positive- Pressure Respiration[MeSH Terms]) OR positive end expiratory pressure*[Title/Abstract]) OR PEEP[Title/Abstract]) OR positive pressure

respiration [Title/Abstract]) OR positive pressure ventilation[Title/Abstract]))) AND ((("Respiratory Distress Syndrome, Newborn"[Mesh] OR

"Bronchopulmonary Dysplasia"[Mesh] OR "Infant, Newborn"[Mesh] OR "Delivery Rooms"[Mesh] OR "Gestational Age"[Mesh] OR "Premature Birth"[Mesh] OR

"Infant, Premature, Diseases"[Mesh:NoExp] OR "Term Birth"[Mesh] OR "Live Birth"[Mesh] OR "Birth Injuries"[Mesh] OR "Birthing Centers"[Mesh] OR "Neonatal

Nursing"[Mesh] OR "Neonatal Screening"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Animals, Newborn"[Mesh]

OR "Transient Tachypnea of the Newborn"[Mesh] OR "Persistent Fetal Circulation Syndrome"[Mesh] or newborn[TIAB] or neonatal[TIAB] or neonate[TIAB] or

neonates[TIAB] OR "Low Birth Weight "[TIAB] or "Small for Gestational Age"[TIAB] or prematur*[TIAB] or preterm[TIAB] OR infant[TIAB] OR infants[TIAB] OR

birth[TIAB] OR "delivery room"[TIAB]))))) NOT ((animals[mh] NOT humans[mh]))

Cochrane Library with Cochrane Library publication date from Jan 2014 to Dec 2019

ID Search Hits

#1 MeSH descriptor: [Masks] explode all trees 1498

#2 MeSH descriptor: [Insufflation] explode all trees 291

#3 MeSH descriptor: [Ventilators, Mechanical] explode all trees 262

#4 (self inflating bag):ti,ab,kw 50

#5 (bag valve mask):ti,ab,kw 170



33

#6 (ambu bag):ti,ab,kw 28

#7 (manual resuscitator*):ti,ab,kw 35

#8 (t-piece resuscitator):ti,ab,kw 45

#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 2223

#10 MeSH descriptor: [Positive-Pressure Respiration] explode all trees 2616

#11 (positive end expiratory pressure):ti,ab,kw 3907

#12 (PEEP):ti,ab,kw 1528

#13 (positive pressure respiration):ti,ab,kw 2070

#14 (positive pressure ventilation):ti,ab,kw 4403

#15 #10 or #11 or #12 or #13 or #14 7558

#16 MeSH descriptor: [Respiratory Distress Syndrome, Newborn] explode all trees 1370

#17 MeSH descriptor: [Bronchopulmonary Dysplasia] explode all trees 479

#18 MeSH descriptor: [Infant, Newborn] explode all trees 15501

#19 MeSH descriptor: [Delivery Rooms] explode all trees 68

#20 MeSH descriptor: [Gestational Age] explode all trees 2489

#21 MeSH descriptor: [Premature Birth] explode all trees 1206

#22 MeSH descriptor: [Infant, Premature, Diseases] explode all trees 2987

#23 MeSH descriptor: [Term Birth] explode all trees 155

#24 MeSH descriptor: [Live Birth] explode all trees 231

#25 MeSH descriptor: [Neonatal Nursing] explode all trees 129

#26 MeSH descriptor: [Neonatal Screening] explode all trees 124

#27 MeSH descriptor: [Intensive Care, Neonatal] explode all trees 317

#28 MeSH descriptor: [Intensive Care Units, Neonatal] explode all trees 698

#29 MeSH descriptor: [Animals, Newborn] explode all trees 27

#30 MeSH descriptor: [Transient Tachypnea of the Newborn] explode all trees 31

#31 MeSH descriptor: [Persistent Fetal Circulation Syndrome] explode all trees 59

#32 MeSH descriptor: [Birth Injuries] explode all trees 43

#33 MeSH descriptor: [Birthing Centers] explode all trees 14

#34 (newborn or neonatal or neonate or neonates or low birth weight or small for gestational age or prematur* or preterm or postmature or infant or

infants or birth):ti,ab,kw 87655

#35 #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 88058

#36 #9 AND #15 AND #35 with Cochrane Library publication date Between Jan 2014 and Dec 2019 67

Inclusion and exclusion criteria

Inclusion criteria: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Exclusion criteria: Unpublished studies (e.g., conference abstracts, trial protocols) were excluded.



34

Data tables Table 1. Characteristics of included studies and outcomes (n=4)

Author, Year

Design, Country

Population/Period of study

Intervention Comparator Outcomes Notes

Guinsberg 2018 F49

Prospective cohort study Brazil (20 academic tertiary centers)

Inborn infants with 23-33 weeks’ gestation and birth weight 400-1499 g (n=1962) Jan 2014-Dec 2015

T-piece resuscitator

Self-inflating bag

Survival at discharge: 1000/1456 (69%) vs 282/506 (56%); p<0.001

- Air leak: 99/1456 (7%) vs 28/506 (6%); p=

0.369 - BPD:

691/1456 (47%) vs 308/506 (61%); p<0.001

- Intubation in delivery

room: 782/1456 (54%) vs 340/506 (67%);

p<0.001

Frequency of T-piece use ranged from 0 to 100% among the 20 participating centers.

Dawson 2011 912

Randomized controlled trial Australia

Inborn infants with gestational age<29 weeks requiring PPV (n=80) Feb 2007-Feb 2009


Self-inflating bag

- Survival at discharge: 39/41 (95%) vs 33/39 (85%); p=0.13

- Air leak: 1/41 (2.4%) vs 2/39 (5%); p= 0.47

- BPD: 15/41 (36%) vs 11/39 (28%); p=0.9

Primary outcome measure of the study was SpO2 at 5 minutes after birth.



35

- Intubation in delivery room: 26/49 (53%) vs 19/50 (37%); p=0.13

Szyld 2014 234

Multicenter cluster-randomized 2-period crossover trial Argentina, Chile, Italy, Perù, United States (10 centers)

Inborn infants with gestational age>26 weeks requiring PPV (n=1027) Dec 2009-Aug 2012


Self-inflating bag

- Survival at discharge: 500/511 (97.8%) vs 501/516 (97.1%); p=0.81

- Air leak: 13/511 (2.5%) vs 8/516 (1.6%); p= 0.25

- BPD: 21/511 (4.1%) vs 44/516 (8.5%); p=0.06

- Intubation in delivery room: 86/511 (17%) vs 134/516 (26%); p=0.02

Primary outcome of the study was heart rate >100bpm at 2 minutes of life. Small subgroups of VLBW infants. Analysis was available for the subgroup of VLBW infants - Survival at

discharge: NA

- Air leak: 3/85 (3.5%) vs 2/110 (1.8%); p= 0.46

- BPD: 21/85

(24.7%) vs 44/110 (40%); p=0.036

- Intubation in delivery room: 45/85 (52.9%) vs 76/110 (69.1%); p=0.019

Thakur 2015 21

Quasi-randomized controlled trial India

Inborn infants with gestational age>26 weeks requiring PPV (n=90) Aug 2010-Aug 2011


Self-inflating bag

- Survival at discharge: 47/50 (94%) vs 37/40 (92.5%); p=0.13

- Air leak: NA - BPD: NA

The primary outcome was the duration of positive pressure ventilation (PPV) during delivery room resuscitation.



36

- Intubation in delivery room: 17/50 (34%) vs 6/40 (15); p=0.04

Randomization was based on the date of month (odd or even dates). Analysis was available for the subgroup of infants<34 weeks - Survival at

discharge: 15/16 (93.7%) vs 16/19 (84.2%); p=0.99

- Air leak: NA - BPD: NA - Intubation in

delivery room: 12/18 (66.7%) vs 5/19 (26.3%); p=0.01



37

Task Force Insights 1. Why this topic was reviewed.

• In 2015, the ILCOR Neonatal Task Force conducted a systematic review (SR) on T-piece resuscitator devices versus self-inflating bags for newborns receiving ventilation during resuscitation. The 2015 ILCOR CoSTR, based on the two available studies, suggested that ventilation can be performed comparably with a self-inflating bag with positive end-expiratory pressure (PEEP), T-piece resuscitator devices or a self-inflating bags without PEEP in newborns receiving ventilation (PPV) during delivery room resuscitation (weak recommendation, very low and low certainty of evidence). The 2015 consensus on science stated that the use of T-piece resuscitator devices shows marginally but not statistically significant benefits for the clinical outcome of achieving spontaneous breathing.

• The NLS TF decided to re-evaluate this topic through a scoping review in order to investigate whether a significant amount of new evidence had been published since the above mentioned 2015 ILCOR systematic review.

2. Narrative summary of evidence identified

• This scoping review, based on the 2015 ILCOR NLS CoSTR found two additional eligible studies, one RCT and one observational study {Thakur 2015 21; Guinsburg 2018 F49}. Thus, a total of four clinical studies could now be included in the data analysis including a total of 2,889 patients (927 in 3 RCTs and 1,962 in 1 observational study) {Dawson 2011 912 e1; Szyld 2014 234; Thakur 2015 21; Guinsburg 2018 F49}, a more than four-fold increase in the number of patients contributing to the evidence-basis.

• Studies differed regarding the investigated populations (two studies included term and preterm infants {Szyld 2014 234; Thakur 2015 21}, two studies were in preterm infants only {Dawson 2011 912 e1; Guinsburg 2018 F49}), reported outcomes, and were from diverse geographical areas.

3. Narrative reporting of the task force discussions

• Data from a substantial number of additional patients reported in one RCT and one large observational study found improved survival and less need for intubation and BPD with T-piece resuscitator use, particularly in preterm infants.

• These findings justify a new systematic review on the use of T-piece resuscitator versus self-inflating bag for administering positive pressure ventilation at birth.

Knowledge Gaps

• Specific research is still required in this area. Adequately powered studies focusing on relevant short (i.e bronchopulmonary dysplasia, survival at discharge) and long-term outcomes (i.e. neurodevelopmental outcome) in different gestational age groups are necessary to inform healthcare providers on the best device for ventilating neonates at birth.

References

1. Dawson JA, Schmolzer GM, Kamlin CO et al. Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at birth: a randomized controlled trial. J Pediatr. 2011;158:912–918e1–2.

2. Guinsburg R, de Almeida MFB, de Castro JS, Gonçalves-Ferri WA, Marques PF, Caldas JPS, Krebs

VLJ, Souza Rugolo LMS, de Almeida JHCL, Luz JH, Procianoy RS, Duarte JLMB, Penido MG, Ferreira DMLM, Alves Filho N, Diniz EMA, Santos JP, Acquesta AL, Santos CND, Gonzalez MRC, da Silva RPVC, Meneses J, Lopes JMA, Martinez FE. T-piece versus self-inflating bag ventilation in preterm neonates at birth. Arch Dis Child Fetal Neonatal Ed. 2018;103:F49-F55.

3. Szyld E, Aguilar A, Musante GA, Vain N, Prudent L, Fabres J, Carlo WA; Delivery Room Ventilation

Devices Trial Group. Comparison of devices for newborn ventilation in the delivery room. J Pediatr. 2014;165:234-239.



38

4. Thakur A, Saluja S, Modi M, Kler N, Garg P, Soni A, Kaur A, Chetri S. T-piece or self inflating bag for

positive pressure ventilation during delivery room resuscitation: an RCT. Resuscitation. 2015;90:21-24.


APPENDIX C-1

NLS 611 Prediction of need for respiratory support in the delivery room 2020 Evidence Update Worksheet

Worksheet author(s): John Madar, Arjan tePas, Daniele Trevisanuto, Council: NRP-ERC Date Submitted: 20/01/2020 PICO: NRP 611 Prediction of need of respiratory support in the DR Research Question: Among newborn infants to be delivered (P) do risk factors such as (maternal, perinatal, delivery risk factors) (I) compared with age of gestation (C) change (O)? Outcomes: Type (intervention, diagnosis, prognosis): Prognosis – need for positive pressure ventilation in the DR Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2010 / 2015 / New question: 2010 Last ILCOR Consensus on Science and Treatment Recommendation: When an infant without antenatally identified risk factors is delivered at term by cesarean section under regional anesthesia, a provider capable of performing assisted ventilation should be present at the delivery. It is not necessary for a provider skilled in neonatal intubation to be present at that delivery. 2010/2015 Search Strategy: 2010 ("neonatal resuscitation"[tw] OR "neonatal stabilization"[tw] OR "delivery room resuscitation"[tw] OR (("Infant, Newborn"[mesh] OR "Newborn Infant"[tw] OR "Newborn Infants"[tw] OR "Newborns"[tw] OR "Newborn"[tw] OR "Neonate"[tw] OR "Neonates"[tw] OR neonat*[tw] OR "Low Birth Weight Infant"[tw] OR "Small for Gestational Age Infant"[tw] OR "Very Low Birth Weight Infant"[tw] OR "Postmature Infant"[tw] OR "Premature Infant"[tw] OR "Low Birth Weight Infants"[tw] OR "Small for Gestational Age Infants"[tw] OR "Very Low Birth Weight Infants"[tw] OR "Postmature Infants"[tw] OR "Premature Infants"[tw]) AND ("Resuscitation"[majr] OR "resuscitation"[ti] OR Resuscit*[ti] OR "Heart Massage"[ti] OR "Artificial Respiration"[ti] OR "stabilization"[ti] OR "stabilisation"[ti]))) AND ("preparation"[tw] OR "prepare"[tw] OR prepar*[tw] OR "anticipation"[tw] OR "anticipate"[tw] OR anticipat*[tw] OR "risk"[tw] OR "risk factor"[tw] OR "risk factors"[tw]) 2019 Search Strategy: ("neonatal resuscitation"[tw] OR "neonatal stabilization"[tw] OR "delivery room resuscitation"[tw] OR (("Infant, Newborn"[mesh] OR "Newborn Infant"[tw] OR "Newborn Infants"[tw] OR "Newborns"[tw] OR "Newborn"[tw] OR "Neonate"[tw] OR "Neonates"[tw] OR neonat*[tw] OR "Low Birth Weight Infant"[tw] OR "Small for Gestational Age Infant"[tw] OR "Very Low Birth Weight Infant"[tw] OR "Postmature Infant"[tw] OR "Premature Infant"[tw] OR "Low Birth Weight Infants"[tw] OR "Small for Gestational Age


Infants"[tw] OR "Very Low Birth Weight Infants"[tw] OR "Postmature Infants"[tw] OR "Premature Infants"[tw]) AND ("Resuscitation"[majr] OR "resuscitation"[ti] OR Resuscit*[ti] OR "Heart Massage"[ti] OR "Artificial Respiration"[ti] OR "stabilization"[ti] OR "stabilisation"[ti]))) AND ("preparation"[tw] OR "prepare"[tw] OR prepar*[tw] OR "anticipation"[tw] OR "anticipate"[tw] OR anticipat*[tw] OR "risk"[tw] OR "risk factor"[tw] OR "risk factors"[tw]) AND ("2014/01/01"[PDAT] : "3000/12/31"[PDAT]) Database searched: PubMed Date Search Completed: Dec 9, 2019 Search Results (Number of articles identified / number identified as relevant): 455 Titles/abstracts 5 Full texts selected 5 articles included Inclusion/Exclusion Criteria: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Animal studies and unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Studies were excluded if the need for resuscitation was not defined further. Link to Article Titles and Abstracts (if available on PubMed): https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186%2Fs12884-019-2400-x. https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186%2Fs12887-019-1573-9 https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1080%2F14767058.2018.1497602. https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016%2Fj.jpeds.2017.11.039 https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1136%2Farchdischild-2015-309525 Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces

1. This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews.

Relevant Guidelines or Systematic Reviews


https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186%2Fs12884-019-2400-x.

https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186%2Fs12887-019-1573-9

https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1080%2F14767058.2018.1497602.

https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016%2Fj.jpeds.2017.11.039

https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1136%2Farchdischild-2015-309525

Organisation (if relevant); Author; Year Published

Guideline or systematic review

Topic addressed or PICO(S)T

Number of articles identified

Key findings Treatment recommendations

None

RCT:

Study Acronym; Author; Year Published

Aim of Study; Study Type; Study Size (N)

Patient Population

Study Intervention (# patients) / Study Comparator (# patients)

Endpoint Results (Absolute Event Rates, P value; OR or RR; & 95% CI)

Relevant 2° Endpoint (if any); Study Limitations; Adverse Events

None

Nonrandomized Trials, Observational Studies


Study Type/Design; Study Size (N)

Patient Population

Primary Endpoint and Results (include P value; OR or RR; & 95% CI)

Summary/Conclusion Comment(s)

Londero, 2019 {Londero 20 doi: 10.1186/s12884-019-2400-x19}

Retrospective cohort; N=22,993

All infants born in hospital

Maternal age risk factor for outcome: Resuscitation is not included in the multivariate analysis

Maternal age is independent risk factor for maternal and neonatal morbidities, risk for resuscitation not included

Lee, 2019 {Lee 2019 doi: 10.1186/s12887-019-1573-9}

Retrospective cohort; N= 5298

VLBW (< 1500 g) Korea

Independent antenatal risk factors for extensive resuscitation: Lower gestational age 25 to 27 gestational weeks,

Prediction model developed using gestational age, abnormal amniotic fluid volume, no antenatal steroids. These were important predictors for extensive resuscitation.


OR 3.003 [1.977-4.562]; less than 25 gestational weeks, OR: 4.921 [2.926-8.276]), Birth weight < 1000 g (OR: 1.509 [1.013-2.246]), Male sex (OR: 1.329 [1.002-1.761]) Oligohydramnios (OR: 1.820 [1.286-2.575]), Polyhydramnios (OR: 6.203 [3.185-12.081]) No antenatal steroid use (OR: 2.164 [1.549-3.023])

Remark: Gestational Age, Birthweight and chorioamnionitis were excluded for development of the prediction model, authors state that these factors “cannot be clearly determined before birth”

Yangthara, 2020 {Yangthara 220 570}


High risk deliveries in hospitals in Thailand

Several antepartum and intrapartum risk factors for (extensive) resuscitation: see article

Risk factors stated in textbook of neonatal resuscitation for (extensive) resuscitation were reviewed in developing country; conclusion of authors was that many factors were risk for respiratory support but not extensive resuscitation

Bajaj, 2018 {Bajaj 2018 33}


Moderately preterm infants (29+0/7 to 33+6/7 weeks) NICHD Neonatal Research Network infants

Several antepartum and intrapartum risk factors for (extensive) resuscitation: see article Lack of prenatal care OR PPV, 3.23 (1.83-5.7) Maternal Hypertension OX/CPAP, 1.26 (1.05-1.5) Small for Gestational Age

A significant proportion of MPT infants receive some level of resuscitation in the DR Some factors appear protective in this group e.g. Chorioamnionitis and PRM – not discussed in paper.


ETT OR, 1.53 (1.17-2,00) Chorioamnionitis ETT OR, 0.81 (0.67-0.99) PRM ETT OR, 0.52 (0.4-0.68)

Berazategui, 2017 {Berazategui 2017 F44}

Prospective case-control; N =58,429

Infants ≥ 34 weeks of gestation South and North America

Several antepartum and intrapartum risk factors for advanced resuscitation (ETT +/- CC +/- drugs) Antepartum GA 34–37 weeks OR, 2.21 (1.0 to 4.7) Intrauterine growth restriction OR 19.98 (3.6 to 110.0) Gestational diabetes OR, 16.40 (3.4 to 79.0) Intrapartum MSAF OR, 17.03 (9.4 to 30.9) Forceps or vacuum delivery OR, 17.27 (5.1 to 58.4) Clinical chorioamnionitis OR, 17.56 (2.5 to 121.0) Fetal bradycardia OR, 24.75 (9.6 to 63.4) Abruption placentae OR, 12.14 (2.5 to 58.2)

10 risk factors were associated with a need for advanced resuscitation


General anaesthesia OR, 11.08 (2.2 to 55.8) Emergency caesarean section OR, 2.31 (0.9 to 5.8)

CC, Chest Compressions; CPAP, Continuous Positive Airway Pressure; ETT, Endotracheal Tube; NICHD, National Institute of Child Health and Development; OR, Odds Ratio; RR, Relative Risk


Reviewer Comments (including whether meet criteria for formal review): Most articles confirm risk factors already stated in the guideline. Berazategui et al reported risk factors similar to current used ref in guidelines (Aziz et al.), except for gestational diabetes. The retrospective studies have addressed different populations, health care settings and outcomes which makes it unlikely that it will be possible to produce universally applicable risk prediction models through an ILCOR review at present using this search strategy. Whilst there is new data since the last reviews confirming the risk factors already included in the guidelines, there is insufficient new evidence to change current recommendations or to warrant a systematic review. Note: A different search strategy than the one used previously (See below), identified a number of other references which, although not analysed in this update, may indicate that a new systematic review is indicated utilizing a modified search strategy. This would need to include all previous years. Reference list 1. Londero, A.P., Rossetti, E., Pittini, C. et al. Maternal age and the risk of adverse pregnancy outcomes: a

retrospective cohort study. BMC Pregnancy Childbirth 19, 261 (2019) http://dx.doi.org/10.1186/s12884-019-2400-x

2. Lee, J., Lee, J.H. A clinical scoring system to predict the need for extensive resuscitation at birth in very low

birth weight infants. BMC Pediatr 19, 197 (2019) http://dx.doi.org/10.1186/s12887-019-1573-9

3. Yangthara B, Horrasith S, Paes B, Kitsommart R: Predictive factors for intensive birth resuscitation in a developing-country: a 5-year, single-center study. Journal of maternal Fetal and neonatal medicine. 33: 4 570–576 (2020) Online 10 Sept 2018. doi.org/10.1080/14767058.2018.1497602

4. Bajaj M, Natarajan G, Shankaran S, Wyckoff M, et al: Delivery Room Resuscitation and Short-Term

Outcomes in Moderately Preterm Infants. J Pediatr. 2018 Apr;195:33-38.e2. Epub 2018 Jan 3. https://doi.org/10.1016/j.jpeds.2017.11.039

5. Berazategui JP., Aguilar A. et al Arch Dis Risk factors for advanced resuscitation in term and near-term

infants: a case-control study Child Fetal Neonatal Ed. 2017 Jan;102(1):F44-F50. doi: 10.1136/archdischild-2015-309525 Epub 2016 Jun 6.

Other references: Medline: neonatal resuscitation).ti,ab OR (newborn resuscitation).ti,ab OR (newborn stabilisation).ti,ab OR (delivery room resuscitation).ti,ab OR (delivery room stabilisation).ti,ab) AND ((risk factors).ti,ab OR (risk).ti,ab OR (prediction).ti,ab OR (anticipation).ti,ab)) AND ((maternal).ti,ab OR (perinatal).ti,ab OR (delivery).ti,ab)) [DT FROM 2014]" 6. Almudeer, Ali et al. Do We Need an Intubation-Skilled Person at All High-Risk Deliveries? The Journal of

Pediatrics, 171, 55 – 59 (2016) http://dx.doi.org/10.1016/j.jpeds.2015.11.049


http://dx.doi.org/10.1186/s12884-019-2400-

http://dx.doi.org/10.1186/s12884-019-2400-

http://dx.doi.org/10.1186/s12887-019-1573-9

http://dx.doi.org/10.1080/14767058.2018.1497602

https://doi.org/10.1016/j.jpeds.2017.11.039

http://dx.doi.org/10.1016/j.jpeds.2015.11.049

This was not identified in the original Pubmed Search. The conclusion of the paper was that most of the NRP listed risk factors (which are extensive) for intubation were not associated with increased risk for intubation, only 16/40 risk factors were associated. (Maternal drugs in pregnancy, Maternal neurological disease, GA, Fetal anaemia/isoimmunisation, IP haemorrhage, Polyhydramnios, Abruption, MSAF, Fetal distress, SGA, CS in labour) This is an experience over 20 years and the intention to intubate will have changed over the years. The NRP list is currently not mentioned in the guidelines This supports what is already stated in the guidelines “Although it is sometimes possible to predict the need for resuscitation or stabilisation before a baby is born, this is not always the case. Any newborn may potentially develop problems during birth, therefore, personnel trained in newborn life support should be easily available for every delivery”

7. Boisramé, T. et al. Placental abruption: risk factors, management and maternal–fetal prognosis. Cohort study

over 10 years. (2014) European Journal of Obstetrics and Gynecology and Reproductive Biology, Volume 179, 100 – 104. doi: https://doi.org/10.1016/j.ejogrb.2014.05.026

Placental abruption is identified as a risk factor for neonatal resuscitation (4.6 (3.1–6.8). This is one of the 40+ risk factors on the NRP list. This is not new information. However, neonatal resuscitation was not defined, therefore excluded from analysis

8. Farquhar CM, Li Z, Lensen S, et al. Incidence, risk factors and perinatal outcomes for placenta accreta in Australia and New Zealand: a case–control study. BMJ Open 2017; 7:e017713. http://dx.doi.org/10.1136/bmjopen-2017-017713 Not identified in Pubmed search: Placenta accreta is a risk factor for neonatal resuscitation (AOR: 4.5, 95% CI 2.7 to 7.4) Is not listed on NRP list, Ante/intrapartum hemorrhage is on NRP list. Resuscitation is not defined in the paper so excluded from further analysis.

9. Fitzpatrick KE, Kurinczuk JJ, Battacharya S, Quigley MA Planned mode of delivery after previous cesarean section and short-term maternal and perinatal outcomes: A population-based record linkage cohort study in Scotland. (2019) PLoS Med 16(9) e1002913 https://doi.org/10.1371/journal.pmed.1002913 This was not in the Pubmed search. Complicated analysis, examined the complications of Vaginal birth while CS in history (VBAC): increased risk for resuscitation – defined as the need for intubation +/- drugs OR 5.2 (4.19-6.5). This risk factor is not on the NRP list

10. Foo XY, Greer RM, Kumar S. Impact of maternal Body Mass Index on Intrapartum and neonatal outcomes

in Brisbane, Australia, 2007 to 2013. Birth 43:4 358-365. Dec 2016 https://doi.org/10.1111/birt.12246 Was in the Pubmed search. Increased risk for need for significant neonatal resuscitation when mother’s BMI too high, while decreased risk when BMI is too low corrected for some other factors, but other intra-antepartum factors not reported. Whilst BMI not on the NRP list of risks, the level of resuscitation required not defined so excluded from analysis


https://doi.org/10.1016/j.ejogrb.2014.05.026

http://dx.doi.org/10.1136/bmjopen-2017-017713

https://doi.org/10.1371/journal.pmed.1002913

https://doi.org/10.1111/birt.12246

11. Grace L, Greer RM, Kumar S. Perinatal consequences of a category 1 caesarean section at term. (2015) BMJ

open 5 (7) e007248 http://dx.doi.org/10.1136/bmjopen-2014-007248

Was in the Pubmed search. Determined risk of need for resuscitation for Cat 1 section higher than for other emergency sections (59.9% vs 51.8% p=0.0001). Not corrected for other variables. Need for resuscitation not defined so excluded from analysis.

12. Haggar FA, Pereira G, Preen D, et al; Adverse obstetric and perinatal outcomes following treatment of

adolescent and young adult cancer: a population-based cohort study. (2104) PloS one;9 (12) p. e113292 http://dx.doi.org/10.1371/journal.pone.0113292 Not in Pubmed search. , When cancer in history, increased relative risk for neonatal resuscitation (ETT +/- CC) (1.66 (1.27–2.19) compared to control group. No multivariate analysis of other potential causes so unclear if primary effect of cancer - therefore excluded.

13. Navaratne P, Foo XY, Kumar S. Impact of a high Edinburgh Postnatal Depression Scale score on obstetric

and perinatal outcomes. (2016) Scientific reports 6 33544 http://dx.doi.org/10.1038/srep33544 Not in Pubmed search. High depression score increases the risk for resuscitation (34.4% vs. 30.6%, p < 0.001) however, other potential associated factors may not have been excluded. The need for resuscitation was not defined therefore excluded

14. Persson M, Johansson S, Villamor E et al: Maternal Overweight and Obesity risks of severe Birth Asphyxia

Related complications in Term infants: A population based Cohort Study in Sweden. PLoS Med 11(5): (2014) e1001648 https://doi.org/10.1371/journal.pmed.1001648 In the Pubmed search., Apgar score, not resuscitation reported. Increased risk for Apgar 0-3 at 5 min when mother’s BMI too high, while decreased risk when BMI is too low. Corrected for some other factors, but other intra-antepartum factors not reported. BMI is not on the NRP list. Low Apgar a proxy for the need for resuscitation. Whilst likely intervention required, degree and nature unclear. Excluded.

15. Sawyer T, Lee HC, Aziz K. Anticipation and preparation for every delivery room resuscitation. Seminars in Fetal and Neonatal Medicine 23(5) 312-320 (2018) https://doi.org/10.1016/j.siny.2018.06.004

Also in Pubmed search, This was excluded as this was a narrative review rather than original research.

16. Wang, AY, Safi N; Ali F; Lui K et al; Neonatal outcomes among twins following assisted reproductive technology: an Australian population-based retrospective cohort study. BMC pregnancy and childbirth; (2018) 18 (1) 320 http://dx.doi.org/10.1186/s12884-018-1949-0 Also in Pubmed search. Assisted reproduction confers an increased risk for neonatal resuscitation OR 1.26 (1.17–1.36). However resuscitation was not defined in the study therefore excluded from analysis.

17. Jacoby S, Becker G, Crawford S, et al; Water Birth Maternal and Neonatal Outcomes Among Midwifery Clients in Alberta, Canada, from 2014 to 2017: A Retrospective Study. (2019) Journal of obstetrics and gynaecology Canada : JOGC 41 (6) 805-812 http://dx.doi.org/10.1016/j.jogc.2018.12.014


http://dx.doi.org/10.1136/bmjopen-2014-007248

http://dx.doi.org/10.1371/journal.pone.0113292

http://dx.doi.org/10.1038/srep33544

https://doi.org/10.1371/journal.pmed.1001648

https://doi.org/10.1016/j.siny.2018.06.004

http://dx.doi.org/10.1186/s12884-018-1949-0

http://dx.doi.org/10.1016/j.jogc.2018.12.014

Also in Pubmed search. Retrospective cohort 1796 water births state registry data Canada There appeared to be no difference in risk of resuscitation for low risk pregnancies. no correction for other factors.

18. Smid MC, Vladutiu CJ, Dotters-Katz SK et al. Super Obesity and Neonatal Morbidity after Term Cesarean Delivery. (2016) American journal of perinatology 33 (12) 1198-1204 http://dx.doi.org/10.1055/s-0036-1586122 Abstract only Not in Pubmed search: 41,262 pregnancies Retrospective cohort – C/S registry study, Term infants. ?time frame. Obesity appears associated with increased neonatal risk of poor Apgar and need for resuscitation – not specifically defined – excluded.


http://dx.doi.org/10.1055/s-0036-1586122

http://dx.doi.org/10.1055/s-0036-1586122

APPENDIX C-2

2020 Evidence Update Worksheet NLS 599 Warming adjuncts

Worksheet author(s): Khalid Aziz, MD, Beena Kamath-Rayne, MD, Shigeharu Hosono, MD Council: American Heart Association, Resuscitation Council of Asia Date Submitted: 29th Dec 2019 PICO / Research Question: Among preterm neonates who are under radiant warmers in the hospital delivery room (P), does increased room temperature, thermal mattress, or another intervention (I), compared with plastic wraps alone (C), reduce hypothermia (<36.0) on admission to NICU? Outcomes: Primary: Admission hypothermia (important) Other outcomes: Survival (critical)

Morbidities associated with hypothermia (important) Hyperthermia and associated morbidities (important)

Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): None declared Year of last full review: 2015 (NRP 599) Last ILCOR Consensus on Science and Treatment Recommendation: 2015 Recommendation and NRP599 worksheet: “Among newly born preterm infants of less than 32 weeks of gestation under radiant warmers in the hospital delivery room, we suggest using a combination of interventions, which may include environmental temperature 23°C to 25°C, warm blankets, plastic wrapping without drying, cap, and thermal mattress to reduce hypothermia (temperature less than 36.0°C) on admission to NICU (weak recommendation, very-low-quality


evidence). We suggest that hyperthermia (greater than 38.0°C) be avoided due to the potential associated risks (weak recommendation, very-low-quality evidence). Values, Preferences, and Task Force Insights: We place value on the large numbers enrolled in the observational studies and consistent direction of effect. Because many of the studies used multiple strategies, it was not possible to identify the different specific interventions, which are effective in maintaining temperature. There was concern whether the recommendation should be so strong when the CIs for hyperthermia (0.80–53.30) comprising 3 studies are so wide, raising the potential chance for harm. A strong recommendation was made because of the large numbers in the studies and the consistent direction of effect. There was concern about 1 randomized thermal mattress trial, which was stopped for safety issues because of hyperthermia. However, this is the only study that has demonstrated an adverse effect with small numbers, suggesting some unclear negative (possible environmental) effect. In the treatment recommendation, it was suggested to add the words “may include” before the word “combination”.” 2010/2015 Search Strategy (PubMed only): Date searched November 30, 2014 ("infant, premature"[MH] OR "infant, very low birth weight"[MH] OR "preterm"[ti] OR “pre-term”[ti] OR "premature"[ti] OR "prematurity"[ti] OR "low-birth-weight"[TI] OR "premature birth"[MH]) AND ("body temperature"[MH] OR "hypothermia/prevention and control"[Mesh Terms] OR “hyperthermia”[ti] OR "admission temperature*"[ti] OR “hypothermia”[ti] OR "rewarming/methods"[MH] OR "heating/methods"[MH] OR "hypothermia/therapy"[MH] OR “polythene”[ti] OR “polyethelene”[ti] OR “wrapping”[ti] OR bag[ti] OR “Trans-warmer”[ti] OR “mattress”[ti] OR “warming”[TI] OR “warmed”[ti] OR “warms”[ti]) AND "humans"[MH] NOT (“editorial”[PT] OR “comment”[PT] OR “letter”[PT] OR “news”[PT] OR “review”[PT]) [n=555] 2019 Search Strategy: ("infant, premature"[MH] OR "infant, very low birth weight"[MH] OR "preterm"[tiab] OR "pre-term"[tiab] OR "premature"[tiab] OR "prematurity"[tiab] OR "low-birthweight"[tiab] OR "premature birth"[MH]) AND ("rewarming/methods"[MH] OR "heating/methods"[MH] OR "polythene"[tiab] OR "polyethylene"[tiab] OR “wrap*”[tiab] OR “bag*”[tiab] OR "warmer"[tiab] OR "mattress"[tiab] OR "gas*"[TIAB] OR "skin to skin"[tiab] OR “cap*”[tiab] OR “hat*”[tiab] OR “bonnet*”[tiab] OR “room temperature*”[tiab] OR “risk factor*”[tiab]) AND ("body temperature"[MH] OR "hypothermia"[MH] OR "hyperthermi*"[tiab] OR “hypothermi*” [tiab] "admission temperature*"[tiab] OR "warm*"[tiab] OR “body temperature” [tiab] or “thermal”[tiab] or “normothermi*”[tiab] or “euthermi*”[tiab] or “thermal”[tiab] or “heat”[tiab] or “thermoregulat*”[tiab]) NOT ("animals"[MH] NOT "humans"[MH])


NOT ("editorial"[Publication Type] OR "comment"[Publication Type] OR "letter"[Publication Type] OR "news"[Publication Type] OR "case reports" [Publication Type] OR "review" [Publication Type]) AND ("2013/01/01"[PDAT] : "3000/12/31"[PDAT]) [n=86] + [a further 97 articles were found when the 2014 search was added to the current one] Database searched: PubMed Date Search Completed: 17 Nov 2019 Search Results (Number of articles identified / number identified as relevant): 183 abstracts identified. Inclusion/Exclusion Criteria: Only include studies relating to newly born care at or immediately following delivery. Link to Article Titles and Abstracts (if available on PubMed): Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces



Relevant Guidelines or Systematic Reviews Organization (if relevant); Author; Year Published

Guideline or

systematic review

Topic addressed or PICO(S)T Number of articles

identified

Key findings

Lunze, 2013 {Lunze 2013 1}

Systematic review

Title: The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival

22 hospital-based and 10 community-based

Included 32 observational studies (22 hospital-based and 10 community-based). Observational studies of varying quality. “Overall in community-based studies (all conducted in Nepal or India), hypothermia prevalence ranged from 11% to 92%.” “All identified studies from Africa to date are hospital based, report poor newborn practices and high prevalences of newborn hypothermia ranging from 44% to 69% in Zambia to 53% in Ethiopia, 62% to 68% in Nigeria, and 85% in Zimbabwe. Large studies from other countries confirm the global tendency for newborn hypothermia in different climate conditions, from Asia (China), the Middle East (Iran) and South America (Brazil)”

Moore, 2016 {Moore 2016 1}

Systematic review

Title: Early skin-to-skin contact for mothers and their healthy newborn infants NLS 793: In newborn infants (>30 weeks gestation) during and/or post resuscitation/ stabilization (P), does drying and skin to skin contact or

38 trials with 3472 dyads (majority full term) in 21 countries comparing immediate or early SSC with

There was marked heterogeneity. Improved temp after birth by 0.3C (0.13-0.47C) (6 RCTs; 558 babies; low quality) Skin-to-skin contact promotes breastfeeding at 1 to 4 months (RR, 1.24 (1.07-1.43) (n=887, 14 RCTs; moderate quality), and


covering with plastic (I), compared with drying and no skin to skin or use of radiant warmer or isolette (C), change body temperature (O)? NLS 1572: For newborn babies born outside hospital or in low resource settings (P) does wrapping in polyethylene or placing skin to skin after drying (I) vs drying and wrapping (C) improves admission temperature (O).

usual hospital care

breast feeding at discharge (6 RCTs, 711 babies; moderate quality). Improved blood glucose (3 RCTs; low quality) Eight trials included SSC after C-section. Six trials included late preterm newborns.

Stevens, 2014 {Stevens 2014 456}

Narrative review

Title: Immediate or early skin-to-skin contact after a Caesarean section: a review of the literature

Included immediate or early (<1h) SSC with health term newborns after C-section. Seven studies identified (two using same cohort)

They identified 4 RCTs (actually 3 as two were the same cohorts; 121 dyads), 1 observational and 2 qualitative studies. No meta-analysis done. Mostly term babies.

McCall, 2018 {McCall 2018 1}

Systematic review

Title: Interventions to prevent hypothermia at birth in preterm and/or low birth weight infants NLS 599: Among preterm neonates who are under radiant warmers in the hospital delivery room (P), does increased room temperature, thermal mattress, or another intervention (I), compared with plastic wraps alone (C), reduce hypothermia (<36.0) on admission to NICU (O)?

Included babies <37w and ≤2500g. 25 studies including 15 comparison groups: barriers to heat loss (18 studies); external heat sources (3 studies); and combinations of

Plastic wraps or bags vs routine care: Reduced hypothermia (RR 0.67(CI0.62-0.72); 10 RCTs; 1417 babies). Hyperthermia was increased in the wrapped group (RR 3.91(CI 2.05-7.44); 12 studies 1523 babies). No difference in mortality or morbidity except less pulmonary hemorrhage with adjuncts). Skin-to-skin was compared to incubator care in one study (only 31 babies).


NLS 899: Preterm infants (P), does the use of warming mattresses as well as wrap and radiant heat or use of servo-controlled radiant heaters with wrap or use of warmed humidified resuscitation gases as well as occlusive wrap and radiant heat or delivery rooms >25°C as well as occlusive wrap and radiant heat or use of hats with wrap and radiant heat or combinations of techniques (I), compared with wrap and radiant heat alone (C), change death, Intraventricular Hemorrhage, Normal temperature (36.0-38.0) (O)?

interventions (4 studies).

Exothermic mattresses (2 studies; 126 infants; improved temperature) but hyperthermia risk when added to plastic wraps.

Meyer, 2018 { Meyer 2018 319}

Systematic review

Title: Use of Heated Humidified Gases for Early Stabilization of Preterm Infants: A Meta-Analysis NLS899: Preterm infants (P), does the use of warming mattresses as well as wrap and radiant heat or use of servo-controlled radiant heaters with wrap or use of warmed humidified resuscitation gases as well as occlusive wrap and radiant heat or delivery rooms >25°C as well as occlusive wrap and radiant heat or use of hats with wrap and radiant heat or combinations of techniques (I), compared with wrap and radiant heat alone (C), change death, Intraventricular Hemorrhage, Normal temperature (36.0-38.0) (O)?

2 studies in preterm babies (476 babies <32 weeks)

36% reduction in hypothermia (CI 17-50%). No change in mortality or admission hyperthermia.

Boundy, 2016 {Boundy 2016 e20152238}

Systematic review

Kangaroo mother care 124 studies Important to discussion but not relevant to question as kangaroo mother care is only done on babies who are stable post-resuscitation


Conde-Agudelo, 2016 {Conde-Agudelo 2016 1}

Systematic review

Kangaroo mother care 21 reviews Important to discussion but not relevant to question as kangaroo mother care is only done on babies who are stable post-resuscitation


RCTs:



Patient Population


Endpoint Results (Absolute Event Rates, P value; OR or RR; & 95% CI) (note: results directly transcribed from articles)


Duryea, 2016 {Duryea 2016 505}

Study Aim: Compare two ambient temperatures in the operating room (20C and 23C) Study type: Pseudo-RCT (weekly randomization of rooms)

Inclusion Criteria: All gestations (mean 37.7 vs 38.1w) with elective and emergent C-section

Comparison: Room temp 20C (n=401) Intervention: Room temp 23C (n=390)

The rate of neonatal hypothermia on arrival to the admitting nursery was lower in the study group as compared to the standard management group: 35% vs 50%, P < .001. Moderate to severe hypothermia was infrequent when the operating room temperature was 23C (5%); in contrast such hypothermia occurred in 19% of the standard management group, P < .001.

All gestations Pseudorandomized

Hsu, 2015 {Hsu 2015

637}

Study Aim: Test temperature-controlled thermal blanket as a warming adjunct Study type: RCT

Inclusion Criteria: <1.5kg.

Comparison: radiant warmer (n=40) Intervention: Adding thermal blanket (Blanketrol II) (n=40)

At 30th minute, fewer infants in thermal blanket group were hypothermic (43% vs 68%; p = 0.025).

No bags or wraps used.

Jia, 2013 {Jia 2013 264}

Study Aim: Test delivery room temp 24 to 26°C vs 20 to 23°C

Inclusion Criteria: <33w

Comparison: Room A temp mean 22.5°C (n=48)

Premature newborns delivered in rooms with mean temperature 25.1±0.6°C (n=43), compared with those delivered in

The randomization was by room that was preset so other factors may have affected temp.


Intervention: Room B temp mean 25.1°C (n=43)

rooms with mean temperature 22.5±0.6°C (n=48), had a lower incidence (34.9% vs 68.8%, P<0.01) of admission rectal temperature 36.1°C and higher admission rectal temperatures (36.0±0.9°C vs 35.5±0.8°C, P<0.01).

Leadford, 2013 {Leadford 2013 129}

Study Aim: Test plastic wraps as a low-cost intervention in less resourced settings

Inclusion Criteria: 26 to 36 weeks (or 1kg to 2.5kg)

Comparison: Blanket or radiant warmer (n=55) Intervention: Blanket or radiant warmer, plus plastic bag (n=49)

Infants randomized to plastic bag (n = 49) were more likely to have a temperature in the normal range as compared with infants in the standard thermoregulation care group (n = 55; 59.2% vs 32.7%; relative risk 1.81; 95% confidence interval 1.16–2.81; P = .007). The temperature at 1 hour after birth in the infants randomized to plastic bag was 36.5 ± 0.5°C compared with 36.1 ± 0.6°C in standard care infants (P<.001).

Linner, 2019 {Linner 2019 1}

Study Aim: Test skin-to- skin care at 28 to 33+6 weeks from birth

Inclusion Criteria: 28+0 to 33+6 weeks GA

Comparison: Radiant warmer (n=29) Intervention: SSC (n=26)

Mean body temperature in the SSC group was 0.3°C lower 1 hour after birth, 36.3°C ± 0.52 (range 34.4‐7.2) vs 36.6°C ± 0.42 (range 36.0‐37.4, P = .03).

Feasible but risk for hypothermia is significant

McCarthy, 2013 {McCarthy 2013 e135}

Study Aim: Test exothermic mattresses as a warming adjunct

Inclusion Criteria: <31 weeks GA

Comparison: Radiant warmer with plastic wrap (n=35) Intervention: Radiant warmer, plastic

Study stopped by safety monitoring committee. Fewer infants with mattresses had temperatures within the target range (15/37 [41%] vs 27/35 [77%], P = .002) and more had temperatures

Study not completed.


wrap, and warming mattress (n=37)

.37.5°C (17/37 [46%] vs 6/35 [17%], P = .009).

Nimbalkar, 2019 {Nimbalkar 2019 122}

Study Aim: Test polyethylene wraps in preterm babies

Inclusion Criteria: <34 weeks GA

Comparison: Radiant warmer (n=77) Intervention: Radiant warmer plus wrap (n=77)

Fewer newborns suffered from hypothermia in the study group as compared with the control group [50 (67.6%) vs. 67 (87%), p¼0.004].

Reilly, 2015 {Reilly 2015 262}

Study Aim: Test plastic (occlusive) wraps in preterm babies on mortality (multicentre)

Inclusion Criteria: 24+0 to 27+6 weeks GA

Comparison: no-wrap group (n=402) Intervention: Wrap group (n=411)

There was no difference in baseline population characteristics. There were no significant differences in mortality (OR 1.0, 95% CI 0.7-1.5). Wrap infants had statistically significant greater baseline temperatures (36.3C wrap vs 35.7C no wrap, P <.0001)


Nonrandomized Trials, Observational Studies These studies were not tabulated but are referenced below as there are considerable numbers of observational studies (including several on “bundles” and “quality improvement (QI)” which, essentially, support the existing recommendations. Reviewer Comments (including whether meet criteria for formal review): Risk factors for and outcomes of hypothermia: The 2015 Task Force review identified numerous observational studies relating to admission hypothermia, some of which looked at risk factors, and some at outcomes. Since 2013, the search identified two further studies that looked at risk factors for hypothermia in term and preterm babies in well- and limited-resource settings [Alebachew 2019 1; Mank 2016 e0164817]. Ten observational studies included outcomes of hypothermia in term and preterm babies in well- and limited-resourced settings [Amadi 2015 273; Caldas 2019 1023; Chang 2015 1; de Almeida 2014 271; Demissie 2018 1; Laptook 2018 53; Lyu 2015 1; Shikiku 2018 844; Ting 2018 844; Wilson 2016 61]. Two multicentre cohort studies in well-resourced settings suggested increasing morbidity with increasing hypothermia in preterm babies [Laptook 2018 53; Lyu 2015 53]. Two studies suggested increased mortality or morbidity in term and preterm babies in well- and limited-resourced settings [Lyu 2015 1; Amadi 2015 273]. Two studies looked at the association of admission hypothermia with long-term neurodevelopmental outcomes in preterm babies [Chang 2015 1;Ting 2018 844]. The observational data continue to suggest that hypothermia is a risk factor for mortality and morbidity in preterm babies. Warming the room before delivery: Two RCTs since 2013 have commented on the effect of ambient temperature on the rate of admission hypothermia in preterm babies [Duryea 2016 505.e1; Jia 2013 264]. One observational study (abstract in English) was also found [Johannsen 2017 235]. All three studies have significant biases but indicate an impact of managing ambient temperature on admission hypothermia. There are new data suggesting an impact of delivery room temperature, however studies were done in mixed (term and preterm populations) and have significant biases making them unsuitable for analysis. Thermal adjuncts while awaiting cord clamping: This topic was not looked at in this update but it is interesting to note that cord management studies do comment on neonatal temperatures [Rabe 2019 1]. No data were available to answer this question in preterm babies. Skin-to-skin care (SSC) after birth: This topic was the subject of a Cochrane meta-analysis [Moore 2016 1] that included 38 trials with 3472 dyads (majority full term) in 21 countries comparing immediate or early SSC with usual hospital care. They found improved temp after birth by 0.3C (0.13-0.47C) (6 RCTs; 558 babies; low quality), a difference that was probably not clinically significant. SSC promoted breastfeeding at 1 to 4 months (RR1.24 (1.07-1.43), n=887, 14 RCTs; moderate quality), and breast feeding at discharge (6 RCTs, 711 babies; moderate quality). There was a suggestion of improved blood glucose with SSC (3 RCTs; low quality). This review and a narrative review [Stevens 2014 456] looked at term babies born by C-section suggesting no negative impacts. One RCT of SSC after birth in LBW babies in a well-resourced setting showed significant challenges in maintaining normothermia [Linner 2019 1]. The summary is that SSC may have benefits with respect to breastfeeding without disadvantages in term babies. The data on skin-to-skin care are limited in preterm babies at the time of delivery or during resuscitation.


Use of radiant warmers: Since 2013 there have been no RCTs identified that specifically looked at radiant warmers as a warming adjunct, probably because they are standard of care in well-resourced settings. The use of servocontrol was not addressed. There are no new data on radiant warmers in preterm babies. Use of bags or wraps: Four RCTs comparing bags or wraps with no bags or wraps in preterm babies were identified since 2013 [Doglioni 2014 165; Leadford 2013 e129; Nimbalkar 2019 122; Reilly 2015 262]. One large, multicentre RCT [Reilly 2015 262] showed less hypothermia in preterm babies but no impact on mortality. Two studies included term and very low birthweight babies in limited-resource or transport settings [Belches 2013 e656; Hu 2018 332]. Some of these babies were included in a Cochrane meta-analysis looking at prevention of hypothermia in preterm and/or low birth weight babies [McCall 2018 1]. One RCT used low-tech insulation (cloth and newspaper) to raise admission temperature [Agrawal 2018 1335]. Some studies compared bags with exothermic mattresses or wraps [Caglar 2014 216; Mathew 2013 317]. The synopsis is that bags and wraps appear to reduce admission hypothermia and increase the risk of hyperthermia. Neither RCTs nor the meta-analysis showed an impact on mortality. New data on bags and wraps support their use to reduce hypothermia in preterm babies but no effect has been demonstrated on survival. Use of exothermic mattresses: Exothermic mattresses were included in the Cochrane meta-analysis [McCall 2018 1]. Some concern was raised in one RCT which was stopped because of unstable temperature and hyperthermia with use of a thermal mattress [McCarthy 2013 e135]. Use of heated, humidified gases: A meta-analysis of two RCTs indicated that heated, humidified inspired gases immediately following delivery reduced the likelihood of admission hypothermia in preterm babies [Meyer 2018 319]. New data support the use of heated humidified gases in the delivery room in preterm babies. Other warming adjuncts: No other warming adjuncts were identified Use of combinations of warming adjuncts: Given the routine use of radiant warmers during resuscitation in well-resourced settings, most studies use an additional warming adjunct in their intervention limb, for example, radiant warmers and wraps/bags/heated gases/mattresses. There are new data supporting the use of heated humidified gases. Use of “bundles” that include warming adjuncts and other interventions (often as a quality improvement bundle): at least 15 quality improvement studies were identified that used warming adjuncts and/or measured admission hypothermia. The interventions were usually multiple or introduced sequentially over time, relating to equipment or team or system performance. The outcomes were sometimes multiple or composite. The observational methodology was either time series analysis or pre-/post-intervention cohorts. The majority of studies implied that this approach to resuscitation care improved admission hypothermia, with only two neutral studies. There is substantial observational evidence of the effect of “bundles” that include warming adjuncts on the outcomes of preterm babies, however they may not be amenable to analysis. Kangaroo mother care: Although there have been systematic reviews of over 100 KMC studies, this topic is not relevant to resuscitation or the delivery room. Decision to provide KMC is made after the stability of a low birth weight baby is established. KMC studies were therefore excluded from this update.


Resources-challenged settings (remote, isolated, out-of-hospital, single responder, limited technology, etc): Unless clearly stated in the methods, it was very difficult to clarify whether a study was done in a well- or limited-resourced setting. As this definition is inconsistent studies could not be classified by setting. Summary of evidence update: There have been a substantial number of RCTs and observational studies relating to hypothermia since the last review in 2015, including many knowledge translation/quality improvement studies. Given the strong association of hypothermia with mortality and morbidity, especially in preterm and low birth weight babies, interventions that prevent hypothermia after birth remain relevant and important to neonatal normal newborn care and resuscitation. The paradox is that observational studies show strong correlation of admission temperature with mortality and morbidity; and quality improvement studies imply benefit in prevention of hypothermia; whereas meta-analyses of RCTs of warming adjuncts do not demonstrate a survival or morbidity benefit from prevention of hypothermia. This raises the question as to whether hypothermia is a cause of harm or a marker of illness. Hyperthermia and its outcome remain less well studied with limited new evidence. Our search since 2013 would indicate a shift in strength of evidence for certain adjuncts, such as skin-to-skin care (at least in term or larger babies) and heated/humidified inspired gases. Some risk of harm has been expressed with exothermic mattresses. Conclusion: On balance, the studies identified in this evidence update support the 2015 CoSTR. That recommendation was limited to very preterm babies born at <33 weeks gestational age. Although the 2015 CoSTR remains relevant, it seems timely that “warming adjuncts” be formally reviewed in the near future. It would seem wise to divide the target populations to separately analyze effects and pertinent outcomes for term and preterm infants. Suggestion for new question(s): There are many unanswered questions that could be included in a revised PICO. These relate to: - Gestation - Birth weight - Choice of controls (such as radiant warmer or skin-to-skin) - Combinations of warming adjuncts and how to evaluate “bundled” interventions - Warming adjuncts in well babies vs those requiring resuscitative measures - Thermal care while the cord is intact - Impact on mortality and morbidity in all gestations and settings A possible approach might be a more generic question: “Among newborn babies following delivery (P), does increased room temperature, thermal mattress, or other warming interventions (singly or in combination) (I),


compared with radiant warmer, skin-to-skin care, or other basic practice (C), reduce hypothermia (<36.0) after delivery or on admission to NICU or any other important outcome.” Reference list Systematic Reviews: Boundy EO, Dastjerdi R, Spiegelman D, Fawzi WW, Missmer SA, Lieberman E, Kajeepeta S, Wall S, Chan GJ. Kangaroo Mother Care and Neonatal Outcomes: A Meta-analysis. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-2238. Epub 2015 Dec 23. Review. PubMed PMID: 26702029; PubMed Central PMCID: PMC4702019 Conde-Agudelo A, Díaz-Rossello JL. Kangaroo mother care to reduce morbidity and mortality in low birthweight infants. Cochrane Database Syst Rev. 2016 Aug 23;(8):CD002771. doi: 10.1002/14651858.CD002771.pub4. Review. PubMed PMID:27552521; PubMed Central PMCID: PMC6464509 Lunze K, Bloom DE, Jamison DT, Hamer DH. The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival. BMCMed. 2013 Jan 31;11:24. doi: 10.1186/1741-7015-11-24. PubMed PMID: 23369256; PubMed Central PMCID: PMC3606398 McCall EM, Alderdice F, Halliday HL, Vohra S, Johnston L. Interventions to prevent hypothermia at birth in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2018 Feb 12;2:CD004210. doi: 10.1002/14651858.CD004210.pub5. Review. PubMed PMID: 29431872; PubMed Central PMCID: PMC6491068 Meyer MP, Owen LS, Te Pas AB. Use of Heated Humidified Gases for Early Stabilization of Preterm Infants: A Meta-Analysis. Front Pediatr. 2018 Oct 25;6:319. doi: 10.3389/fped.2018.00319. eCollection 2018. PubMed PMID: 30410876; PubMed Central PMCID: PMC6209662 Moore ER, Bergman N, Anderson GC, Medley N. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev. 2016 Nov 25;11:CD003519. Review. PubMed PMID: 27885658; PubMed Central PMCID: PMC6464366 Rabe H, Gyte GM, Díaz-Rossello JL, Duley L. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2019 Sep 17;9:CD003248. doi: 10.1002/14651858.CD003248.pub4. PubMed PMID: 31529790; PubMed Central PMCID: PMC6748404 Stevens J, Schmied V, Burns E, Dahlen H. Immediate or early skin-to-skin contact after a Caesarean section: a review of the literature. Matern Child Nutr. 2014 Oct;10(4):456-73. doi: 10.1111/mcn.12128. Epub 2014 Apr 10. Review. PubMed PMID: 24720501 RCTs: Agrawal N, Das K, Patwal P, Pandita N, Gupta A. Wrapping newborn infants in cloth and newspaper after delivery led to higher temperatures on arrival at the neonatal intensive care unit. Acta Paediatr. 2018 Aug;107(8):1335-1338. doi: 10.1111/apa.14211. Epub 2018 Jan 19. PubMed PMID: 29297943 Belsches TC, Tilly AE, Miller TR, Kambeyanda RH, Leadford A, Manasyan A, Chomba E, Ramani M, Ambalavanan N, Carlo WA. Randomized trial of plastic bags to prevent term neonatal hypothermia in a


resource-poor setting. Pediatrics. 2013 Sep;132(3):e656-61. doi: 10.1542/peds.2013-0172. Epub 2013 Aug 26. PubMed PMID: 23979082; PubMed Central PMCID: PMC3876758 Çağlar S, Gözen D, Ince Z. Heat loss prevention (help) after birth in preterm infants using vinyl isolation bag or polyethylene wrap. J Obstet Gynecol Neonatal Nurs. 2014 Mar-Apr;43(2):216-23. doi: 10.1111/1552-6909.12291. PubMed PMID:24617764 Doglioni N, Cavallin F, Mardegan V, Palatron S, Filippone M, Vecchiato L, Bellettato M, Chiandetti L, Trevisanuto D. Total body polyethylene wraps for preventing hypothermia in preterm infants: a randomized trial. J Pediatr. 2014 Aug;165(2):261-266.e1. doi: 10.1016/j.jpeds.2014.04.010. Epub 2014 May 14. PubMed PMID: 24837862 Duryea EL, Nelson DB, Wyckoff MH, Grant EN, Tao W, Sadana N, Chalak LF, McIntire DD, Leveno KJ. The impact of ambient operating room temperature on neonatal and maternal hypothermia and associated morbidities: a randomized controlled trial. Am J Obstet Gynecol. 2016 Apr;214(4):505.e1-505.e7. doi: 10.1016/j.ajog.2016.01.190. Epub 2016 Feb 10. PubMed PMID: 26874298 Hsu KH, Chiang MC, Lin SW, Lin JJ, Wang YC, Lien R. Thermal Blanket to Improve Thermoregulation in Preterm Infants: A Randomized Controlled Trial. Pediatr Crit Care Med. 2015 Sep;16(7):637-43. doi: 10.1097/PCC.0000000000000447. PubMed PMID: 25901548 Hu XJ, Wang L, Zheng RY, Lv TC, Zhang YX, Cao Y, Huang GY. Using polyethylene plastic bag to prevent moderate hypothermia during transport in very low birth weight infants: a randomized trial. J Perinatol. 2018 Apr;38(4):332-336. doi: 10.1038/s41372-017-0028-0. Epub 2017 Dec 27. PubMed PMID: 29282354 Jia YS, Lin ZL, Lv H, Li YM, Green R, Lin J. Effect of delivery room temperature on the admission temperature of premature infants: a randomized controlled trial. J Perinatol. 2013 Apr;33(4):264-7. doi: 10.1038/jp.2012.100. Epub 2012 Aug 2. PubMed PMID: 22858889 Leadford AE, Warren JB, Manasyan A, Chomba E, Salas AA, Schelonka R, Carlo WA. Plastic bags for prevention of hypothermia in preterm and low birth weight infants. Pediatrics. 2013 Jul;132(1):e128-34. doi: 10.1542/peds.2012-2030. Epub 2013 Jun 3. PubMed PMID: 23733796; PubMed Central PMCID: PMC3691528 Linnér A, Klemming S, Sundberg B, Lilliesköld S, Westrup B, Jonas W, Skiöld B. Immediate skin-to-skin contact is feasible for very preterm infants but thermal control remains a challenge. Acta Paediatr. 2019 Oct 16. doi: 10.1111/apa.15062. [Epub ahead of print] PubMed PMID: 31618466 Mathew B, Lakshminrusimha S, Sengupta S, Carrion V. Randomized controlled trial of vinyl bags versus thermal mattress to prevent hypothermia in extremely low-gestational-age infants. Am J Perinatol. 2013 Apr;30(4):317-22. doi: 10.1055/s-0032-1324700. Epub 2012 Aug 14. PubMed PMID: 22893555 McCarthy LK, Molloy EJ, Twomey AR, Murphy JF, O'Donnell CP. A randomized trial of exothermic mattresses for preterm newborns in polyethylene bags. Pediatrics. 2013 Jul;132(1):e135-41. doi: 10.1542/peds.2013-0279. Epub 2013 Jun 17. PubMed PMID: 23776115 McGrory L, Owen LS, Thio M, Dawson JA, Rafferty AR, Malhotra A, Davis PG, Kamlin COF. A Randomized Trial of Conditioned or Unconditioned Gases for Stabilizing Preterm Infants at Birth. J Pediatr. 2018 Feb;193:47-53. doi: 10.1016/j.jpeds.2017.09.006. Epub 2017 Nov 6. PubMed PMID: 29106924 Meyer MP, Hou D, Ishrar NN, Dito I, te Pas AB. Initial respiratory support with cold, dry gas versus heated humidified gas and admission temperature of preterm infants. J Pediatr. 2015 Feb;166(2):245-50.e1. doi: 10.1016/j.jpeds.2014.09.049. Epub 2014 Oct 28. PubMed PMID: 25449225


Nimbalkar SM, Patel VK, Patel DV, Nimbalkar AS, Sethi A, Phatak A. Effect of early skin-to-skin contact following normal delivery on incidence of hypothermia in neonates more than 1800 g: randomized control trial. J Perinatol. 2014 May;34(5):364-8. doi: 10.1038/jp.2014.15. Epub 2014 Feb 20. PubMed PMID: 24556982 Nimbalkar SM, Khanna AK, Patel DV, Nimbalkar AS, Phatak AG. Efficacy of Polyethylene Skin Wrapping in Preventing Hypothermia in Preterm Neonates (<34 Weeks): A Parallel Group Non-blinded Randomized Control Trial. J Trop Pediatr. 2019 Apr 1;65(2):122-129. doi: 10.1093/tropej/fmy025. PubMed PMID: 29800322 Reilly MC, Vohra S, Rac VE, Dunn M, Ferrelli K, Kiss A, Vincer M, Wimmer J, Zayack D, Soll RF; Vermont Oxford Network Heat Loss Prevention (HeLP) Trial Study Group. Randomized trial of occlusive wrap for heat loss prevention in preterm infants. J Pediatr. 2015 Feb;166(2):262-8.e2. doi: 10.1016/j.jpeds.2014.09.068. Epub 2014 Nov 12. PubMed PMID: 25449224 Observational studies (*QI)(§risk factors or outcomes): §Amadi HO, Olateju EK, Alabi P, Kawuwa MB, Ibadin MO, Osibogun AO. Neonatal hyperthermia and thermal stress in low- and middle-income countries: a hidden cause of death in extremely low-birthweight neonates. Paediatr Int Child Health. 2015 Aug;35(3):273-81. doi: 10.1179/2046905515Y.0000000030. Epub 2015 May 2. PubMed PMID: 25936414 *Andrews C, Whatley C, Smith M, Brayton EC, Simone S, Holmes AV. Quality-Improvement Effort to Reduce Hypothermia Among High-Risk Infants on a Mother-Infant Unit. Pediatrics. 2018 Mar;141(3). pii: e20171214. doi: 10.1542/peds.2017-1214. Epub 2018 Feb 14. PubMed PMID: 29444816. *Billimoria Z, Chawla S, Bajaj M, Natarajan G. Improving admission temperature in extremely low birth weight infants: a hospital-based multi-intervention quality improvement project. J Perinat Med. 2013 Jul;41(4):455-60. doi: 10.1515/jpm-2012-0259. PubMed PMID: 23334053 *Caldas JPS, Millen FC, Camargo JF, Castro PAC, Camilo ALDF, Marba STM. Effectiveness of a measure program to prevent admission hypothermia in very low-birth weight preterm infants. J Pediatr (Rio J). 2018 Jul - Aug;94(4):368-373. doi: 10.1016/j.jped.2017.06.016. Epub 2017 Sep 6. PubMed PMID: 28886399. *Castrodale V, Rinehart S. The golden hour: improving the stabilization of the very low birth-weight infant. Adv Neonatal Care. 2014 Feb;14(1):9-14; quiz 15-6. doi: 10.1097/ANC.0b013e31828d0289. PubMed PMID: 24472882. *Choi HS, Lee SM, Eun H, Park M, Park KI, Namgung R. The impact of a quality improvement effort in reducing admission hypothermia in preterm infants following delivery. Korean J Pediatr. 2018 Aug;61(8):239-244. doi: 10.3345/kjp.2018.61.8.239. Epub 2018 Aug 15. PubMed PMID: 30130949; PubMed Central PMCID: PMC6107400. *De Carolis MP, Rubortone SA, Bersani I, Lacerenza S, Cota F, Garufi C, Romagnoli C. Heat loss prevention in the delivery room in term and preterm infants. Turk J Pediatr. 2013 Jan-Feb;55(1):63-8. PubMed PMID: 23692834. §de Siqueira Caldas JP, Ferri WAG, Marba STM, Aragon DC, Guinsburg R, de Almeida MFB, Diniz EMA, Silveira RCS, Alves Junior JMS, Pavanelli MB, Bentlin MR, Ferreira DMLM, Vale MS, Fiori HH, Duarte JLMB, Meneses JA, Cwajg S, Carvalho WB, Ferrari LSL, Silva NMM, da Silva RPGVC, Anchieta LM, Santos JPF, Kawakami MD. Admission hypothermia, neonatal morbidity, and mortality: evaluation of a multicenter cohort of very low birth weight preterm infants according to relative performance of the center. Eur


J Pediatr. 2019 Jul;178(7):1023-1032. doi: 10.1007/s00431-019-03386-9. Epub 2019 May 6. PubMed PMID: 31056716 §Chang HY, Sung YH, Wang SM, Lung HL, Chang JH, Hsu CH, Jim WT, Lee CH, Hung HF. Short- and Long-Term Outcomes in Very Low Birth Weight Infants with Admission Hypothermia. PLoS One. 2015 Jul 20;10(7):e0131976. doi: 10.1371/journal.pone.0131976. eCollection 2015. PubMed PMID: 26193370; PubMed Central PMCID: PMC4507863 §de Almeida MF, Guinsburg R, Sancho GA, Rosa IR, Lamy ZC, Martinez FE, da Silva RP, Ferrari LS, de Souza Rugolo LM, Abdallah VO, Silveira Rde C; Brazilian Network on Neonatal Research. Hypothermia and early neonatal mortality in preterm infants. J Pediatr. 2014 Feb;164(2):271-5.e1. doi: 10.1016/j.jpeds.2013.09.049. Epub 2013 Nov 6. PubMed PMID: 24210925 §Demissie BW, Abera BB, Chichiabellu TY, Astawesegn FH. Neonatal hypothermia and associated factors among neonates admitted to neonatal intensive care unit of public hospitals in Addis Ababa, Ethiopia. BMC Pediatr. 2018 Aug 4;18(1):263. doi: 10.1186/s12887-018-1238-0. PubMed PMID: 30077179; PubMed Central PMCID: PMC6090740. *Godfrey K, Nativio DG, Bender CV, Schlenk EA. Occlusive bags to prevent hypothermia in premature infants: a quality improvement initiative. Adv Neonatal Care. 2013 Oct;13(5):311-6. doi: 10.1097/ANC.0b013e31828d040a. PubMed PMID: 24042134. *Harer MW, Vergales B, Cady T, Early A, Chisholm C, Swanson JR. Implementation of a multidisciplinary guideline improves preterm infant admission temperatures. J Perinatol. 2017 Nov;37(11):1242-1247. doi: 10.1038/jp.2017.112. Epub 2017 Jul 20. PubMed PMID: 28726791. *Harriman TL, Carter B, Dail RB, Stowell KE, Zukowsky K. Golden Hour Protocol for Preterm Infants: A Quality Improvement Project. Adv Neonatal Care. 2018 Dec;18(6):462-470. doi: 10.1097/ANC.0000000000000554. PubMed PMID: 30212389. *Lambeth TM, Rojas MA, Holmes AP, Dail RB. First Golden Hour of Life: A Quality Improvement Initiative. Adv Neonatal Care. 2016 Aug;16(4):264-72. doi: 10.1097/ANC.0000000000000306. PubMed PMID: 27391563. §Laptook AR, Bell EF, Shankaran S, Boghossian NS, Wyckoff MH, Kandefer S, Walsh M, Saha S, Higgins R; Generic and Moderate Preterm Subcommittees of the NICHD Neonatal Research Network. Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. J Pediatr. 2018 Jan;192:53-59.e2. doi: 10.1016/j.jpeds.2017.09.021. PubMed PMID: 29246358; PubMed Central PMCID: PMC5808888. *Leng H, Wang H, Lin B, Cheng G, Wang L. Reducing Transitional Hypothermia in Outborn Very Low Birth Weight Infants. Neonatology. 2016;109(1):31-6. doi: 10.1159/000438743. Epub 2015 Oct 21. PubMed PMID: 26485388. §Lyu Y, Shah PS, Ye XY, Warre R, Piedboeuf B, Deshpandey A, Dunn M, Lee SK; Canadian Neonatal Network. Association between admission temperature and mortality and major morbidity in preterm infants born at fewer than 33 weeks' gestation. JAMA Pediatr. 2015 Apr;169(4):e150277. doi: 10.1001/jamapediatrics.2015.0277. Epub 2015 Apr 6. PubMed PMID: 25844990. *Manani M, Jegatheesan P, DeSandre G, Song D, Showalter L, Govindaswami B. Elimination of admission hypothermia in preterm very low-birth-weight infants by standardization of delivery room management. Perm


J. 2013 Summer;17(3):8-13. doi: 10.7812/TPP/12-130. PubMed PMID: 24355884; PubMed Central PMCID: PMC3783084. *Pinheiro JM, Furdon SA, Boynton S, Dugan R, Reu-Donlon C, Jensen S. Decreasing hypothermia during delivery room stabilization of preterm neonates. Pediatrics. 2014 Jan;133(1):e218-26. doi: 10.1542/peds.2013-1293. Epub 2013 Dec 16. PubMed PMID: 24344110. *Russo A, McCready M, Torres L, Theuriere C, Venturini S, Spaight M, Hemway RJ, Handrinos S, Perlmutter D, Huynh T, Grunebaum A, Perlman J. Reducing hypothermia in preterm infants following delivery. Pediatrics. 2014 Apr;133(4):e1055-62. doi: 10.1542/peds.2013-2544. Epub 2014 Mar 31. PubMed PMID: 24685958. §Shikuku DN, Milimo B, Ayebare E, Gisore P, Nalwadda G. Practice and outcomes of neonatal resuscitation for newborns with birth asphyxia at Kakamega County General Hospital, Kenya: a direct observation study. BMC Pediatr. 2018 May 15;18(1):167. doi: 10.1186/s12887-018-1127-6. PubMed PMID: 29764391; PubMed Central PMCID: PMC5953400. §Ting JY, Synnes AR, Lee SK, Shah PS; Canadian Neonatal Network and Canadian Neonatal Follow-Up Network. Association of admission temperature and death or adverse neurodevelopmental outcomes in extremely low-gestational age neonates. J Perinatol. 2018 Jul;38(7):844-849. doi: 10.1038/s41372-018-0099-6. Epub 2018 May 24. PubMed PMID: 29795318 §Wilson E, Maier RF, Norman M, Misselwitz B, Howell EA, Zeitlin J, Bonamy AK; Effective Perinatal Intensive Care in Europe (EPICE) Research Group. Admission Hypothermia in Very Preterm Infants and Neonatal Mortality and Morbidity. J Pediatr. 2016 Aug;175:61-67.e4. doi: 10.1016/j.jpeds.2016.04.016. Epub 2016 May 14. PubMed PMID: 27189680 *Yip WY, Quek BH, Fong MCW, Thilagamangai, Ong SSG, Lim BL, Lo BC, Agarwal P. A quality improvement project to reduce hypothermia in preterm infants on admission to the neonatal intensive care unit. Int J Qual Health Care. 2017 Nov 1;29(7):922-928. doi: 10.1093/intqhc/mzx131. PubMed PMID: 29045653.


APPENDIX C-3

2020 Evidence Update Worksheet NLS 898 Heart Rate Monitoring During Neonatal Resuscitation

Worksheet author(s): Marya Strand, Vishal Kapadia Council: AHA Date Submitted: Jan 6, 2020 PICO / Research Question: In neonates requiring resuscitation at delivery, does the use of Electrocardiography (ECG) compared to pulse oximetry (PO) or auscultation result in a faster and more accurate heart rate assessment? Outcomes: 9 (critical)—fast and accurate evaluation of heart rate Type (intervention, diagnosis, prognosis): Diagnosis Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2015 (First review performed) Last ILCOR Consensus on Science and Treatment Recommendation: Consensus on Science

For the important outcomes of “fast and accurate measurement of heart rate” in babies requiring resuscitation we have identified 1) low quality evidence from five non-RCTs enrolling 213 patients showing a benefit of ECG compared to oximetry {Dawson 2013 955; Kamlin 2008 756; Katheria 2012 e1177; Mizumoto 2012 205; van Vonderen 2015 49} and 2) low quality evidence from one non-RCT enrolling 26 patients showing a benefit of ECG compared to auscultation {Kamlin 2006 319}. The available evidence is from non-RCT studies, upgraded for low risk of bias but downgraded for concerns of applicability. Treatment Recommendation In babies requiring resuscitation we suggest using ECG over oximetry and auscultation to measure heart rate faster and more accurately (weak recommendation, low quality of evidence).

2015 Search Strategy:


PubMed ((((((infant, newborn) OR (("Delivery Rooms"[Mesh] OR "Gestational Age"[Mesh] OR "Premature Birth"[Mesh] OR "Term Birth"[Mesh] OR "Live Birth"[Mesh] or newborn[TIAB] or neonatal[TIAB] or neonate[TIAB] or neonates[TIAB] OR "Low Birth Weight "[TIAB] or "Small for Gestational Age"[TIAB] or Postmature[TIAB] or prematur*[TIAB] or preterm[TIAB] OR infants[TIAB] OR infant[TIAB] OR birth[TIAB])))) AND ((("Resuscitation"[Mesh] OR resuscitat*[TIAB] OR "cardiopulmonary resuscitation"[Mesh] OR "cardiopulmonary resuscitation"[TIAB] OR CPR[TIAB] OR "heart massage"[Mesh] OR "heart massage"[TIAB] OR "chest compression"[TIAB] OR "chest compressions"[TIAB] OR "cardiac massage"[TIAB] OR "cardiac compression"[TIAB] OR "cardiac compressions"[TIAB] OR "thoracic compression"[TIAB] OR "thoracic compressions"[TIAB]))))) AND ((Heart Auscultation[Mesh terms]) OR (echocardiography[Mesh terms] OR electrocardiography[Mesh terms] OR body surface potential mapping[Mesh terms] OR electrocardiography, ambulatory[Mesh terms] or vectorcardiography[Mesh terms] OR EKG[tiab] or ECG[tiab))) NOT (("letter"[pt] OR "comment"[pt] OR "editorial"[pt])) AND English[lang]'

Embase (infant, newborn'/exp OR 'delivery rooms'/exp OR 'gestational age'/exp OR 'premature birth'/exp OR 'term birth'/exp OR 'live birth'/exp OR newborn:ab,ti OR neonatal:ab,ti OR neonate:ab,ti OR neonates:ab,ti OR 'low birth weight':ab,ti OR 'small for gestational age':ab,ti OR 'postmature':ab,ti OR 'premature':ab,ti OR 'preterm':ab,ti OR 'infant':ab,ti OR 'infants':ab,ti OR 'birth':ab,ti AND ('resuscitation'/exp OR resuscitation:ab,ti OR 'cardiopulmonary resuscitation'/exp OR 'cardiopulmonary resuscitation':ab,ti OR cpr:ab,ti OR 'heart massage'/exp OR 'heart massage':ab,ti OR 'chest compression':ab,ti OR 'chest compressions':ab,ti OR 'cardiac massage':ab,ti OR 'cardiac compression':ab,ti OR 'cardiac compressions':ab,ti OR 'thoracic compression':ab,ti OR 'thoracic compressions':ab,ti) AND ('heart auscultation'/exp OR 'echocardiography'/exp OR 'electrocardiography'/exp OR 'body surface potential mapping'/exp OR 'electrocardiography, ambulatory'/exp OR 'vectorcardiography'/exp OR ekg:ab,ti OR ecg:ab,ti) AND [embase]/lim]

Cochrane Library: ([mh "infant, newborn"] or [mh "Delivery Rooms"] or [mh "Gestational Age"] or [mh "Premature Birth"] or [mh "Term Birth"] or [mh "Live Birth"] or "newborn":ti,ab or neonatal:ti,ab or neonate:ti,ab or neonates:ti,ab or "Low Birth Weight ":ti,ab or "Small for Gestational Age":ti,ab or "Postmature":ti,ab or "premature":ti,ab or "preterm":ti,ab or "infant":ti,ab or "infants":ti,ab or "birth":ti,ab) AND ([mh "Resuscitation"] OR "resuscitation":ti,ab OR [mh "cardiopulmonary resuscitation"] OR "cardiopulmonary resuscitation":ti,ab OR CPR:ti,ab OR [mh "heart massage"] OR "heart massage":ti,ab OR "chest compression":ti,ab OR "chest compressions":ti,ab OR "cardiac massage":ti,ab OR "cardiac compression":ti,ab OR "cardiac compressions":ti,ab OR "thoracic compression":ti,ab OR "thoracic compressions":ti,ab) AND ([mh "Heart Auscultation"] or [mh echocardiography] or [mh electrocardiography] or [mh "body surface potential mapping"] or [mh "electrocardiography, ambulatory"] or [mh vectorcardiography] or EKG:ti,ab or ECG:ti,ab) 2019 Search Strategy: ((((((infant, newborn) OR (("delivery rooms"[Mesh] OR "gestational age"[Mesh] OR "premature birth"[Mesh] OR "term birth"[Mesh] OR "live birth"[Mesh] OR newborn[Title/Abstract] OR neonatal[Title/Abstract] OR neonate[Title/Abstract] OR neonates[Title/Abstract] OR "Low Birth Weight"[Title/Abstract] OR "Small for Gestational Age"[Title/Abstract] OR Postmature[Title/Abstract] OR prematur*[Title/Abstract] OR preterm[Title/Abstract] OR infants[Title/Abstract] OR infant[Title/Abstract] OR birth[Title/Abstract])))) AND ((("resuscitation"[Mesh] OR resuscitat*[Title/Abstract] OR


"cardiopulmonary resuscitation"[Mesh] OR "cardiopulmonary resuscitation"[Title/Abstract] OR CPR[Title/Abstract] OR "heart massage"[Mesh] OR "heart massage"[Title/Abstract] OR "chest compression"[Title/Abstract] OR "chest compressions"[Title/Abstract] OR "cardiac massage"[Title/Abstract] OR "cardiac compression"[Title/Abstract] OR "cardiac compressions"[Title/Abstract] OR "thoracic compression"[Title/Abstract] OR "thoracic compressions"[Title/Abstract])))) AND ((((heart auscultation[MeSH Terms] OR echocardiography[MeSH Terms] OR electrocardiography[MeSH Terms] OR body surface potential mapping[MeSH Terms] OR electrocardiography, ambulatory[MeSH Terms] OR vectorcardiography[MeSH Terms] OR EKG[Title/Abstract] OR ECG[Title/Abstract])))))) NOT ((letter[pt] OR comment[pt] OR editorial[pt])) Database searched: PubMed Date Search Completed: 11/3/2019 Search Results (Number of articles identified / number identified as relevant): 447 articles retrieved/36 relevant articles. 2 more articles identified through the SRs/1 relevant 2019 Search Strategy: ([mh "infant, newborn"] or [mh "Delivery Rooms"] or [mh "Gestational Age"] or [mh "Premature Birth"] or [mh "Term Birth"] or [mh "Live Birth"] or "newborn":ti,ab or neonatal:ti,ab or neonate:ti,ab or neonates:ti,ab or "Low Birth Weight ":ti,ab or "Small for Gestational Age":ti,ab or "Postmature":ti,ab or "premature":ti,ab or "preterm":ti,ab or "infant":ti,ab or "infants":ti,ab or "birth":ti,ab) AND ([mh "Resuscitation"] OR "resuscitation":ti,ab OR [mh "cardiopulmonary resuscitation"] OR "cardiopulmonary resuscitation":ti,ab OR CPR:ti,ab OR [mh "heart massage"] OR "heart massage":ti,ab OR "chest compression":ti,ab OR "chest compressions":ti,ab OR "cardiac massage":ti,ab OR "cardiac compression":ti,ab OR "cardiac compressions":ti,ab OR "thoracic compression":ti,ab OR "thoracic compressions":ti,ab) AND ([mh "Heart Auscultation"] or [mh echocardiography] or [mh electrocardiography] or [mh "body surface potential mapping"] or [mh "electrocardiography, ambulatory"] or [mh vectorcardiography] or EKG:ti,ab or ECG:ti,ab)" Database searched: Cochrane Date Search Completed: 11/7/2019 Search Results (Number of articles identified / number identified as relevant): 31 trials retrieved/all published studies included in PubMed search Inclusion/Exclusion Criteria: Newborns in DR Used both ECG AND either PO or auscultation of HR Did not include newborns in non-DR settings Did not include simulation studies or human-factors studies Link to Article Titles and Abstracts (if available on PubMed):


Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces

3. This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews. Relevant Guidelines or Systematic Reviews Organisation (if relevant); Author; Year Published; first page of the document

Guideline or systematic

review


Number of articles

identified


Anton, 2019{Anton 2019 199}

Systematic

Review

P: Term and preterm infants I: Detecting HR on babies at birth C: Gold standard (ECG) O: Time to obtain reliable heart rate S: Last 10 years, qualitative and feasibility

5 studies Iglesias 2016

271, Kamlin 2008 756, Katheria

2017 1, Mizumoto

2012 205, Van Vonderen 2015

49

ECG and PO were both more precise compared to clinical assessment alone, but multiple studies have shown that the delay in obtaining a reliable HR from birth often exceeds 1–2 min. When used at delivery, ECG was more reliable and the time to display HR was at least halved compared to PO. In addition, ECG leads were placed more quickly onto the infant compared to a PO sensor.

ECG preferable to clinical assessment alone

Johnson, 2019 {Johnson 2019

143}

Systematic Review

P: Newborn infants requiring resuscitation I: HR assessment technologies C: Gold standard (ECG)

4 studies Van Vonderen

2015 49; Murphy 2018 547; Katheria

2017 1; Iglesias 2018

233

ECG is faster to assess HR at birth and more reliable to detect changes in HR compared to other recommended technologies. However, current practice should not exclusively rely on ECG. While novel technologies can support HR assessment, presently there are no studies to validate their

ECG preferable to clinical assessment alone


O: accuracy, latency and efficacy of HR detection S: Last 10 years, qualitative and feasibility

clinical efficacy during neonatal resuscitation. Further studies are required for these technologies before they are implemented for neonatal resuscitation.

ECG, Electrocardiography; HR, Heart Rate; PO, Pulse oximeter RCT:



Patient Population




Katheria, 2017 {Katheria 2017 1}

Sub-study of Neu-Prem study; infants randomized to visible ECG vs not visible to providers; n=40

Premature infants included in Neu-Prem study (mean GA 28 weeks)

Intervention: ECG visible to providers Comparison: PO or auscultation for heart rate assessment

Time to clinical interventions: oxygen supplementation, PPV or intubation (all not significantly different); Time to accurate heart rate determination 66s vs 114s (p<0.0001)

Substudy, so selection bias is possible; single person putting both monitor on infant so not congruent time for readings


Murphy, 2017 {Murphy 2017 547}

Randomized study of IntelliView montitor (ECG and PO) vs traditional PO; n=100

Term infants delivered by elective c-section

Intervention: IntelliView monitor Comparison: Nellcor PO

Time to display HR: 24s vs 48s (p<0.001); Time to apply monitor NS; No skin damage; No failure of monitor

Study done in healthy term infants with no instability; ECG displayed more initial bradycardia.

ECG, Electrocardiography; HR, Heart Rate; IQR, Interquartile Range; PO, Pulse oximeter; PPV, positive pressure ventilation Nonrandomized Trials, Observational Studies


Study Type/Design;

Study Size (N)

Patient Population



Iglesias, 2018 {Iglesias 2018 233}

Prospective, observational

sequential study of

bradycardia in DR of ECG vs

PO; n=29

Infants <32 weeks of gestation

Time to valid reading 18s [IQR 13-32s] vs 60s [IQR 39-112s], p<0.001; Also assessed accuracy of reading during bradycardia: PO

with decreasing accuracy as bradycardia continues

ECG is faster to initial reading, faster to identify bradycardia

and faster to identify resolution of bradycardia than PO

Gulati, 2018 {Gulati 2018 83}

Prospective observational convenience

sample investigating

using “preset” ECG leads vs PO monitor;

All deliveries attended by

NICU team that included research

personnel

Time to detect HR: All: 29s vs 60s, p<0.001

<31weeks: 10s vs 60s, no p given ≥31 weeks: 30s vs 65s, p<0.001

ECG (with preset leads) is faster to detect HR than PO


n=334 (49<31 weeks)

Iglesias, 2016 {Iglesias 2016 271}

Prospective observational study using

video review of ECG vs PO

for HR monitoring;

n=39

Infants <32 weeks and

<1500 grams at delivery

Time for lead placement: 17s vs 27s, p<0.05 Time to valid reading: 26s vs 87s, p<0.05

ECG is faster and more reliable than PO


Reviewer Comments (including whether meet criteria for formal review):

• The evidence update is sufficient for this PICOST question. This evidence update identified five additional studies (2 RCTs and 3 non-randomized studies), all of which concluded that ECG is faster and more reliable and faster than pulse oximetry in providing accurate heart rate assessment. These studies support the previous treatment recommendation from 2015. There is no need for a formal review at this time.

• There is a need to develop additional intervention PICOST asking if routine use of ECG during neonatal resuscitation improve clinical outcomes.

• With the improvements in technologies for heart rate detection and measurement that are coming to the market, the PICOST question may be limited in scope. Additional methodologies beyond ECG monitoring and PO are being explored in the literature. These methodologies include the digital stethoscope, photoplethysmography, video plethysmography, audible Doppler, display Doppler, precordial Doppler ultrasound, fetal Doppler device and dry electrode technologies. Future formal reviews will need to include these technologies to compare to the “gold standard” of ECG monitoring


Reference list 1. Anton O, Fernandez R, Rendon-Morales E, Aviles-Espinosa R, Jordan H, Rabe H. Heart Rate Monitoring in Newborn Babies: A Systematic Review. Neonatology. 2019;116(3):199-210. 2. Gulati R, Zayek M, Eyal F. Presetting ECG electrodes for earlier heart rate detection in the delivery room. Resuscitation. 2018;128:83-87. 3. Iglesias B, Rodri Guez MAJ, Aleo E, Criado E, Marti Nez-Orgado J, Arruza L. 3-lead electrocardiogram is more reliable than pulse oximetry to detect bradycardia during stabilisation at birth of very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2018;103(3):F233-F237. 4. Iglesias B, Rodriguez MJ, Aleo E, et al. [Pulse oximetry versus electrocardiogram for heart rate assessment during resuscitation of the preterm infant]. An Pediatr (Barc). 2016;84(5):271-277. 5. Johnson PA, Cheung PY, Lee TF, O'Reilly M, Schmolzer GM. Novel technologies for heart rate assessment during neonatal resuscitation at birth - A systematic review. Resuscitation. 2019;143:196-207. 6. Katheria A, Arnell K, Brown M, et al. A pilot randomized controlled trial of EKG for neonatal resuscitation. PLoS One. 2017;12(11):e0187730. 7. Murphy MC, De Angelis L, McCarthy LK, O'Donnell CPF. Randomised study comparing heart rate measurement in newly born infants using a monitor incorporating electrocardiogram and pulse oximeter versus pulse oximeter alone. Arch Dis Child Fetal Neonatal Ed. 2019;104(5):F547-F550.


APPENDIX C-4 2020 Evidence Update Worksheet

Outcomes for PEEP versus no PEEP in the delivery room (NLS 897)

Worksheet author(s): Georg M. Schmölzer Council: AHA, HSF of Canada Date Submitted: January 3rd 2020 PICO / Research Question: Outcomes for PEEP versus no PEEP in the delivery room (NLS 897) In preterm/term newborn infants who do not establish respiration at birth (P), does the use of PEEP as part of the initial ventilation strategy (I), compared with no PEEP (C), change outcomes Outcomes: survival to discharge, 5-minute Apgar scores, time for heart rate to rise above 100 beats per minute, intubation rate in the delivery room, chest compressions in the delivery room, heart rate, incidence of air leaks, oxygen saturation/oxygenation, FiO2 exposure in the delivery room, mechanical ventilation in the first 72 hours, bronchopulmonary dysplasia Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): None Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2015 2015 ILCOR Consensus on Science and Treatment Recommendation: We suggest using Positive End-Expiratory Pressure (PEEP) ventilation for premature newborns during delivery room resuscitation (weak recommendations, low-quality evidence). We cannot make any recommendation for term infants because of insufficient data. 2010/2015 Search Strategy: Pubmed: (positive end expiratory pressure OR peep OR Intermittent Positive-Pressure Breathing OR Intermittent Positive-Pressure Ventilation) AND (resuscitate* OR (delivery room)) Filters activated: Case Reports, Clinical Trial, Comparative Study, Controlled Clinical Trial, Randomized Controlled Trial, Systematic Reviews, Meta-Analysis, Infant: birth-23 months, Newborn: birth-1 month Embase: (positive end expiratory pressure OR peep OR Intermittent Positive-Pressure Breathing OR Intermittent Positive-Pressure Ventilation) AND (resuscitate* OR (delivery room)) Filters activated: up to one year of age Cochrane: (PEEP OR “Positive pressure” (phrase) AND (respiration OR ventilation OR breathing (all with word variations)) AND Infant, Newborn (includes premature) 2019 Search Strategy:


Pubmed: (positive end expiratory pressure OR peep OR Intermittent Positive-Pressure Breathing OR Intermittent Positive-Pressure Ventilation) AND (resuscitate* OR (delivery room)) Filters activated: Case Reports, Clinical Trial, Comparative Study, Controlled Clinical Trial, Randomized Controlled Trial, Systematic Reviews, Meta-Analysis, Infant: birth-23 months, Newborn: birth-1 month Embase: (positive end expiratory pressure OR peep OR Intermittent Positive-Pressure Breathing OR Intermittent Positive-Pressure Ventilation) AND (resuscitate* OR (delivery room)) Filters activated: up to one year of age Cochrane: (PEEP OR “Positive pressure” (phrase) AND Delivery Room AND Infant, Newborn (includes premature) Database searched: Pubmed, Embase, Cochrane Date Search Completed: November 1st 2019 Search Results (Number of articles identified / number identified as relevant): Pubmed: 79 Embase: 111 Cochrane: 102 Inclusion/Exclusion Criteria: Included newborns in delivery room Included preterm animal models Did not include newborns in non-delivery room settings Evidence Update Process for topics not covered by ILCOR Task Forces This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews. Links to Included Articles Dawson, 2011: https://www.ncbi.nlm.nih.gov/pubmed/21238983

Finer, 2004: https://www.ncbi.nlm.nih.gov/pubmed/15342835

Guinsburg, 2018: https://www.ncbi.nlm.nih.gov/pubmed/28663283

Szyld, 2014: https://www.ncbi.nlm.nih.gov/pubmed/24690329

Thakur, 2015: https://www.ncbi.nlm.nih.gov/pubmed/25636895


https://www.ncbi.nlm.nih.gov/pubmed/21238983









None RCT: Study Acronym; Author; Year Published Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at birth: a randomized controlled trial Dawson, 2011{Dawson 2011 912}

Aim of Study; Comparison of PEEP versus no PEEP at birth Study Type; RCT Study Size (N=80)

Patient Population 23-28 weeks preterm infants

Study Intervention T-piece (41 patients) / Study Comparator Self-Inflating Bag (39 patients)

Endpoint Results (Absolute Event Rates, P value; OR or RR; & 95% CI) SpO2 at 5 min At 5 minutes after birth, there was no significant difference between the median (interquartile range) SpO2 in the T-piece and SIB groups (61% [13% to 72%] versus 55% [42% to 67%]; P = .27).


Study Acronym; Author; Year Published T-piece or self inflating bag for positive pressure ventilation during delivery room

Aim of Study; Comparison of PEEP versus no PEEP at birth Study Type; Quasi-RCT Study Size (N=90)

Patient Population 26 weeks to term And subgroup of 26-33 weeks

Study Intervention T-piece (18 patients) / Study Comparator Self-Inflating Bag (19 patients)

Endpoint Results (Absolute Event Rates, P value; OR or RR; & 95% CI) Duration of PPV during DR resuscitation The median (IQR) duration of PPV in delivery room was significantly less in TPR group as compared to SIB; 30 (30-



resuscitation: an RCT Thakur, 2015 {Thakur 2015 21}

With subgroup of 26-33 weeks with 27 infants total

preterm infants

60)s vs. 60 (30-90)s, respectively; (p<0.001)

Comparison of devices for newborn ventilation in the delivery room Szyld, 2014 {Szyld 2014 234}

Aim of Study; Comparison of PEEP versus no PEEP at birth Study Type; RCT Study Size (N=1027)

Inclusion Criteria: 26 weeks to term infants Subgroup 26-33

Intervention: T-piece (85 patients) / Study Comparison: Self-Inflating Bag (110 patients)

1° endpoint: Proportion of newborns with heart rate (HR)≥100 bpm at 2 minutes after birth There was no statistically significant difference in the incidence of HR≥100 bpm at 2 minutes after birth between the T-piece and self-inflating bag groups: 94% (479 of 511) and 90% (466 of 516), respectively (OR, 0.65; 95% CI, 0.41-1.05; P=.08).

Study Limitations:

Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial Finer, 2004 {Finer 2004 651}

Study Aim:

Inclusion Criteria: 23-27

Intervention: T-Piece with 5 cm H2O Peep (55 patients) Comparison: T-Piece with 0 cm H2O Peep (49 patients)

1° endpoint: The primary outcome of this feasibility trial was to determine the percentage of enrolled infants who could be treated according to the study protocol in the DR, received CPAP on NICU admission, and were intubated only after fulfilling stated minimum intubation criteria for a population of 100 infants of <28 weeks’ gestation over a 12-month interval.

Study Limitations:



Study Acronym; Author; Year Published Guinsburg, 2018 {Guinsburg 2018 F49}

Study Type/Design Observational Study Size (1962)

Patient Population 23-33 weeks’ gestation and birth weight 400-1499 g

Primary Endpoint and Results (include P value; OR or RR; & 95% CI) 1456 (74%) were only ventilated with T-piece resuscitator and 506 (26%) with the self-inflating bag. The characteristics of those ventilated with T-Piece resuscitator versus self-inflating bag were birth weight 969 ± 277 vs 941 ± 279 g, gestational age 28.2±2.5 vs 27.8±2.7 weeks and survival to hospital discharge without major morbidities 47% vs 35%. Logistic regression adjusted for maternal characteristics, obstetric and neonatal morbidities showed that the T-piece resuscitator increased the chance of survival to hospital discharge without major morbidities (OR=1.38; 95% CI 1.06 to 1.80; Hosmer-Lemeshow goodness of fit: 0.695).



Reviewer Comments (including whether meet criteria for formal review): During resuscitation after birth positive pressure ventilation (PPV) is provided to inflate and ventilate the lungs. The lungs of sick or preterm newborns tend to collapse as they are not supported by a stiff chest wall and their breathing efforts may be weak; the lungs may also be immature and surfactant-deficient {te Pas 2008 607}. Positive end expiratory pressure (PEEP) provides low pressure inflation of the lungs during expiration. PEEP maintains lung volume during PPV in animal studies and improves lung function and oxygenation {Siew 2009 1487; Probyn 2004 198}. PEEP may be beneficial during neonatal resuscitation, but the evidence from human studies is limited. Three devices are routinely used to provide PPV after birth: self-inflating bags, T-pieces, and flow-inflating bags {Wyckoff 2015 S196}. Several bench-top studies showed that i) T-pieces provide the most consistent PEEP, ii) flow-inflating bags deliver less consistent PEEP than T-pieces, and iii) self-inflating bags do not provide effective PEEP {Ryan 2012 797}, even with a PEEP valve attached. Optimal PEEP has not been determined, as all human studies used a PEEP level of 5 cm H2O {Finer 2004 651; Dawson 2011 912; Szyld 2014 234; Thakur 2015 21; Guinsburg 2018 F49}.

• Animal studies report that PEEP facilitates lung aeration, accumulation of functional residual capacity, prevents of distal airway collapse, increases surface area and compliance, decreases expiratory resistance, conserves surfactant, reduces hyaline membrane formation, alveolar collapse, and the expression of proinflammatory mediators {Siew 2009 1487; Probyn 2004 198}.

• One trial (very low quality) compared PPV using a T-Piece and PEEP of 5 versus 0 cm H2O and reported similar rates of death and chronic lung disease {Finer N 2004 651}.

• Two randomized trials and one quasi-randomized trial (very low quality) including 312 infants compared PPV with a T-Piece versus a self-inflating bag and reported similar rates of death and chronic lung disease {Dawson JA 2011 912; Szyld EG 2014 234; Thakur A 2015 21}.

• A substantial number of additional patients from one large observational study suggests improved survival and less BPD when PEEP is used for PPV in the delivery room for preterm infants.{Guinsburg R 2018 F49}

• These findings justify a new SR on the use of PEEP versus no PEEP during positive pressure ventilation at birth but the direction of effect appears to support the prior recommendation.

References Dawson JA, Schmolzer GM, Kamlin CO, Te Pas AB, O'Donnell CP, Donath SM, et al. Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at birth: a randomized controlled trial. J Pediatr. 2011;158(6):912-8 e1-2. Finer NN, Carlo WA, Duara S, Fanaroff AA, Donovan EF, Wright LL, et al. Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics. 2004;114(3):651-7. Guinsburg R, de Almeida MFB, de Castro JS, Goncalves-Ferri WA, Marques PF, Caldas JPS, et al. T-piece versus self-inflating bag ventilation in preterm neonates at birth. Arch Dis Child Fetal Neonatal Ed. 2018;103(1):F49-F55. Probyn ME, Hooper SB, Dargaville PA, McCallion N, Crossley K, Harding R, et al. Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure. Pediatr Res. 2004;56(2):198-204.


Siew ML, Te Pas AB, Wallace MJ, Kitchen MJ, Lewis RA, Fouras A, et al. Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth. J Appl Physiol (1985). 2009;106(5):1487-93. Szyld E, Aguilar A, Musante GA, Vain N, Prudent L, Fabres J, et al. Comparison of devices for newborn ventilation in the delivery room. J Pediatr. 2014;165(2):234-9 e3. te Pas AB, Davis PG, Hooper SB, Morley CJ. From liquid to air: breathing after birth. J Pediatr. 2008;152(5):607-11. Thakur A, Saluja S, Modi M, Kler N, Garg P, Soni A, et al. T-piece or self inflating bag for positive pressure ventilation during delivery room resuscitation: an RCT. Resuscitation. 2015;90:21-4. Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, et al. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (Reprint). Pediatrics. 2015;136 Suppl 2:S196-218.


APPENDIX C-5

2020 Evidence Update Worksheet CPAP vs IPPV in the delivery room (NLS 590)

Worksheet author(s): Abhrajit Ganguly, MD; Edgardo Szyld, MD Council: AHA Date Submitted: January 23rd 2020 PICO / Research Question: NRP 590: Outcomes for CPAP vs IPPV in the delivery room In spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room (P), does the use of CPAP (I), compared with intubation and IPPV (C), change outcome? Outcomes: Death or bronchopulmonary dysplasia (critical), death (critical), bronchopulmonary dysplasia (critical), air leak (critical), necrotizing enterocolitis (important), severe IVH (critical), severe retinopathy of prematurity (important) Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): None Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2015 Last ILCOR Consensus on Science and Treatment Recommendation: For spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room, we suggest initial use of CPAP rather than intubation and IPPV (weak recommendation, moderate certainly of evidence) 2010/2015 Search Strategy: Pubmed: ("continuous positive airway pressure"[MeSH Terms] OR ("continuous"[All Fields] AND "positive"[All Fields] AND "airway"[All Fields] AND "pressure"[All Fields]) OR "continuous positive airway pressure"[All Fields]) AND ("infant, newborn"[MeSH Terms] OR ("infant"[All Fields] AND "newborn"[All Fields]) OR "newborn infant"[All Fields] OR ("infant"[All Fields] AND "newborn"[All Fields]) OR "infant, newborn"[All Fields]) AND (Clinical Trial[ptyp] OR Comparative Study[ptyp] OR Controlled Clinical Trial[ptyp] OR Evaluation Studies[ptyp] OR Multicenter Study[ptyp] OR Randomized Controlled Trial[ptyp] OR systematic[sb] OR Twin Study[ptyp] OR Validation Studies[ptyp] OR Meta-Analysis[ptyp]) Embase: 'positive end expiratory pressure'/exp OR (continuous AND positive AND airway AND pressure) OR 'continuous positive airway pressure' AND ('newborn'/exp OR neonat* OR newborn* OR 'infant'/exp OR


infant*) AND ('randomized controlled trial'/de OR 'controlled clinical trial'/de OR 'clinical trial (topic)'/de OR randomized:ab,ti OR placebo:ab,ti OR randomly:ab,ti OR trial:ti) NOT ('animal'/exp NOT 'human'/exp) 2019 Search Strategy: Database: Cochrane central Search Executed: November 19, 2019 Search Set Forwarded for Review: #14 Database: Ovid EBM Reviews - Cochrane Central Register of Controlled Trials <October 2019> Search Strategy: -------------------------------------------------------------------------------- 1 continuous positive airway pressure/ (1004) 2 (contin$ and positiv$ and airway$ and pressur$).mp. (4001) 3 1 or 2 (4001) 4 exp infant/ (33311) 5 (newborn$ or neonat$ or infant$).mp. (73273) 6 4 or 5 (73273) 7 3 and 6 (1079) 8 exp clinical trial/ (163) 9 exp clinical trials as topic/ (48070) 10 (random$ or placebo$ or trial$).ti. (445168) 11 or/8-10 (477514) 12 7 and 11 (434) 13 ..l/ 12 yr=2015-current (199) 14 remove duplicates from 13 (170) *************************** Database: Cochrane database of systematic reviews Search Executed: November 19, 2019 Search Set Forwarded for Review: #5 Search Strategy: -------------------------------------------------------------------------------- 1 (contin$ and positiv$ and airway$ and pressur$).ti,ab,kw. (58) 2 (newborn$ or neonat$ or infant$).ti,ab,kw. (1282) 3 1 and 2 (33) 4 ..l/ 3 yr=2015-current (17) 5 remove duplicates from 4 (17) Database: Embase Search Executed: November 19, 2019


Search Sets Forwarded for Review: #18 | #19 Database: Embase Classic+Embase <1947 to 2019 November 15> Search Strategy: -------------------------------------------------------------------------------- 1 positive end expiratory pressure/ (54616) 2 (contin$ and positiv$ and airway$ and pressur$).mp. (15819) 3 1 or 2 (56907) 4 exp infant/ (1131936) 5 (newborn$ or neonat$ or infant$).mp. (1486576) 6 4 or 5 (1496875) 7 3 and 6 (9494) 8 exp controlled clinical trial/ (769003) 9 exp "clinical trial (topic)"/ (311327) 10 (random$ or placebo$).ti,ab. (1598917) 11 trial$.ti. (390049) 12 or/8-11 (2161759) 13 7 and 12 (1728) 14 limit 13 to animals (72) 15 13 not 14 (1656) 16 ..l/ 15 yr=2015-current (710) 17 remove duplicates from 16 (677) 18 17 not 9 (506) 19 17 not 18 (171) *************************** Database: 506 Search Executed: November 19, 2019 Search Strategy #1 Search continuous positive airway pressure 12353 Search Details: "continuous positive airway pressure"[MeSH Terms] OR ("continuous"[All Fields] AND "positive"[All Fields] AND "airway"[All Fields] AND "pressure"[All Fields]) OR "continuous positive airway pressure"[All Fields] #2 Search newborn infant 602853 Search Details: "infant, newborn"[MeSH Terms] OR ("infant"[All Fields] AND "newborn"[All Fields]) OR "newborn infant"[All Fields] OR ("newborn"[All Fields] AND "infant"[All Fields]) #3 #1 AND #2 1966


#4 Limit Set #3 by publication types 700 Search Details: (#1 AND #2) AND (Clinical Trial[ptyp] OR Comparative Study[ptyp] OR Controlled Clinical Trial[ptyp] OR Evaluation Studies[ptyp] OR Meta-Analysis[ptyp] OR Multicenter Study[ptyp] OR Randomized Controlled Trial[ptyp] OR systematic[sb] OR Twin Study[ptyp] OR Validation Studies[ptyp]) #5 Limit Set #4 by publication date 227 Search Details: (#1 AND #2) AND ((Clinical Trial[ptyp] OR Comparative Study[ptyp] OR Controlled Clinical Trial[ptyp] OR Evaluation Studies[ptyp] OR Meta-Analysis[ptyp] OR Multicenter Study[ptyp] OR Randomized Controlled Trial[ptyp] OR systematic[sb] OR Twin Study[ptyp] OR Validation Studies[ptyp]) AND ("2015/01/01"[PDAT] : "3000/12/31"[PDAT])) Date Search Completed: November 19, 2019 Database searched: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to November 19, 2019> Search Results (Number of articles identified / number identified as relevant):

Inclusion criteria: - Randomized controlled trials comparing the outcomes of preterm infants who were allocated within 15 minutes of delivery to CPAP or to intubation and IPPV.


Exclusion Criteria: - Randomized controlled trials comparing the outcomes of preterm infants who were allocated to CPAP or

intubation and IPPV where the interventions were allocated more than 15 minutes after delivery. Randomized trials where the intubation group were intubated solely to administer surfactant with an intention to extubate to CPAP as early as possible after treatment (this procedure has been called INSURE).

- Non-randomized studies



Guideline or

systematic review

Topic addressed or

PICO(S)T

Number of

articles identified


Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. Schmolzer, 2013 {Schmolzer 2013 f5980}

Systematic review

Non-invasive versus

invasive respiratory support in preterm

infants at birth

4 trials met the

inclusion criteria

Pooled analysis showed a significant benefit for the

combined outcome of death or BPD, or both, at 36 weeks

corrected gestation for babies treated with nasal CPAP (relative

risk 0.91, 0.84 to 0.99, risk difference −0.04, -0.07 to 0.00),

the number needed to treat of 25).

One additional infant could survive to 36 weeks without bronchopulmonary dysplasia

for every 25 babies treated with nasal CPAP in the delivery

room rather than being intubated.

Randomized Controlled Trials (RCT):


Aim of Study; Study Type; Study Size

Patient Population

Study Intervention / Study Comparator



Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Dunn, 2011 {Dunn 2011 e1069}

Aim: To compare 3 approaches to the initial respiratory management of preterm neonates: prophylactic surfactant followed by a period of mechanical ventilation (prophylactic surfactant [PS]); prophylactic surfactant with rapid extubation to bubble nasal continuous positive airway pressure (intubate-surfactant-extubate [ISX]) or initial

Neonates born at 260⁄7

to 296 ⁄7

weeks gestation

Infants were randomly assigned to PS, ISX, or nCPAP groups before delivery.

Compared to PS group, the RR of BPD or death was 0.78 (95% CI 0.59-1.03) in the ISX group and 0.83 (95% CI 0.64-1.09). No statistically significant difference in adverse events between groups.


management with bubble continuous positive airway pressure and selective surfactant treatment (nCPAP). Study Type: Multicenter randomized trial N = 648 infants in 27 centers

Early CPAP versus surfactant in extremely preterm infants. Finer, 2010 {Finer 2010 1970}

Aim: To determine the superior choice of early treatment for extremely-low-birth-weight infants between continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support Study Type: Multicenter randomized trial N = 1316 infants

Infants born between 24 weeks 0 days and 27 weeks 6 days of gestation.

Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment in the delivery room.

The primary outcome was death or BPD (O2 requirement at 36 weeks). For death or BPD, compared to early surfactant, CPAP had a relative risk of 0.95 (95% confidence interval [CI], 0.85 to 1.05). The results of this study support the consideration of CPAP as an alternative to intubation and surfactant in preterm infants.

The rates of other adverse neonatal outcomes did not differ significantly between the two groups.


Nasal CPAP or Intubation at Birth for Very Preterm Infants Morley, 2008 {Morley 2008 700}

Aim: To investigate whether nasal CPAP, rather than intubation and ventilation, shortly after birth would reduce the rate of death or bronchopulmonary dysplasia in very preterm infants. Study type: Multicenter randomized trial N = 610 infants

Infants born at 25-to-28-weeks’ gestation.

Infants were randomly assigned to CPAP or intubation and ventilation at 5 minutes after birth. Outcomes were assessed at 28 days of age, at 36 weeks’ gestational age, and before discharge.

For death or BPD odds ratio favoring CPAP, 0.80; (95% CI, 0.58 to 1.12; P = 0.19) but not statistically significant. At 28 days, there was a lower risk of death or need for oxygen therapy in the CPAP group than in the intubation group (odds ratio, 0.63; 95% CI, 0.46 to 0.88; P = 0.006)

Adverse events: The incidence of pneumothorax was 9% in the CPAP group, as compared with 3% in the intubation group (P<0.001).

Prophylactic or Early Selective Surfactant Combined With nCPAP in Very Preterm Infants Sandri, 2010 {Sandri 2010 e1402}

Aim: To investigate whether prophylactic surfactant followed by nCPAP compared with early nCPAP application with early selective surfactant would reduce the need for mechanical ventilation in the first 5 days of life. Study Type: Multicenter randomized trial N = 208 infants

Infants born at 25 to 28 weeks’ gestation who were not intubated at birth

Infants were randomly assigned to prophylactic surfactant or nCPAP within 30 minutes of birth. Outcomes were assessed within the first 5 days of life and until death or discharge of the infants

Death and type of survival at 28 days of life and 36 weeks’ postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the 2 groups. Prophylactic surfactant was not superior to nCPAP and early selective surfactant in decreasing the need


from the hospital.

for mechanical ventilation in the first 5 days of life or incidence of adverse events in premature babies.

BPD, Bronchopulmonary Dysplasia; CI, Confidence Interval; CPAP, Continuous Positive Airway Pressure; ISX, Intubate-Surfactant-Extubate; OR, Odds Ratio; PS, prophylactic surfactant; RR, Relative Risk


Reviewer Comments (including whether meet criteria for formal review): Newborn babies who breathe spontaneously need to establish a functional residual capacity after birth {Boon AW 1979 1031}. Some newborns experience respiratory distress, which manifests as labored breathing or persistent cyanosis. CPAP, a form of respiratory support, helps newborn babies to keep the lungs open. CPAP is especially helpful for preterm babies with breathing difficulty after birth or after resuscitation {Hooper SB 2015 147}. CPAP may also reduce the risk of death or bronchopulmonary dysplasia in very preterm babies when compared to endotracheal intubation and PPV {Dunn MS 2011 E1069; Morley CJ 2008 700; Finer NN 2010 1970; Sandri F 2010 E1402; Schmolzer GM 2013 F5980}. For the newborn, CPAP is also a less invasive form of respiratory support than intubation and PPV. The current evidence for the recommendation is based on 4 RCTs and 1 systematic review (quality of evidence, Level A). We did not find any new studies on our recent search that would potentially change the current recommendation. The absolute reduction in risk of adverse outcome associated with starting early CPAP is small but the less invasive approach is preferred. Future studies with high risk preterm infants at lower gestation would be helpful in elucidating the balance of risks and benefits of CPAP vs IPPV in a more comprehensive way. We do not recommend a formal review of this PICOT question at this time. Reference list: 1. Boon AW, Milner AD, Hopkin IE. Lung expansion, tidal exchange, and formation of the functional residual capacity during

resuscitation of asphyxiated neonates. The Journal of pediatrics. 1979;95(6):1031-1036. 2. Hooper SB, Polglase GR, Roehr CC. Cardiopulmonary changes with aeration of the newborn lung. Paediatr Respir Rev.

2015;16(3):147-150. 3. Dunn MS, Kaempf J, de Klerk A, et al. Randomized trial comparing 3 approaches to the initial respiratory management of preterm

neonates. Pediatrics. 2011;128(5):e1069-1076. 4. Morley CJ, Davis PG, Doyle LW, et al. Nasal CPAP or intubation at birth for very preterm infants. The New England journal of

medicine. 2008;358(7):700-708. 5. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. The New England journal of medicine. 2010;362(21):1970-1979. 6. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.

Pediatrics. 2010;125(6):e1402-1409. 7. Schmolzer GM, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung PY. Non-invasive versus invasive respiratory support in preterm

infants at birth: systematic review and meta-analysis. Bmj. 2013;347:f5980.


APPENDIX C-6

2020 Evidence Update Worksheet

NLS 895-Chest Compression Ratio for Neonatal Resuscitation

Worksheet author(s): Shalini Ramachandran, M.D. Council: American Heart Association (AHA) Date Submitted: 2/5/2020 PICO / Research Question:

• Population: In neonates receiving cardiac compressions • Intervention: other ratios (5:1. 9:3, 15:2, synchronous, etc.) • Comparator: 3 compressions one ventilation • Outcomes:

o Return of spontaneous circulation (critical) o Survival (critical) o Neuro-developmental Impairment (critical) o Time to ROSC o Perfusion (important) o Gas Exchange (important) o Tissue injury o Compressor fatigue (important)Type: Intervention

Additional Evidence Reviewer(s): Myra H. Wyckoff, MD, Georg M. Schmölzer, MD Conflicts of Interest (financial/intellectual, specific to this question): None GMS received public funding from the Heart and Stroke Foundation Canada, and the Canadian Institute for Health Research to perform some of the studies included in this evidence update. SR and MHW selected the articles for inclusion. Year of last full review: 2015


Last ILCOR Consensus on Science and Treatment Recommendation: NLS 895-Chest Compression Ratio for Neonatal Resuscitation We suggest continued use of a 3:1 compression-to-ventilation ratio for neonatal CPR (weak recommendation, very-low certainty evidence). 2015 Search Strategy: PubMed: ( Search Completed: ) (((((compression:ventilation[Title/Abstract]) OR ((((((Heart Massage[MeSH Terms]) OR heart massage*[Title/Abstract]) OR cardiac massage*[Title/Abstract]) OR compression*[Title/Abstract])) AND (("Respiration, Artificial"[Mesh:NoExp]) OR ventilation*[Title/Abstract])))) AND ((ratio [Title/Abstract]) OR ratios[Title/Abstract]))) NOT (("letter"[pt] OR "comment"[pt] OR "editorial"[pt] or Case Reports[ptyp])) AND ("Respiratory Distress Syndrome, Newborn"[Mesh] OR "Bronchopulmonary Dysplasia"[Mesh] OR "Infant, Newborn"[Mesh] OR "Delivery Rooms"[Mesh] OR "Gestational Age"[Mesh] OR "Premature Birth"[Mesh] OR "Infant, Premature, Diseases"[Mesh:NoExp] OR "Term Birth"[Mesh] OR "Live Birth"[Mesh] OR "Neonatal Nursing"[Mesh] OR "Neonatal Screening"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Animals, Newborn"[Mesh] OR "Transient Tachypnea of the Newborn"[Mesh] OR "Persistent Fetal Circulation Syndrome"[Mesh] or newborn[TIAB] or neonatal[TIAB] or neonate[TIAB] or neonates[TIAB] OR "Low Birth Weight "[TIAB] or "Small for Gestational Age"[TIAB] or prematur*[TIAB] or preterm[TIAB] OR "Birth Injuries"[Mesh] OR "Birthing Centers"[Mesh] OR Postmature[TIAB] OR infants[TIAB] OR infant[TIAB] OR birth[TIAB]) Embase: ( Search Completed: ) ((‘Heart Massage’/de OR (heart NEAR/1 massage*):ab,ti OR (cardiac NEAR/1 massage*):ab,ti OR compression*:ab,ti) AND (‘Respiration, Artificial’/de OR ventilation*:ab,ti) OR ‘compression:ventilation’:ab,ti) AND (ratio:ab,ti OR ratios:ab,ti) NOT ([editorial]/lim OR [letter]/lim OR 'case report'/de) AND [embase]/lim AND ('neonatal respiratory distress syndrome'/exp OR 'newborn hypoxia'/exp OR 'prematurity'/exp OR 'newborn apnea attack'/exp OR 'newborn disease'/de OR 'neonatal stress'/exp OR 'lung dysplasia'/exp OR 'newborn'/exp OR 'low birth weight'/exp OR 'newborn screening'/exp OR 'newborn monitoring'/exp OR 'newborn care'/exp OR 'newborn period'/exp OR 'birth weight'/exp OR 'newborn morbidity'/exp OR 'live birth'/exp OR 'newborn death'/exp OR 'newborn mortality'/exp OR 'delivery room'/exp OR newborn OR 'low birth weight':ab,ti OR 'small for gestational age':ab,ti OR prematur*:ab,ti OR preterm:ab,ti OR postmature:ab,ti OR 'macrosomia'/exp) Cochrane: ( Search Completed: ) (([mh “Heart Massage”] OR “heart massage*”:ab,ti OR “cardiac massage*”:ab,ti OR “compression*”:ab,ti) AND ([mh^“Respiration, Artificial”] OR ventilation*:ab,ti) OR “compression:ventilation”:ab,ti) AND (ratio:ab,ti OR ratios:ab,ti) AND ([mh "Respiratory Distress Syndrome, Newborn"] or [mh "Bronchopulmonary Dysplasia"] or [mh "Infant, Newborn"] or [mh "Delivery Rooms"] or [mh "Gestational Age"] or [mh "Premature Birth"] or [mh ^"Infant, Premature, Diseases"] or [mh "Term Birth"] or [mh "Live Birth"] or [mh "Neonatal Nursing"] or [mh "Neonatal Screening"] or [mh "Intensive Care, Neonatal"] or [mh "Intensive Care Units, Neonatal"] or [mh "Animals, Newborn"] or [mh "Transient Tachypnea of the Newborn"] or [mh "Persistent Fetal Circulation Syndrome"] or newborn:ti,ab or neonatal:ti,ab or neonate:ti,ab or neonates:ti,ab or "Low Birth Weight ":ti,ab or "Small for Gestational Age":ti,ab or prematur*:ti,ab or preterm:ti,ab OR [mh "Birth Injuries"] OR [mh "Birthing Centers"] OR Postmature:ti,ab OR infant:ti,ab OR infants:ti,ab OR birth:ti,ab) 2019 Search Strategy: Database: Ovid MEDLINE(R) <1946 to October 21, 2019>


Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 resuscitation/ or cardiopulmonary resuscitation/ or advanced cardiac life support/ or heart massage/ (43992) 2 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kf. (52940) 3 (ACLS or cardiac life support).tw,kf. (1583) 4 (heart massage or cardiac massage or closed chest massage).tw,kf. (1638) 5 1 or 2 or 3 or 4 (68454) 6 compress*.tw,kf. (120199) 7 5 and 6 (4148) 8 Infant/ (771624) 9 infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, extremely low birth weight/ or infant, postmature/ or infant, premature/ or infant, extremely premature/ (592548) 10 8 or 9 (1111694) 11 7 and 10 (429) 12 (infant or infants or neonate or neonatal or newborn).tw,kf. (569480) 13 7 and 12 (381) 14 11 or 13 (506) *************************** Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <1946 to October 22, 2019>, Ovid MEDLINE(R) Epub Ahead of Print <October 22, 2019> Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kf. (6809) 2 (ACLS or cardiac life support).tw,kf. (223) 3 (heart massage or cardiac massage or closed chest massage).tw,kf. (99) 4 1 or 2 or 3 (6975) 5 compress*.tw,kf. (31694) 6 4 and 5 (529) 7 (infant or infants or neonate or neonatal or newborn).tw,kf. (50900) 8 6 and 7 (80) Database: Embase <1974 to 2019 October 22> Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 resuscitation/ (106463) 2 heart massage/ (2206) 3 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kw. (85802) 4 (ACLS or cardiac life support).tw,kw. (2917) 5 (heart massage or cardiac massage or closed chest massage).tw,kw. (1343) 6 1 or 2 or 3 or 4 or 5 (137811) 7 compress*.tw,kw. (188320) 8 6 and 7 (8078)


9 infant/ or baby/ or high risk infant/ or hospitalized infant/ or newborn/ (953139) 10 8 and 9 (638) 11 (infant or infants or neonate or neonatal or newborn).tw,kw. (693790) 12 8 and 11 (744) 13 10 or 12 (874) 14 limit 13 to embase (534) Database searched: EMBASE, MEDLINE, Cochrane Database of Systemic Reviews Date Search Completed: 10/31/19 Search Results (Number of articles identified / number identified as relevant): 318 total articles on neonatal chest compressions published since 2015, of which 13 were found to be relevant Inclusion/Exclusion Criteria: Studies were included if they compared outcomes between test subjects receiving any compression to ventilation (C:V) strategy with any other C:V strategy. Randomized controlled trials and published systematic reviews or relevant guidelines were eligible for inclusion. All languages were eligible if there was an English abstract. Link to Article Titles and Abstracts (if available on PubMed):

• Li 2015 530: https://dx.doi.org/10.1136/archdischild-2015-308363 • Li 2015 142: http://dx.doi.org/10.1038/jp.2014.165 • Boldingh 2016 3202: http://dx.doi.org/10.3109/14767058.2015.1119115 • Boldingh 2016 910: http://dx.doi.org/10.1111/apa.13339 • Li 2016 e0157249: https://dx.doi.org/10.1371/journal.pone.0157249 • Dellimore 2017 1255: http://dx.doi.org/10.1080/14767058.2016.1210595 • Li 2017 337: https://dx.doi.org/10.1159/000477998 • Solevag 2017 F85: http://dx.doi.org/10.1136/archdischild-2016-311043 • Vali 2017 e370: http://dx.doi.org/10.1097/PCC.0000000000001248 • Mustofa 2018 82: http://dx.doi.org/10.1016/j.resuscitation.2018.06.013 • Pasquin 2018 37: http://dx.doi.org/10.1159/000487988 • Schmolzer 2018 F455: http://dx.doi.org/10.1136/archdischild-2017-313037 • Patel 2019 F1: https://dx.doi.org/10.1136/archdischild-2018-316610

Summary of Evidence Update:


https://dx.doi.org/10.1136/archdischild-2015-308363

http://dx.doi.org/10.1038/jp.2014.165

http://dx.doi.org/10.3109/14767058.2015.1119115

http://dx.doi.org/10.1111/apa.13339

https://dx.doi.org/10.1371/journal.pone.0157249

http://dx.doi.org/10.1080/14767058.2016.1210595

https://dx.doi.org/10.1159/000477998

http://dx.doi.org/10.1136/archdischild-2016-311043

http://dx.doi.org/10.1097/PCC.0000000000001248

http://dx.doi.org/10.1016/j.resuscitation.2018.06.013

http://dx.doi.org/10.1159/000487988


https://dx.doi.org/10.1136/archdischild-2018-316610

Evidence Update Process for topics not covered by ILCOR Task Forces 4. This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews.

Relevant Guidelines or Systematic Reviews No systematic reviews were identified that specifically addressed outcomes of different compression to ventilation ratios in neonatal resuscitation. RCT: Most of the studies listed use animal models or are simulation studies. There is only one feasibility trial conducted in humans till date (listed below: Schmölzer 2018). There is one large RCT in human neonates (SURV1VE) which is currently ongoing and as yet unpublished. Study Acronym; Author; Year Published


Patient Population




Li 2015 {Li 2015 530}

Study Aim: To examine VT changes during CC and their effect on lung aeration.

Study Type: Randomized Controlled non blinded study

Inclusion Criteria: 17 asphyxiated Newborn mixed breed piglets (1-4 days old)

Intervention: Continuous CC with asynchronous ventilations (CCaV) (90 CC/min with 30/min asynchronous ventilations) (n=6) or continuous CC superimposed with 30 secs sustained inflations (CC+SI) with a CC rate of 120/min (n=5). Comparison: Standard 3:1 compression: ventilation ratio (C:V) (n=6)

1° endpoint: Inspirational tidal volume (VTi) and expirational tidal volume (VTe) Results: The CC+SI group had slightly higher VTi and VTe

(p 0.29) and significantly higher exhaled CO2

(ECO2)

Study Limitations: 1) Piglets were anesthetized and sedated which differs from delivery room resuscitations. 2) Different peak inflation pressures and length of SI may yield different results 3) Piglets were ventilated with sealed ET tubes to prevent leaks; mask leaks in the delivery room may yield different results. 4) Piglet study-impact on human neonates unknown

Li 2015

Study Aim:

Inclusion Criteria:

Intervention:

1° endpoint:

Study Limitations:


{Li 2015 142}

To assess development of fatigue during chest compressions(CCs) in simulated neonatal cardiopulmonary resuscitation (CPR). Study Type: Prospective randomized manikin crossover study

30 neonatal healthcare professionals who successfully completed the Neonatal Resuscitation Program

Performance of CPR by (i) continuous CC with asynchronous ventilation (CCaV) at a rate of 90 CC/minute and (ii) CCaV at 120 CC/minute for a duration of 10mins on a neonatal manikin Comparison: Standard 3:1 compression:ventilation ratio.

Rescuer fatigue over a 10 minute period Results: 1) Compared with the respective baseline, peak pressure significantly decreased at 156, 96 and 72 s after commencement of CC in the 3:1, CCaV-90, and CCaV-120 groups, respectively. However, CCaV-120 and CCaV-90 had higher peak pressure throughout the resuscitation compared with 3:1 group.

2) Participants perceived more fatigue while performing CCaV-120 compared with 3:1 C:V CPR or CCaV-90 (P=0.006)

1) Manikin studies do not fully resemble real-life scenarios of neonatal resuscitation including the psycho-physical stress and environmental factors, which are limitations for clinical translation.

2) No predetermination of a sample size before the study.


Boldingh 2016 {Boldingh 2016 3202}

Study Aim: To assess development of objective, subjective and indirect measures of fatigue during simulated infant cardiopulmonary resuscitation (CPR) with two different methods. Study Type: Randomized crossover manikin study

Inclusion Criteria: 17 subject-pairs were randomized in a crossover design to provide 5-min CPR

Intervention: continuous CCs at a rate of 120 min−1 with asynchronous ventilations (CCaV-120) Comparison: 3:1 chest compression (CC) to ventilation (C:V) ratio

1° endpoint: Rescuer fatigue over a 5 minute period Results: CCaV-120 compared with a 3:1 C:V ratio resulted in a change during 5-min of CPR in HR 49 versus 40 bpm (p = 0.01), and MAP 1.7 versus −2.8 mmHg (p = 0.03); fatigue rated on a Likert scale 12.9 versus 11.4 (p = 0.2); and a significant decay in CC depth after 90 s (p = 0.03).

Study Limitations: 1) No studies have compared different techniques in manikins to real-life situations which makes it difficult to extrapolate the results to real-life situations. 2) Subjects had limited CPR experience and who had not participated in a CPR course the last 12 months. This might have affected the results.

Boldingh 2016

Study Aim: To investigate compression and

Inclusion Criteria: 42 pairs of doctors, nurses,

Intervention: Chest compressions (CC) using 9:3 and 15:2 C:V methods and continuous

1° endpoint: The number, depth and rate of chest compressions and the number, volume

Study Limitations: 1) Caution must be exercised when


{Boldingh 206 910}

ventilation quality during simulated CPR with four compression‐to‐ventilation (C:V) methods.

Study Type: Randomized crossover manikin study

midwives and sixth‐year medical students from two Norwegian hospitals provided two minute CPR

chest compressions at 120 per minute with asynchronous ventilations (CCaV‐120) Comparison: Chest compressions using 3:1 C:V method

and rate of ventilation in the four C:V ratios. Results: C:V methods 3:1 and 9:3 provided comparable chest compressions and ventilation mechanics, whereas 15:2 produced fewer ventilations and lower minute volumes (p<0.05). The CCaV‐120 method was significantly less effective than the 3:1 C:V ratio method (p<0.05): the chest compression depth was 1.9 mm lower, there were 25 fewer chest compressions and 21 fewer ventilations per minute, and the minute volume was 69 mL lower (p<0.05). The 3:1 C:V method also provided better coordination between resuscitators.

extrapolating manikin study results to human infants 2) Investigators were not blinded to the real‐time data monitor during resuscitation and this might have biased the results.

Li 2016 {Li 2016 e0157249}

Study Aim: To determine whether different CC rates during SI reduce time to return of

Inclusion Criteria: 22 Asphyxiated newborn mixed breed piglets

Intervention: CC superimposed by SI at a rate of 90 CC per minute (SI+CC 90, n = 8), CC superimposed by SI at

1° endpoint: Time to ROSC

Study Limitations: 1) This asphyxia model uses piglets that have already undergone the fetal to neonatal transition, and


spontaneous circulation (ROSC) and improve hemodynamic recovery in newborn piglets with asphyxia-induced bradycardia. Study Type: Randomized controlled trial (animal)

a rate of 120 CC per minute (SI+CC 120, n = 8), Comparison: Sham-operated group which had the same surgical protocol, stabilization, and equivalent experimental periods without hypoxia and asphyxia.

Results: Both treatment groups had similar time of ROSC, survival rates, hemodynamic and respiratory parameters during cardiopulmonary resuscitation. The hemodynamic recovery in the subsequent 4h was similar in both groups and was only slightly lower than sham-operated piglets at the end of experiment.

piglets were sedated/anesthetized. 2) Piglets were intubated with a tightly sealed endotracheal tube to prevent any endotracheal tube leak; this may not occur in the delivery room as mask ventilation is frequently used. 3) Small sample size

Dellimore 2017 {Dellimore 2017 1255}

Study Aim: To investigate the influence of ventilation and

Inclusion Criteria: Five physician volunteers who

Intervention: (i) CC with asynchronous ventilation was delivered (i.e. with CCs applied

1° endpoint: Chest compression force and depth

Study Limitations: 1) The infant training manikin chest may not adequately replicate


ventilation-compression synchronization on compression force and sternal displacement during simulated neonatal cardiopulmonary resuscitation (NCPR) on an infant manikin. Study Type: Infant manikin study

were all Neonatal Resuscitation Program (NRP) certified in neonatal resuscitation who were blinded to the research question

continuously without pauses after every third CC for rescue breaths) during NCPR using both methods of compression (ii) CC with synchronous ventilation (i.e. with CCs applied following the guidelines with pauses after every 3 CCs for rescue breaths) Comparison: CCs applied with pauses after every three CCs, however, without the delivery of rescue breaths. These unventilated tests served as a reference for the ventilated tests.

Results: Synchronous ventilation and compression yielded sternal displacements and forces in the range of 22.8–32.4 mm and 15.0–29.8 N, respectively, while asynchronous ventilation and compression produced depths and forces in the range of 21.2–32.4 mm and 14.0–28.8 N, respectively which was significantly different from the unventilated group (p<0.001)

newborn thoracic properties since it uses a spring with a linear force–deflection curve and the manikin lungs are made from plastic bags which do not mechanically function like infant lungs. 2) Inter-individual variations in CC technique may have slightly impacted the CC measurements from the different volunteer clinicians.


Li 2017 {Li 2017 337}

Study Aim: To determine whether CC+SI versus a 3:1 C:V reduces the time to the return of spontaneous circulation (ROSC) and improves hemodynamic recovery in newborn piglets with asphyxia-induced bradycardia. Study Type: Randomized controlled interventional trial

Inclusion Criteria: Twenty-two newborn mixed-breed piglets

Intervention: CC during SI at a rate of 90 CC/min (SI+CC 90, n = 8), a 3:1 C:V using 90 CC and 30 inflations (3:1, n = 8), Comparison: A sham group of newborn piglets which were not asphyxiated

1° endpoint Time to recovery Results: CC+SI significantly reduced the median (IQR) time of ROSC, i.e., 34 s (28-156 s) versus 210 s (72-300 s) in the 3:1 group (p = 0.048). CC+SI also significantly reduced the requirement for 100% oxygen, improved respiratory parameters, and resulted in a similar hemodynamic recovery.

Study Limitations 1) Piglets had already undergone the fetal to neonatal transition and were sedated/anesthetized. 2) They were all intubated to prevent any endotracheal tube leak, which is different from delivery room resuscitation, where infants are either intubated (larynx bypassed, leaks present) or receiving respiratory support via a face mask, resulting in the possibility of airway obstruction or mask leaks which impact results


Solevag 2017 {Solevag 2017 F85}

Study Aim: To determine the distending pressure needed to achieve sufficient tidal volume (VT) delivery during continuous chest compressions (CC) superimposed by sustained inflation (SI) (CC+SI).

Study Type: Randomized animal/manikin trial

Inclusion Criteria: Cadaver piglets/manikin

Intervention: Distending pressures of 5, 10, 15, 20, 25 and 30 cm H2O in a randomized sequence (e.g., 20–5–30–15–25–10 cm H2O) to a leak-free airway (endotracheal tube (ETT) or flow sensor directly connected to the manikin airways) with a Fabian high frequency oscillation ventilator was provided for 2 minutes Comparison: Convenience sample of: (1) stillborn piglets (n=3), (2) live-born piglets that died within the first 1–5 days of life, that is, neonatal deaths (n=3) and (3) a newborn manikin were used.

1° endpoint VT, gas flow and airway pressure. Results: Distending pressure and VT correlated in cadaver piglets (r=0.83, p<0.001), manikin (r=0.98, p<0.001) and combined data (r=0.49, p<0.001). VT was delivered during chest recoil during CC in both models. In cadaver piglets, a distending pressure ∼25 cm H2O was needed to achieve an adequate VT.

Study Limitations None of the models are true reflections of asphyxiated neonates with the complex interplay between hemodynamic factors and ventilation during CPR.

Vali 2017

Study Aim:

Inclusion Criteria:

Intervention:

1° endpoint

Study Limitations


{Vali 2017 e370}

To compare the hemodynamics and success in achieving return of spontaneous circulation in an asphyxial cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs between subjects receiving continuous chest compressions during sustained inflation and those receiving conventional 3:1 compression-to-ventilation resuscitation. Study Type: Prospective, randomized, animal model study.

Fourteen newborn term gestation lambs.

Continuous chest compressions during sustained inflation. The umbilical cord was occluded to induce asphyxia and asystole Comparison: Control group which was resuscitated per NRP guidelines with 3:1 C:V ratio

Return of spontaneous circulation Results: All lambs achieved return of spontaneous circulation in a comparable median time (interquartile range) of 390 seconds (225-405 s) and 345 seconds (204-465 s) in the sustained inflation + continuous chest compressions and control groups, respectively. Four of seven (sustained inflation + continuous chest compressions) and three of six (control) lambs required epinephrine to achieve return of spontaneous circulation. Diastolic blood pressures were lower in the sustained inflation + continuous chest compressions (4 +/- 2 mm

1) No measurement of central venous pressure, right atrial pressure, and intrathoracic pressure, limiting our interpretation and understanding of the hemodynamics during SI and chest compressions. 2) The lambs were euthanized shortly after ROSC, and no long-term neurologic outcomes were assessed. 3) A further extended period of cardiac arrest may have decreased success of ROSC and revealed a difference between the two resuscitation techniques.


Hg) compared to the control group (7 +/- 2 mm Hg), p < 0.05.

Mustofa 2018 {Mustofa 2018 82}

Study Aim: To examine if different lengths of SI will improve ROSC and hemodynamic recovery in severely asphyxiated piglets. Study Type: Prospective randomized animal model study

Inclusion Criteria: 30 newborn mixed breed piglets

Intervention: Piglets were randomized into four groups: 3:1 C:V (n = 8), CC with an SI duration of either 20 s (CC+SI 20) (n = 8) or 60 s (CC+SI 60) (n = 8), Comparison: sham group (n=6) which was not exposed to asphyxia

1° endpoint ROSC and hemodynamic recovery in severely asphyxiated piglets Results: Compared with 3:1 group, both CC+SI 20 and CC+SI 60 groups had significantly shorter ROSC time (p = 0.002)

Study Limitations 1) Piglets had already

undergone the fetal to neonatal transition and were sedated/anesthetized.

2) They were all intubated to prevent any endotracheal tube leak, which is different from delivery room resuscitation, where infants are either intubated (larynx bypassed, leaks present) or receiving respiratory support via a face mask, resulting in the possibility of airway obstruction or mask leaks which impact results.


Pasquin 2018 {Pasquin 2018 37}

Study Aim: To investigate whether different C:V ratios (e.g., 2: 1 or 4: 1) will reduce the time to return of spontaneous circulation (ROSC) in severely asphyxiated piglets. Study Type: Prospective randomized animal model study

Inclusion Criteria: 31 newborn asphyxiated piglets

Intervention: Piglets were randomized into 4 groups: 2: 1 (n = 8), 3: 1 (n = 8), 4: 1 (n = 8) C:V ratio Comparison: Sham group (n = 7) which were not exposed to asphyxia

1° endpoint: Time to ROSC Results: The median (IQR) time to ROSC was similar between the groups with 127 (82–210), 96 (88–126), and 119 (83–256) s in the 2: 1, 3: 1, and 4: 1 C:V ratio groups, respectively (p = 0.67 between groups).

Study Limitations 1) Piglets had already undergone the fetal to neonatal transition and were sedated/anesthetized. 2) They were all intubated to prevent any endotracheal tube leak, which is different from delivery room resuscitation, where infants are either intubated (larynx bypassed, leaks present) or receiving respiratory support via a face mask, resulting in the possibility of airway obstruction or mask leaks which impact results.

Schmölzer, 2018 {Schmölzer 2018 F455}

Study Aim: To examine if CC+SI reduces ROSC compared with 3:1 C:V CPR in preterm

Inclusion Criteria: Inborn infants between 23+0 and 32+6 weeks’

Intervention: Infants in the CC+SI group received CC at a rate of 90/min during an SI with a duration of 20 s (CC+SI). After 20 s,

1° endpoint: Mean time to ROSC

Study Limitations 1) Number of subjects is too small to draw any conclusions regarding the relative efficacy of the two


infants <33 weeks of gestation. Study Type: Randomized feasibility trial

postmenstrual age who required CC in the delivery room. Exclusion criteria: Infants were excluded if they have a congenital abnormality or condition that might have an adverse effect on breathing or ventilation, for example, congenital pulmonary or airway anomalies, congenital diaphragmatic hernia or congenital heart disease requiring intervention in neonatal period. Infants were also excluded if their parents refused to give consent to this study.

the SI was interrupted for 1 s and the next SI was started for another 20 s until ROSC Comparison: Infants in the ‘3:1 group’ received CC using 3:1 C:V ratio until ROSC.

Results: Overall the mean (SD) time to ROSC was significantly shorter in the CC+SI group with 31 (9) s compared with 138 (72) s in the 3:1 C:V group (p=0.011).

different methods of resuscitation.


Patel, 2019 {Patel 2019 F1}

Study Aim: To determine whether different chest compression (CC) rates during continuous CC with asynchronous ventilations (CCaV) reduce time to return of spontaneous circulation (ROSC) and improved hamodynamic recovery in piglets aged 24–72 hours with asphyxia-induced asystole. Study Type: Prospective randomized animal study

Inclusion Criteria: Thirty 24-72hr old asphyxiated piglets

Intervention: Piglets were randomized into four groups: CCaV with CC rate of 90 (CCaV+90, n=8), 100 (CCaV+100, n=8) or 120 compressions per minute (CCaV+120, n=8), Comparison: Sham group which was not exposed to asphyxia

1° endpoint: Time to ROSC and hemodynamic recovery Results: All three intervention groups had a similar number of piglets achieving ROSC (6/8, 5/8 and 5/8 for CCaV+120, CCaV+100 and CCaV+90, respectively) and mean ROSC time (120, 90 and 90 s for CCaV+120, CCaV+100 and CCaV+90, respectively).

Study Limitations 1) Piglets were 24–72 hours old, do not have a patent ductus arteriosus and had cleared lung fluid as opposed to a newborn in the delivery room. 2) Piglets were intubated with a tightly sealed endotracheal tube to prevent any endotracheal tube leak which is different from the delivery room. 3) Experimental protocol was slightly different from the currently recommended resuscitation guidelines, as we gave 100% oxygen after 30 s of CC, whereas 100% oxygen in the delivery room is initiated before CC, which might have influenced our results.


The hemodynamic recovery (indicated by carotid flow, cerebral and renal perfusion) was similar between CCaV+120 and sham by the end of experiment. In comparison, CCaV+90 and CCaV+100 had significantly reduced hemodynamic recovery compared with sham operated (p≤0.05)

CC, Chest Compressions; CCaV, Chest Compressions with Asynchronous Ventilations; C:V, Compression to Ventilation Ratio; CPR, Cardiopulmonary Resuscitation; ETT, Endotracheal Tube; NCPR, Neonatal Cariopulmonary Resuscitation; NRP, Neonatal Resuscitation Program, OR, Odds Ratio; ROSC, Return of Spontaneous Circulation; SI, Sustained Inflation


Reviewer Comments (including whether meet criteria for formal review): Four neonatal manikin studies comparing experimental compression to ventilation ratios or asynchronous ventilation strategies found no advantage over traditional synchronized 3 compression to 1 ventilation CPR {Li 2015 14; Boldingh 2016 3202; Boldingh 2016 910; Dellimore 2017 1255}.

One piglet study comparing 2:1 versus 4:1 versus 3:1 compression to ventilation ratios found no improvement in outcomes for the experimental ratios. {Pasquin 2018 37}

Several animal trials compare a technique where cardiac compressions are delivered while holding a sustained inflation (CC+SI) compared to synchronized 3:1 compression to ventilation ratio CPR. The piglet model (which has already gone physiologic transition suggests CC+SI may achieve ROSC quicker. {Mustofa 2018 82} However, the transitional lamb model (closer to newborn physiology) showed no such advantage.{Vali 2017 e370}. A small pilot trial of 9 preterm newborns who needed circulatory support in the delivery room compared CC+SI with 3:1 compression to ventilation CPR and reported faster time to return of spontaneous circulation. The SURV1VE trial is an ongoing large international, prospective randomized controlled trial in which the primary objective is to compare the time to ROSC in infants born > 28 weeks gestational age (GA) with bradycardia (< 60/min) or asystole immediately after birth who receive either CC + SI or 3:1 C:V ratio as the CPR strategy. This is the first large scale trial done of this kind in human neonates and results are awaited. Estimated completion date is August 2021.

In summary, no new data was found that warranted a new systematic review at this time. The manikin and animal studies that compared compression to ventilation ratios appeared to support the current treatment recommendation. New data regarding the experimental technique of delivering compressions while holding a sustained inflation suggests there may be some benefits (faster ROSC) compared to 3:1 ratio CPR. However, since the clinical trial is on-going and results are not yet available, a PICOST and systematic review should be delayed until the trial is complete.


Reference list

Boldingh AM, Solevag AL, Aasen E, Nakstad B. Resuscitators who compared four simulated infant cardiopulmonary resuscitation methods favoured the three-to-one compression-to-ventilation ratio. Acta Paediatr. 2016;105(8):910-6. Boldingh AM, Jensen TH, Bjorbekk AT, Solevag AL, Nakstad B. Rescuers' physical fatigue with different chest compression to ventilation methods during simulated infant cardiopulmonary resuscitation. J Matern Fetal Neonatal Med. 2016;29(19):3202-7. Dellimore KH, Scheffer C, Smith J, Van Den Heever DJ, Lloyd DL. Evaluating the influence of ventilation and ventilation-compression synchronization on chest compression force and depth during simulated neonatal resuscitation. J Matern Fetal Neonatal Med. 2017;30(11):1255-60. Li ES, Cheung PY, O'Reilly M, Schmolzer GM. Change in tidal volume during cardiopulmonary resuscitation in newborn piglets. Arch Dis Child Fetal Neonatal Ed. 2015;100(6):F530-3. Li ES, Cheung PY, O'Reilly M, Aziz K, Schmolzer GM. Rescuer fatigue during simulated neonatal cardiopulmonary resuscitation. J Perinatol. 2015;35(2):142-5. Li ES, Cheung PY, Lee TF, Lu M, O'Reilly M, Schmolzer GM. Return of spontaneous Circulation Is Not Affected by Different Chest Compression Rates Superimposed with Sustained Inflations during Cardiopulmonary Resuscitation in Newborn Piglets. PLoS One. 2016;11(6):e0157249. Li ES, Gorens I, Cheung PY, Lee TF, Lu M, O'Reilly M, et al. Chest Compressions during Sustained Inflations Improve Recovery When Compared to a 3:1 Compression:Ventilation Ratio during Cardiopulmonary Resuscitation in a Neonatal Porcine Model of Asphyxia. Neonatology. 2017;112(4):337-46. Mustofa J, Cheung PY, Patel S, Lee TF, Lu M, Pasquin MP, et al. Effects of different durations of sustained inflation during cardiopulmonary resuscitation on return of spontaneous circulation and hemodynamic recovery in severely asphyxiated piglets. Resuscitation. 2018;129:82-9. Pasquin MP, Cheung PY, Patel S, Lu M, Lee TF, Wagner M, et al. Comparison of Different Compression to Ventilation Ratios (2: 1, 3: 1, and 4: 1) during Cardiopulmonary Resuscitation in a Porcine Model of Neonatal Asphyxia. Neonatology. 2018;114(1):37-45. Patel S, Cheung PY, Lee TF, Pasquin MP, Lu M, O'Reilly M, et al. Asynchronous ventilation at 120 compared with 90 or 100 compressions per minute improves haemodynamic recovery in asphyxiated newborn piglets. Arch Dis Child Fetal Neonatal Ed. 2019. Schmolzer GM, M OR, Fray C, van Os S, Cheung PY. Chest compression during sustained inflation versus 3:1 chest compression:ventilation ratio during neonatal cardiopulmonary resuscitation: a randomised feasibility trial. Arch Dis Child Fetal Neonatal Ed. 2018;103(5):F455-F60. Solevag AL, Lee TF, Lu M, Schmolzer GM, Cheung PY. Tidal volume delivery during continuous chest compressions and sustained inflation. Arch Dis Child Fetal Neonatal Ed. 2017;102(1):F85-F7. Vali P, Chandrasekharan P, Rawat M, Gugino S, Koenigsknecht C, Helman J, et al. Continuous Chest Compressions During Sustained Inflations in a Perinatal Asphyxial Cardiac Arrest Lamb Model. Pediatr Crit Care Med. 2017;18(8):e370-e7. .


APPENDIX C-7


NLS #605 Two Thumb versus Two Finger Cardiac Compressions for Neonatal Resuscitation

Worksheet author(s): Shalini Ramachandran, M.D Council: American Heart Association (AHA) Date Submitted:2/8/2020 PICO / Research Question: NLS #605 Two Thumb versus Two Finger

• Population: In neonates receiving cardiac compressions • Intervention: 2-thumb technique • Comparator: 2-finger technique • Outcomes:

o Return of spontaneous circulation (critical) o Survival (critical) o Neuro-developmental Impairment (critical) o Perfusion (important) o Gas Exchange (important) o Compressor fatigue (important)

Type: Intervention Additional Evidence Reviewer(s): Myra Wyckoff, MD; Georg M. Schmölzer, MD Conflicts of Interest (financial/intellectual, specific to this question): GMS received public funding from the Heart and Stroke Foundation Canada, and the Canadian Institute for Health Research to perform some of the studies included in this evidence update. GMS did not decide on which articles to include in the review. None for the other authors Year of last full review: : 2015 Last ILCOR Consensus on Science and Treatment Recommendation: Treatment Recommendation 2015: NLS 605 2-Thumb versus 2-Finger Technique for Chest Compressions During Neonatal Resuscitation We suggest that chest compressions in the newborn should be delivered by the 2-thumb, hands-encircling-the-chest method as the preferred option (weak recommendation, very-low very certainty evidence). We suggest that chest compression should be delivered over the lower third of the sternum (weak recommendation, very-low certainty of evidence) 2015 Search Strategy: PubMed: ( Search Completed: ) 63 Results June 6, 2014


("Infant"[Mesh] OR Infant*[TIAB] OR Neonat*[TIAB] OR Newborn*[TIAB] OR "Delivery Rooms"[Mesh] OR "Premature Birth"[Mesh] OR "Term Birth"[Mesh] OR "Live Birth"[Mesh] OR "Birthing Centers"[Mesh] OR "Neonatal Nursing"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Low Birth Weight"[TIAB] OR "Small for Gestational Age"[TIAB] OR prematur*[TIAB] OR preterm[TIAB]) AND ("Resuscitation"[Mesh] OR resuscitat*[TIAB] OR "cardiopulmonary resuscitation"[Mesh] OR “heart massage”[Mesh] OR CPR[TIAB] OR “chest compression”[TIAB] OR “chest compressions”[TIAB] OR “heart massage”[TIAB] OR “cardiac massage”[TIAB] OR “cardiac compression”[TIAB] OR “cardiac compressions”[TIAB] OR “thoracic compression”[TIAB] OR “thoracic compressions”[TIAB]) AND (Thumb*[TIAB] OR two-thumb[TIAB] OR Finger*[TIAB] OR two-finger[TIAB] OR "Fingers"[Mesh]) Embase: ( Search Completed: ) 66 results June 6, 2014 ('infant'/exp OR Infant*:ti,ab OR Neonat*:ti,ab OR Newborn*:ti,ab OR 'delivery room'/exp OR 'prematurity'/exp OR 'term birth'/exp OR 'live birth'/exp OR 'maternity ward'/exp OR 'newborn nursing'/exp OR 'newborn intensive care'/exp OR "Low Birth Weight":ti,ab OR 'low birth weight'/exp OR "Small for Gestational Age":ti,ab OR prematur*:ti,ab OR preterm:ti,ab) AND ('resuscitation'/exp OR resuscitat*:ti,ab OR 'heart massage'/exp OR CPR:ti,ab OR “chest compression”:ti,ab OR “chest compressions”:ti,ab OR “heart massage”:ti,ab OR “cardiac massage”:ti,ab OR “cardiac compression”:ti,ab OR “cardiac compressions”:ti,ab OR “thoracic compression”:ti,ab OR “thoracic compressions”:ti,ab) AND (Thumb*:ti,ab OR two-thumb:ti,ab OR Finger*:ti,ab OR two-finger:ti,ab OR 'finger'/exp OR 'thumb'/exp) Cochrane: ( Search Completed: ) 9 results June 6, 2014 ([mh "Infant"] OR Infant*:ti,ab OR Neonat*:ti,ab OR Newborn*:ti,ab OR [mh "Delivery Rooms"] OR [mh "Premature Birth"] OR [mh "Term Birth"] OR [mh "Live Birth"] OR [mh "Birthing Centers"] OR [mh "Neonatal Nursing"] OR [mh "Intensive Care, Neonatal"] OR [mh "Intensive Care Units, Neonatal"] OR "Low Birth Weight":ti,ab OR "Small for Gestational Age":ti,ab OR prematur*:ti,ab OR preterm:ti,ab) AND ([mh "Resuscitation"] OR resuscitat*:ti,ab OR [mh "cardiopulmonary resuscitation"] OR [mh “heart massage”] OR CPR:ti,ab OR “chest compression”:ti,ab OR “chest compressions”:ti,ab OR “heart massage”:ti,ab OR “cardiac massage”:ti,ab OR “cardiac compression”:ti,ab OR “cardiac compressions”:ti,ab OR “thoracic compression”:ti,ab OR “thoracic compressions”:ti,ab) AND (Thumb*:ti,ab OR two-thumb:ti,ab OR Finger*:ti,ab OR two-finger:ti,ab OR [mh "Fingers"]) 2019 Search Strategy: Database: Ovid MEDLINE(R) <June 6, 2014 to October 21, 2019> Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 resuscitation/ or cardiopulmonary resuscitation/ or advanced cardiac life support/ or heart massage/ (43992) 2 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kf. (52940) 3 (ACLS or cardiac life support).tw,kf. (1583) 4 (heart massage or cardiac massage or closed chest massage).tw,kf. (1638) 5 1 or 2 or 3 or 4 (68454) 6 compress*.tw,kf. (120199) 7 5 and 6 (4148) 8 Infant/ (771624) 9 infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, extremely low birth weight/ or infant, postmature/ or infant, premature/ or infant, extremely premature/ (592548) 10 8 or 9 (1111694) 11 7 and 10 (429) 12 (infant or infants or neonate or neonatal or newborn).tw,kf. (569480)


13 7 and 12 (381) 14 11 or 13 (506) *************************** Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <June 6, 2014 to October 22, 2019>, Ovid MEDLINE(R) Epub Ahead of Print <October 22, 2019> Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kf. (6809) 2 (ACLS or cardiac life support).tw,kf. (223) 3 (heart massage or cardiac massage or closed chest massage).tw,kf. (99) 4 1 or 2 or 3 (6975) 5 compress*.tw,kf. (31694) 6 4 and 5 (529) 7 (infant or infants or neonate or neonatal or newborn).tw,kf. (50900) 8 6 and 7 (80) Database: Embase <June 6, 2014 to 2019 October 22> Search Strategy: CPR and compression and neonates -------------------------------------------------------------------------------- 1 resuscitation/ (106463) 2 heart massage/ (2206) 3 (resuscitation or CPR or cardiopulmonary resuscitation).tw,kw. (85802) 4 (ACLS or cardiac life support).tw,kw. (2917) 5 (heart massage or cardiac massage or closed chest massage).tw,kw. (1343) 6 1 or 2 or 3 or 4 or 5 (137811) 7 compress*.tw,kw. (188320) 8 6 and 7 (8078) 9 infant/ or baby/ or high risk infant/ or hospitalized infant/ or newborn/ (953139) 10 8 and 9 (638) 11 (infant or infants or neonate or neonatal or newborn).tw,kw. (693790) 12 8 and 11 (744) 13 10 or 12 (874) 14 limit 13 to embase (534) Database searched: EMBASE, MEDLINE, Cochrane database of Systemic reviews Date Search Completed: October 31, 2019 Search Results (Number of articles identified / number identified as relevant): 318 total articles on neonatal chest compressions published since 2015, of which 19 found to be relevant. Inclusion/Exclusion Criteria: Studies were included if they compared outcomes between different techniques of administering chest compressions. Randomized controlled trials and published systematic reviews or relevant guidelines were eligible for inclusion. Unpublished data (e.g., trial protocols) were not considered eligible for inclusion All languages were eligible if there was an English abstract.


Link to Article Titles and Abstracts (if available on PubMed): 1. Douvanas 2018 805: https://www.ncbi.nlm.nih.gov/pubmed/28282762 2. Jiang 2015 531: http://dx.doi.org/10.1016/j.ajem.2015.01.025 3. Jo 2015 703: http://dx.doi.org/10.1136/emermed-2014-203873 4. Na 2015 e70: http://dx.doi.org/10.1111/apa.12857 5. Kim 2015 997: https://dx.doi.org/10.3346/jkms.2016.31.6.997 6. Jo 2017 462: http://dx.doi.org/10.1097/PEC.0000000000000833 7. Smereka 2017 e5915: http://dx.doi.org/10.1097/MD.0000000000005915 8. Smereka 2017 1420: http://dx.doi.org/10.1016/j.ajem.2017.04.024 9. Smereka 2017 604: T=JS&PAGE=reference&D=emed18&NEWS=N&AN=614152015 10. Smereka 2017 589: http://dx.doi.org/10.5603/KP.a2017.0015 11. Jang 2018 36: www.ncbi.nlm.nih.gov/pubmed/29292025]] 12. Ladny 2018 e9386: http://dx.doi.org/10.1097/MD.0000000000009386 13. Lee 2018 372: https://dx.doi.org/10.1097/MEJ.0000000000000461 14. Park 2018 1: https://dx.doi.org/10.1080/10903127.2018.1471559 15. Smereka 2018 159: https://dx.doi.org/10.3389/fped.2018.00159 16. Pellegrino 20195 530: http://dx.doi.org/10.1136/archdischild-2018-314893 17. Smereka 2019 761: https://www.ncbi.nlm.nih.gov/pubmed/30155866 18. Tsou 2019 (published online ahead of print):https://dx.doi.org/10.1097/MEJ.0000000000000631 19. Yang 2019 1217: http://dx.doi.org/10.1007/s00246-019-02135-x




http://dx.doi.org/10.1016/j.ajem.2015.01.025

http://dx.doi.org/10.1136/emermed-2014-203873

http://dx.doi.org/10.1111/apa.12857

https://dx.doi.org/10.3346/jkms.2016.31.6.997

http://dx.doi.org/10.1097/PEC.0000000000000833

http://dx.doi.org/10.1097/MD.0000000000005915

http://dx.doi.org/10.1016/j.ajem.2017.04.024

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed18&NEWS=N&AN=614152015

http://dx.doi.org/10.5603/KP.a2017.0015

http://www.ncbi.nlm.nih.gov/pubmed/29292025%5D%5D

http://dx.doi.org/10.1097/MD.0000000000009386

https://dx.doi.org/10.1097/MEJ.0000000000000461

https://dx.doi.org/10.1080/10903127.2018.1471559

https://dx.doi.org/10.3389/fped.2018.00159



https://dx.doi.org/10.1097/MEJ.0000000000000631

http://dx.doi.org/10.1007/s00246-019-02135-x






Douvanas, 2018 {Douvanas 2018 805}

Systematic review

Comparing the two different techniques of hand placement on infants and neonatal resuscitation, from 2010 to 2015 and to highlight which method is more effective.

Ten studies; nine observational and one randomized controlled trial

Most studies suggest that the TT method as the more useful for infants and neonatal resuscitation than the TF because increases the delivery of higher quality compressions over a longer time period, achieves less variability in hand placement and reduces the fatigue or rescuers.

The two thumb technique is preferred over the two finger technique of delivering chest compressions

RCTs:



Patient Population




Jiang 2015 {Jiang 2015 531}

Study Aim:

To investigate whether the two finger (TF) technique results in an enough

Inclusion Criteria: Health care providers

Intervention: 27 health care providers to perform 2 sets of 5-minute cardiopulmonary resuscitation using a 30:2

1° endpoint: Compression depth

Study Limitations: The infant manikin simulates a 3-month-old infant; hence, w the performance on older babies. Is unknown


compression depth to meet the guideline requirements and that the 2-thumb (TT) encircling hands technique will not affect the ventilation.

Study Type: Prospective crossover trial

compression/ventilation ratio to compare TF and 2-thumb–encircling hands techniques.

Results: Mean compression depths were 39.25 ± 3.06 cm in the TF technique and 42.37 ± 1.15 cm in the 2-thumb–encircling hands technique, P < .001. Two-finger technique had significant lower fractions of correct hand position than 2-thumb–encircling hands technique (96.56% ± 6.74% vs 99.41% ± 2.52%, P < .05).

Jo 2015 {Jo 2015 703}

Study Aim:

To determine if the over-the-head two-thumb encircling technique (OTTT) provides better quality cardiopulmonary resuscitation (CPR) than the conventional two-finger technique

Inclusion Criteria: Nurses working in emergency departments and pediatric wards.

Intervention: 50 nurses randomized. Participants who performed OTTT stood at the head of the manikin to compress the chest and provide bag–valve mask ventilations,

1° endpoint: Compression depth

Study Limitations: Differences in rescuer attitude toward the manikin during a simulated cardiac arrest compared with a human during a real cardiac arrest may also have affected CPR performance. Despite being blinded to the study objective, participants would have been aware of being observed, thus their performance may have been affected.


(TFT) when performed by a lone rescuer in an in-hospital infant cardiac arrest setting. Study Type: Prospective, randomised crossover design study

Comparison: Those who performed TFT stood by the side of the manikin to compress the chest and provide pocket–mask ventilations

Results: OTTT resulted in greater depth of compressions (p<0.001), greater proportion of effective compressions (p<0.001), smaller proportion of complete recoil (p=0.001), and smaller fatigue score change (p=0.003) than TFT.

Na 2015 {Na 2015 e70}

Study Aim: Compare this technique with the vertical two‐thumb (VTT) technique, a novel modification of the TTE technique.

Study Type: Prospective randomised crossover simulation study

Inclusion Criteria: Participants who had completed a basic life support course

Intervention: 36 medical doctors participants who had completed a basic life support course performed 10 cycles of cardiac compressions on a manikin for each technique.

1° endpoint: To measure the difference in compression pressure between two cardiac compression techniques. Results: The VTT generated significantly higher pressure than the TTE and the pressure difference ranged from 26.8 to 62.9 mmHg for each cycle, with a mean difference of 43.5 mmHg (95% CI, 37.8–49.2). The difference in pressure showed a tendency to increase with increasing cycles of cardiac compressions.

2° outcomes: To measure participants’ degree of fatigue and difficulty with the two techniques. Study Limitations: 1)The compliance of a manikin's chest wall may differ from that of a real patient, so the use of a measured value should be restricted to the comparison of two cardiac compression techniques. 2)The compression was instructed, following the


current guidelines, to target one‐third of the chest anterior–posterior diameter at minimum, but the sensor inside the simulator was designed to measure the pressure within the simulated heart. The sensor reflected a more physiological result because it gave a higher value when the simulated heart was pressed accurately vertically upward. Therefore, the results cannot be directly compared with those of other studies, which have mostly used metric figures for cardiac compression depth. 3)The quality of cardiac compression is usually evaluated by various diameters, such as duty time and complete recoil, but only the peak pressure was measured in this study.

Kim 2015 {Kim 2015 997}

Study Aim: To compare the effectiveness two-finger chest compression technique (TFCC) performed using the right

Inclusion Criteria: Healthcare providers who were certified basic-life-support providers

Intervention: 30 healthcare providers performed single-rescuer CPR with 30:2 compression: ventilation using TFCC for 2 minutes. They

1° endpoint: Mean compression depth (MCD) and ratio of deep enough compressions (DEC)

Study Limitations: 1)The results were obtained using a mechanical model and may not be representative of real-life situations. 2)The experiment was conducted with the


vs. left hand and the index-middle vs. middle-ring fingers. Study Type: Prospective randomised cross-over trial

performed TFCC with the index-middle fingers of the right hand (Test 1), index-middle fingers of the left hand (Test 2), middle-ring fingers of the right hand (Test 3), or middle-ring fingers of the left hand (Test 4)

Results: The mean compression depth (MCD) was significantly greater in TFCC performed with the index-middle fingers than with the middle-ring fingers regardless of the hand (95% confidence intervals; right hand: 37.8–40.2 vs. 35.2–38.6 mm, P = 0.002; left hand: 36.9–39.2 vs. 35.5–38.1 mm, P = 0.003). A deeper MCD was achieved with the index-middle fingers of the right versus the left hand (P = 0.004). The ratio of sufficiently deep compressions showed the same patterns.

manikin on the floor, because this was considered to reproduce the conditions faced by a single-rescuer performing CPR in an out-of-hospital environment. 3)Although the grip power of the right hand is stronger, even in left-handed individuals. The majority of the participants in the study were right handed and the results must still be confirmed in left-handed rescuers.

Jo 2017 {Jo 2017 462}

Study Aim: To determine if the over-the-head 2-thumb encircling technique (OTTT) provides better overall quality of cardiopulmonary resuscitation compared with conventional 2-finger technique (TFT) for a

Inclusion Criteria: 50 medical emergency service students were voluntarily recruited

Intervention Participants performed lone rescuer infant cardiopulmonary resuscitation for 2 minutes on a manikin simulating a 3-month-old baby in an ambulance. Participants who performed OTTT sat over the head of manikins to

1° endpoint: Mean hands-off time during the 2-minute test interval.

2° endpoints: Depth of compression, rate of compression, fatigue score Study Limitations:


lone rescuer in the setting of infant cardiac arrest in ambulance. Study Type: Prospective randomized crossover design

compress the chest using a 2-thumb encircling technique and provide bag-valve mask ventilations, whereas those who performed TFT sat at the side of the manikins to compress using 2-fingers and provide pocket-mask ventilations.

Results: Mean hands-off time was not significantly different between OTTT and TFT (7.6 +/- 1.1 seconds vs 7.9 +/- 1.3 seconds, P = 0.885). Over-the-head 2-thumb encircling technique resulted in greater depth of compression (42.6 +/- 1.4 mm vs 41.0 +/- 1.4 mm, P < 0.001) and faster rate of compressions (114.4 +/- 8.0 per minute vs 112.2 +/- 8.2 per minute, P = 0.019) than TFT. Over-the-head 2-thumb encircling technique resulted in a smaller fatigue score than TFT (1.7 +/- 1.5 vs 2.5 +/- 1.6, P < 0.001).

This study is vulnerable to the limitations of simulating CPR on a manikin, an imperfect representation of the human body. The results may also be limited by the limited correlation between the primary outcomes measured, depth of compression, and proportion of effective chest compressions performed, and coronary perfusion pressure and patient outcome. Each technique involved a different method of ventilation. However, different ventilation methods were required to assess the hands-off time between the 2 techniques without changing the rescuer's position The ambulance was stationary during the tests, which does not fully reflect the dynamic environment of a moving vehicle.

Smereka 2017 {Smereka 2017 e5915}

Study Aim: To compare 3 chest compression techniques, namely, the 2-finger-

Inclusion Criteria: 73 paramedics with at least 1 year of

Intervention: 73 paramedics with at least 1 year of clinical experience performed 3 CPR settings

1° endpoint: Chest compression rate and depth, chest decompression, and adequate ventilation after chest compression served as outcome parameters.

Study Limitations: 1)Even the best manikin and simulation setting cannot entirely simulate real-CPR conditions, especially with regard to the manikin chest


technique (TFT), the 2-thumb-technique (TTHT), and the nTTT in an randomized infant-CPR manikin setting. Study Type: Randomized crossover manikin trial

clinical experience

with a chest compression:ventilation ratio of 15:2, according to current guidelines. Chest compression was performed with 1 out of the 3 chest compression techniques in a randomized sequence.

Results: The chest compression depth was 29 (IQR, 28-29) mm in the TFT group, 42 (40-43) mm in the TTHT group, and 40 (39-40) mm in the nTTT group (TFT vs TTHT, P < 0.001; TFT vs nTTT, P < 0.001; TTHT vs nTTT, P < 0.01). The median compression rate with TFT, TTHT, and nTTT varied and amounted to 136 (IQR, 133-144) min-1 versus 117 (115-121) min-1 versus 111 (109-113) min-1. There was a statistically significant difference in the compression rate between TFT and TTHT (P < 0.001), TFT and nTTT (P < 0.001), as well as TTHT and nTTT (P < 0.001). Incorrect decompressions after CC were significantly increased in the TTHT group compared with the TFT (P < 0.001) and the nTTT (P < 0.001) group.

compliance, the correlation between the applied force, and the obtained chest compression depth. 2)The study was performed in a group of experienced paramedics regularly involved in out-of-hospital infant CPR. The results of this study can therefore not transferred without restrictions to all infant-CPR providers. 3)Did not measure any blood pressure and therefore, any conclusion about efficient blood with the nTTT is speculation.

Smereka 2017 {Smereka 2017 1420}

Study Aim: To investigate whether this technique might facilitate adequate chest-compression

Inclusion Criteria: The participants for this study were recruited from the

Intervention: 42 paramedics from the national Emergency Medical Service of Poland

1° endpoint: Chest compression depth, chest compression rate and rate of full vhest pressure relief

Study Limitations: Infant manikin which cannot simulate a real cardiac arrest infant.


https://www.sciencedirect.com/topics/medicine-and-dentistry/paramedic

depth, chest-compression rate and rate of full chest-pressure relief. Study Type: Prospective, randomized, crossover trial design

Staff of the National Emergency Medical Service (EMS) teams of Poland between July and October 2016.

performed three single-rescuer CPR sessions for 10 minutes each. Each session was randomly assigned to the conventional two-thumb (TTHT), the conventional two-finger (TFT) or the nTTT.

Results: The nTTT provided significant higher systolic (82 vs. 30 vs. 41 mmHg). A statistically significant difference was noticed between nTTT and TFT (p < .001), nTTT and TTHT (p < 0.001), TFT and TTHT (p = 0.003). The median diastolic preassure using nTTT was 16 mmHg compared with 9 mmHg for TFT (p < 0.001), and 9.5 mmHg for TTHT (p < 0.001). Mean arterial pressure using distinct methods varied and amounted to 40 vs. 22. vs. 26 mmHg (nTTT vs. TFT vs. TTHT, respectively). A statistically significant difference was noticed between nTTT and TFT (p < 0.001), nTTT and TTEHT (p < 0.001), and TFT and TTHT (p < 0.001). The highest median pulse pressure was obtained by the nTTT 67.5 mmHg. Pulse pressure was 31.5 mmHg in the TTHT and 24 mmHg in the TFT. The difference between TFT and TTHT (p = 0.025), TFT and nTTT (p < 0.001), as well as between TTHT and nTTT (p < 0.001) were statistically significant.


Study Aim: To compare the quality of chest

Inclusion Criteria: Fifty-two novice

Intervention: Participants performed CCs using three

1° endpoint: Median depth of compressions and %deep enough compressions

Study Limitations: Manikin model which may not translate to real patients


https://www.sciencedirect.com/topics/medicine-and-dentistry/mean-arterial-pressure

https://www.sciencedirect.com/topics/medicine-and-dentistry/mean-arterial-pressure

compression (CC) and ventilation among the two current standard techniques with our novel “nTTT” technique in infant CPR. Study Type: Prospective randomized crossover, manikin trial

physicians (31 female; 59.6%) participated in this study. All participants had <1year experience in Medicine

techniques in a randomized sequence: standard two finger technique (TFT); standard two thumb technique (TTHT), and the ‘new two-thumb technique’ (nTTT).

Results: Median depth compression using the distinct chest compression techniques varied and amounted to 26 [IQR, 25–28] mm for TFT, and 39 [IQR, 39–39] mm for TTHT as well as for nTTT. Best percentage of fully released compressions were received using TFT (100[100 − 100] %), then in the case of nTTT (99[98–100] %), and the worst in situation where TTHT (18[14–19] %). was used. The fastest chest compression rate was achieved with TFT (134[IQR, 129–135]/min) and the slowest when using nTTT (109 [IQR, 105–111]/min).


Study Aim: To assess the CC quality during simulated resuscitation in infants performed by paramedics.

Inclusion Criteria: 120 fully trained and licensed paramedics (39 females, 32.5%) with a minimum of five years of professional experience

Intervention: The participants performed CCs using three techniques: TFT (the rescuer compresses the sternum with the tips of two fingers); TTHT; and the ‘new two-thumb

1° endpoint: The frequency of CCs (min–1), the percentage of CCs with an adequate rate (%), the CC depth (mm), the percentage of CCs with an adequate depth (%), the percentage of fully released CCs (%), as well as the percentage of correct hand position cases (%).

Study Limitations:

The experiment was conducted with the use of a manikin, and the participants performed continuous CC without ventilation because the manikin was intubated and ventilated in a continuous 2-min period,


Study Type: A prospective, randomised, crossover, single-centre study

(mean 7.5 ± 4.8 years) in emergency medicine

technique’ (nTTT). The novel method of CCs in an infant consists of using two thumbs directed at the angle of 90 degrees to the chest while closing the fingers of both hands in a fist.

Results: There was a statistically significant difference in the median CC frequency between TFT and TTHT (p < 0.001), TFT and nTTT (p < 0.001), and between TTHT and nTTT (p < 0.001). The highest percentage of compressions with the frequency recommended by the ERC guidelines (100–120 min–1) was achieved by the study participants only with the nTTT. The median CC depth during the TFT was 28 mm (interquartile range [IQR] 27–30 mm) and was significantly lower than in the static TTHT (40.5 [IQR 39–41] mm; p < 0.001) and nTTT (40 [IQR 39–41] mm; p < 0.001).

according to the current guidelines.

Jang 2018 {Jang 2018 36}

Study Aim: To use video review to compare CC quality between 2-thumb encircling (2T) and one-hand anterior (1H) hand position in infants receiving CPR.

Study Type: Prospective randomized crossover trial

Inclusion Criteria: Events where an infant received >2 min of CC using a CPR monitor device while videorecorded were included.

Intervention: 12/28 providers were assessed using both 2T and 1H; 6 providers used 2T and 1H in the same patient. 80 CC segments were analyzed;

Results: The median duration of CC segments was 74 s (IQR 50–95 s). Median CC rate across all segments was 127/min (IQR 115–142/min); median CC depth was 3.0 cm (IQR 2.4–3.4 cm). 2T position was used in 33/80 (41%) of segments. There was no significant difference in CC depth between 2T and 1H position (3.0 ± 0.8 vs 3.0 ± 0.6 cm, p = 0.81). 1H position was significantly associated with faster CC rate than 2T position (134 ± 18 vs. 118 ± 15 CC/min, p < 0.001).

Study Limitations: Conducted at a single tertiary center, and included a small number of infants.


Ladny 2018 {Ladny 2018 e9386}

Study Aim: To test in an infant manikin a new chest compression (CC) technique ("2 thumbs-fist" or nTTT) in comparison with standard 2-finger (TFT) and 2-thumb-encircling hands techniques (TTEHT). Study Type: Prospective randomized crossover manikin trial

Inclusion Criteria: Sixty-three nurses

Intervention: Sixty-three nurses who performed a randomized sequence of 2-minute continuous CC with the 3 techniques in random order.

1° endpoint: Simulated systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressures (PP, SBP-DBP) in mm Hg were measured. Results: The nTTT resulted in a higher median SBP value (69 [IQR, 63-74] mm Hg) than TTEHT (41.5 [IQR, 39-42] mm Hg), (P < .001) and TFT (26.5 [IQR, 25.5-29] mm Hg), (P <.001). The simulated median value of DBP was 20 (IQR, 19-20) mm Hg with nTTT, 18 (IQR, 17-19) mm Hg with TTEHT and 23.5 (IQR, 22-25.5) mm Hg with TFT. DBP was significantly higher with TFT than with TTEHT (P <.001), as well as with TTEHT than nTTT (P <.001). Median values of simulated MAP were 37 (IQR, 34.5-38) mm Hg with nTTT, 26 (IQR, 25-26) mm Hg with TTEHT and 24.5 (IQR,23.5-26.5) mm Hg with TFT. A statistically significant

Study Limitations: The use of a manikin cannot fully replicate the properties of a human body, such as elasticity of blood vessels and rib recoil, thus the hemodynamics may not truly represent human infants. No information regarding the depth, frequency, and chest recoil of CC in our participants, which are some of the components of a quality CPR. Did not incorporate ventilation into our study. Mask ventilation will interrupt CC which will compromise blood flow during CPR and thus survival.


difference was noticed between nTTT and TFT (P <.001), nTTT and TTEHT (P <.001), and between TTEHT and TFT (P <.001). Sixty-one subjects (96.8%) preferred the nTTT over the 2 standard methods.

Lee 2018 {Lee 2018 372}

Study Aim: To confirm whether the two-finger technique (TFT) using the index-middle fingers of the right hand T(FT-R23 )would be as effective as the two-thumb technique (TTT). In addition, individual finger strengths were measured to identify the reasons why the TTT and TFT-R23 produced deeper CCD than any other methods.

Inclusion Criteria: participants who had completed the basic life support (BLS) course for healthcare providers from the American Heart Association. Second, participants with less than 2-week old hand or wrist injuries were excluded. Third, participants who did not agree to participate voluntarily in the study were excluded.

Intervention: This prospective randomized cross-over trial compared TTT with TFT-R23. A total of 37 doctors conducted 2 min single-rescuer cardiopulmonary resuscitation using TTT and TFT-R23 in a random order using a 3-month-old sized infant manikin laid on the floor. The chest compression to ventilation ratio was set to 15 : 2. In addition, finger strengths were measured using a pinch meter.

1° endpoint: Average chest compression depth in mm Results: The actual CCD of the TTT was significantly deeper than that of the TFT-R23 (41.3+/-1.3 vs. 39.8+/-1.5 mm, P<0.001). Although the hands-off time of the TTT was

Study Limitations: Recruited only medical doctors. Therefore, results cannot be applied to other types of rescuers, uneducated bystanders, or lay rescuers. S Second, the study was carried out on the floor without a mattress. CPR performed on an elevated surface or on a mattress might lead to different results. Third, most of the participants were right handed. The finger strengths and study results might be different in left-handed individuals. Fourth, the CPR qualities were obtained using simulation trials with a manikin. Human data are needed to confirm our study results.


Study Type: Prospective randomized cross-over trial

significantly longer than that of the TFT-R23 (55.6+/-5.7 vs. 53.6+/-5.8 s, P=0.002), the mean difference was only 2.0+/-3.7 s (95% confidence interval: 0.755-3.245). The finger strength of the TTT was significantly higher than that of TFT-R23 (23.8+/-10.1 vs. 13.7+/-5.1 kg, P<0.001).

Park 2018 {Park 2018 1}

Study Aim: To investigate the palm presser will increase compression depth without increasing hands-off time and will reduce rescuer fatigue compared with the two-finger technique (TFT). Study Type: Randomized crossover manikin study

Inclusion Criteria: Basic Life Support (BLS)-certified health care providers who are working in the emergency department

Intervention: Participants performed two minutes of CPR with a 30:2 compression:ventilation ratio using the palm presser and the TFT in randomized sequence on an infant manikin.

1° endpoint: Compression depth and change over time Results: The palm presser resulted in greater mean compression depth (41.5 ± 1.6 mm vs. 36.8 ± 5.5 mm, p < 0.001), greater sufficiently deep compressions (80.9 ± 27.8% vs. 42.4 ± 35.4%, p < 0.001),

Limitations: Although infant CPR manikins are widely used in CPR training and CPR quality studies, they may not accurately represent a real infant’s body. Secondly, inability to blind study subjects to the technique that they were performing. Thus, there may be a bias in which study subjects favored the palm presser because it was a new compression assist device.


and better correct hand position (99.9 ± 0.5% vs. 83.9 ± 25.3%, p = 0.013) than the TFT. The mean change in compression depth over time was greater with the TFT than with the palm presser (regression coefficient: −0.024 [95% CI −0.030 to −0.018] vs. −0.004 [95% CI −0.006 to −0.002]).


Study Aim: To compare a novel two-thumb chest compression technique with standard techniques during newborn resuscitation performed by novice physicians in terms of median depth of chest compressions, degree of full chest recoil, and effective compression efficacy. Study Type: Prospective crossover

Inclusion Criteria: 74 novice physicians

Intervention: 74 novice physicians with less than 1-year work experience participated in the study. They performed chest compressions using three techniques: (A) The new two-thumb technique (nTTT). The novel method of chest compressions in an infant consists in using two thumbs directed at the angle of 90° to the chest while closing the fingers of both

1° endpoint: median depth of chest compressions, degree of full chest recoil, and effective compression efficacy. Results: The median depth of chest compressions for nTTT was 3.8 (IQR, 3.7–3.9) cm, for TFT−2.1 (IQR, 1.7–2.5) cm, while for TTHT−3.6 (IQR, 3.5–3.8) cm. There was a significant difference between nTTT and TFT, and TTHT and TFT (p < 0.001) for each time interval during resuscitation. The degree of full chest recoil was 93% (IQR, 91–97) for nTTT, 99% (IQR, 96–100) for TFT, and 90% (IQR, 74–91) for TTHT. There was a statistically significant difference in the degree of complete chest relaxation between nTTT and TFT (p <

Limitations: Restricting the study group only to novice physicians; Secondly, it is a simulation study which is not completely representative of newborn anatomy.


simulation study

hands in a fist. (B) TFT. With this method, the rescuer compresses the sternum with the tips of two fingers. (C) TTHT. Two thumbs are placed over the lower third of the sternum, with the fingers encircling the torso and supporting the back.

0.001), between nTTT and TTHT (p = 0.016), and between TFT and TTHT (p < 0.001).

Pellegrino 2019 {Pellegrino 2019 530}

Study Aim: To establish the efficacy and training of two-finger versus two-thumb-encircling techniques for lone responder infant chest compressions with ventilations in initially trained infant caregivers.

Inclusion criteria: Fourteen years or older, fluent in English and had not taken infant CPR in the last 5 years.

Intervention: Groups of eight participants were randomised to learn one technique, practised and then tested for 8 min. After a 30 min rest, the group repeated the process using the other technique.

1° endpoint: Mean chest compression depth and rate, compression fraction, and correct hand position; tiredness and pain as reported by the caregiver.

Limitations: Recruitment of participants focused on potential infant caregivers from secondary schools and community participants, yielding a high percentage of women, which does not generalise to the US population.


Study type: Randomised, cross-over educational intervention

Results: The two-thumb-encircling technique achieved a deeper mean compression depth over the 8 min period (2.0 mm, p<0.01), closer to the minimum recommendation of 40 mm; the two-finger technique achieved higher percentages of compression fraction and complete recoil.

Smereka {Smereka 2019 761}

Study aim: To compare two infant CC techniques during simulated newborn resuscitation performed by nurses. Study type: Prospective crossover manikin study

Inclusion criteria: Practice as a nurse and voluntary participation in the study

Intervention: 52 nurses. They underwent training with two CC techniques: standard two-finger technique (TFT) and novel two-thumb technique (NTTT; two thumbs at 90° to the chest, fingers in a fist). One week later, the participants performed resuscitation with the two techniques.

1° endpoint: CC quality and fatigue. Results: Median CC depth was 30 mm for TFT and 37 mm for NTTT (p = 0.002). Correct hand placement reached 98% in both techniques; full chest relaxation was obtained in 97% vs. 94% for TFT and NTTT, respectively. CC fraction was slightly better for NTTT (74% vs. 70% for TFT; p = 0.044), On a 100-degree scale (1 — no fatigue; 100 — extreme fatigue), the participant tiredness achieved 72 points (IQR 61–77) for TFT vs. 47 points

Limitations: This is a manikin study and not a clinical trial; manikins are not fully representative of human anatomy and physiology. Secondly, this study was conducted only among nursing personnel and only two CC techniques were analyzed.


(IQR 40–63) for NTTT (p = 0.034).

Tsou {Tsou 2019 publsihed online ahead of print}

Study aim: To quantify the actual force involved in two-thumb (TT)-encircling hands and two-finger (TF) methods during infant cardiopulmonary resuscitation. Study type: Prospective Randomized Crossover manikin study

Inclusion criteria: Forty-two emergency medical professionals, comprising emergency medical-technician firefighters and emergency department registered nurses, voluntarily participated in this study.

Intervention: 42 emergency medical professionals performed lone rescuer infant external chest compression (ECC) with TF and TT methods. The order of two methods was arranged randomly, with an interval of 30 min in between.

1° endpoint: The force was collected by MatScan as primary outcomes. The secondary outcomes, quality of chest compressions, and fatigue level were also recorded Results: The mean compression forces delivered in the first and second minutes were 3.53 ± 1.27 kg and 3.22 ± 1.11 kg (P = 0.012) for TF and 4.11 ± 1.80 kg and 4.04 ± 1.83 kg (P = 0.568) for TT, respectively. Pairwise comparison indicates that the compression force delivered through the TF method during the first and second minute of ECC were inferior to that delivered through the TT

Limitations: Ventilation variables in CPR procedures performed through the TT and TF techniques were not evaluated.

Second, participants were clinical experts in chest compression, and the experiments were performed in a manikin simulation environment; thus, the effect of kinematics variables involved in clinical situations remain unknown.


method. The TF method involved greater perceived exertion than the TT method (5.27 ± 4.69 vs. 4.02 ± 2.31; P = 0.007).

Yang 2019 {Yang 2019 1217}

Study Aim: To compare the performance of the flexed two-finger technique and the currently used two-thumb technique or two-finger technique for infant CPR. Study Type: Prospective randomized crossover manikin trial

Inclusion criteria: medical doctors who were members of the CPR team in our hospital participated in the study voluntarily after receiving a complete description of the study protocol, and age, sex, and race were not considered as limitations for the study participants. Exclusion criteria: participants who could not perform

Intervention: A total of 42 doctors conducted 2-min single-rescuer CPR on a cardiac arrest infant model using the two-thumb technique followed, in a random order, by the two-finger technique and the flexed two-finger technique.

1° endpoint: Quality of chest compressions Results: Although the ratio of the adequate compression depth was highest in the two-thumb technique, followed by the flexed two-finger technique and two-finger technique (100% [98–100] vs. 99% [80–100] vs. 76% [42–95], respectively, P < 0.001), the hand-off time of the two-thumb technique was significantly longer than in the two-finger technique and flexed two-finger technique

Limitations: This study recruited only medical doctors. Therefore, the results cannot be applied to other types of rescuers. Second, in this study, CPR was performed on the bed. Therefore, different results might be obtained with experiments conducted on the floor. Third, since the results of the present study were obtained from simulation experiments with a manikin, the results may not be identical with those obtained for CPR on humans.


infant CPR as a result of injuries sustained to their hands or fingers within the 2 weeks prior to the study; participants who refused to participate in the study; and participants who injured their hands or fingers during the experiments

(31 s [28–35] vs. 29 s [27–32] vs. 29 s [26–32], respectively, P < 0.001). The number of total chest compressions of the two-thumb technique was significantly lower than in the two-finger technique and flexed two-finger technique (150 [148–159] vs. 159 [149–173] vs. 162 [150–172], respectively, P < 0.001).


Reviewer Comments (including whether meet criteria for formal review): The literature search for new evidence published since the last 2015 review on this topic identified 1 systematic review and 18 RCTs all of which were manikin studies comparing neonatal or infant cardiac compression techniques. The majority supported the 2015 treatment recommendation for using the two-thumb encircling the chest technique. {Jiang 2015 531; Jo 2015 703; Jo 2017 462; Smereka 2017 1420; Lee 2018 372; Smereka 2018 159; Douvanas 2018 805; Pellegrino 2019 530; Tsou 2019 DOI: 10.1097/MEJ.0000000000000631}. Of note five studies (4 from the same group) compared a novel two-thumb technique with thumbs vertical to the chest (not encircling the chest) to the currently recommended two-thumb chest encircling technique. {Na 2015 e70; Smereka 2017 1420; Smereka 2017 604; Smereka 2017 589; Smereka 2019 761}. A new PICOST comparing these techniques may be warranted. One very small human trial compared an experimental one hand technique to the two-thumb technique but did not find advantages. {Jang 2018 36} As there is no human data and the manikin data is supportive, a new systematic review at this time would be unlikely to change the recommendation. Reference list Douvanas A, Koulouglioti C, Kalafati M. A comparison between the two methods of chest compression in infant and neonatal resuscitation. A review according to 2010 CPR guidelines. J Matern Fetal Neonatal Med. 2018;31(6):805-16. Jang HY, Wolfe H, Hsieh TC, Abbadessa MK, Myers S, Nadkarni V, et al. Infant chest compression quality: A video-based comparison of two-thumb versus one-hand technique in the emergency department. Resuscitation. 2018;122:36-40. Jiang J, Zou Y, Shi W, Zhu Y, Tao R, Jiang Y, et al. Two-thumb-encircling hands technique is more advisable than 2-finger technique when lone rescuer performs cardiopulmonary resuscitation on infant manikin. Am J Emerg Med. 2015;33(4):531-4. Jo CH, Jung HS, Cho GC, Oh YJ. Over-the-head two-thumb encircling technique as an alternative to the two-finger technique in the in-hospital infant cardiac arrest setting: a randomised crossover simulation study. Emerg Med J. 2015;32(9):703-7. Jo CH, Cho GC, Lee CH. Two-Thumb Encircling Technique Over the Head of Patients in the Setting of Lone Rescuer Infant CPR Occurred During Ambulance Transfer: A Crossover Simulation Study. Pediatr Emerg Care. 2017;33(7):462-6. Kim YS, Oh JH, Kim CW, Kim SE, Lee DH, Hong JY. Which Fingers Should We Perform Two-Finger Chest Compression Technique with When Performing Cardiopulmonary Resuscitation on an Infant in Cardiac Arrest? J Korean Med Sci. 2016;31(6):997-1002. Ladny JR, Smereka J, Rodriguez-Nunez A, Leung S, Ruetzler K, Szarpak L. Is there any alternative to standard chest compression techniques in infants? A randomized manikin trial of the new "2-thumb-fist" option. Medicine (Baltimore). 2018;97(5):e9386. Lee SY, Hong JY, Oh JH, Son SH. The superiority of the two-thumb over the two-finger technique for single-rescuer infant cardiopulmonary resuscitation. Eur J Emerg Med. 2018;25(5):372-6


Na JU, Choi PC, Lee HJ, Shin DH, Han SK, Cho JH. A vertical two-thumb technique is superior to the two-thumb encircling technique for infant cardiopulmonary resuscitation. Acta Paediatr. 2015;104(2):e70-5. Park JW, Jung JY, Kim J, Kwak YH, Kim DK, Lee JC, et al. A Novel Infant Chest Compression Assist Device Using a Palm Rather Than Fingers: A Randomized Crossover Trial. Prehosp Emerg Care. 2018:1-9. Pellegrino JL, Bogumil D, Epstein JL, Burke RV. Two-thumb-encircling advantageous for lay responder infant CPR: a randomised manikin study. Arch Dis Child. 2019;104(6):530-4. Smereka J, Bielski K, Ladny JR, Ruetzler K, Szarpak L. Evaluation of a newly developed infant chest compression technique: A randomized crossover manikin trial. Medicine (Baltimore). 2017;96(14):e5915. Smereka J, Szarpak L, Smereka A, Leung S, Ruetzler K. Evaluation of new two-thumb chest compression technique for infant CPR performed by novice physicians. A randomized, crossover, manikin trial. Am J Emerg Med. 2017;35(4):604-9. Smereka J, Szarpak L, Rodriguez-Nunez A, Ladny JR, Leung S, Ruetzler K. A randomized comparison of three chest compression techniques and associated hemodynamic effect during infant CPR: A randomized manikin study. Am J Emerg Med. 2017;35(10):1420-5. Smereka J, Kasinski M, Smereka A, Ladny JR, Szarpak L. The quality of a newly developed infant chest compression method applied by paramedics: a randomised crossover manikin trial. Kardiol Pol. 2017;75(6):589-95. Smereka J, Szarpak L, Ladny JR, Rodriguez-Nunez A, Ruetzler K. A Novel Method of Newborn Chest Compression: A Randomized Crossover Simulation Study. Front Pediatr. 2018;6:159. Smereka J, Madziala M, Szarpak L. Comparison of two infant chest compression techniques during simulated newborn cardiopulmonary resuscitation performed by a single rescuer: A randomized, crossover multicenter trial. Cardiol J. 2019;26(6):761-8. Tsou JY, Kao CL, Chang CJ, Tu YF, Su FC, Chi CH. Biomechanics of two-thumb versus two-finger chest compression for cardiopulmonary resuscitation in an infant manikin model. Eur J Emerg Med. 2019. DOI: 10.1097/MEJ.0000000000000631 Yang D, Kim KH, Oh JH, Son S, Cho J, Seo KM. Development and Evaluation of a New Chest Compression Technique for Cardiopulmonary Resuscitation in Infants. Pediatr Cardiol. 2019;40(6):1217-23.


APPENDIX C-8


Volume Infusion During Neonatal Resuscitation Evidence Update (NLS 598)

Worksheet author(s): Marilyn Escobedo Masanori Tamura Chris McKinlay Council: ANZCOR, RCA, AHA Date Submitted: 1/5/2019 PICO / Research Question: NRP 598 Volume Infusion During Neonatal Resuscitation Evidence Update In term and preterm newborns who receive resuscitation immediately after birth and who have a heart rate <60 beats per minute after chest compressions and epinephrine and/or suspected hypovolemia based on history and examination, does blood volume expansion versus no blood volume expansion improve outcome?

Population Term and preterm newborns who receive resuscitation immediately after birth and who have a heart rate <60 beats per minute after chest compressions and epinephrine and/or suspected hypovolemia based on history and examination.

Intervention Blood volume expansion with blood (red cells or whole blood), colloid (e.g. albumin, plasma), crystalloid (e.g. 0.9% sodium chloride) or other solution

Comparison No blood volume expansion Outcomes Critical

1. Survival (to any stage) 2. Neurodevelopmental outcomes (with age-appropriate, validated tools)

Important 3. Time to return of spontaneous circulation (or heart rate >60) 4. Subsequent use of vasopressor infusion(s) 5. Blood pressure at specified time 6. Pulmonary edema 7. Serious neonatal morbidity (including IVH, NEC, PPHN, HIE, pulmonary hemorrhage)

Study Design Randomized controlled trials (RCTs) and non-randomized controlled studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion in the meta-analysis. Case series will be included in a narrative summary. Relevant animal controlled trials will be included in the narrative summary. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded.

Timeframe All years and all languages are included as long as there is an English abstract (preset text)

Type (intervention, diagnosis, prognosis): intervention Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): none


Year of last full review: 2010 Last ILCOR Consensus on Science and Treatment Recommendation (2010): Consensus on Science Multiple case series support the use of volume expansion in babies with a history of blood loss, including some who are unresponsive to chest compressions (LOE 4110). Many with pallor and tachycardia responded to volume expansion without having received chest compressions. In the absence of a history of blood loss there is limited evidence of benefit from administration of volume during resuscitation unresponsive to chest compressions/epinephrine (LOE 4111) and some suggestion of potential harm from animal studies (LOE 5112,113). Treatment Recommendation Early volume replacement with crystalloid or red cells is indicated for babies with blood loss who are not responding to resuscitation. There is insufficient evidence to support the routine use of volume administration in the infant with no blood loss who is refractory to ventilation, chest compressions, and epinephrine. Because blood loss may be occult, a trial of volume administration may be considered in babies who do not respond to resuscitation. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N, Szyld E, Tamura M, Velaphi S. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122(16 Suppl 2):S516-38. 2010 Search Strategy: (explode "Infant-Newborn"/ all subheadings ) AND ((volume* near expan*) in ti,ab) AND ( ( "Resuscitation"/ all subheadings in mjme) OR (explode "Cardiopulmonary-Resuscitation"/ all subheadings in mjme) OR (explode "Blood-Volume"/ all subheadings in mjme) OR ( "Fluid-Therapy"/ all subheadings in mjme) OR (explode "Blood-Substitutes"/ all subheadings in mjme) OR (blood-supply in sh) 2019 Search Strategy: (Infant, Newborn [mh] OR neonat* [tiab] OR newborn [tiab]) AND (resuscitation [mh] OR cardiopulmonary resuscitation [mh] OR resuscitation [tiab]) AND (volume, blood [mh] OR fluid therapy [mh] OR Blood Substitutes [mh] OR fluid bolus [tiab]) AND (systematic review [pt] OR review [pt] OR randomized controlled trial [pt] OR trial [Title/Abstract]) AND 2008/01/01:2020/01/01 [dp] NOT adult [tiab] Database searched: PubMed Date Search Completed: 5/1/2020 Search Results (Number of articles identified / number identified as relevant): Articles retrieved: 29 Relevant articles: 2 non-systematic reviews Finn D, Roehr CC, Ryan CA, Dempsey EM. Optimising intravenous volume resuscitation of the newborn in the delivery room: practical considerations and gaps in knowledge. Neonatology. 2017;112(2):163-171. doi: 10.1159/000475456. Epub 2017 Jun 2. Review. PubMed PMID: 28571020.


Conway-Orgel M. Management of hypotension in the very low-birth-weight infant during the golden hour. Adv Neonatal Care. 2010 Oct;10(5):241-5; quiz 246-7. doi: 10.1097/ANC.0b013e3181f0891c. Review. PubMed PMID: 20838073. 2017 Jun 2. Review. PubMed PMID: 28571020. Hand searching: 1 systematic review, 1 survey, 1 animal intervention study, 1 non-systematic review Keir A, Froessler B, Stanworth S. QUESTION 2: Are intravenous fluid boluses beneficial in late preterm or term infants with suspected haemodynamic compromise? Arch Dis Child. 2016;101(2):201-2. Keir AK, Karam O, Hodyl N, Stark MJ, Liley HG, Shah PS, Stanworth SJ. International, multicentre, observational study of fluid bolus therapy in neonates. J Paediatr Child Health. 2019;55(6):632-9. Mendler MR, Schwarz S, Hechenrieder L, Kurth S, Weber B, Hofler S, Kalbitz M, Mayer B, Hummler HD. Successful resuscitation in a model of asphyxia and hemorrhage to test different volume resuscitation strategies. a study in newborn piglets after transition. Front Pediatr. 2018;6:192. Shalish W, Olivier F, Aly H, Sant'Anna G. Uses and misuses of albumin during resuscitation and in the neonatal intensive care unit. Semin Fetal Neonatal Med. 2017;22(5):328-35. Inclusion/Exclusion Criteria: Inclusion Randomised and non-randomised intervention studies and reviews (systematic, non-systematic) That report on one or more primary or secondary outcomes In term and preterm newborns (human and animal) undergoing resuscitation after birth who have a heart rate <60 beats per minute after chest compressions and epinephrine and/or suspected hypovolemia Who receive blood volume expansion (blood, crystalloid, colloid) versus no blood volume expansion Exclusion Case series Sepsis / hypovolemia / acidosis in NICU after immediate birth stabilization Link to Article Titles and Abstracts (if available on PubMed): see above



6. This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews. Relevant Guidelines or Systematic Reviews Organisation (if relevant); Author; Year Published

Guideline or systematic

review

Topic addressed or

PICO(S)T

Number of articles

identified


Finn, 2017 {Finn 2017 163}

Non-systematic narrative review.

Intravenous volume resuscitation of the newborn in the delivery room.

No new primary studies identified.

In absence of obvious blood loss, there are currently no clinical or technical tools that allow differentiation of the hemodynamically compromised infant who will benefit from volume therapy from the normovolemic asphyxiated infant who may, potentially, be further compromised by volume therapy.

In the setting of presumed or obvious blood loss such as placental abruption or fetal-to-maternal transfusion, consider volume expansion. Use fresh whole blood if available, and crystalloid solutions if not.

Keir, 2016 {Keir 2016 201}

Systematic review, search date 2 March 2015. No meta-analysis.

In a late preterm or term infant with signs of haemodynamic compromise with diverse underlying clinical conditions (excluding acute haemorrhage) [patient] does an initial fluid bolus (10

Two articles included. No new primary studies identified.

There remains no robust evidence to base this practice of fluid bolus therapy in late preterm and term infants who display signs of hemodynamic compromise, without signs of acute hemorrhage. The potential adverse effects of fluid boluses in all neonates remain and include volume overload (with downstream adverse effects on organ function), dilutional coagulopathy, electrolyte imbalances (eg, hyperchloraemic metabolic acidosis) and complications of blood products.

Avoid routine fluid bolus in suspected hemodynamic compromise without signs of acute hemorrhage.


mL/kg) [intervention] compared with no fluid bolus [comparison] provide any objective clinical benefit? [outcome].

Shalish, 2017 {Shalish 2017 328}

Systematic review. No meta-analysis.

Use of albumin as volume expander in neonates in various clinical settings including delivery room, hypotension, sepsis and postoperative fluid management.


Albumin appears to be as effective as crystalloid at increasing blood pressure in neonatal hypotension but may be associated with increases mortality. In acute asphyxia albumin may exacerbate transudation of fluid in the interstitial space.

For fluid resuscitation use normal saline.

Keir, 2019 {Keir 2019 632}

International cross-sectional survey.

International, pragmatic, multicentre, observational study undertaken at 41 neonatal units in Australasia, North America and Europe. Fluid bolus given for the purposes of intravascular

Only 5 of 163 neonates received a fluid bolus for purposes of resuscitation. No specific information provided.

None.


volume expansion for suspected haemodynamic compromise.

Conway-Orgel, 2017 {Conway-Orgel 2017 241}

Non-systematic narrative review.

Management of neonatal hypotension in first hour after birth.


Larger fluid boluses in VLBW associated with increased morbidity and mortality.

None.

RCT:



Patient Population




Mendler, 2018 {Mendler 2018 2018]

Study Aim: To develop a newborn piglet model with asphyxia, hemorrhage, and cardiac arrest to test different volume resuscitation on return of spontaneous

Inclusion Criteria: Arrested newborn piglets. Progressive hypoxia was induced by reducing FiO2 to 0.08, adding CO2 (FiCO2 = 0.07) and by reducing ventilator rate by 10/min every

Intervention: Animal’s own anticoagulated blood. Comparison: sodium chloride solution 0.9% A maximum of 3 × 10 ml/kg volume boluses were infused

1° endpoint: ROSC, defined as ECG rhythm and a visible arterial blood pressure. Median (IQR) time to ROSC was similar with 164 (129–198) s vs. 163 (162–199) s comparing the crystalloid group

No difference in adrenaline use. Significantly higher levels for potassium and lactate were measured in the early transfusion group and a higher PaO2 was observed in the crystalloid group. Mean arterial blood pressure, which was significantly higher in the crystalloid group. There were no significant differences between the groups


circulation (ROSC). We hypothesized that immediate red cell transfusion reduces time to ROSC as compared to the use of an isotonic crystalloid fluid. Study Type: Animal RCT

10min. At 12min or once a pH < 7.0 was achieved (whichever occurred first), hypovolemia was induced by continuous and standardized removal of blood (2 ml/kg/min) from the arterial line. Blood volume depletion was continued until cardiac arrest occurred. After 30 sec Neonatal Resuscitation Program algorithm was commenced.

immediately after each other until ROSC occurred, but the infused total volume never exceeded the total volume previously extracted. Only 75% of the animals needed volume for ROSC (16 received saline; 17 received blood transfusion).

and the early transfusion group. The hypothesis that early blood transfusion reduces time to ROSC during resuscitation compared to using a crystalloid solution was not confirmed.

regarding blood gases, metabolic, or hemodynamic parameters during the monitoring period Study Limitations: Animals had significant blood loos before cardiac arrest which may not be reflective of most newborn resuscitations. Median (IQR) blood loss was 30.7 (22.3–39.6) ml/kg in the crystalloid and 34.6 (25.2– 44.7) ml/kg in the early transfusion group.




Patient Population



None


Reviewer Comments (including whether meet criteria for formal review): No new human studies related to the PICOST were identified. Findings from one recent animal randomized trial support the 2010 treatment recommendations. Reference list Conway-Orgel M. Management of hypotension in the very low-birth-weight infant during the golden hour. Adv Neonatal Care. 2010 Oct;10(5):241-5. Finn D, Roehr CC, Ryan CA, Dempsey EM. Optimising intravenous volume resuscitation of the newborn in the delivery room: practical considerations and gaps in knowledge. Neonatology. 2017;112(2):163-171. doi: 10.1159/000475456. Keir A, Froessler B, Stanworth S. QUESTION 2: Are intravenous fluid boluses beneficial in late preterm or term infants with suspected haemodynamic compromise? Arch Dis Child. 2016;101(2):201-2. Keir AK, Karam O, Hodyl N, Stark MJ, Liley HG, Shah PS, Stanworth SJ. International, multicentre, observational study of fluid bolus therapy in neonates. J Paediatr Child Health. 2019;55(6):632-9. Mendler MR, Schwarz S, Hechenrieder L, Kurth S, Weber B, Hofler S, Kalbitz M, Mayer B, Hummler HD. Successful resuscitation in a model of asphyxia and hemorrhage to test different volume resuscitation strategies. a study in newborn piglets after transition. Front Pediatr. 2018;6:192. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N, Szyld E, Tamura M, Velaphi S. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122(16 Suppl 2):S516-38. Shalish W, Olivier F, Aly H, Sant'Anna G. Uses and misuses of albumin during resuscitation and in the neonatal intensive care unit. Semin Fetal Neonatal Med. 2017;22(5):328-35.


APPENDIX C-9

2020 Evidence Update Worksheet Sodium Bicarbonate During Neonatal Resuscitation (NLS 606)

Worksheet authors: Callum Gately, Helen Liley, Lindsay Mildenhall, Jonathan Wyllie Literature searches conducted by Jenny Ring, Senior Researcher, Health Research Consulting (for the Australian Resuscitation Council) Council: ANZCOR and RCUK Date Submitted: 3 January 2020 PICO / Research Question: Among neonates who are requiring resuscitation in the hospital (P), does sodium bicarbonate administration (I), compared with no bicarbonate (C), change outcome (O)? Outcomes:

1. Survival (to hospital discharge or as defined by authors) (Critical) 2. Return of spontaneous circulation (Critical) 3. HIE Stage moderate-severe (term infants only) (Important) 4. IVH Grades III-IV (preterm only) (Important) 5. Other morbidities in early infancy (e.g., necrotizing enterocolitis, retinopathy of prematurity,

bronchopulmonary dysplasia, periventricular leukomalacia) (Important)

6. Neurodevelopmental outcomes (Important) Type (intervention, diagnosis, prognosis): Intervention Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2005 Last ILCOR Consensus on Science and Treatment Recommendation: Consensus on science - none Treatment recommendations (2005) Sodium bicarbonate is discouraged during brief CPR but may be useful during prolonged arrests after adequate ventilation is established and there is no response to other therapies. 2005/2010 Search Strategy: Worksheets NRP-021A (Perlman) and NRP021B (Richmond) See Appendix 1 (Worksheets completed 2010 but no recommendation due to illness of Dr. Sam Richmond) 2010/2015 Search Strategy: Search strategy NRP-021A (Perlman)

Ovid, Medline from 2004-2008 Mesh terms Neonates and/or resuscitation and/or CPR and sodium bicarbonate and/or asphyxia and/or infant and/or delivery room. Relevant hits: infant and/or newborn and bicarbonate (17 hits), sodium bicarbonate and delivery room + resuscitation (165 hits), sodium bicarbonate + delivery room (4


hits) - Two new studies retrieved Embase from 2004 to 2008 Same terms and combinations – same two studies retrieved

Cochrane library – one review found CD004864 2006 ECC endnote library –no new study found References from the most recent review articles

Search strategy NRP-021B (Richmond)

Ovid, Medline from 2004-2008 Mesh terms Neonates and/or resuscitation and/or CPR and sodium bicarbonate and/or asphyxia and/or infant and/or delivery room. Relevant hits: infant and/or newborn and bicarbonate (17 hits), sodium bicarbonate and delivery room + resuscitation (165 hits), sodium bicarbonate + delivery room (4 hits) - Two new studies retrieved. Embase from 2004 to 2008 Same terms and combinations – same two studies retrieved, Cochrane library – one study found, ECC endnote library –no new study found.

2019 Search Strategy: The following search strategy for updating NRP 606 was developed for the EMBASE.com platform, which includes both the Medline and Embase bibliographic databases (See Table). The approach includes identifying the newborn population, then refining with limits for publication types (conference abstracts were excluded) and publication dates (from last ILCOR search). Then the intervention (sodium bicarbonate) was specified and combined with the above search. A low number of records was identified by this approach, so no further filtering of records was necessary. This batch of records was split into two groups, depending on whether they included any terms that indicated animal studies:

• ‘human’ set; and • ‘animal’ set.

Explanation of search strategy approach for updating NRP 606 # Search string (developed for the

EMBASE.com platform, which includes Medline and Embase databases)

Explanation

#1 'newborn'/exp 'infant'/exp neonat* in title or abstract newborn$ in title or abstract baby in title or abstract babies in title or abstract infant$ in title or abstract child in title or abstract birth in title or abstract

Population – Newborns Newborns should be the focus of the article, so all newborn terms (neonates; newborns; babies; infants; child) must appear in either the title or the abstract, or the article must be tagged with EMTREE terms for newborn or infant.

#2 #1 NOT ([conference abstract]/lim OR [conference review]/lim OR [editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR [book]/lim OR 'case report'/de)

Exclude publication types Conference abstracts and other ineligible study types were removed here.


# Search string (developed for the EMBASE.com platform, which includes Medline and Embase databases)

Explanation

#3 #2 AND [2009-2020]/py Date limit The last ILCOR search was run to some point in 2008, so the publication date range was limited to 2008 or later. This search string can be combined with intervention strings or other population strings to produce a final number of records.

#4 sodium bicarbonate in title or abstract or keyword nahco in title or abstract or keyword 'na hco3' in title or abstract or keyword 'na hco' in title or abstract or keyword ‘bicarbonate' in title or abstract or keyword

Intervention – sodium bicarbonate Sodium bicarbonate must appear in the title, abstract or the list of keywords allocated by the study authors.

#5 #3 AND #4 Newborn + sodium bicarbonate Records for use of sodium bicarbonate in newborns. This string identified the checklist studies.

#6 #5 NOT ('animal'/exp NOT 'human'/exp OR 'nonhuman'/exp OR 'rodent'/exp OR 'animal experiment'/exp OR 'experimental animal'/exp OR rat:ti,ab OR rats:ti,ab OR mouse:ti,ab OR mice:ti,ab OR dog$:ti,ab OR pig$:ti,ab OR porcine:ti,ab OR swine:ti,ab OR chick$:ti,ab)

Newborn + sodium bicarbonate: Human studies The search results were stratified using this filter for animal studies.

#8 #5 NOT #6 Newborn + sodium bicarbonate: Animal studies

Database searched: Medline and Embase Date Search Completed: 4th December 2019 Search Results (Number of articles identified / number identified as relevant):

“Human” set “Animal” set Total Unique records identified 223 102 325 Selected for full text review 19 4 23 Met inclusion criteria 0 1 1


Inclusion/Exclusion Criteria: Eligible participants were newborn neonates of any gestational age who had received resuscitation at birth. For the animal set participants needed to be newborn and an asphyxia model and/or undergoing resuscitation. Studies were eligible if they compared any of the predefined critical or important outcomes between infants receiving sodium bicarbonate versus no sodium bicarbonate during resuscitation. Randomized controlled trials and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols), case series that could not provide an estimate of incidence of outcomes were excluded. Cohort studies may compare different interventions, or report outcomes for a single arm receiving one intervention. For this review, observational studies were considered to be a cohort study eligible for inclusion if they used a defined strategy to ensure that the participants were either all of those who received an exposure of interest in a defined population (e.g. infants born at a particular hospital between specified dates), or they were sampled to be considered representative of such a population.5 Where the method of selecting participants did not meet these criteria, the study was considered to be a case series and was ineligible. All languages were eligible if there was an English abstract. Link to Article Titles and Abstracts (if available on PubMed): Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces


Relevant Guidelines or Systematic Reviews No systematic reviews were identified that specifically addressed the use of sodium bicarbonate in newborn resuscitation. Organisation (if relevant); Author; Year Published





None


RCT: No randomized controlled trials were identified that specifically addressed the use of sodium bicarbonate in newborn resuscitation. Study Acronym; Author; Year Published


Patient Population




None

Nonrandomized Trials, Observational Studies: No non-randomized trials or other observational studies were identified that specifically addressed the use of sodium bicarbonate in newborn resuscitation. The following observational studies were identified that may provide some indirect evidence. They are included because no direct evidence was found. Study Acronym; Author; Year Published


Patient Population



Buckley 2013 {Buckley 2013 668}

Study Type: Prospective observational study

Inclusion Criteria: 22 patients with hypoplastic left heart syndrome (HLHS) in perioperative intensive care who received IV sodium bicarbonate boluses (administered over 10-20 secs)

1° endpoint: Cerebral near infrared spectroscopy (NIRS) measurements immediately post sodium bicarbonate bolus Results: A significant dose dependent increase in cerebral blood flow was documented

Bolus doses of sodium bicarbonate cause an increase in cerebral blood flow

Glatstein 2011 {Glatstein 2011 463}

Study Type: Retrospective Cohort

Inclusion Criteria: 14 consecutive neonates who received sodium bicarbonate to treat metabolic acidosis or persistent

Serum levels of calcium and magnesium were retrospectively studied before and after sodium bicarbonate administration Results:

Sodium bicarbonate therapy in neonates causes a significant decrease in serum magnesium and calcium concentrations


pulmonary hypertension

Statistically significant decrease in calcium by 0.06 mmol/L (p 0.04) and magnesium 0.07 mmol/L (p 0.001)

Jalali 2012 {Jalali 2012 5931}

Study Type: Retrospective cohort study

Inclusion Criteria: Infants at a single institution (CHOP) receiving surgery for HLHS or transposition of the great arteries

1° endpoint and Results: 12 hours of post operative physiological and clinical parameters were studied. A computational algorithm was developed to predict likelihood of subsequent periventricular leukomalacia (PVL)

Maximum rate of change of HCO3 and minimum rate of change of CO2 may be predictive of PVL

Katheria 2017 {Katheria 2017 518}


Inclusion Criteria: 36 preterm neonates 23+6 – 31+6 who underwent continuous cardiac and cerebral monitoring whilst enrolled in other prospective studies in a single unit, AND received sodium bicarbonate in the first 24 hrs

1° endpoint: Change from baseline after intravenous sodium bicarbonate administration in: Haemodynamic monitoring (HR, BP), Cerebral tissue oxygen extraction (St02) with NIRS. Results: Transient but statistically significant decrease in BP and increase in St02 after sodium bicarbonate administration

Although sodium bicarbonate administration increased pH and decreased base deficit there were well documented adverse physiological effects associated with administration of sodium bicarbonate in the first 24hrs of life in the form of fluctuations in cerebral and cardiovascular hemodynamics


Meert 2009 {Meert 2009 544}

Study Type: Multicenter retrospective cohort study

Inclusion Criteria: Patients between 1day and 18years of age who had a cardiopulmonary arrest in hospital. A total of 353 patients, 48.7% of whom survived. Sixty-three of the patients were less than 30 days of age

1° endpoint: To describe and identify demographic and clinical factors associated with hospital mortality Results: Among the many factors associated with hospital mortality, non-survivors were more likely to have received sodium bicarbonate

A causative effect cannot be inferred from this descriptive study

Mintzer 2015 {Mintzer 2015 601}

Study Type: Prospective observational study

Inclusion Criteria: Birthweight <1250g and receiving a ‘half bicarbonate correction’ as per local clinical guidelines in the first 7 days of life

1° endpoint: Cerebral, renal and splanchnic NIRS measurements pre, during and post bicarbonate infusion Results: No change in NIRS measurements

In this stable cohort of premature infants, who were receiving sodium bicarbonate infusions for mild acidosis presumed due to renal wasting, there was no effect on NIRS measurements (Cerebral/renal/splanchnic) from sodium bicarbonate infusion

Mok 2016 {Mok 2016 534}


Inclusion Criteria: Age <18years old with an in-hospital cardiac arrest

1° endpoint: Return of spontaneous circulation and survival to discharge Results: As expected the factors related to survival included duration of chest compressions, number of doses of adrenaline, and sodium bicarbonate and calcium administration

Patients with more prolonged asystole received more drugs. No cause and effect can be determined from this study

Moler 2011 {Moler 2011 141}

Study Type: Inclusion Criteria:

1° endpoint: Survival Results:

No cause and effect can be inferred from the association between


Multicenter retrospective cohort study

Age less than 18years of age with out of hospital cardiac arrest and CPR with return of circulation

Multiple clinical factors were associated with survival including weekend arrests, cardiopulmonary resuscitation not ongoing at hospital arrival, arrest rhythm not asystole, no atropine or sodium bicarbonate, fewer epinephrine doses, shorter duration of cardiopulmonary resuscitation, and drowning or asphyxial arrest event.

sodium bicarbonate and survival in this study.

Szpecht 2016 {Szpecht 2016 1399}


Inclusion Criteria: Prererm infants <32 weeks’ gestation admitted to a single Polish Neonatal intensive care unit.

1° endpoint: Comparison of clinical characteristics between infants who developed grade 3 and 4 intraventricular hemorrhage (IVH), vs those who did not. Results: Being out born, lack of antenatal steroids, hypotension treated with inotropes and acidosis treated with sodium bicarbonate were all associated with grade 3 and 4 IVH. OR for bicarbonate therapy 6.67

No cause and effect relationship could be attributed from this descriptive study. Sodium bicarbonate was not administered in a resuscitation setting – Study relates to intensive care management. Also note the high baseline rate of severe IVH in this population which may limit external validity.


Animal studies

Liu 2012 {Liu 2012 e39081}

Study Type: Blinded RCT

Inclusion Criteria: Hypoxic newborn piglet model. Sham operated control arm without hypoxia (n=6), 2 hypoxia-reoxygenation groups (n=8 each), treated with sodium bicarbonate 2 mEq/kg vs saline after a 10 min period of reoxygenation.

1° endpoint: Examine acid base changes, haemodynamic changes and cortical hydrogen peroxide (H202) levels Results: Although bicarbonate administration improved the acid base status at 60 minutes, it had no significant effect on acid base or hemodynamics at 4 hrs of age compared to saline. There was a significant reduction in cortical H202 levels in the sodium bicarbonate treated group, possibly related to ongoing suppression of superoxide dismutase levels

Although no observable effect was noted on 4 hr acid base or hemodynamic status in the sodium bicarbonate-treated group, there was a reduction in cortical H202 levels, a reactive oxygen species implicated in the pathogenesis of hypoxic brain injury.

Reviewer Comments (including whether meet criteria for formal review): There is no new compelling evidence found for this Evidence Update to suggest any change in recommendations on use of sodium bicarbonate in newborn resuscitation, or to justify a new Systematic Review. Sodium bicarbonate has historically been used during cardiopulmonary resuscitation based upon animal evidence but has been removed from most regional guidelines. Although serum acid base status may improve with intravenous sodium bicarbonate, there is evidence that rapid infusion of sodium bicarbonate may cause a paradoxical intracellular acidosis, cardiac impairment, and variations in cerebral blood flow, {Graf 1985 754; van Alfen-van der Velden 2006 122}) and some historical studies have shown an association between intraventricular hemorrhage in preterm neonates and use of sodium bicarbonate for correction of base deficit during intensive care.{Funato 1992 614; Papile 1978 834} The literature review by Perlman and Richmond for the ILCOR CoSTR 2010 identified a single randomized, controlled trial of bicarbonate use in newborn resuscitation that failed to demonstrate any benefit.{Lokesh 2004 219} No further randomized controlled trials have been published since then. A Cochrane systematic review in 2006, which has not been updated since, confirmed the solitary status of this study.{Beveridge 2006 Cd004864} The observational trials identified in this Evidence Update provide indirect evidence suggesting that there may be detrimental physiological effects and clinical outcomes associated with intravenous sodium bicarbonate infusion in different neonatal and pediatric populations. {Buckley 2013 668; Glatstein 2011 463; Katheria


2017 518; Mok 2016 534; Moler 2011 141} An observational study of neonatal intensive care found an association of sodium bicarbonate administration with intraventricular hemorrhage, {Szpecht 2016 1399} and an additional study in infants undergoing surgery for hypoplastic left heart syndrome found an association with periventricular leukomalacia, {Jalali 2012 5931} but neither could establish whether the sodium bicarbonate was causative. A single randomized, controlled trial of sodium bicarbonate therapy in a newborn piglet model of hypoxia-reoxygenation demonstrated a reduction in cortical reactive oxygen species, specifically hydrogen peroxide in the sodium bicarbonate treated group.{Liu 2012 e39081} This small animal study is certainly not sufficient evidence to change recommendations, but it is a reminder that the pathophysiology of hypoxic-ischemic injury is complex and highlights the importance of ongoing intermittent evidence updates in this area of resuscitation. Reference list Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during resuscitation of infants at birth. Cochrane Database Syst Rev. 2006;10.1002/14651858.CD004864.pub2(1): Cd004864.10.1002/14651858.CD004864.pub2 Buckley EM, Naim MY, Lynch JM, Goff DA, Schwab PJ, Diaz LK, Nicolson SC, Montenegro LM, Lavin NA, Durduran T, Spray TL, Gaynor JW, Putt ME, Yodh AG, Fogel MA, Licht DJ. Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single-ventricle physiology. Pediatr Res. 2013;73(5):668-673. 10.1038/pr.2013.25 Funato M, Tamai H, Noma K, Kurita T, Kajimoto Y, Yoshioka Y, Shimada S. Clinical events in association with timing of intraventricular hemorrhage in preterm infants. J Pediatr. 1992;121(4):614-619. 10.1016/s0022-3476(05)81157-6 Glatstein M, Mimouni FB, Dollberg S, Mandel D. Effect of bicarbonate on neonatal serum ionized magnesium in vivo. Am J Ther. 2011;18(6):463-465. 10.1097/MJT.0b013e3181ea30ff Graf H, Leach W, Arieff AI. Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis. Science. 1985;227(4688):754.10.1126/science.3969564 Jalali A, Licht DJ, Nataraj C. Application of decision tree in the prediction of periventricular leukomalacia (PVL) occurrence in neonates after heart surgery. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:5931-5934. 10.1109/embc.2012.6347344 Katheria AC, Brown MK, Hassan K, Poeltler DM, Patel DA, Brown VK, Sauberan JB. Hemodynamic effects of sodium bicarbonate administration. J Perinatol. 2017;37(5):518-520. 10.1038/jp.2016.258 Liu JQ, Manouchehri N, Lee TF, Yao M, Bigam DL, Cheung PY. Infusing sodium bicarbonate suppresses hydrogen peroxide accumulation and superoxide dismutase activity in hypoxic-reoxygenated newborn piglets. PLoS One. 2012;7(6):e39081.10.1371/journal.pone.0039081


Lokesh L, Kumar P, Murki S, Narang A. A randomized controlled trial of sodium bicarbonate in neonatal resuscitation-effect on immediate outcome. Resuscitation. 2004;60(2):219-223. 10.1016/j.resuscitation.2003.10.004 Meert KL, Donaldson A, Nadkarni V, Tieves KS, Schleien CL, Brilli RJ, Clark RS, Shaffner DH, Levy F, Statler K, Dalton HJ, van der Jagt EW, Hackbarth R, Pretzlaff R, Hernan L, Dean JM, Moler FW and Pediatric Emergency Care Applied Research Network. Multicenter cohort study of in-hospital pediatric cardiac arrest. Pediatr Crit Care Med. 2009;10(5):544-553. 10.1097/PCC.0b013e3181a7045c Mintzer JP, Parvez B, Alpan G, LaGamma EF. Effects of sodium bicarbonate correction of metabolic acidosis on regional tissue oxygenation in very low birth weight neonates. J Perinatol. 2015;35(8):601-606. 10.1038/jp.2015.37 Mok YH, Loke AP, Loh TF, Lee JH. Characteristics and Risk Factors for Mortality in Paediatric In-Hospital Cardiac Events in Singapore: Retrospective Single Centre Experience. Ann Acad Med Singapore. 2016;45(12):534-541 Moler FW, Donaldson AE, Meert K, Brilli RJ, Nadkarni V, Shaffner DH, Schleien CL, Clark RS, Dalton HJ, Statler K, Tieves KS, Hackbarth R, Pretzlaff R, van der Jagt EW, Pineda J, Hernan L, Dean JM and Pediatric Emergency Care Applied Research Network. Multicenter cohort study of out-of-hospital pediatric cardiac arrest. Crit Care Med. 2011;39(1):141-149. 10.1097/CCM.0b013e3181fa3c17 Papile LA, Burstein J, Burstein R, Koffler H, Koops B. Relationship of intravenous sodium bicarbonate infusions and cerebral intraventricular hemorrhage. J Pediatr. 1978;93(5):834-836. 10.1016/s0022-3476(78)81096-8 Szpecht D, Szymankiewicz M, Nowak I, Gadzinowski J. Intraventricular hemorrhage in neonates born before 32 weeks of gestation-retrospective analysis of risk factors. Childs Nerv Syst. 2016;32(8):1399-1404. 10.1007/s00381-016-3127-x van Alfen-van der Velden AA, Hopman JC, Klaessens JH, Feuth T, Sengers RC, Liem KD. Effects of rapid versus slow infusion of sodium bicarbonate on cerebral hemodynamics and oxygenation in preterm infants. Biol Neonate. 2006;90(2):122-127. 10.1159/000092411


APPENDIX C-10

2020 Evidence Update Worksheet Rewarming of hypothermic newborns after resuscitation (NLS 858)

Worksheet authors: Helen Liley, Joy Domingo-Bates, Lindsay Mildenhall Council: ANZCOR Date Submitted: 3 January 2020 PICO / Research Question: In newborns hypothermic (<36.0 oC) on admission (P), does rapid rewarming (I), compared with slow rewarming (C), change survival and other outcomes (O)? Outcomes: (as for 2015)

7. Survival (to hospital discharge or as defined by authors) (Critical) 8. Convulsions/seizures (Critical) 9. Haemorrhage/Pulmonary hemorrhage (Critical) 10. Need for respiratory support (Important) 11. Hypoglycemia (Important) 12. Episodes of apnea (Important)

Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): None Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2015 Last ILCOR Consensus on Science and Treatment Recommendation: Consensus on science We identified 2 randomized trials {Motil 1974 546; Tafari 1974 595} and 2 observational studies {Racine 1982 317; Sofer 1986 211} comparing rapid (greater than 0.5 °C/hour) versus slow (less than 0.5 °C/hour) rewarming strategies for hypothermic newborns (less than 36.0 °C) on admission. All studies were dated (the most recent study was published 28 years ago) and conducted in different settings (2 in low-resource countries and 2 in high-resource countries); enrolled patients had different baseline characteristics(postnatal age, gestational age, proportion of outborn/inborn, degree of hypothermia). The quality of the studies was very poor in terms of number of enrolled patients, inclusion criteria, randomization methods, study design, and outcome measures. For the critical outcome of mortality, we identified low quality evidence (downgraded for serious risk of bias) from 1 randomized clinical trial {Tafari 1974 595} including 30 patients showing no benefit (RR 0.88; 95% CI


0.36–2.10) and 2 observational studies {Racine 1982 317; Sofer 1986 211}including 99 patients showing benefit in favor of a rapid rewarming strategy (OR, 0.23; 95% CI, 0.06–0.83). For the critical outcome of convulsions/seizures, we identified very-low-quality evidence (downgraded for serious risk of bias) from 1 randomized clinical trial {Tafari 1974 595} including 30 patients showing no benefit to rapid versus slow rewarming (RR, 0.88; 95% CI, 0.14–5.42). For the critical outcome of hemorrhage/pulmonary hemorrhage, we identified very-low-quality evidence (downgraded for serious risk of bias) from 1 randomized clinical trial {Tafari 1974 595} including 30 patients and 1 observational study {Racine 1982 317} including 38 patients showing no benefit to rapid versus slow rewarming (RR, 1.31; 95% CI, 0.26–6.76 and OR, 0.16; 95% CI, 0.02–1.50, respectively). For the important outcome of need for respiratory support, we identified very-low-quality evidence (downgraded for serious risk of bias) from 1 observational study {Sofer 1986 211} including 56 patients showing benefit in a slower over a rapid rewarming strategy (OR, 7.50; 95% CI, 2.14–26.24). For the important outcome of episodes of hypoglycemia, we identified very-low-quality evidence (downgraded for serious risk of bias and very serious imprecision) from 1 randomized controlled trial {Motil 1974 546} including 36 patients and 1 observational Study {Sofer 1986, 211} including 56 patients showing no benefit to rapid versus slow rewarming (RR, 0.11; 95% CI, 0.01–1.81 and OR, 0.21; 95% CI, 0.01–4.06, respectively). For the important outcome of episodes of apnea, we identified very-low-quality evidence (downgraded for serious risk of bias and very serious imprecision) from 2 randomized clinical trials {Motil 1974 546; Tafari 1974 595} including 66 patients showing no benefit to rapid versus slow rewarming (RR, 0.44; 95% CI, 0.04–4.32). Treatment recommendations (2015) The confidence in effect estimates is so low that a recommendation for either rapid (0.5 °C/hour or greater) or slow rewarming (0.5 °C/hour or less) of unintentionally hypothermic newborns (T° less than 36°C) at hospital admission would be speculative. References Motil KJ, Blackburn MG, Pleasure JR. The effects of four different radiant warmer temperature set-points used for rewarming neonates. J Pediatr 1974;85:546–50. Tafari N, Gentz J. Aspects of rewarming newborn infants with severe accidental hypothermia. Acta Paediatr Scand 1974;63:595–600. Racine J, Jarjoui E. Severe hypothermia in infants. Helv Paediatr Acta1982;37:317–22. Sofer S, Yagupsky P, Hershkowits J, Bearman JE. Improved outcome of hypothermic infants. Pediatr Emerg Care 1986;2:211–4.115. 2015 Search Strategy: PubMed: Search Completed February 20 2014 Number Results: 370 (((((((((((Hypothermia[MeSH Terms]) OR hypotherm*[Title/Abstract])) AND ((((((((((Rewarming[MeSH Terms]) OR Heating[MeSH Terms]) OR Hot Temperature[MeSH Terms]) OR Polyethylene[MeSH Terms])


OR Homeostasis[MeSH Terms]) OR rewarm*[Title/Abstract]) OR re-warm*[Title/Abstract]) OR heat*[Title/Abstract]) OR warm*[Title/Abstract]) OR polyethylene[Title/Abstract]))) AND (("Respiratory Distress Syndrome, Newborn"[Mesh] OR "Bronchopulmonary Dysplasia"[Mesh] OR "Infant, Newborn"[Mesh] OR "Delivery Rooms"[Mesh] OR "Gestational Age"[Mesh] OR "Premature Birth"[Mesh] OR "Infant, Premature, Diseases"[Mesh:NoExp] OR "Term Birth"[Mesh] OR "Live Birth"[Mesh] OR "Neonatal Nursing"[Mesh] OR "Neonatal Screening"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Animals, Newborn"[Mesh] OR "Transient Tachypnea of the Newborn"[Mesh] OR "Persistent Fetal Circulation Syndrome"[Mesh] or newborn[TIAB] or neonatal[TIAB] or neonate[TIAB] or neonates[TIAB] OR "Low Birth Weight "[TIAB] or "Small for Gestational Age"[TIAB] or prematur*[TIAB] or preterm[TIAB] OR "Birth Injuries"[Mesh] OR "Birthing Centers"[Mesh] OR Postmature[TIAB] OR infants[TIAB] OR infant[TIAB] OR birth[TIAB])))) NOT ((animals[mh] NOT humans[mh])))) NOT (("letter"[pt] OR "comment"[pt] OR "editorial"[pt] or Case Reports[ptyp])))) NOT ((((Hypothermia, Induced[MeSH Terms]) OR induced hypothermia[Title/Abstract]) OR therapeutic hypothermia[Title/Abstract]) OR protective hypothermia[Title/Abstract]) Embase: Not searched Cochrane: Date Searched: February 20, 2014 Number of Results: 60 (([mh Hypothermia] OR hypotherm*:ab,ti) AND ([mh Rewarming] OR [mh Heating] OR [mh "Hot Temperature"] OR [mh Polyethylene] OR [mh Homeostasis] OR rewarm*:ab,ti OR re-warm*:ab,ti OR heat*:ab,ti OR warm*:ab,ti OR polyethylene:ab,ti) AND ([mh "Respiratory Distress Syndrome, Newborn"] or [mh "Bronchopulmonary Dysplasia"] or [mh "Infant, Newborn"] or [mh "Delivery Rooms"] or [mh "Gestational Age"] or [mh "Premature Birth"] or [mh ^"Infant, Premature, Diseases"] or [mh "Term Birth"] or [mh "Live Birth"] or [mh "Neonatal Nursing"] or [mh "Neonatal Screening"] or [mh "Intensive Care, Neonatal"] or [mh "Intensive Care Units, Neonatal"] or [mh "Animals, Newborn"] or [mh "Transient Tachypnea of the Newborn"] or [mh "Persistent Fetal Circulation Syndrome"] or newborn:ti,ab or neonatal:ti,ab or neonate:ti,ab or neonates:ti,ab or "Low Birth Weight ":ti,ab or "Small for Gestational Age":ti,ab or prematur*:ti,ab or preterm:ti,ab or [mh "Birth Injuries"] or [mh "Birthing Centers"] or Postmature:ti,ab or infant:ti,ab or infants:ti,ab or birth:ti,ab)) NOT ([mh "Hypothermia, Induced"] OR "induced hypothermia":ab,ti OR "therapeutic hypothermia":ab,ti) Other: Date Searched: February 20, 2014 Number of Results: 471 'hypothermia'/de OR hypotherm*:ab,ti AND ('warming'/de OR 'heating'/de OR 'heat'/de OR 'polyethylene'/de OR 'homeostasis'/de OR rewarm*:ab,ti OR (re NEXT/1 warm*):ab,ti OR heat*:ab,ti OR warm*:ab,ti OR polyethylene:ab,ti) AND ('neonatal respiratory distress syndrome'/exp OR 'newborn hypoxia'/exp OR 'prematurity'/exp OR 'newborn apnea attack'/exp OR 'newborn disease'/de OR 'neonatal stress'/exp OR 'lung dysplasia'/exp OR 'newborn'/exp OR 'low birth weight'/exp OR 'newborn screening'/exp OR 'newborn monitoring'/exp OR 'newborn care'/exp OR 'newborn period'/exp OR 'birth weight'/exp OR 'newborn morbidity'/exp OR 'live birth'/exp OR 'newborn death'/exp OR 'newborn mortality'/exp OR 'delivery room'/exp OR newborn OR 'low birth weight':ab,ti OR 'small for gestational age':ab,ti OR prematur*:ab,ti OR preterm:ab,ti OR po T 'human'/exp) NOT ([editorial]/lim OR [letter]/lim OR 'case report'/de) AND [embase]/lim 2019 Search Strategy: The complete search strategy is provided in Appendix 2 Database searched: EMBASE.com platform, which includes both the Medline and Embase bibliographic databases.


Date Search Completed: 2 December 2019 The following search strategy for updating NRP 858 was developed for the EMBASE.com platform, which includes both the Medline and Embase bibliographic databases (See table). The approach includes identifying the newborn population, then refining with limits for study subjects (not animals), publication types (conference abstracts were excluded) and publication dates (from last ILCOR search). Based on the search strategy developed for the 2015 search, a search string was used for further refine the population with terms for hypothermia. Then a string was developed to define the intervention (warming etc). Finally, studies of therapeutic hypothermia were excluded where they included specific terms in the title or the studies were tagged to EMTREE terms for therapeutic hypothermia.

Explanation of search strategy approach for updating NRP 858 # Search string (developed for the EMBASE.com

platform, which includes Medline and Embase databases

Explanation

#1 'newborn'/exp 'infant'/exp neonat* in title or abstract newborn$ in title or abstract baby in title or abstract babies in title or abstract infant$ in title or abstract child in title or abstract



Exclude non-human studies The search results must include citations from the newborn population string, so a ‘non-human studies’ filter was applied to it.



#4 #3 AND [2014-2020]/py Date limit The date of the last ILCOR search was 20 February 2014. This search string can be combined with intervention strings or other population strings to produce a final number of records.

#5 'hypothermia'/de hypotherm* in title or abstract

Broad population terms –hypothermia To identify studies where hypothermia is referred to in the title or abstract. These terms must appear in the title or


# Search string (developed for the EMBASE.com platform, which includes Medline and Embase databases

Explanation

abstract, or the article must be tagged with EMTREE terms for hypothermia. This string was taken from the search strategy for the 2015 ILCOR CoSTR.

#6 'warming'/de 'heating'/de 'heat'/de 'polyethylene'/de 'homeostasis'/de rewarm* in title or abstract 're warm*' in title or abstract heat* in title or abstract warm* in title or abstract polyethylene in title or abstract

Intervention terms – warming To identify studies where warming or rewarming or heat terms were used. These terms must appear in the title or abstract, or the article must be tagged with EMTREE terms for warming etc. This string was taken from the search strategy for the 2015 ILCOR CoSTR.

#7 #4 AND #5 AND #6 Neonatal + hypothermia + warming #8 'induced hypothermia'/de

'targeted temperature management'/de 'therapeutic hypotherm*' in title 'induced hypotherm*' in title 'deliberate hypotherm*' in title

Specific terms for induced hypothermia A conservative approach was taken to exclude studies of induced hypothermia, by restricting the terms in this string to the title, as these terms may appear in the abstract without being the focus of the study. Article tagged with EMTREE terms for induced hypothermia are likely to focus on that intervention, so they were included in this string to allow them to be excluded from this search.

#9 #7 NOT #8 Neonatal + hypothermia + warming (minus induced hypothermia) This combination identified the two known ‘checklist’ studies of warming hypothermic neonates.

Literature search results The literature search strategy was run on 02 December 2019 and 133 records were identified (See Table).


EMBASE.com search for updating NRP 858 # EMBASE.com 02 December 2019 Records #1 'newborn'/exp OR 'infant'/exp OR neonat*:ti,ab OR newborn$:ti,ab OR baby:ti,ab

OR babies:ti,ab OR infant$:ti,ab OR child:ti,ab OR birth:ti,ab 1,913,240


1,610,496


1,147,745

#4 #3 AND [2014-2020]/py 257,983 #5 hypothermia'/de OR hypotherm*:ab,ti 62,993 #6 warming'/de OR 'heating'/de OR 'heat'/de OR 'polyethylene'/de OR

'homeostasis'/de OR rewarm*:ab,ti OR 're warm*':ti,ab OR heat*:ab,ti OR warm*:ab,ti OR polyethylene:ab,ti

575,943

#7 #4 AND #5 AND #6 239 #8 induced hypothermia'/de OR 'targeted temperature management'/de OR

'therapeutic hypotherm*':ti OR 'induced hypotherm*':ti OR 'deliberate hypotherm*':ti

16,719

#9 #7 NOT #8 Neonatal + hypothermia + warming (minus induced hypothermia)

133

Search Results (Number of articles identified / number identified as relevant): 133 articles identified/2 identified as relevant. Inclusion/Exclusion Criteria: Eligible participants were neonates of any gestational age who had become hypothermic (temperature <36 °C). Studies were eligible if they compared any of the predefined critical or important outcomes between infants receiving any strategy for rate of rewarming with any other rate of rewarming. Randomized controlled trials and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols), case series that could not provide an estimate of incidence of outcomes and animal studies were excluded. Cohort studies may compare different interventions, or report outcomes for a single arm receiving one intervention. For this review, observational studies were considered to be a cohort study eligible for inclusion if they used a defined strategy to ensure that the participants were either all of those who received an exposure of interest in a defined population (e.g. infants born at a particular hospital between specified dates), or they were sampled to be considered representative of such a population. Where the method of selecting participants did not meet these criteria, the study was considered to be a case series and was ineligible. All languages were eligible if there was an English abstract. Link to Article Titles and Abstracts (if available on PubMed):




Relevant Guidelines or Systematic Reviews: None relevant Organisation (if relevant); Author; Year Published






RCT: None relevant Study Acronym; Author; Year Published


Patient Population







Patient Population



Rech Morassutti 2015 {Rech Morassutti 2015 557}

Study Type: Retrospective, observational cohort. Outcomes of all eligible infants with hypothermia (temp<36.0 °C) analysed by rewarming rate. N=182

Inclusion Criteria: Newborns ≤28 weeks’ gestation and/or birth weight ≤1000 g, who were hypothermic (temperature <36.0oC) on admission to NICU, between 01/01/03 and 31/12/13. Exclusion criteria: Outborn infants admitted at >24 hours; inborn infants transferred to another hospital immediately after birth; death before achieving normothermia

1° endpoint: Not stated Results: Rewarming rate was slow (<0.5 °C/hour) in 109 and rapid (≥0.5 °C/hour) in 73 infants. Odds ratios (95% CI) for: Death 1.78(0.69-4.46) IVH 1.01(0.46-2.54). No significant differences in other outcomes including late onset sepsis, hypoglycaemia. Apnea, BPD, or BPD/death. When rewarming rate analysed as a continuous variable, rapid rewarming rate was protective for RDS 0.39(0.17-0.87)

In extremely low birth weight infants who were hypothermic on admission, there were no significant differences between a rapid or slow rewarming rate for major neonatal outcomes. A higher rewarming rate was associated with a lower incidence of respiratory distress syndrome.


(≥36.5 °C); major congenital anomalies

Feldman 2016 {Feldman 2016 295}

Study Type: Retrospective observational cohort. N=98

Inclusion Criteria: Inborn very low birth weight infants who had a rectal temperature <36 °C on admission to NICU

1° endpoint: death, intraventricular hemorrhage, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis and retinopathy of prematurity Results: Prolonged rewarming time was associate with increased odds of mortality (OR 1.273 95% CI 1.032-1.571). Once birthweight was included in a multiple logistic regression model, the association between mortality and rewarming time was no longer significant. Outcomes that were not associated with either rate or time of rewarming (even in a univariate model) were: bronchopulmonary dysplasia, intraventricular hemorrhage, severe intraventricular hemorrhage, necrotizing enterocolitis and

In moderately hypothermic VLBW infants, after accounting for birthweight, no association between rewarming and outcome is seen.


retinopathy of prematurity.

Reviewer Comments (including whether meet criteria for formal review): Although the literature search for this evidence update identified no new prospective trials of rates of rewarming, there are two new retrospective studies that increase the number of infants in observational trials nearly fourfold to 379 infants. {Feldman 2016 295; Rech Morassutti 2015 557} The recency of the two new trials (publication dates 2015 and 2016) stands in contrast to the relative antiquity of the studies considered for the 2015 ILCOR CoSTR. The findings of both studies was that the rate of rewarming (after adjustment for confounders) did not affect the critical and important outcomes for that were considered in each study. However one study {Rech Morassutti 2015 557} suggested that rapid rewarming reduces risk for respiratory distress syndrome. Full systematic review and GRADE analysis that included the new studies would most likely allow the development of a weak recommendation in relation to the rate of rewarming of hypothermic infants, as opposed to the ‘no recommendation’ that was made in 2015. Reference list Feldman A, De Benedictis B, Alpan G, La Gamma EF, Kase J. Morbidity and mortality associated with rewarming hypothermic very low birth weight infants. J Neonatal Perinatal Med. 2016;9(3):295-302. 10.3233/NPM-16915143 Rech Morassutti F, Cavallin F, Zaramella P, Bortolus R, Parotto M, Trevisanuto D. Association of Rewarming Rate on Neonatal Outcomes in Extremely Low Birth Weight Infants with Hypothermia. J Pediatr. 2015;167(3):557-561. e551 552.10.1016/j.jpeds.2015.06.008


APPENDIX C-11


Induced Hypothermia For HIE in limited resource settings (NLS 734) Worksheet authors: Helen Liley, Richard Mausling, Firdose Nakwa, Lindsay Mildenhall Literature searches conducted by Jenny Ring, Senior Researcher, Health Research Consulting (for the Australian Resuscitation Council) Council: ANZCOR and RCSA Date Submitted: 3 January 2020 PICO / Research Question: For infants with hypoxic ischemic encephalopathy (P) managed in resource-limited settings (S), does a course of therapeutic hypothermia delivered by passive hypothermia and/or ice packs (I), compared with standard care (C), improve survival and other outcomes (O)? Outcomes: Survival (critical); neurodevelopmental impairment (important) Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2015 Last ILCOR Consensus on Science and Treatment Recommendation: (2015) Consensus on science For the critical outcome of death or disability, we identified very-low-quality evidence (downgraded for risk of bias and indirectness) from 2 randomized controlled trials {Bharadwaj 2012 382; Jacobs 2011 692} enrolling 338 infants showing benefit to the use of therapeutic hypothermia (OR, 0.43; 95% CI, 0.26–0.7). For the critical outcome of death to latest follow-up, we identified very-low-quality evidence (downgraded for risk of bias, inconsistency, and indirectness) from 4 randomized controlled trials {Bharadwaj 2012 382; Jacobs 2011 692; Robertson 2011 138; Thayyil 2013 F280} enrolling 416 infants showing no benefit to the use of therapeutic hypothermia (OR, 0.72; 95% CI, 0.44–1.16). Treatment recommendations

We suggest that newly born infants at term or near-term with evolving moderate-to-severe hypoxic–ischemic encephalopathy in low-income countries and/or other settings with limited resources may be treated with therapeutic hypothermia (weak recommendation, low-quality evidence). Cooling should only be considered, initiated, and conducted under clearly defined protocols with treatment in neonatal care facilities with the capabilities for multidisciplinary care and availability of adequate


resources to offer intravenous therapy, respiratory support, pulse oximetry, antibiotics, anticonvulsants, and pathology testing. Treatment should be consistent with the protocols used in the randomized clinical trials in developed countries, i.e. cooling to commence within 6 h, strict temperature control at 33–34 °C for 72 h and rewarming over at least 4 h.

References: Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IM, Kirpalani HM, Darlow BA, Doyle LW; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165:692–700. doi: 10.1001/archpediatrics.2011.43. Bharadwaj SK, Bhat BV. Therapeutic hypothermia using gel packs for term neonates with hypoxic ischaemic encephalopathy in resource limited settings: a randomized controlled trial. J Trop Pediatr. 2012;58:382–388. doi: 10.1093/tropej/fms005. Robertson NJ, Hagmann CF, Acolet D, Allen E, Nyombi N, Elbourne D, Costello A, Jacobs I, Nakakeeto M, Cowan F. Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in Uganda: study protocol. Trials. 2011;12:138. doi: 10.1186/1745-6215-12-138. Thayyil S, Shankaran S, Wade A, Cowan FM, Ayer M, Satheesan K, Sreejith C, Eyles H, Taylor AM, Bainbridge A, Cady EB, Robertson NJ, Price D, Balraj G. Whole-body cooling in neonatal encephalopathy using phase changing material. Arch Dis Child Fetal Neonatal Ed. 2013;98:F280–F281. doi: 10.1136/archdischild-2013-303840. 2015 Search Strategy: PubMed: ( Search Completed: ) (“resource poor”[TIAB] OR “resource-poor”[TIAB] OR “limited resource”[TIAB] OR “limited resources”[TIAB] OR “resource constraints”[TIAB] OR cost-effective[TIAB] OR “cost effective”[TIAB] OR “low cost”[TIAB] OR “low-cost”[TIAB] OR low-resource[TIAB] OR “low resource”[TIAB] OR inexpensive[TIAB] OR “economics"[Subheading] OR "Developing Countries"[Mesh] OR developing countr*[TIAB] OR underdeveloped countr*[TIAB] OR “low income country”[TIAB] OR “low-income country”[TIAB] OR “low income countries”[TIAB] OR “low-income countries”[TIAB] OR “middle income country”[TIAB] OR “middle-income country”[TIAB] OR “middle income countries”[TIAB] OR “middle-income countries”[TIAB] OR "Africa, Central"[Mesh] OR "Africa, Eastern"[Mesh] OR "Africa, Southern"[Mesh] OR "Africa, Western"[Mesh] OR "Africa, Northern"[Mesh] OR "Caribbean Region"[Mesh] OR "West Indies" [Mesh] OR "Central America"[Mesh] OR "Latin America"[Mesh] OR "Mexico"[Mesh] OR "South America"[Mesh] OR "Asia, Central"[Mesh] OR "Asia, Northern" [Mesh] OR "Russia"[Mesh] OR "Asia, Southeastern"[Mesh] OR "Asia, Western"[Mesh] OR "Middle East"[Mesh] OR "Far East"[Mesh] OR "Australasia"[Mesh] OR "Europe, Eastern"[Mesh]) AND ("Hypothermia, Induced"[Mesh] OR "therapeutic hypothermia"[TIAB] OR "hypothermia therapy"[TIAB] OR "paramedic cooling"[TIAB] OR "targeted temperature management"[TIAB] OR "whole body cooling"[TIAB] OR "whole-body cooling"[TIAB] OR "whole body hypothermia" [TIAB] OR "whole-body hypothermia"[TIAB] OR “brain cooling”[TIAB] OR “selective cooling”[TIAB] OR ((cool*[TIAB] OR cold[TIAB] OR "target temperature"


[TIAB] OR "Body Temperature"[Mesh] OR “body temperature”[TIAB]) AND ("Brain Injuries"[Mesh] OR “brain injury”[TIAB] OR “brain injuries”[TIAB] OR "brain damage, chronic"[MeSH Terms] OR "Brain Ischemia"[Mesh] OR "Hypoxia-Ischemia, Brain"[Mesh] OR “hypoxic ischaemic encephalopathy”[TIAB] OR “hypoxicischemic encephalopathy”[TIAB] OR “hypoxia-ischemia”[TIAB] OR "asphyxia neonatorum"[MeSH Terms] OR “perinatal asphyxia”[TIAB] OR “birth asphyxia”[TIAB] OR “neurological status”[TIAB] OR “neurological outcome”[TIAB] OR “neurological outcomes”[TIAB] OR neuroprotect*[TIAB] OR “neurological deficit”[TIAB] OR neurodevelopment*[TIAB] OR “developmental delay”[TIAB]))) AND ("Infant, Newborn"[Mesh] OR infant*[TIAB] OR newborn*[TIAB] OR neonatal[TIAB] OR neonate[TIAB] OR neonates[TIAB] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh]) NOT ((“animals”[Mesh] OR “Animals, Newborn”[Mesh] OR “Models, Animal”[Mesh]) NOT “humans”[Mesh]) Embase: ( Search Completed: ) (“resource poor”:ab,ti OR “resource+poor”:ab,ti OR “limited resource”:ab,ti OR “limited resources”:ab,ti OR “resource constraints”:ab,ti OR cost+effective:ab,ti OR “cost effective”:ab,ti OR “low cost”:ab,ti OR low+cost:ab,ti OR “low resource”:ab,ti OR low+resource:ab,ti OR inexpensive:ab,ti OR 'developing country'/exp OR (developing adj countr*):ab,ti OR (underdeveloped adj countr*):ab,ti OR “low income country”:ab,ti OR “low+income country”:ab,ti OR “low income countries”:ab,ti OR “low+income countries”:ab,ti OR “middle income country”:ab,ti OR “middle+income country”:ab,ti OR “middle income countries”:ab,ti OR “middle+income countries”:ab,ti OR 'Central Africa'/exp OR 'Africa'/exp OR 'Africa south of the Sahara'/exp OR 'North Africa'/exp OR 'Central America'/exp OR 'Caribbean Islands'/exp OR "Latin America”:ab,ti OR 'Mexico'/exp OR 'South America'/exp OR 'Asia'/exp OR 'Southeast Asia'/exp OR "Middle East'/exp OR 'Far East'/exp OR 'Eastern Europe'/exp OR 'Baltic States'/exp) AND ('induced hypothermia'/exp OR "therapeutic hypothermia":ab,ti OR "hypothermia therapy":ab,ti OR "paramedic cooling":ab,ti OR "targeted temperature management":ab,ti OR "whole body cooling":ab,ti OR "whole+body cooling":ab,ti OR “brain cooling”:ab,ti OR “selective cooling”:ab,ti OR ((cool*:ab,ti OR cold:ab,ti OR "target temperature":ab,ti OR 'body temperature'/exp OR “body temperature”:ab,ti) AND ('brain injury'/de OR “brain injury”:ab,ti OR “brain injuries”:ab,ti OR 'chronic brain disease'/exp OR 'brain ischemia'/de OR 'hypoxic ischemic encephalopathy'/exp OR “hypoxic ischaemic encephalopathy”:ab,ti OR “hypoxic+ischemic encephalopathy”:ab,ti OR “hypoxia+ischemia”:ab,ti OR 'newborn hypoxia'/exp OR "asphyxia neonatorum":ab,ti OR “perinatal asphyxia”:ab,ti OR “birth asphyxia”:ab,ti OR “neurological status”:ab,ti OR “neurological outcome”:ab,ti OR “neurological outcomes”:ab,ti OR neuroprotect*:ab,ti OR “neurological deficit”:ab,ti OR neurodevelopment*:ab,ti OR “developmental delay”:ab,ti))) AND ('newborn'/exp OR infant*:ab,ti OR newborn*:ab,ti OR neonatal:ab,ti OR neonate:ab,ti OR neonates:ab,ti OR 'newborn intensive care'/exp) NOT ('animal'/exp NOT 'human'/exp) Cochrane: ( Search Completed: ) (“resource poor”:ab,ti OR “resource-poor”:ab,ti OR “limited resource”:ab,ti OR “limited resources”:ab,ti OR “resource


constraints”:ab,ti OR cost-effective:ab,ti OR “cost effective”:ab,ti OR “low cost”:ab,ti OR low-cost:ab,ti OR inexpensive:ab,ti OR [mh "Developing Countries"] OR (developing adj countr*):ab,ti OR (underdeveloped adj countr*):ab,ti OR “low income country”:ab,ti OR “low-income country”:ab,ti OR “low income countries”:ab,ti OR “low-income countries”:ab,ti OR “middle income country”:ab,ti OR “middle-income country”:ab,ti OR “middle income countries”:ab,ti ORNorthern"] OR [mh "Caribbean Region"] OR [mh "West Indies"] OR [mh "Central America"] OR [mh "Latin America"] OR [mh "Mexico"] OR [mh "South America"] OR [mh "Asia, Central"] OR [mh "Asia, Northern"] OR [mh "Russia"] OR [mh "Asia, Southeastern"] OR [mh "Asia, Western"] OR [mh "Middle East"] OR [mh "Far East"] OR [mh "Australasia"] OR [mh "Europe, Eastern"]) AND ([mh "Hypothermia, Induced"] OR "therapeutic hypothermia":ab,ti OR "hypothermia therapy":ab,ti OR "paramedic cooling":ab,ti OR "targeted temperature management":ab,ti OR "whole body cooling":ab,ti OR "whole-body cooling":ab,ti OR “brain cooling”:ab,ti OR “selective cooling”:ab,ti OR ((cool*:ab,ti OR cold:ab,ti OR "target temperature":ab,ti OR [mh "Body Temperature"] OR “body temperature”:ab,ti) AND ([mh "Brain Injuries"] OR “brain injury”:ab,ti OR “brain injuries”:ab,ti OR [mh "brain damage, chronic"] OR[mh "Brain Ischemia"] OR [mh "Hypoxia-Ischemia, Brain"] OR “hypoxic ischaemic encephalopathy”:ab,ti OR “hypoxic-ischemic encephalopathy”:ab,ti OR “hypoxia-ischemia”:ab,ti OR [mh "asphyxia neonatorum"] OR “perinatal asphyxia”:ab,ti OR “birth asphyxia”:ab,ti OR “neurological status”:ab,ti OR “neurological outcome”:ab,ti OR “neurological outcomes”:ab,ti OR neuroprotect*:ab,ti OR “neurological deficit”:ab,ti OR neurodevelopment*:ab,ti OR “developmental delay”:ab,ti))) AND ([mh "Infant, Newborn"] OR infant*:ab,ti OR newborn*:ab,ti OR neonatal:ab,ti OR neonate:ab,ti OR neonates:ab,ti OR [mh "Intensive Care, Neonatal"] OR [mh "Intensive Care Units, Neonatal"]) Other: ( Search Completed: ) 2019 Search Strategy: Database searched: The search strategy for updating NRP 734 was developed for the EMBASE.com platform, which includes both the Medline and Embase bibliographic databases (Table 4.1). The approach includes identifying the newborn population, then refining with limits for study subjects (not animals), publication types (conference abstracts were excluded) and publication dates (from last ILCOR search). The following search strategy for updating NRP 734 was developed for the EMBASE.com platform, which includes both the Medline and Embase bibliographic databases (See Table). The approach includes identifying the newborn population, then refining with limits for study subjects (not animals), publication types (conference abstracts were excluded) and publication dates (from last ILCOR search). Based on the search strategy developed for the 2015 search, the intervention was specified in two ways. First, a string using specific terms for therapeutic hypothermia was created (e.g. ‘induced hypothermia’; ‘therapeutic hypothermia’; ‘targeted temperature management’ etc.) and used to filter the records identified above. A second search string was developed using more generic cooling terms (e.g. hypothermia; cooling; ‘body temperature’ etc.) and the specificity of this string was increased by also requiring indication terms (terms for neonatal hypoxic ischemic encephalopathy). The records identified by these two intervention strings were pooled to form a batch of records for therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy in any setting. These studies were then further filtered for terms relevant to low resource settings. This created the first set of records:

• ‘low resource setting’ set.


There are serious limitations in specifying low resource settings in a search string, so an additional search strategy was created that did not require the low resource setting terms. This second strategy included stricter requirements for the induced hypothermia and neonate terms (e.g. searching in titles only, not using EMTREE terms), which generated a much smaller set of records that may be feasible to screen, and may include important studies. As they are not picked up with the low resources string, they are referred to these as the ‘any setting’ set of records, although of course they may be in low resource settings:

• ‘low resource setting’ set; and • ‘any setting’ set.


EMBASE.com platform, which includes Medline and Embase databases

Explanation

#1 'newborn'/exp 'infant'/exp neonat* in title or abstract newborn$ in title or abstract baby in title or abstract babies in title or abstract infant$ in title or abstract child in title or abstract






#4 #3 AND [2012-2020]/py Date limit The date of the last ILCOR search was not reported in the digital worksheet, but most recent included study was published in 2012, so the publication date range was limited to 2012 or later. This search string can be combined with intervention strings or other population strings to produce a final number of records.



Explanation

#5 induced hypothermia'/de 'targeted temperature management'/de ((targeted management) NEAR/2 temperature) 'therapeutic hypotherm*' in title or abstract 'induced hypotherm*' in title or abstract 'deliberate hypotherm*' in title or abstract 'hypotherm* therapy' in title or abstract 'paramedic cooling' in title or abstract 'targeted temperature management' in title or abstract 'whole body cooling' in title or abstract 'brain cooling' in title or abstract 'selective cooling' in title or abstract

Specific intervention terms – therapeutic hypothermia To identify studies where therapeutic hypothermia was used, this string uses terms specific to the intervention in the title or abstract.

#6 'body temperature'/exp 'body temperature' in title or abstract hypothermi* in title or abstract 'target temperature' in title or abstract (temperature NEAR/3 management) cool* in title or abstract

Broad intervention terms – hypothermia To identify studies where therapeutic hypothermia was used but specific terms for the intervention were not used, this string uses broad terms for therapeutic hypothermia, but the specificity of this string needs to be improved by combining with terms for the indication (below).

#7 ‘hypoxic ischemic encephalopathy'/exp 'brain ischemia'/de 'newborn hypoxia'/exp encephalopathy in title or abstract asphyx* in title or abstract hypox* in title or abstract

Indication – NHIE To identify studies where babies are at risk of/ have experienced hypoxia, brain ischemia or encephalopathy, these terms must appear in the title or abstract, or the article must be tagged with EMTREE terms for hypoxic ischemic encephalopathy, brain ischaemia or newborn hypoxia.

#8 #4 AND (#5 OR (#6 AND #7)) Population + (specific intervention terms OR broad intervention terms + indication)



Explanation

Records from two approaches pooled. #9 'low resource setting'/de

'developing country'/de 'low income country'/de ((developing OR 'third world') NEAR/3 (countr* OR nation$)) (('low income' OR 'low resource' OR 'under funded') NEAR/3 (countr* OR nation$ OR setting$ OR institution$ OR hospital$ OR centre$ OR center$ OR provider$ OR facilit*)) (limited NEAR/2 (resource* OR income)) ((low OR minim* OR reduced OR modest) NEAR/3 (price OR cost OR resource*)) poor in title, abstract, keywords or mapped terms poverty in title, abstract, keywords or mapped terms underresourced in title, abstract, keywords or mapped terms 'under resourced' in title, abstract, keywords or mapped terms 'cost effective' in title, abstract, keywords or mapped terms cheap in title, abstract, keywords or mapped terms inexpensive in title, abstract, keywords or mapped terms economical in title, abstract, keywords or mapped terms 'low cost' in title, abstract, keywords or mapped terms

Low resource setting This string was developed to identify studies conducted in developing countries or countries, institutions, hospitals or centres with low resourcing. The string also includes terms such as ’low cost’, inexpensive and ‘cost effective’ to identify low cost interventions without the need for a description of the setting. These terms can appear in the title, abstract, keywords allocated by study authors or the EMTREE/MeSH mapping terms.

#10 #8 AND #9 Newborn + intervention + low resource setting This strategy would capture most, if not all, studies relevant to a low resource setting.



Explanation

This combination identified the seven known ‘checklist’ studies of neonatal therapeutic hypothermia relevant to low resource settings.

#11 'newborn'/exp OR 'infant'/exp OR neonat*:ti OR newborn$:ti OR baby:ti OR babies:ti OR infant$:ti OR child:ti OR birth:ti

Population – Newborns As #1 but restricted to title only.


Exclude non-human studies As #2


Exclude publication types As #3

#14 #13 AND [2012-2020]/py Date limit As #4

#15 'therapeutic hypotherm*':ti OR 'induced hypotherm*':ti OR 'deliberate hypotherm*':ti OR 'hypotherm* therapy':ti

Specific intervention terms – therapeutic hypothermia As #5 but no EMTREE terms and free text search limited to title and to fewer, more specific, terms.

#16 #14 AND #15 Newborn + restrictive, specific intervention #17 #16 NOT #10 (Newborn + restrictive, specific

intervention) minus (Newborn + intervention + low resource setting)

Two sets of records were created – one for studies that use terms for low cost or low resource settings, and the other with specific intervention terms in the title. Only the first set will be screened (the other may be interrogated with targeted searching if necessary):

• ‘low resource setting’ set – 142 records to be screened • ‘any setting’ set – 253 records – not to be screened.

EMBASE.com search for updating NRP 734 # EMBASE.com 03 December 2019 Records #1 'newborn'/exp OR 'infant'/exp OR neonat*:ti,ab OR newborn$:ti,ab OR baby:ti,ab

OR babies:ti,ab OR infant$:ti,ab OR child:ti,ab OR birth:ti,ab 1,913,567


# EMBASE.com 03 December 2019 Records #2 #1 NOT ('animal'/exp NOT 'human'/exp OR 'nonhuman'/exp OR 'rodent'/exp OR

'animal experiment'/exp OR 'experimental animal'/exp OR rat:ti,ab OR rats:ti,ab OR mouse:ti,ab OR mice:ti,ab OR dog$:ti,ab OR pig$:ti,ab OR porcine:ti,ab OR swine:ti,ab OR chick$:ti,ab)

1,610,714


1,147,917

#4 #3 AND [2012-2020]/py 309,744 #5 'induced hypothermia'/de OR 'targeted temperature management'/de OR

((targeted OR management) NEAR/2 temperature) OR 'therapeutic hypotherm*':ti,ab OR 'induced hypotherm*':ti,ab OR 'deliberate hypotherm*':ti,ab OR 'hypotherm* therapy':ti,ab OR 'paramedic cooling':ti,ab OR 'targeted temperature management':ti,ab OR 'whole body cooling':ti,ab OR 'brain cooling':ti,ab OR 'selective cooling':ti,ab

21,107

#6 'body temperature'/exp OR 'body temperature':ti,ab OR hypothermi*:ti,ab OR 'target temperature':ti,ab OR (temperature NEAR/3 management) OR cool*:ti,ab

178,808

#7 'hypoxic ischemic encephalopathy'/exp OR 'brain ischemia'/de OR 'newborn hypoxia'/exp OR encephalopathy:ti,ab OR asphyx*:ti,ab OR hypox*:ti,ab

419,638

#8 #4 AND (#5 OR (#6 AND #7)) 1,219 #9 'low resource setting'/de OR 'developing country'/de OR 'low income country'/de

OR ((developing OR 'third world') NEAR/3 (countr* OR nation$)) OR (('low income' OR 'low resource' OR 'under funded') NEAR/3 (countr* OR nation$ OR setting$ OR institution$ OR hospital$ OR centre$ OR center$ OR provider$ OR facilit*)) OR (limited NEAR/2 (resource* OR income)) OR ((low OR minim* OR reduced OR modest) NEAR/3 (price OR cost OR resource*)) OR poor:ti,ab,kw,de OR poverty:ti,ab,kw,de OR underresourced:ti,ab,kw,de OR 'under resourced':ti,ab,kw,de OR 'cost effective':ti,ab,kw,de OR cheap:ti,ab,kw,de OR inexpensive:ti,ab,kw,de OR economical:ti,ab,kw,de OR 'low cost':ti,ab,kw,de

1,270,093

#10 #8 AND #9 Newborn + intervention + low resource setting

142

#11 newborn'/exp OR 'infant'/exp OR neonat*:ti OR newborn$:ti OR baby:ti OR babies:ti OR infant$:ti OR child:ti OR birth:ti

1,341,806


1,151,831


827,727

#14 #13 AND [2012-2020]/py 188,503


# EMBASE.com 03 December 2019 Records #15 therapeutic hypotherm*':ti OR 'induced hypotherm*':ti OR 'deliberate

hypotherm*':ti OR 'hypotherm* therapy':ti 4,239

#16 #14 AND #15 280 #17 #16 NOT

#10 (Newborn + restrictive, specific intervention) minus (Newborn +

intervention + low resource setting) 253

Cochrane Library search strategy and results The search strategy developed for EMBASE.com platform was used to generate the search shown (See Table) for the Cochrane Library. Overall this is a simpler search strategy, simply combining neonatal terms with induced hypothermia terms, and limiting the search by date (2012 onwards). No terms for low resource setting were used given the low number of records to be screened without using such a filter. The EMTREE terms were translated to the appropriate MeSH terms (of which there are fewer relevant mapped terms). Only the terms from the more specific intervention string from the EMBASE.com strategy were used for the Cochrane search (a Cochrane Review is likely to utilise specific terminology). However, the fields searched included keywords as well as abstracts and titles. Ten Cochrane Reviews were identified, and a number of trials, although these will not be screened since 55 records from clinicaltrials.gov have already been screened (Helen Liley; email 02 December 2019). The Cochrane Protocol was not relevant to the PICO.

Table 4.1 Cochrane Library search for updating NRP 734 ID Search (03 Dec 2019) Hits #1 neonat* or newborn* or baby or babies or infant or child or birth or [mh "Infant,

Newborn"] 196,391

#2 “therapeutic hypotherm*” OR “induced hypotherm*” OR “deliberate hypotherm*” OR “hypotherm* therapy” OR “paramedic cooling” OR “targeted temperature management” OR “whole body cooling” OR “brain cooling” OR “selective cooling” OR [mh ^"Hypothermia, Induced"]

1,141

#5 #1 and #2 with Cochrane Library publication date Between Jan 2012 and Dec 2019, in Cochrane Reviews, Cochrane Protocols, Trials, Clinical Answers, Editorials, Special collections

167

Cochrane Reviews 10 Cochrane Protocols 1 Trials 155 Clinical Answers 1

Date Search Completed: 3 December 2019 Search Results (Number of articles identified / number identified as relevant): 142 unique records/14 identified as relevant. Inclusion/Exclusion Criteria:


Studies were eligible if they described any of the predefined critical or important outcomes in infants receiving induced hypothermia for management of hypoxic ischemic encephalopathy in a low- or middle- resourced setting. Controls could be either “standard care” with no induced hypothermia, or any different method of providing induced hypothermia. Randomized controlled trials and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols), case series that could not provide an estimate of incidence of outcomes and animal studies were excluded. Cohort studies may compare different interventions, or report outcomes for a single arm receiving one intervention. For this review, observational studies were considered to be a cohort study eligible for inclusion if they used a defined strategy to ensure that the participants were either all of those who received an exposure of interest in a defined population (e.g. infants born at a particular hospital between specified dates), or they were sampled to be considered representative of such a population.5 Where the method of selecting participants did not meet these criteria, the study was considered to be a case series and was ineligible. All languages were eligible if there was an English abstract. Link to Article Titles and Abstracts (if available on PubMed): Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces







Galvao 2013 {Galvao 2013 453}

Systematic review

Effect of hypothermia on morality of infants with HIE in different settings

22 articles describing 16 studies (8 in low resource settings)

Hypothermia significantly reduced mortality (RR.0.77; 95% CI: 0.65–0.92). Meta-regression: hypothermia efficacy does not increase as the gross domestic

The authors concluded that evidence from low-resource settings is limited, but hypothermia efficacy was not shown to be associated with better resources


product per capita rises.

Pauliah 2013 {Pauliah 2013 e58834}

Systematic review

Safety and efficacy of cooling therapy in low-and middle-income countries.

7 studies No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25).

Cooling therapy was not associated with a statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide and not incompatible with results seen in high income countries. Apparent lack of treatment effect may be due to heterogeneity and poor quality of included studies, inefficiency of low technology cooling devise, lack or optimal neonatal care, or intrinsic differences in the population.

RCT:



Patient Population




Aker 2019 {Aker 2019 10.1136}

Study Aim: To evaluate the neuroprotective effect of TH achieved by a PCM-based

Inclusion Criteria: Arterial blood gas (umbilical cord or first postnatal hour) pH <7.0 or base deficit ≥12, 5

Intervention: Therapeutic hypothermia to 33.5±0.5oC by using a phase contrast changing

1° endpoint: Outcome measures were neonatal MRI biomarkers, indicating severity of brain injury.

Study Limitations: Reported deaths (TH 2, Standard care 5).


cooling device in infants with moderate to severe HIE in a neonatal intensive care unit (NICU) in India. Study Type: RCT Setting: Vellore, South India N=50 Note: primary outcome only available for 11 in each group

min, Apgar score ≤5, or positive pressure ventilation for at least 10 min during resuscitation at birth (for outborn infants, no cry at birth) plus seizures or evidence of moderate or severe HIE identical to the NICHD trial. Exclusion criteria: Major congenital anomalies or imminent death anticipated at the time of assessment

material for 72 hours Comparison: Standard care

Results: Diffusion tensor imaging; significantly higher fractional anisotropy in cooled than non-cooled infants in left PLIC and several white matter tracts. After adjusting for sex, birth weight and gestational age, the mean difference in PLIC FA between groups was 0.026 (95% CI 0.004 to 0.048, p=0.023). Conventional MRI was available for 46 infants and demonstrated significantly less moderate/severe abnormalities in cooled (n=2, 9%) than in non-cooled (n=10, 43%) infants. No difference in adverse events between groups.

Primary outcome only available for 44% of study group. Sophisticated MRI, close monitoring and laboratory testing available but low resource setting? Small sample size Surrogate (MRI) outcome measure

Das 2017 {Das 2017 157}

Study Aim: to determine the effectiveness and safety of mild systemic hypothermia

Inclusion Criteria: Inborn neonates with ≥ 37 completed weeks of

Intervention: Hypothermia to target rectal temperature being 34 to

1° endpoint: Death and/or developmental delay at >30 months Results:

Study Limitations: Small unblinded study


by selective head cooling in hospital born neonates with hypoxic-ischemic encephalopathy using low-cost CoolCap Study Type: RCT Setting: (tertiary perinatal center) N=60

gestation with indicators of perinatal asphyxia and moderate to severe clinical encephalopathy.

35°C for 72 hours Comparison: Standard care

Therapeutic hypothermia reduced the risk of death and NDD at ≥ 30 months of age: 6 of 30 infants (20%) in the hypothermia group and 18 of 30 infants (60%) in the control group died or had a NDD at ≥ 30 months (risk ratio: 0.33 [95% CI: 0.15-0.72]; p = 0 0.0015). The mortality rate decreased. Survival rate free of any sensorineural disability increased.




Patient Population



Enweronu-Laryea 2019 {Enweronu-Laryea 2019 4013}

Study Type: Observational, cohort Setting: Accra, Ghana N=13

Inclusion Criteria: gestation age ≥36 + 0 weeks, birth weight ≥2000 g, postnatal age <24 h and evidence of moderate-to-severe intrapartum-associated

1° endpoint: Achievement of hypothermia in target range. Results: Infant core temperature was 34.2 °±1.2 °C over the first 24 h and 35.0 °± 1.0 °C over 80 h. Temperatures were within target range for HT with respect to 18 ±14% of measurements within the first 72 h

Survival to discharge (10/13) More severe NE was associated with lower core temperatures. Potential neuroprotective effect of facilitated passive cooling is unknown.


neonatal encepahopathy (defined), receiving “facilitated passive cooling”

El Shimi 2014 {El Shimi 2014 1295}

Study Type: Unclear – Methods says this was a prospective case-control N=30, 10 in each group, but Abstract says randomized trial of 45 infants, though group allocation of only 30 explained. Setting: Cairo, Egypt

Inclusion criteria: “Neonatal asphyxia” (defined). Major congenital anomalies, suspected inborn error of metabolism, inability to enroll by 6 hours (hypothermia group only)

Study Aim: to evaluate the efficacy and safety of single subcutaneous erythropoietin rEPO compared to moderate hypothermia (note 3 arm study – had a “supportive care” control group. Difficult to match description of mortality in the text to results in table, but mortality may have been highest in “supportive care” group (not statistically significant). Neurodevelopmental outcomes also not significantly different. Biochemical measures showed slight differences in biochemical markers of brain injury are of uncertain clinical significance.

Inconclusive evidence from a small study with uncertain method of study group allocation.

Kali 2015 {Kali 2015 F519}

Study Aim: To ascertain whether TH was directly applicable and safe in our setting and

Inclusion criteria: All infants receiving therapeutic hypothermia for HIE (policy was TOBY trial

Primary outcome: “cooling process and clinical findings during cooling” Results: 32% of cooled infants had mild

Large attrition bias limited the availability of longer-term outcomes; 37 infants lost to follow-up Tecotherm TSmed 200 N cooling system used


to document the complications and technical and logistical issues encountered before and after initiating TH Study Type: Retrospective cohort Setting: Tygerberg, South Africa N=100

criteria) over a 3 year period

encephalopathy, 45% moderate. 5% of outborn infants had an admission temperature ≤32 °C. Target temperatures generally maintained. NICU mortality 11/100

(servo-controlled mattress used in various high-resource centres) and while population included low-resourced groups, intensive care available may have resembled higher resourced settings.

Oliveira 2018 {Oliveira 2018 e000245}

Study aim: feasibility and effectiveness of using an affordable servo-controlled system (Tecotherm Helix) for whole-body cooling Study type: Prospective, single arm, multicenter Setting: Chennai, Bangalore, Mumbai, Puducherry and Calicut, India. N=82

Inclusion criteria: Term babies (aged <6 hours; birth weight ≥1.8 kg) requiring resuscitation at birth and with moderate or severe HIE Exclusion criteria: moribund, major life-threatening congenital malformations, or cooling device not available (already in use).

Primary outcome: Effective cooling time (percentage of time during which the rectal temperature is effectively within the target temperature (33°C to 34 °C) during the entire cooling period) Results: Mean (SD) hypothermia cooling induction time was 1.7 hour ±1.5 and the effective cooling time 95%

Large percentage of participants outborn, but invasive ventilation, laboratory testing, anticonvulsant drugs, inotropes etc. available in the NICU.


Prashantha 2019 {Prashantha 2019 234}

Study aim: Assess the efficacy and safety of low-cost devices for TH and to describe the clinicolaboratory profile of infants who have undergone TH in a tertiary care NICU Study type: Prospective, two arm (PCM material or icepacks) observational. Setting: Bengalaru, India N=62

Inclusion criteria: Infants ≥35 weeks, who weighed >1.8 kg, presented within 6 h of life and fulfilled the cooling criteria modified from NICHD criteria Exclusion criteria: Not specified

Primary outcome: number of newborns “successfully cooled and discharged” Results: Forty-nine infants were discharged, two died and 11 were discharged against medical advice. TH was prematurely stopped in 7 newborns with serious adverse events such as disseminated intravascular coagulation (DIC), gangrene and arrhythmia

Authors conclude low cost devices (phase changing material blocks or icepacks) are safe and effective for maintaining TH in low-resource settings with adequate monitoring. Unclear basis for use of PCM vs icepacks. No conclusion can be drawn about safety or effectiveness in reducing mortality or adverse neurodevelopmental outcomes.

Purkayastha 2016 {Purkayastha 2016 175}

Study aim: Feasibility and safety of therapeutic hypothermia and short-term outcome in neonates with hypoxic ischemic encephalopathy. Study type: Part prospective, part retrospective observational. Passive cooling with or without cloth-covered ice gel-packs. Setting: Manipal, India N=31

Inclusion criteria: Significant perinatal asphyxia, requiring assistance for breathing at birth; Apgar score of ≤5 at 5 min, if available and features suggestive of hypoxic encephalopathy (seizures/ hypotonia/ coma/ irritability/ metabolic acidosis).

Primary outcome: Not specified Results: Outcomes in relation to achievement of target temperatures and other characteristics of cooling described. Twenty of 31 infants had a normal neurological examination at discharge. Seizures were the most common co-morbidity, occurring in 64%.

Authors conclude that therapeutic hypothermia is feasible, and safe in a low-resource setting. No conclusion can be drawn about efficacy, and safety is uncertain due to small sample size.


Exclusion criteria: Not specified

Shabeer 2017 {Shabeer 2017 174}

Study aim: To compare the efficacy and safety of two low-cost cooling methods— frozen gel packs (FGP) and phase changing material (PCM) for providing TH in babies with HIE Study type: Retrospective observational. Setting: Vellore, India N=68 (23 FGP, 45 PCM)

Inclusion criteria: Infants ≥35 weeks’ gestational age and ≥1800 g with one physiological (cord blood pH <7 or base deficit >12; 5 min Apgar <5; need for resuscitation for >10 min) and neurological criteria (moderate or severe encephalopathy as per modified Sarnat staging; or seizures). Exclusion criteria: Not specified

Primary outcome: 1. Time to reach target temperature. 2. Fluctuation of the core body temperature during the cooling phase. 3. Proportion of temperature recordings outside the target range. Results: Induction time was significantly shorter with FGP than PCM (45 vs. 90 minutes; p-value< 0.001). Proportion of temperature readings outside the target range was significantly higher (9.8% vs. 3.8%; p-value<0.001) and fluctuation of core body temperature was wider (standard deviation of target temperature 0.4 oC vs. 0.28 °C) in the FGP group, compared with PCM group.

Authors conclude that Both FGP and PCM are effective and safe, comparable with standard servo-controlled cooling equipment. PCM has the advantage of better maintenance of target temperature with less nursing input, when compared with FGP. No conclusion can be drawn about efficacy, and safety is uncertain due to small sample size.

Thomas 2015 {Thomas 2015 266}

Study aim: To assess the feasibility of using phase changing material (PCM) as an alternative method for

Note this study may represent a part-earlier publication of results from (Shabeer 2017)


providing therapeutic hypothermia. Study type: Retrospective observational. Setting: Vellore, India N=41

Procianoy 2019 {Procianoy 2019 10.1055/s-0039-1692388 }

Study aim: To describe the experience with a protocol of therapeutic hypothermia (TH) in southern Brazil Study type: Observational cohort (single arm) Setting: Southern Brazil N=72

Inclusion criteria: Newborns with gestational age > 35 weeks with evidence of perinatal asphyxia plus moderate or severe encephalopathy.

Primary Outcome: 16 deaths (among 41 with moderate encephalopathy plus 31 with severe encephalopathy

Authors conclude; “Mortality and adverse events were similar to those described in large randomized controlled trials. TH is a safe and an effective method of neurologic protection in asphyxiated newborns in a developing country when performed adequately”. No control group.

Reviewer Comments (including whether meet criteria for formal review): The literature review for this Evidence Update found insufficient new evidence to change the 2015 CoSTR treatment recommendation. If the newly identified studies were added, it is also unlikely that the level of certainty of evidence designated in 2015 would be increased. Although it may be becoming increasingly difficult (due to clinician and parent preferences) to perform large, multicenter randomized trials with a “no-TH” control group, a protocol for one such study (an multicenter RCT of TH using a servo-controlled cooling device vs standard care without TH in hospitals in India, Bangladesh or Sri Lanka, with planned enrolment of 418 infants) has been published, and the study is likely provide valuable additional information when completed.{Thayyil 2017 432} A new ILCOR systematic review may be best timed to consider results of this study, but on clinicaltrials.gov, it is reported as not yet recruiting and since the follow-up to 18 months of age is planned, completion may be several years away. It is possible that accumulation of smaller studies in the meantime might warrant an updated systematic review. In well-resourced countries, induced therapeutic hypothermia (TH) is a well-established, evidence-based treatment to improve outcomes for infants with moderate or severe neonatal hypoxic ischemic encephalopathy.{Jacobs 2013 CD003311} However, its safety and efficacy in low- and middle-resourced settings is uncertain. This uncertainty relates partly to the heterogeneity and low quality of the studies that have been done in lower resourced settings, but other contributors may be the quality of concomitant investigation, monitoring and treatments, or to differences in the populations.{Pauliah 2013 e58834; Shankaran 2014 578} Nevertheless, the


fact that there are several new studies published since the last ILCOR review of this subject published in 2015 speaks to the growing interest and wider adoption of TH in lower resourced settings, even without high certainty evidence of safety and effectiveness. Several of these studies describe the use of inexpensive devices or “low technology” methods of providing TH, but few compare outcomes with a control group, and none provide a comparison with devices typically used in higher-resourced settings. The literature search for this evidence update identified two new relatively small RCTs {Aker 2019 10.1136; Das 2017 157}, both performed in India and enrolling 50 and 60 participants respectively, so their addition to the meta-analysis for the 2015 ILCOR CoSTR would, for the outcome of mortality, increase the number of trials to 6 and the total number of participants by 26% to 526. Each of these studies suggested that TH was beneficial in their respective settings, and this is not inconsistent with the current treatment recommendation. Several additional observational studies provide information about methods of providing TH in settings with reduced resources, although some study sites appear to be capable of providing reasonably sophisticated adjunctive care. There is no new evidence to establish the gradient of effect of available resources on the safety or efficacy of TH, or to define with any certainty the types of concomitant monitoring and treatment that need to be available to achieve good outcomes in infants with HIE treated with TH. Future studies of this subject should ideally try to examine the contributions of population characteristics, cooling method and availability of concomitant intensive care to outcomes. Interestingly, a survey of hospitals in California identified a range of practices and opinions regarding what services should be required of centers providing TH for neonates.{Wusthoff 2018 54} As well as variation in opinions about the need for other resources such as EEG monitoring, only 92% of centers reported using an evidence-based protocol, and there was a lack of universal agreement that TH centers should treat a minimum volume of patients annually. Considering this variation in a high resource location the lack of certainty in low and middle-income countries about whether, when and how to provide TH is not surprising. Reference list 1. Aker K, Stoen R, Eikenes L, Martinez-Biarge M, Nakken I, Haberg AK, Gibikote S, Thomas N.

Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019;10.1136/archdischild-2019-317311.10.1136/archdischild-2019-317311

2. Das S, Sarkar N, Bhattacharya M, Basu S, Sanyal D, Chatterjee A, Aich B, Chatterjee K. Neurological

Outcome at 30 Months of Age after Mild Hypothermia via Selective Head Cooling in Term Neonates with Perinatal Asphyxia Using Low-Cost CoolCap: A Single-Center Randomized Control Pilot Trial in India. J Pediatr Neurol. 2017;15(04):157-165. 10.1055/s-0037-1603681

3. El Shimi MS, Awad HA, Hassanein SM, Gad GI, Imam SS, Shaaban HA, El Maraghy MO. Single dose

recombinant erythropoietin versus moderate hypothermia for neonatal hypoxic ischemic encephalopathy in low resource settings. J Matern Fetal Neonatal Med. 2014;27(13):1295-1300. 10.3109/14767058.2013.855894

4. Enweronu-Laryea C, Martinello KA, Rose M, Manu S, Tann CJ, Meek J, Ahor-Essel K, Boylan GB,

Robertson NJ. Core temperature after birth in babies with neonatal encephalopathy in a sub-Saharan African hospital setting. J Physiol. 2019;597(15):4013-4024. 10.1113/JP277820


5. Galvao TF, Silva MT, Marques MC, de Oliveira ND, Pereira MG. Hypothermia for perinatal brain hypoxia-ischemia in different resource settings: a systematic review. J Trop Pediatr. 2013;59(6):453-459. 10.1093/tropej/fmt047

6. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic

ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;CD003311. 10.1002/14651858.CD003311.pub3.

7. Kali GT, Martinez-Biarge M, Van Zyl J, Smith J, Rutherford M. Management of therapeutic hypothermia

for neonatal hypoxic ischaemic encephalopathy in a tertiary centre in South Africa. Arch Dis Child Fetal Neonatal Ed. 2015;100(6):F519-523. 10.1136/archdischild-2015-308398

8. Oliveira V, Kumutha JR, E N, Somanna J, Benkappa N, Bandya P, Chandrasekeran M, Swamy R,

Mondkar J, Dewang K, Manerkar S, Sundaram M, Chinathambi K, Bharadwaj S, Bhat V, Madhava V, Nair M, Lally PJ, Montaldo P, Atreja G, Mendoza J, Bassett P, Ramji S, Shankaran S, Thayyil S. Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device. BMJ Paediatr Open. 2018;2(1):e000245. 10.1136/bmjpo-2017-000245

9. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S. Therapeutic hypothermia for neonatal

encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PLoS One. 2013;8(3):e58834. 10.1371/journal.pone.0058834

10. Prashantha YN, Suman Rao PN, Nesargi S, Chandrakala BS, Balla KC, Shashidhar A. Therapeutic

hypothermia for moderate and severe hypoxic ischaemic encephalopathy in newborns using low-cost devices - ice packs and phase changing material. Paediatr Int Child Health. 2019;39(4):234-239. 10.1080/20469047.2018.1500805

11. Procianoy RS, Corso AL, Schoenardie BO, de Oliveira GPF, Longo MG, Silveira RC. Outcome and

Feasibility after Seven Years of Therapeutic Hypothermia in Southern Brazil. Am J Perinatol. 2019;10.1055/s-0039-1692388. 10.1055/s-0039-1692388

12. Purkayastha J, Lewis LE, Bhat RY, Anusha KM. Feasibility and Safety of Therapeutic Hypothermia and

Short Term Outcome in Neonates with Hypoxic Ischemic Encephalopathy. Indian J Pediatr. 2016;83(2):175-177. 10.1007/s12098-015-1829-9

13. Shabeer MP, Abiramalatha T, Smith A, Shrestha P, Rebekah G, Meghala A, Thomas N. Comparison of

Two Low-cost Methods of Cooling Neonates with Hypoxic Ischemic Encephalopathy. J Trop Pediatr. 2017;63(3):174-181. 10.1093/tropej/fmw067

14. Shankaran S. Current status of hypothermia for hypoxemic ischemia of the newborn. Indian J Pediatr.

2014;81(6):578-584. 10.1007/s12098-014-1468-6 15. Thayyil S, Oliveira V, Lally PJ, Swamy R, Bassett P, Chandrasekaran M, Mondkar J, Mangalabharathi S,

Benkappa N, Seeralar A, Shahidullah M, Montaldo P, Herberg J, Manerkar S, Kumaraswami K, Kamalaratnam C, Prakash V, Chandramohan R, Bandya P, Mannan MA, Rodrigo R, Nair M, Ramji S, Shankaran S and HELIX Trial group. Hypothermia for encephalopathy in low and middle-income


countries (HELIX): study protocol for a randomised controlled trial. Trials. 2017;18(1):432.10.1186/s13063-017-2165-3

16. Thomas N, Chakrapani Y, Rebekah G, Kareti K, Devasahayam S. Phase changing material: an alternative

method for cooling babies with hypoxic ischaemic encephalopathy. Neonatology. 2015;107(4):266-270. 10.1159/000375286

17. Wusthoff CJ, Clark CL, Glass HC, Shimotake TK, Schulman J, Bonifacio SL. Cooling in neonatal

hypoxic-ischemic encephalopathy: practices and opinions on minimum standards in the state of California. J Perinatol. 2018;38(1):54-58. 10.1038/jp.2017.153


APPENDIX C-12

2020 Evidence Update Worksheet Post-resuscitation Glucose Management (NLS 607)

Worksheet authors: Helen Liley, Lindsay Mildenhall, with literature searches conducted by Jenny Ring, Senior Researcher, Health Research Consulting (for the Australian Resuscitation Council) Council: ANZCOR Date Submitted: 3 January 2020 PICO / Research Question: In babies who have received drugs for resuscitation (P) does the addition of glucose (I) as opposed to no glucose (C) improve outcomes? Outcomes:

13. Survival (to hospital discharge or as defined by authors) (Critical) 14. Convulsions/seizures (Critical) 15. Hemorrhage/Pulmonary hemorrhage (Critical) 16. Need for respiratory support (Important) 17. Hypoglycemia (Important) 18. Episodes of apnea (Important)

Type (intervention, diagnosis, prognosis): Intervention Additional Evidence Reviewer(s): Conflicts of Interest (financial/intellectual, specific to this question): None Year of last full review: 2010 / 2015 / New question: 2010 Last ILCOR Consensus on Science and Treatment Recommendation: Consensus on science (2010) Newborns with lower blood glucose levels are at increased risk for brain injury and adverse outcomes after a hypoxic-ischemic insult, although no specific glucose level associated with worse outcome has been identified.{Salhab 2004 361; Ondoa-Onama 2003, 22} Increased glucose levels after hypoxia or ischemia were not associated with adverse effects in a recent pediatric series {Klein 2008 379} or in animal studies, {LeBlanc1994 1443} and they may be protective.{Hattori 1990 122} However, there are no randomized controlled trials that examine this question. Due to the paucity of data, no specific target glucose concentration range can be identified at present. Treatment recommendations (2010)


Intravenous glucose infusion should be considered as soon as practical after resuscitation, with the goal of avoiding hypoglycemia (Class IIb, LOE C). References: Hattori H, Wasterlain CG. Posthypoxic glucose supplement reduces hypoxic-ischemic brain damage in the neonatal rat. Ann Neurol. 1990;28:122-8. Klein GW, Hojsak JM, Schmeidler J, Rapaport R. Hyperglycemia and outcome in the pediatric intensive care unit. J Pediatr. 2008;153:379-84. LeBlanc MH, Huang M, Patel D, Smith EE, Devidas M. Glucose given after hypoxic ischemia does not affect brain injury in piglets. Stroke. 1994;25:1443-7. Ondoa-Onama C, Tumwine JK. Immediate outcome of babies with low Apgar score in Mulago Hospital, Uganda. East Afr Med J. 2003;80:22-9. Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics. 2004;114:361-6. 2010/2015 Search Strategy:

Search strategy from NRP-019A McGowan PubMed search terms : MeSH resuscitation or asphyxia or asphyxia neonatorum or hypoxia-ischemia, brain AND text words (glucose or hyperglycemia or hypoglycemia or insulin) AND MeSH infant, newborn or animal, newborn (MeSH) resuscitation + hypoxia-ischemia, brain + text words (glucose or hyperglycemia or hypoglycemia or insulin) 9 hits asphyxia or asphyxia neonatorum + (glucose or hyperglycemia or hypoglycemia or insulin) + infant, newborn 14 hits resuscitation + (glucose or hyperglycemia or hypoglycemia or insulin) + infant, newborn 137 hits hypoxia-ischemia, brain + (glucose or hyperglycemia or hypoglycemia or insulin) + infant, newborn 32 hits hypoxia-ischemia, brain + (glucose or hyperglycemia or hypoglycemia or insulin) + animal, newborn Web of Knowledge (ISI): (hypoglycemia or hyperglycemia or glucose) AND (asphyxia or hypoxia-ischemia) AND (newborn or neonat*) Embase: (newborn hypoxia or perinatal asphyxia) AND (hypoglycemia or hyperglycemia or blood glucose level) and (brain or outcome) 15 unique hits

Also AHA EndNote Master library, Cochrane

Search strategy from NRP-019B Perlman Since this was a modified revision and the prior search was through December 2004, this search was conducted from January 05 through January 09 Key words used included hypoglycemia, resuscitation, delivery room, newborn, asphyxia, brain injury Ovid Medline – Mesh hypoglycemia + resuscitation 28 hits (0 used), hypoglycemia + delivery room – 9 hits (2 used) glucose + delivery room 6 hits (0 used), hypoglycemia + hypoxia-ischemic brain injury 24 hits (0 used) hypoglycemia + asphyxia 18 hits (0 used), asphyxia, hypoxic-ischemia, brain injury, newborn


Embase Mesh hypoglycemia + resuscitation 20 hits (0 used), hypoglycemia + delivery room – 9 hits (1 used) glucose + delivery room 7 hits (1 used), hypoglycemia + hypoxia-ischemic brain injury 50 hits (1 used) hypoglycemia + asphyxia 62 hits (0 used) Cochrane library- terms hypoglycemia, newborn - 0 hits Review articles 2 Endnote library terms hypoglycemia 17 hits 2019 Search Strategy: The approach includes identifying the newborn population, then refining with limits for study subjects (not animals), publication types (conference abstracts were excluded) and publication dates (from last ILCOR search). The intervention (glucose) was specified, and combined with the above search. The search results were then combined with a string of terms specific to resuscitation, creating a set of records expected to include direct evidence for the use of glucose in neonatal resuscitation. However, resuscitation terms may not have been used in studies of neonatal resuscitation (e.g. studies of glucose for birth asphyxia may not explicitly state resuscitation took place). Therefore, a second approach was also taken, combining the intervention string (glucose) with terms for hypoglycaemia, without the requirement for any resuscitation terms. This approach also identified indirect evidence (impact of glucose in non-resuscitated infants). In summary, these two approaches created the following two sets of records:

• the ‘resuscitation terms’ set – includes direct evidence for glucose in neonatal resuscitation; and • the ‘hypoglycaemia terms’ set – includes indirect evidence and may include some direct evidence.


EMBASE.com platform, which includes Medline and Embase databases)

Explanation

#1 'newborn'/exp 'infant'/exp neonat* in title or abstract newborn$ in title or abstract baby in title or abstract babies in title or abstract infant$ in title or abstract child in title or abstract birth in title or abstract






Explanation



#4 #3 AND [2009-2020]/py Date limit The last ILCOR search was run on Jan 2009, so the publication date range was limited to 2009 or later. This search string can be combined with intervention strings or other population strings to produce a final number of records.

#5 glucose:ti,ab,kw NOT (diabetes:ti,ab 'diabetes mellitus'/exp)

Intervention – Glucose Glucose must appear in the title, abstract or the list of keywords allocated by the study authors. Diabetes was excluded.

#6 'resuscitation'/exp 'heart arrest'/exp 'newborn intensive care'/exp 'return of spontaneous circulation'/exp resuscitation in title or abstract 'return of spontaneous circulation' in title or abstract rosc in title or abstract 'heart arrest$' in title or abstract 'cardiac arrest$' in title or abstract 'cardiovascular arrest$' in title or abstract 'cardiopulmonary arrest$' in title or abstract 'cardio-pulmonary arrest$' in title or abstract

Population – Resus To identify studies where newborns who had undergone resuscitation was the focus, all resus terms must appear in either the title or the abstract, or the article must be tagged with EMTREE terms for resuscitation, heart arrest, ROSC or newborn intensive care. Note that while ROSC can be an outcome, it can also define a population and is not a required term, just an option.

#7 glycem* in title or abstract glycaem* in title or abstract hypoglycem* in title or abstract hypoglycaem* in title or abstract 'hypoglycemia'/de

Population – Glycaemia To identify studies where hypoglycaemia or the study of blood sugar are a major focus, these terms must appear in the title or abstract, or the article must be tagged with EMTREE



Explanation

'glucose blood level'/mj terms for hypoglycaemia or glucose blood level.

#8 #4 AND #5 AND #6 Newborn + glucose + resuscitation Records for glucose intervention in newborns who undergo resuscitation. This is where we would expect to find any direct evidence. This combination did not identify any of the four studies that were found in a quick search. This is not surprising as those studies did not include resuscitated newborns, so are indirect evidence.

#9 #4 AND #5 AND #7 NOT #8 Newborn + glucose + glycaemia Records for glucose intervention in hypoglycaemic newborns or studies of blood glucose in newborns. As no terms for resuscitation are included, this strategy would identify indirect evidence. This combination identified all of the four indirect studies.

Reviewers’ suggested amendment to the 2020 PICOST question: In neonates requiring resuscitation at birth, (P) will a strategy aimed at maintaining normoglycemia I) during and/or immediately after resuscitation, versus standard care or a different strategy (C) improve outcome (O)? Suggested outcomes:

Survival to hospital discharge (Critical) Neurodevelopmental outcome (Important) Avoidance of hypoglycaemia (blood glucose level <2.6 mmol/L) (Important)

Database searched: The search strategy for updating NRP 607 was developed for the EMBASE.com platform, which includes both the Medline and Embase bibliographic databases. Date Search Completed: 28 November 2019 Search Results (Number of articles identified / number identified as relevant): 648 records identified

Resuscitation terms set Hypoglycemia terms set Total Unique records identified 119 529 648 Selected for full text review 6 46 52 Met inclusion criteria 1 12 13

Inclusion/Exclusion Criteria:


Eligible participants were neonates of any gestational age who had received resuscitation at birth. Studies were eligible if they compared any of the predefined critical or important outcomes between infants receiving any method, strategy or approach to management for maintaining blood glucose levels within a specified range with any other method, strategy or approach to management or with authors’ definition of standard or routine care. Randomized controlled trials and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols), case series that could not provide an estimate of incidence of outcomes and animal studies were excluded. Cohort studies may compare different interventions, or report outcomes for a single arm receiving one intervention. For this review, observational studies were considered to be a cohort study eligible for inclusion if they used a defined strategy to ensure that the participants were either all of those who received an exposure of interest in a defined population (e.g. infants born at a particular hospital between specified dates), or they were sampled to be considered representative of such a population.5 Where the method of selecting participants did not meet these criteria, the study was considered to be a case series and was ineligible. All languages were eligible if there was an English abstract. Link to Article Titles and Abstracts (if available on PubMed): Summary of Evidence Update: Evidence Update Process for topics not covered by ILCOR Task Forces This evidence update process is only applicable to PICOs which are not being reviewed as ILCOR systematic and scoping reviews. Relevant Guidelines or Systematic Reviews No systematic reviews were identified that specifically addressed how to manage blood glucose in the first hours after birth specifically in neonates who had undergone resuscitation. Organisation (if relevant); Author; Year Published





Cochrane Library Sinclair 2011 {Sinclair 2011 CD007615}

Interventions for prevention of neonatal hyperglycemia in very low birth weight infants.

To assess effects on clinical outcomes of interventions for preventing hyperglycemia in VLBW neonates receiving full or partial parenteral nutrition.

2 plus 1 abstract and 1 trial protocol

Glucose infusion rate: There is insufficient evidence... Insulin infusion: The evidence reviewed does not support the routine use of insulin

None provided


infusions to prevent hyperglycemia in VLBW neonates.

Shah 2019 {Shah 2019 116}

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

Association between neonatal hypoglycaemia and neurodevelopmental outcomes at early childhood (2–5 years), mid-childhood (6–11 years), and adolescence (12–18 years) Studies were limited to neonates ≥32 weeks’ gestation, and the proportion who received resuscitation is not specified.

11 studies, of which 9 publications yielded data for meta-analysis All were described as cohort studies

In early childhood, exposure to neonatal hypoglycemia was not associated with neuro-developmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86–1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13–10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20–5.22). In mid-childhood, neonatal hypoglycemia was associated with neuro-developmental

Neonatal hypoglycemia may have important long-lasting adverse effects on neurodevelopment that may become apparent only at later ages.


impairment (n = 54; OR = 3.62, 95% CI = 1.05–12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI =1.20–3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21–3.44). No data were available for adolescents.

A Cochrane review {Bottino, 2009, CD007453}was also retrieved in the literature search but was an earlier version of Sinclair 2011 RCT: No RCTs were identified that specifically addressed how to manage blood glucose in the first hours after birth specifically in neonates who had undergone resuscitation. Study Acronym; Author; Year Published


Patient Population




Alsweiler 2012 {Alsweiler 2012 639}

Study Aim: to determine whether tight glycemic control with insulin improves growth in hyperglycemic preterm infants without increasing the incidence of hypoglycemia

Inclusion Criteria: <30 weeks’ gestation or <1500 g birth weight and became hyperglycemic (2 consecutive blood glucose concentrations (BGC) >8.5 mmol/L at least 4 hours apart).

Intervention: Tight glycemic control with insulin (target BGC 4–6 mmol/L, tight group) Comparison: Standard practice (restrictive guidelines for starting insulin, target

1° endpoint: Linear growth rate to 36 weeks’ postmenstrual age Results Tight group had a lesser lower leg growth rate (P < 0.05), but greater head circumference growth (P < .0005) and greater weight gain (P < .001) to 36 weeks’ postmenstrual age than control infants.

Study Limitations: Study relates to glycemic management through an uncertain duration of NICU course. Age at randomization was median of 4-5 days, so does not address


Study Type: Randomised, controlled non-blinded study N=88

Exclusion criteria: hyperglycemia because of iatrogenic overdose of glucose, major congenital malformation, or judged to be dying.

BGC 8–10 mmol/L).

Tight group infants had lower daily BGC (median [interquartile range] 5.7 [4.8–6.7] vs 6.5 [5.1–8.2] mmol/L, P < .001) and greater incidence of hypoglycemia (BGC <2.6 mmol/L) (25/43 vs 12/45, P <.01) than controls. No significant differences in nutritional intake, or in the incidences of mortality or morbidity

glycemic management in the immediate aftermath of resuscitation.

Tottman 2017 {Tottman 2017 115}

As for Alsweiler 2012 {Alsweiler, 2012, 639} N=57

Inclusion Criteria: Participants in Alsweiler 2012 for whom outcomes were known/ available for follow-up at age 7

As for Alsweiler 2012

1° endpoint: Survival without neurodevelopmental impairment at 7 years Results Survival without neurodevelopmental impairment occurred in 25 of 68 children (37%), with no significant difference between tight (14 of 35; 40%) and standard (11 of 33; 33%) glycemic control groups (P = .60).

Tight glycemic control reduced height, increased height-adjusted lean body mass and reduced fasting blood glucose concentrations at school age. Study Limitations: As for Alsweiler 2012

Galderisi 2017 {Galderisi 2017 e20171162}

Study Aim: continuous glucose monitoring to

Inclusion Criteria: Gestation ≤ 32 weeks, birth weight ≤1500

Intervention: Continuous glucose monitoring with a control

1° endpoint: Increased time in euglycemic range Results: unblinded CGM group

Continuous glucose monitor guided titration can


guide glucose infusion rates Study Type: RCT (unblinded) N=50

g, < 48 hours from birth Exclusion criteria: congenital malformations, chromosome anomalies, birth weight <500 g. Note – unclear what proportion of enrollees had received resuscitation, but possibly most had received some resuscitation intervention in view of VLBW and prematurity. 15/50 intubated in delivery room

algorithm used to adjust glucose infusion rates Control: Masked continuous glucose monitoring – glucose infusion rates adjusted according to glucometer results obtained at least every 8 hours

(Intervention group) had a greater percentage of time spent in euglycemic range (median, 84% vs 68%, P < .001) and decreased time spent in mild (P = .04) and severe (P = .007) hypoglycemia and in severe hyperglycemia (P = .04) compared with the blinded CGM group. Use of CGM also decreased glycemic variability (SD: 21.6 ± 5.4 mg/dL vs 27 ± 7.2 mg/dL, P = .01; coefficient of variation: 22.8% ± 4.2% vs 27.9% ± 5.0%; P < .001)

increase time spent in the euglycemic range. Relevant secondary outcome: No difference in mortality (28 days or at discharge), or IVH grade 3 or 4, but the study had inadequate power for these outcomes.




Patient Population Primary Endpoint and Results (include P value; OR or RR; & 95% CI)


Fendler 2012 {Fendler 2012 1122}

Study Type: Retrospective, observational cohort study N=95

Inclusion Criteria: Birth weight <1500 g, admission to the study center within initial 12 hours, at least three venous or capillary blood glucose measurements per day. Exclusion

1° endpoint: Mortality Results: Standard deviation of glycemia: OR 1.44 95% CI 1.03-2.03 (independently of 5 min Apgar scores) predicted mortality

Exclusion of infants who received insulin treatment limits eligibility for the review and generalizability Unclear how many infants received resuscitation, but 85% were receiving mechanical ventilation and 22%, inotropes so


criteria: insulin treatment; presence of significant congenital malformations; use of postnatal steroids.

likely to have been most. Protocol in place for management of blood glucose excursions.

Galderisi 2019 {Galderisi 2019 146}

Secondary analysis of predictive algorithm for IVH in the above study. N=29 where CGM was started <12 hours formed primary cohort, N=21 where CGM started 12-48 hours used for validation.

As for Galderisi 2017 {Galderisi 2017 e20171162}

1° endpoint: IVH Results: A cut-off of 0.69 for the CLAIR index (of glucose variability) allowed a 100% sensitivity and an 83% specificity for IVH prediction

Glucose variability measured by CGM monitoring predicts risk of IVH

Mahajan 2017 {Mahajan 2017 74}

Observational study of a cohort of hypoglycemic neonates and matched controls N=54 hypoglycemic and 54 control infants

Inclusion Criteria: Infants >32 weeks’ gestation who developed hypoglycemia in the first 7 days matched for weight and gestation with euglycemic infants Exclusion criteria: major congenital malformations, severe birth asphyxia, Rh hemolytic disease, grade III or IV IVH

1° endpoint: Developmental quotient at 1 year Results: Mean motor DQ euglycemia; 89±3 85 asymptomatic hypoglycemia; 85±7 Symptomatic hypoglycemia; 79±10 P <0.001 Mean development quotient euglycemia; 90±2.5 asymptomatic hypoglycaemia; 85±9 symptomatic hypoglycaemia; 78±11 P<0.001

Unclear what proportion of infants had undergone any resuscitation Other morbidities, (respiratory distress, polycythemia, sepsis) higher in the hypoglycemic group. Five infants in the combined hypoglycemia groups had cerebral palsy diagnosed at 1 year.


McKinlay 2015 {McKinlay 2015 1507}

Prospective cohort study N=404 (216 had hypoglycemia)

Inclusion Criteria: ≥ 35 weeks, at risk for hypoglycemia* and underwent blood glucose screening * risk factors included maternal diabetes, gestation <37 weeks, low or high birth weight for gestation Exclusion criteria: major congenital malformations, terminal conditions

1° endpoint: Neurosensory impairment (BSID-III) at 2 years Results: The risk of neurosensory impairment or processing difficulty was not higher among children with neonatal hypoglycemia (when treated to maintain a blood glucose concentration of at least 2.6 mmol/L = 47 mg/dL) than among those without neonatal hypoglycemia (risk ratio, 0.95; 95% confidence interval [CI], 0.75 to 1.20; P = 0.67) and processing difficulty, defined as an executive-function score or motion coherence threshold that was more than 1.5 SD from the mean (risk ratio, 0.92; 95% CI, 0.56 to 1.51; P = 0.74).

All infants were treated with a strategy aimed at maintaining blood glucose >2/6 mmol/L. Uncertain what proportion received resuscitation.

Nadeem 2011 {Nadeem 2011 10}

Observational cohort study N=52

Inclusion criteria: Term infants with depression at birth and clinical signs of neonatal encephalopathy (HIE) Exclusion criteria: None stated

1° endpoint: Adverse neuro-developmental outcome at 24 months (Adverse outcome was defined as death, a Griffith’s Quotient (GQ) less than 87,

No infants received therapeutic hypothermia (in this study of infants with HIE). Strategy of management in place to maintain blood


or significant motor disability) Results: Mean (SD) blood glucose values did not differ between infants with normal and abnormal outcomes [4.89(2.28) mmol/L and 5.02(2.35) mmol/L, p value = 0.15] respectively. In term infants with HIE, early hypoglycemia (between 0-6 hours of life) was associated with adverse outcome at 24 months of age [OR = 5.8, CI = 1.04-32)]. On multivariate analysis to adjust for grade of HIE this association was not statistically significant. Late hypoglycemia (6-72 hours of life) was not associated with abnormal outcome [OR = 0.22, CI (0.04-1.14)]. The occurrence of hyperglycemia was not associated with adverse outcome.

glucose between 2.6 mmol/L and 8.3 mmol/L. Despite this, blood glucose profiles varied widely during the first 72 hours of life.

Pinchefsky 2019 {Pinchefsky 2019 23}

Observational cohort study N=45

Inclusion criteria: Neonatal encephalopathy (HIE)

1° endpoint: Abnormalities on aEEG monitoring including background scores,

Temporal association demonstrated between episodes of hyperglycemia and aEEG abnormalities,


Exclusion criteria: suspected or confirmed congenital malformations, inborn errors of metabolism, congenital infections, gestation < 36 weeks, weight <1500 g, inability to commence continuous glucose monitoring before 6 hours of age

sleep-wake cycling, electrographic seizures. Results: Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep–wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185- 0.681, P = .001), after adjusting for hypoxia–ischemia severity.

but it remains uncertain whether this was cause or effect. Induced hypothermia; 44 of 45 included infants. Four patients died in neonatal period.

Tan 2017 {Tan 2017 e000175}

Retrospective cohort study N=122

Inclusion criteria: Neonatal encephalopathy (HIE) treated with induced hypothermia Exclusion criteria: inborn error of metabolism or congenital brain structural defect

1° endpoint: Neurodevelopmental outcomes at 24 months (Bayley Scale of Infant and Toddler Development III (BSID-III) subscales (cognitive, language, motor and socioemotional), blindness, sensorineural deafness and cerebral palsy using the Gross Motor Function

Early recurrent hypoglycemia was associated with increased risk of death or severe disability in neonates undergoing induced hypothermia for hypoxic ischemic encephalopathy.


Classification System (GMFCS) Results: Infants with recurrent hypoglycemia (<2.6 mmol/L) had significantly lower mean BSID-III cognitive, language and socioemotional subscale scores. On multivariable analysis, recurrent hypoglycemia (<2.6 mmol/L) was associated with increased odds of death or disability (adjusted OR 8.15; 95% CI 1.31 to 50.58; p=0.024). Recurrent hypoglycemia (<3.0 mmol/L) during the first 12 hours of life was also associated with severe disability among survivors (adjusted OR 11.13; 95% CI 2.06 to 59.89; p=0.005).

Castrodale 2014 {Castrodale 2014 9}

Retrospective cohort study of a Golden Hour protocol N=225

Inclusion criteria: inborn, preterm infants (<28 weeks’ gestation) Exclusion criteria: None specified

1° endpoint: Hypoglycemia, hypothermia on admission and time to receive parenteral nutrition Results: Statistically significant improvement in the

Implementation of the Golden Hour Protocol can significantly improve the stabilization of infants delivered less than 28 weeks’ gestation


number of infants with an admission temperature in-range (36.5°C–37.4°C) between the pre protocol and post protocol infants (28.3% vs 49.6%; P = .002). Statistically significant improvement in the incidence of admission glucose greater than 50 mg/dL between the pre- and post protocol groups (55.7% vs 72%; P = .012). Post protocol, higher proportion received IV glucose and amino acids within 1 hour of life (61.3% vs 7%; P = 0.001)

Reviewer Comments (including whether meet criteria for formal review): There are reasons why blood glucose management after resuscitation may be particularly important in neonates. Not only does their early stage of brain development confer vulnerability to life-long consequences, but neonates are at uniquely high risk of disturbances of blood glucose. The normal range for blood glucose is lower in the first hours after birth than at any time later in infancy or in later life, and even normal neonates are at some risk of hypoglycemia after birth.{Metzger 2010 e1545} Insulin expression is continuous during intrauterine life (because of a continuous supply of nutrients across the placenta), and it is only as part of postnatal adaptation (mediated by methylation of specific genes) that that the pancreas becomes fully capable of regulating insulin production in proportion to blood glucose level. {Dhawan 2015 2851} Neonates are also particularly prone to hyperglycemia in the setting of stress or excess glucose load, and this has the potential to result in rebound hypoglycemia, because of ongoing insulin production and immaturity in the regulation of insulin counter-regulatory hormones such as cortisol. As with many other aspects of the perinatal transition, the hormonal adaptation to cope with an intermittent nutrient supply via the intestine can be delayed in some infants, especially in those born preterm, resulting in a high risk of hypoglycemia in the hours after birth. {Kaiser 2018 353} Maternal and fetal conditions (including diabetes in pregnancy and fetal growth restriction, (reviewed in {Adamkin 2016 150}) and administration of glucose-containing fluids to the mother before birth {Grylack 1984 654} predispose to excessive neonatal insulin production and increase the risk of neonatal hypoglycemia. Improved detection and management of such antenatal risk factors are likely to reduce risk of hypoglycemia in neonates but are beyond the scope of this review. Prevention of accidental hypothermia


during and after resuscitation is another strategy that is likely to be beneficial, but it is dealt with in other ILCOR systematic reviews. Studies identified for this evidence update suggest that in the aftermath of asphyxia and resuscitation, hyperglycemia, hypoglycemia and blood glucose instability with fluctuations between the two are associated with adverse neurological outcome. The level of hypoglycemia that is associated with high risk of brain injury and other adverse outcomes is still debated, and the level may be different in individual infants, because as long as aerobic metabolism can be restored (and as long as ketogenesis and lipolysis are not suppressed by high insulin levels), the neonate can utilize alternative substrates such as ketones and free fatty acids and perhaps most importantly, lactate {Harris 2015 F161} until these substrates are depleted. However, in infants under stress, insulin levels may remain high, and infants who have required resuscitation may have ongoing impairment of cerebral oxygenation that could restrict aerobic metabolism of glucose and lactate in at least some regions of the brain, causing energy deficiency. The safe level of hyperglycemia is also uncertain. The effect of hyperglycemia may be mediated through neuronal acidosis and oxidant injury. In addition, immediately after birth, there is evidence that blood glucose concentration is associated with cerebral regional oxygen saturation and oxygen extraction, implying that there may be a zone of adaptive regulation that could be exceeded in hypoglycemic or hyperglycemic infants. {Matterberger 2018 19} As in other age groups, {Chen 2018 57; Kovalaske 2009 1330; Kramer 2012 R203} it is unclear which specific strategies of glycemic management (aimed at improving blood glucose stability or at particular blood glucose target levels) will improve outcomes in resuscitated newborns. In asphyxiated infants, difficulty maintaining a normal blood glucose level may be an effect of the asphyxia as much as an independent predictor of adverse outcomes. However, management of blood glucose remains a high priority in neonatal care after resuscitation, and as has been pointed out by the authors of reviews of glycemic management in critically ill patients in other age groups, {Kovalaske 2009 1330; Kramer 2012 R203}lack of certainty about the best specific approach to stabilizing blood glucose is not the same as lack of certainty that no management will result in worse outcomes. A single study in infants at high risk for hypoglycemia suggests that a strategy of maintaining a blood glucose concentration of at least 2.6 mmol/L (47 mg/dL) does not result in adverse neurodevelopmental outcomes, even in those infants who experienced some hypoglycemia regardless. {McKinlay 2015 1507} However, this study was not targeted at very preterm infants or those who had received resuscitation at birth, and it remains unclear whether in those infants, 2.6 mmol/L represents a safe lower end of a target range. The literature review for this evidence update also found a single retrospective cohort study that specifically addressed a strategy of neonatal management of very preterm infants to reduce the risk of hypoglycemia in the immediate aftermath (first hours) after resuscitation in order to improve outcomes. {Castrodale 2014 9} A few studies address diverse methods to improve glucose levels from later in the first day after birth in very preterm infants (most of whom probably underwent some form of resuscitation) through the subsequent hospital course. These studies were designed to detect improvements in glycemic control and other short-term outcomes, and most have inadequate power to address the other critical and important outcomes of this review. Overall, this evidence update suggests the need to maintain vigilance for neonatal hypoglycemia and hyperglycemia in the aftermath of resuscitation, and the use of protocols for blood glucose management that


avoid both of them and also avoid large swings in blood glucose level. The evidence update also suggests that research to determine the optimal protocols for glycemic management for preterm and term infants in the aftermath of resuscitation, and the optimal target range should be a high priority. Together with the advantages of assessing the certainty of the available evidence using GRADE, there is sufficient new evidence published since the ILCOR CoSTR 2010 relating to blood glucose management during the hospital course after resuscitation, which provides indirect evidence for management immediately after resuscitation, to consider prioritizing blood glucose management for a Systematic Review. Reference list: 1. Adamkin DH. Neonatal hypoglycemia. Curr Opin Pediatr. 2016;28(2):150-155.

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