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DOI: 10.1542/neo.11-7-e3432010;11;e343Neoreviews

Roland R. Wauer and Charles Christoph Roehrand CPAP in Extremely Low Gestational Age Neonates, Vienna 2009

International Perspectives : Report on the International Seminar on Surfactant

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Drs Wauer and Roehr have disclosed

no financial relationships relevant to

this article. This commentary does

not contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Report on the International Seminaron Surfactant and CPAP in ExtremelyLow Gestational Age Neonates,

Vienna 2009Roland R. Wauer, MD, PhD*, Charles

Christoph Roehr, MD* for the Scientific

Committee

The following article in our Interna-

tional Perspectives series differs some-what from the usual format. Most of

these pieces either cover what is hap-

pening in a particular country or pro-

vide a regional viewpoint on a selected

topic. The report of this seminar was

suggested by one of our International

Advisory Board members (Dr Mats

Blennow from Stockholm, Sweden)

and provides some insight into what is

currently considered to be important

by influential neonatologists in Eu-

rope. It also provides direction forfuture research activity in several dif-

ferent areas, which may stimulate

some of our North American readers

(as well as our European colleagues).

Not all references provided by the

speakers are included with this report.

The complete list of references may be

obtained by contacting Dr Roehr at

[email protected]. Publication

of this report should not be seen as an

open invitation to submit the pro-

ceedings of all such meetings toNeoReviews. However, there might be

a place for other reports of interna-

tional seminars/symposia, if they deal

with topics that are considered to be of

general interest and have not been cov-

ered in recent issues of the journal.

Alistair G.S. Philip, MD

Editor-in-Chief,NeoReviews

BackgroundThis seminar originated as a spon-

sored research seminar, initiated by

the European Respiratory Society

(ERS) and the Charite Universitas-

medizin Berlin, Germany. At the in-

vitation of the organizing committee(C. Roehr/R. Wauer/A.Greenough/

H. Verder), an international panel

of expert neonatologists and re-

searchers in neonatal medicine pre-

sented the latest data on managing

extremely low gestational age neo-

nates (ELGANs) with continuous

positive airway pressure (CPAP) and

surfactant. The presentations fo-

cused on the pathophysiology of

neonatal lung disease and the pre-

vention and treatment of respiratory

distress in ELGANs. The interna-

tional audience comprised respirolo-

gists, physicians, physiologists, and

neonatal practitioners. Aims of the

seminar were to: 1) Discuss the best

available evidence regarding the use

of surfactant and CPAP in ELGANs,

2) Identify and focus on areas of ur-

gently needed research, and 3) form

international collaborations for fu-

ture research. There was a lively and

productive discussion in between the

presentations and during breaks aswell as during the final panel session.

The individual contributions from

the speakers are summarized in this

article, and pertinent references are

included at the end of the summary.

PresentationsAlan Jobe (Cincinnati Childrens

Hospital, Cincinnati, Ohio, United

States) began with a brief History

of CPAP for Preterm Infants With

*Neonatology Clinic, Charite, Berlin University,

Berlin, Germany.

international perspectives

NeoReviews Vol.11 No.7 July 2010 e343

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RDS. After having been pushed

aside by mechanical ventilation (used

with positive end-expiratory pres-

sure [PEEP]) in the mid-1970s and

1980s, the high incidence of bron-

chopulmonary dysplasia (BPD) in

survivors of mechanical ventilation

resulted in a rebirth of CPAP as a

noninvasive technique to try to de-

crease lung injury. CPAP once again

is used frequently as an initial ther-

apy for respiratory distress syndrome

(RDS), with and without surfactant

administration, as early as in the de-livery room. Many new types of

CPAP applications are available, but

the benefits of CPAP in preventing

BPD remain unproven by random-

ized, controlled trials. Dr Jobe con-

cluded that CPAP is being embraced

with a new enthusiasm in 2009.

In his talk Breathing of Preterm

Infants at Birth, Arjan te Pas (Lei-

den, the Netherlands) focused on gas

flow patterns during the first breaths

after birth. He presented new evi-dence that spontaneous breaths dif-

fer completely from those seen when

manual inflations are given during

neonatal resuscitation. At birth, pre-

term infants use intrinsic PEEP and

expiratory breaking, predominantly

characterized by a breath hold, to

create and maintain lung volume. He

hypothesized that the effectiveness

of respiratory support in the delivery

room may be improved by using a

strategy of aeration similar to sponta-neous breathing patterns. During

manual inflation, delivery of PEEP

should be guaranteed and breath

hold could be mimicked by giving

several sustained inflations. It ap-

pears possible that this approach

(CPAP and sustained inflations) may

prove to be superior in supporting the

breathing pattern of a preterm infant

who is breathing insufficiently, rather

than simply taking over and provid-

ing manual inflations (seeTable 1in

data supplement for issues and pro-

posed actions).

Jane Pillow(University of West-

ern Australia, Perth, Australia) stated

in her topic Transitional Changes

During the First Minutes in Life

Outside the Womb: Understanding

the Mechanisms of Lung Injury

that static and cyclic volutrauma and

exposure to toxins (eg, high oxygen

concentrations) remain the central

issues in resuscitation research, estab-

lishing the optimal transition to post-

natal life. In her opinion, other mod-

ifiable environmental factors alsomay influence lung injury. For exam-

ple, heat, humidification, and flow of

the inspired air (so-called condition-

ing of gas or gas conditioning);

body temperature; and distribution

of surfactant all may be involved.

These areas urgently warrant further

research. Focusing on the establish-

ment of functional residual capacity

(FRC) and using examples from re-

cent studies by te Pas and coworkers

with phase contrast imaging of thefirst postnatal breaths in newborn

rabbit pups, she stated that establish-

ment of FRC is primarily dependent

on PEEP. In contrast, establishment

of adequate and appropriately dis-

tributed tidal volumes can be

achieved rapidly with sustained infla-

tions. Supporting the data from

tePas, she also suggested that the

combination of sustained inflations

with the first breaths and the use of

PEEP during resuscitation may helpestablish noninjurious cyclic ventila-

tion at appropriate FRC more effec-

tively and efficiently than alternative

approaches.

During the final discussion, both

te Pas and Pillow stated that further

research studies are in progress that

should help to define further the

optimal application of sustained in-

flations and establish whether the

physiologic benefits translate into re-

duced lung injury. They stressed that

depending on the outcome of these

studies, planning of clinical trials to

assess the merits of these approaches

in human infants would be appropri-

ate in the near future.

Bronchopulmonary Dysplasia:

One Disease or Two? asked Mario

Rudiger(Neonatology, Carl Gustav

Carus Universitat, Dresden, Ger-

many). He stated that classical

BPD and new BPD not only dif-

fer in their clinical pictures but also

in their pathogenesis and morphol-

ogy. The arrest in alveolarization

seen in patients who have new BPDis believed to result from a postnatal

disturbance of lung development.

Alveoli develop in utero at low oxy-

gen concentrations, but ELGANs

are exposed to relative hyperoxia,

even if breathing room air. Relative

hyperoxia leads to a decrease in

hypoxia-inducible factor and its

products, such as vascular endothe-

lial growth factor (VEGF). Rudiger

proposed that future research con-

centrate on clinically useful markersfor better discrimination between the

two types of BPD. In a second step,

interventions should be tailored ac-

cording to the pathogenesis of each

and targeted to either type of disease.

Whereas steroids might be appropri-

ate for classical BPD, the new BPD

may be prevented by substituting

lung growth factors, such as VEGF,

or by reducing the effects of relative

hyperoxia.

Colm ODonnell(Neonatal Ser-vices, National Maternity Hospital,

Holles Street, Dublin, Ireland) spoke

about Handling of the Neonate in

the First Minutes of Life: Practical

Observations. He found that new-

borns often were handled roughly,

dried vigorously, and suctioned per-

haps too enthusiastically. Preterm in-

fants most often cried and breathed

spontaneously after birth, even be-

fore any respiratory support was

given, and clinical assessment of in-


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fant condition at birth was highly

subjective, with observers frequently

disagreeing. He concluded that the

standard approach to all infants at

birth appears to be to suspect that

they will behave like, and respond

to the same treatment, as an acutely

asphyxiated term animal. Such an

approach may lead to term and pre-

term infants receiving interventions

that are not helpful and potentially

harmful.

During the final discussion, the

panel accepted that filming is a useful

tool for reviewing and improving re-suscitation skills. Although seminar

participants agreed that videotaping

seems useful for research and educa-

tional purposes, it is not yet ready for

use in day-to-day clinical practice.

Kajsa Bohlin (Neonatal Depart-

ment, Karolinska Institute, Stock-

holm, Sweden) summarized the

Effect of Different Ventilation

Techniques on Surfactant Stability

and Metabolism. The surfactant

synthesis rate is slow, and the recy-cling of surfactant components be-

tween the airspaces and alveolar type

II cells is more important in preterm

compared with term lungs. The effi-

cacy of exogenous surfactant treat-

ment depends on distribution of sur-

factant, surfactant metabolism, and

lung injury, all of which can be influ-

enced by ventilation strategy. Careful

delivery room management is crucial

because even only a few large breaths

may impair surfactant treatment re-sponse and distribution pattern. Sur-

factant metabolism during CPAP

and promising new lung protective

ventilation strategies require further

study, as does a means to reduce the

susceptibility to inhibition of exoge-

nous surfactant. Methods to assess

the need for surfactant treatment and

studies on how to incorporate sur-

factant administration into an early

CPAP protocol to ensure optimal

treatment response are warranted.

Anne Greenough (Kings Col-

lege Hospital, London, United

Kingdom) gave an overview on Me-

chanical Ventilation Versus CPAP:

What are the Pros and Cons? She

summarized four primary points:

1) Results from randomized trials

suggest prophylactic or early nasal

CPAP may reduce BPD, but further

studies are required to determine

the relative contributions of an early

lung recruitment policy, early sur-

factant administration, and nasal

CPAP in reducing BPD. 2) High-

volume high-frequency oscillatoryventilation (HFOV) reduces BPD,

but whether it improves long-term

lung function requires follow-up of

infants entered into randomized,

controlled trials. 3) Weaning from

the respirator is best achieved by us-

ing modes supporting every breath.

4) A trial of rescue HFOV in severe

respiratory distress with long-term

outcomes is needed.

The topic ofAngela Kribs(Neo-

natology, Universitatsmedizin, Koln,Germany) was Treating Preterm

Infants With Surfactant: An Over-

view of Application Techniques

and Results. After demonstration

of published methods of surfactant

application in the delivery room (in-

trapartum into the nasopharynx be-

fore birth of the shoulders, via a

laryngeal mask, nebulization) and

discussion of the pros and cons, she

presented her preferred method of

surfactant application via a thin en-dotracheal catheter during spontane-

ous breathing in ELGANs. After in-

troduction of this method, the need

for mechanical ventilation was re-

duced from 77% to 48%, mortality

from 35% to 12%, and the incidence

of more than second-degree intra-

ventricular hemorrhage from 32% to

5% compared with historical con-

trols. The new method is being

tested in two prospective, random-

ized trials.

Colin Morley (Melbourne, Aus-

tralia) spoke about Understanding

CPAP: Why Does It Work and When

Should We Use It? He presented

data about how CPAP aids the for-

mation and maintenance of FRC,

improves oxygenation, reduces air-

way resistance, improves compliance,

conserves surfactant, improves the

respiratory pattern, and reduces the

need for ventilation in preterm in-

fants. He suggested that the indica-

tions for the use of CPAP were: all

very preterm infants breathing at

birth, all infants who have dyspnea,and for apnea and postextubation in

preterm infants. He concluded that

more research is needed to under-

stand how CPAP works in different

situations and the optimum pressure

or device and interface to use. It is

also necessary to investigate which

infants do well with nasal CPAP early

on and which ones will fail CPAP and

require early intubation, ventilation,

and surfactant (see Table 2 in data

supplement for issues and proposedactions).

In his topic How is CPAP Cur-

rently Being Used: An Overview,

Charles Christoph Roehr (Berlin,

Germany) reported results from two

questionnaire-based surveys of 274

institutions from German-speaking

countries about the clinical indica-

tions for and type of CPAP equip-

ment used. The primary indications

were treating RDS (98%) and apnea-

bradycardia-syndrome (96%) andfollowing extubation (98%). Com-

mercial CPAP systems (mostly

respirator-generated) were used by

71% of units, with exclusively

mononasal by only 9%, exclusively

binasal by 55%, and all other units

using both interfaces. The reported

differences (in the starting and max-

imum tolerated pressure) reflect per-

sonal experiences and preferences

rather than sound evidence from

clinical trials. Several questions re-




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garding the clinical use of CPAP re-

main unanswered, such as the appro-

priate device and pressure for specific

clinical conditions, the ideal individ-

ual level of flow, and a practical pro-

tocol for weaning from CPAP. Such

questions should be answered in

well-conducted clinical trials.

Speaking on CPAP and PEEP

Provision: Physiologic Effect of Dif-

ferent Pressure Levels, Mathias

Nelle(Berne, Switzerland) reviewed

the literature about effects of nasal

CPAP on different organ systems in

neonates, especially how lung com-pliance, cardiac output, and blood

flow to various organs can be af-

fected. He suggested that many

questions remain unanswered and

the topic remains somewhat con-

troversial. Generally, nasal CPAP

appears to be well tolerated in neo-

nates, but factors influencing circula-

tion should be known and consid-

ered in daily treatment procedures.

Gerd Schmalisch (Berlin, Ger-

many) provided insight into theMonitoring of Ventilation and Air

Leakage During CPAP. In contrast

to adults, little is known about vol-

ume and air leakage monitoring dur-

ing CPAP in neonates because the

measuring conditions are difficult

and suitable equipment currently is

not available. Mostly, indirect meth-

ods (transthoracic impedance mea-

surements, breathing belts) are used.

However, these techniques do not

allow reliable volume measurementsand do not give any information

about air leakage. In a survey, several

different direct measurement tech-

niques to assess ventilation and air

leakage based on the different CPAP

interfaces (facial mask, head box,

mono- or binasal prongs, pharyngeal

or endotracheal tubes) were de-

scribed, and their suitability was

tested in clinical studies. Based on

modeling, the relationship between

air leakage, leak flow, and volume

error were investigated and validated

by in vitro measurements. The cur-

rent display of air leakage as a per-

centage of measured patient ventila-

tion has several disadvantages and

should be replaced by direct mea-

surement and display of leakage flow.

The measurement of the leakage flow

may be helpful in assessment of

CPAP treatment and the prevention

of adverse effects (eg, impairment of

the nasal or upper airway mucosa).

Essence, Reflection, and

OutlookDuring the final panel session of all

experts, the following issues that

might be answered by further re-

search were emphasized: 1) Basic re-

search on CPAP in the delivery room

and evaluation of its chronic use;

2) Cross-over study to find the opti-

mal CPAP level, independent of

FiO2 enhancement; 3) Search for

parameters/methods to describe

better the adaptation process of the

term and preterm infant and theestablishment of FRC; 4) Search

for clinical evidence of the necessity

for gas conditioning in the deliv-

ery room and during transport;

5) Search for the optimal CPAP in-

terface between apparatus and infant

(mask, single tube, binasal prongs,

head box); and 6) Practical parame-

ters for identification of preterm in-

fants who only need CPAP and those

who need additional surfactant (see

Table 3in data supplement for issuesand proposed actions).

The enthusiastic atmosphere of

the seminar, its results, and the fruit-

ful discussions delighted the partici-

pants and encouraged the organizers

and speakers to continue this collab-

oration. Thanks to the generosity of

the ERS, funding for a further re-

search seminar at the upcoming ERS

Congress in Barcelona on September

18, 2010, is planned. The seminar

will concentrate on Managing the

Lung of the Extremely Low Gesta-

tional Age Neonate (ELGAN) in the

Delivery Room.

The seminar was generously

funded by unconditional research

grants by the ERS, Chiesi, Fisher &

Paykel Healthcare, and Abbott Phar-

maceuticals.

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Infants Wih RDS

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American Board of Pediatrics

Neonatal-Perinatal Medicine

Content Specifications

Know the clinical

strategies andtherapies used to

decrease the risk

and severity of

RDS.

Know the indications for and

techniques of continuous positive

airway pressure (CPAP),

Know the effects and risks of CPAP.




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Angela Kribs: Treating Preterm Infants

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DOI: 10.1542/neo.11-7-e343

2010;11;e343NeoreviewsRoland R. Wauer and Charles Christoph Roehr

and CPAP in Extremely Low Gestational Age Neonates, Vienna 2009International Perspectives : Report on the International Seminar on Surfactant

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