sedation and analgesia in pediatric mechanical ventilation...

Sedation and analgesia in pediatric mechanical

ventilation: are we doing it optimally ?

Dick Tibboel; Erwin Ista; Nienke Vet; Monique van Dijk

Erasmus MC – Sophia Children’s Hospital

Rotterdam, The Netherlands

[email protected]

Sleep deprivation

Environment (Light and Noise)

Sedatives

Critical illness

Caregiver interaction

Post-traumatic stress (trauma/burns)

Changes in sleep-wake cycle

Circadian rhythm disturbance

Sleep loss / fragmentation

Physiologic sedative Dependence (→ iatrogenic withdrawal)

Prolonged MV

Delirium

Changes in long-term neurocognition Kudchadar et al. (2014) Sleep Medicine Reviews

Finding the optimal balance between

analgesia, sedation, anxiolysis and sleep is

integral to the care of PICU patients

CCM 2013

Adult patients!

CCM 2013

Prevention of iatrogenic withdrawal

Change of sedation practice:

Daily interruption of sedation

Change drug: from benzo’s to dexmedetomidine/clonidine

Nursing-controlled sedation management protocol

Drug rotation

e.g. Morphine fentanyl

Gupta et al. 2012

Intensive Care Med 2016

COMFORTneo scale

Six behavioral items

Alertness (redefined)

Calmness

Respiratory response

or crying (in non-

ventilated patients

Facial tension

Body movements

Muscle tone (mere

observation no touch)

Midazolam

Short acting benzodiazepine

Short elimination half life, time to peak sedation is 5 – 10 min. after

IV use

Duration of action 30 – 120 min.

Metabolised by CYP450 enzym 3A4 and Glucuronidated

Main adverse effects: tolerance, dependency and withdrawal;

respiratory depression

Licensed throughout the EU and in the USA

Clonidine

Alpha-2 adrenoreceptor agonist

Long eliminiation half life of 9 – 17 hours

Loading dose required for therapeutic steady state concentrations

Produces sedation without respiratory depression and exerts

anxiolytic effects together with analgesic effects

Is a hypotensive agent for treatment of arterial hypertension

Adverse effects: hypotension and bradycardia

PCCM, 2014

Editorial PCCM, 2014

SLEEPS-study

RCT of IV Midazolam versus IV Clonidine

Calculated sample size 1000 PICU patients

PICU’s in the UK

Outcome: efficacy of sedation

Study stopped preterm due to low inclusion of N=200 patients

No PK-data available

Propofol (2,6-diisopropyl phenol)

Used for short or long term sedation

Commercially available as 1%. 2% and 6%

Only advised for short duration procedures

FDA warning for children less than 12 years of age due to the

propofol infusion syndrome

Dexmedetomidine

Central acting Alpha-2 adrenoreceptor agonist

Same physiological effects as Clonidine

Half life time 2 – 3 hours, titration by IV administration

Approved by FDA for short term sedation of adult! patients

during mechanical ventilation and for monitored anesthesia care

No specific pediatric indications but extensively used in PICU’s

and operating rooms predominantly in the US

So far high costs euro 65 compared to midazolam euro 2,50

Pediatric Cardiac Intensive Care Society 2014

Consensus Statement: Pharmacotherapies in

Cardiac Critical Care: Sedation, Analgesia and

Muscle Relaxant

Lucas SS et al. Pediatr Crit Care Med, 2016;17:S3-S-15

Conclusions:

Multiple pharmacological therapies exist to

achieve these goals and should be selected

based on the patient’s underlying physiology,

hemodynamic vulnerabilities, desired level of

sedation and analgesia, and the projected short-

or long-term recovery trajectory.

Lucas SS et al. Pediatr Crit Care Med, 2016;17:S3-S-15

CONCLUSION:

Neonates and young infants have a decreased metabolism of

common opioids like fentanyl and therefore are more prone to

respiratory depression.

Remifentanil could be the ideal opioid for analgesia and sedation

of mechanically ventilated infants.

PCCM 2013

IATROGENIC WITHDRAWAL

Withdrawal Syndrome in ventilated children

Undersedation

Agitation

Risk of displacement of tubes, etc.

Risk of oversedation:

•Prolonged mechanical ventilation

• Higher incidence of

• Delirium

• Withdrawal syndrome

• Increased health care costs

Definition of terms

Tolerance:

Decreasing clinical effects of a drug after prolonged exposure to it (Tobias, 2000; Anand, 2010)

Physical dependence:

A physiologic and biochemical adaptation of neurons such that

removing a drug leads to withdrawal or an abstinence syndrome

(Cunliffe et al., 2004; Anand, 2010)

Withdrawal Syndrome in Children

Withdrawal syndrome:

A set of symptoms that manifests when a drug which causes physical

dependence is stopped, reduced too quickly or antagonized

(Cunliffe et al., 2004; Anand & Arnold, 2010)

Onset depends on half-life of drug and its metabolite

Onset depends on clearance of active metabolites

Signs and symptoms of withdrawal may present

1 hour to 5 days after discontinuation

Withdrawal syndrome, a problem??

Opioid withdrawal:

• Neonates (ECMO): 57% (Arnold et al. 1990; Franck et al. 1995)

• Children (57%) (Katz et al., 1994)

Benzodiazepine withdrawal:

• 17 to 35% (Hughes et al., 1994; Fonsmark et al., 1999)

Combined - benzo’s / opioids:

• 34 to 76%

(Sfoggia et al. 2003; Fernandez et al. 2012; Franck et al. 2008 & 2012; Ista et al. 2013)

Risk factors

Duration of infusion ≥ 5 days

Dosages (maximum, cumulative dose)

Fentanyl: 1.6-2.5 mg/kg (Arnold et al., 1990; Katz et al., 1994)

Midazolam: 60 mg/kg, >70mg/kg (Fonsmark et al., 1999; Ista et al., 2008)

Withdrawal symptoms

Behavioral (CNS) Gastrointestinal Physiological / other

Agitation Vomiting Heart rate (tachycardia)

Anxiety Diarrhea Arterial blood pressure (hypertension)

Increased muscle tone Poor feeding Breathing rate (tachypnea)

Tremors Fever

Motor disturbance Sweating

Inconsolable crying Sneezing

Sleeping pattern Yawning

Grimacing Mottling

Pupil dilation

Convulsions / seizure

Hallucinations

High-pitched crying

Hyperactive Moro-Reflex

Ista et al. 2007

Withdrawal syndrome assessment tools - Children

Instrument (author, year)

Patients Observation items Reliability

& validity CZS GI Auto Others

Sedation withdrawal score

(SWS) (Cunliffe, 2004)

Children X X X -

Opioid Benzodiazepine

Withdrawal Score (OBWS) (Franck et al., 2004)

Children

X X X X +/-

Withdrawal Assessment

Tool version 1 (WAT-1) (Franck et al., 2008)

Children X X X X

+

Sophia Observation

withdrawal Symptoms-scale

(SOS) (Ista et al., 2009)

Children X X X +

(Franck et al., 2008 & 2012) Cut off score: ≥3 withdrawal

Sophia Observation withdrawal Symptoms-

scale (SOS)

Ista et al. Intensive Care Med 2009

Cut off score: ≥4 withdrawal

Weaning protocol

Sedatives/opioids

5-9 day Sedatives/opioids

≥ 10 days

Monitor level of sedation with COMFORT behaviour

scale

Monitor withdrawal symptoms with SOS

Decrease

sedatives/opioids

10% per 8hrs

Decrease

sedatives/opioids

10% per 24hrs

If necessary:

1. Switch IV to oral

2. Decrease sedatives/

opioids 10% per 8hrs

1. Switch IV to oral

administration

2. Decrease sedatives/

opioids 10% per 48hrs CAVE:

switching takes

± 48 hrs per

drug; One drug

at the time

e.g. Morphine

methadone

agitation

body movements

Sleep problems

tremors

Vomiting and diarrhea

confusion

anxiety

irritable

fidgety

Pulling out lines

DELIRIUM

Pediatric Delirium in ventilated children

Delirium

Acute Brain failure

DSM-IV definition: (Diagnostic and Statistical Manual of Mental Disorders)

1. Disturbance of consciousness

2. Change of cognition

3. Acute onset and fluctuation

4. Physiological consequence

Phenomenology

There are 3 subtypes which often switch during day and NIGHT (“sun

downing”)

Hyperactive

Agitation – pulling lines out, motor disturbance - restlessness,

impaired alertness etc.

Hypoactive (“still or quietly delirium”)

Apathy, slow/sparse speech, hallucinations

Mixed hypo- and hyperactive

Delirium ….. a problem?!

Danger for the patient himself

Neurometabolic stress

Traumatic event for parents, caregivers

1/3 of patients suffers from PTSD (Colville et al. 2008)

Colville G, Kerry S, Pierce C. Children's factual and delusional memories of intensive care. Am Respir Crit Care Med 2008;177(9):976-982.

Prevalence of Delirium

0

5

10

15

20

25

30

%

Risk factors for developing delirium

Sleep deprivation

Sedatives / opioids (iatrogenic withdrawal)

Environmental factors (light, noise)

Infection

Assessment of Pediatric Delirium in PICU

patients

Cognitive function

Pediatric Confusion Assessment Method-ICU (Smith et al. Crit Care Med 2011)

Observational / behavioral

Pediatric Anesthesia Emergence Delirium Scale (Sikich et al. Anesthesiology

2004)

Cornell Asssessment of Pediatric Delirium, CAP-D (Silver et al. Intensive Care

Medicine 2012; Traube et al. 2013 Crit Care Med)

Adapted Sophia Observation withdrawal Symptoms-Pediatric Delirium

scale (Van Dijk, Knoester, Beusekom, Ista, Intensive Care Medicine 2012)

Instrument (author, year)

Population Sensitivity * Specificity * Cutoff

pCAM-ICU (Smith, 2011)

N=68

> 5 yrs. 83% (66-93%) 99% (95-100) Pos./neg.

PAED (Janssen, 2011)

N=154

1-17yrs. 91% (ND) 98% (ND) ≥8

PAED (Blankespoor, 2012)

N=144

1-18 yrs. 100 (ND) 91.7 (ND) ≥8

CAP-D (Silver 2010)

N=50

3m - 21yrs. 97% (ND) 91% (ND) ≥10

CAP-D (Traube 2013)

N=111

0 - 21yrs. 94% (84-99%) 79% (74-85%) ≥9

SOS-PD (Ista, Unpublished)

N=14

3m - 18yrs. 91% (76-98%) 97 (83-99%) ≥4

* (95% Confidence Interval)

Treatment and Prevention of delirium

Non pharmacological

parental presence,

pictures of familiar people and objects,

familiar music

Promoting normal day-night cycle

Pharmacological

Haloperidol / Risperidone

Change sedation practice

Summary

Be aware of effects of ventilation and sedation

Sleep deprivation

Withdrawal syndrome

Pediatric Delirium - neglected phenomenon

Assessment – first step, recognition

Sleep promotion

Exploration of initiatives of new sedation practices

Challenges and solutions

Easy acces to training modules in different languages in a web based

way

Structured collaboration between hospital pharmacists and treatment

teams

Application of population PK-PD approaches for future trial design and

dosing

Detailed psychometric analysis of the existing pain assessments

instruments and prevent the use of 90 percent of the instruments

Challenges and solutions

To perform research beyond acute pain such as for neuropathic- and

(sub) acute and chronic pain

Take into account the multidimensional character of pain;agitation and

fear

Do not score in the absence of a pharmacological sound treatment

algorithm based on population PK-PD and Physiology based PK

methodology

Future perspectives:

The Perfect Neonatal Pain Measurement Instrument

(Sinno Simons 2004) ; still searching for the holy grail ?!

Pain: 6.8

GIVE MORPHINE

PAIN MEASURE

Pain: 6.8

GIVE MORPHINE

Pain: 6.8

GIVE MORPHINE

Questions - Discussion

Acknowledgements:

Monique van Dijk

Dick Tibboel

Harma te Beest

Matthijs de Hoog

Enno Wildschut

Saskia de Wildt

Clin Pharmacokinet. 2016 May;55(5):507-24

Clin Pharmacokinet. 2016 May;55(5):507-24.

Conclusion

Gaps in our knowledge

The uncertainty of the level of modulation of the nociceptive stimulus by

(non)-pharmacological interventions

The effect of previous pain experiences and its therapy on new painful

events (pain memory??)

The difficulty to “visualize” pain

The proven validity of many of the pain scales and their sensitivity to

change

The lack of a real interdisciplinary approach

Questions of parents after admission

Will our child survive ?

How long will our child stay in the PICU ?

Will there be remaining problems after discharge ?

Do you guarantee that our child will not suffer

from pain and/or anxiety

PAIN:is there a real difference ??

The use of “biomarkers” is widely accepted to determine therapy in

Sepsis

Acute kidney injury

Traumatic brain injury, but

Debatable in the assessment of pain and

eventually anxiety ??

From No-scoring to One size fits All

Important methodological short comings

The quality of the studies using pain scores and it’s relative significance

is very variable

In many institutions appropiate training and subsequent implementation

is not well established

The real pharmacodynamic parameter for the use of analgesic drugs is

the change in pain score and the sensitivity to change of the score

Pain is composed of 4 levels ( Loeser)

Nociception

The central nervous system

Perception

Behaviour

is a bio-psycho-social phenomenom

No scoring of PAIN in your unit means:

Continuation of subjectivity of individual nurses and physicians

Denial of solid scientific data showing that validated PD parameters

have a major effect on drug dosing and even the choice of analgesic

drugs

Lack of transfer of objective parameters to your collagues resulting in

continuation of drug overdosing to keep the patient “quiet”

Lack of transferable approaches for “Precision Medicine” in the best

interest of the individual child

Why do we monitor pain?

Pain is considered the 5th vital sign

Untreated pain results in increased mortality

Inadequate pain treatment, mainly overdosing, leads to prolonged

duration of artificial ventilation and LOS

To prevent suffering as the most important argument to treat and

monitor pain is:

to be HUMANE

The significant lack of articles on PICU patients is a real problem !!!

SLEEP DEPRIVATION

Improving sleep quality in ventilated children

Normal sleep pattern

Newborns:

Up to 18hrs per day (irregular schedule)

0-12 months

Becomes consolidated

3-12 years:

One period at night

Sleep 9-10hrs per nights

Sleep problems

Recollection

“unable to sleep” 16-18%

(Playfor et al. 2000; Karande et al. 2005)

Observational studies (n=9) (Kudchadkar et al. 2014)

Decease REM sleep

“Catnaps”, frequently awake

Noise

Level 50-80 dBA (< 30 dBA WHO recommendation)

Oral Clonidine 5 micrograms/kg versus placebo

Intervention to improve Sleep-wake cycle

Non invasive

Earplugs, noise reduction protocols,

lighting optimization, sleep hygiene

Pharmacological

Melatonin, change of sedation

practice (clonidine, dexmedetomidine)

Culture change

Inhibition proteins

Downregulation of

opioid receptors

Increased production NO

(Anand et al. 2010)

sedation and analgesia in pediatric mechanical ventilation...

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