Pain Management in the NICU

Mohamed El-Dib, MD, FAAPDirector, Neonatal Neurocritical, Brigham and Women's Hospital

Assistant Professor of Pediatrics, Harvard Medical School

Objectives

- Discuss if neonates feel Pain- Explore the effect of pain on the brain- Describe how to assess pain and stress- Non- pharmacological management of Pain- Pharmacological management of pain

Do neonates feel pain?

(Bellieni 2019)

Do neonates feel pain?

How common is pain in the NICU

(Carbajal, Rousset et al. 2008)

430 neonatesNICU in Paris75 (range, 3-364) painful procedures during the study period

10 (range, 0-51) painful procedures per day of hospitalization

Brain Dysmaturation• Brain dysmaturation involves the multiple

active developmental events occurring in human cerebrum during the period of 20 to 40 weeks' gestation and beyond.

• The principal components involved include:• the oligodendroglial (OL) lineage,

especially the preoligodendrocyte (pre-OL)

• cerebral white matter axons• subplate neurons• cerebral cortex• thalamus, • basal ganglia• In addition, microglia and astrocytes

(Volpe 2019)

Pain and Brain Development

(Brummelte, Grunau et al. 2012)

N; 8624–32 w GA

Prospective Number of skin breaksEarly MRI (median, 32.1 weeks) TE MRI e (median, 40 weeks)

Pain and Brain Development

• In linear regression models, cognitive ( 0.04, p 0.003) and motor scores ( 0.06, p 0.0001) at 3 years of age were predicted by thalamic volumetric growth adjusting for sex and GA at birth.

(Duerden, Grunau et al. 2018)

Stress and Brain Development

• Decreased frontal and parietal brain width and altered diffusion and functional connectivity in the temporal lobes.

(Smith, Gutovich et al. 2011)

Figure: Mean functional connectivity correlation maps(A) Term control (B) low-stress (C) high-stress

Pain and Brain Development- School Age

• Thinner cortex in multiple brain regions, predominantly in the frontal and parietal lobes at 8 years of age

(Ranger, Chau et al. 2013)

• Smaller regional volumes in the limbic system and basal ganglia at 8 years of age

(Chau, Ranger et al. 2019)

• Lower FA in superior white matter persists to school age, and associates with IQ.

(Vinall, Miller et al. 2014)

• Changes to background cortical rhythmicity at school-age, which negatively predicts visual-perceptual abilities

(Doesburg, Chau et al. 2013)

Pain or Distress- How can we assess?

• Pain• Acute pain – often accompanied by physiological and behavioral

characteristics

• Chronic pain – much more muted responses and more accompanied by muted behaviors such as decreased activity, altered bowel behaviors etc.

• Stress and Distress• May be related to pain

• Also related to comfort – home environment, lack of sleep, starvation, lack of appropriate nurturing social interactions, poor handling, noise, poor light-dark cycling.

Pain – Evaluation Tools

• All neonatal pain assessment tools comprise of 1 or several observable indicators:

• physiological (e.g., heart rate, blood pressure, respiration rate, oxygen saturation) – objective, but may be influenced by factors other than pain or agitation.

• behavioral (e.g., crying, facial expression, bodily reactions, behavioral state, calming down, skin color) – subjective; facial grimacing specific for pain but cry and bodily reactions may lack sensitivity. Some such as “calming down” are not well operationalized.

• contextual (e.g., gestational age, awake/asleep) – objective, affect physiological and behavioral responses to painful stimuli, but do not indicate the presence of pain.

Five Common Neonatal Pain ToolsTool Score Reliability

Neonatal Facial Coding System-Revised (NFCS-R)

Five domains of facial movement

0-5 High inter-rater and construct validity

Premature Infant Pain Profile-Revised (PIPP-R)

2 physiological, 3 behavioral2 contextual items

0-18 Moderate consistencyGood validity

Neonatal Pain, Agitation and Sedation Scale (N-PASS)

5 items: (1) crying; (2) behavior state; (3) facial expression; (4) tone of extremities; (5) vital sign changes (choice between HR, blood pressure, pulse, and oxygen saturation)

0-13 for preterm

0-10 for term

High consistency

High validity

Treatment recommended with score >3

Neonatal Infant Pain Scale (NIPS) Six behavioral indicators 0-7 High consistencyLimited validity data

Bernese Pain Scale Neonates (BPSN). 3 physiological and 6 behavioral indicators

0-27 High consistencyHigh validity

• 1 painful venipuncture: 1 stressful diaper change

Other Potential Measures

• discriminate noxious painful stimuli from touch with the highest specificityEEG

• detect noxious cortical activation from painful stimuli with oxygenated hemoglobin showing pain-associated increases in the contralateral somatosensory cortex

NIRS

• proposed as a tool for the measurement of autonomic function reflecting pain or stressSkin Conductance

• increase after a painful or stressful experience in preterm and term born infantsSalivary Cortisol

Non-Pharmacologic Management

Modification of Painful Experience• Facilitated tuck (arms/legs in flexed position)

• Music Therapy

• Skin-to-skin contact (“kangaroo care”)

• Infant massage

• Breastfeeding

• Non-nutritive sucking

• Developmentally appropriate care• Limited environmental stimuli

• Lateral positioning

• Supportive bedding

• Attention to behavioral cues

Sucrose

Stimulation of the endogenous opioid system

Mediation of dopaminergic, cholinergic, or serotonergic

pathways Not replicated in preterm infants

Not replicated in human

Effective dose varies substantially in trials (range, 0.05-3 mL of 12%-50% sucrose)A recent randomized trial suggests 0.1 mL of 24% solution reduces the behavioral response to heel lance as effectively as higher doses

(Stevens, Yamada et al. 2018)

SucroseSignificant influence on pain scores during

skin-breaking procedures

•does not decrease oxygen consumption or energy expenditure •has no impact on salivary or plasma cortisol concentrations•has no effect on the neural activity of nociception-evoked circuits in the spinal cord or brain•does not prevent the development of remote hyperalgesia in infants•no impact on measures of motor development or attention/orientation at term-equivalent•no protective effect on brain growth, functional connectivity, and neurodevelopmental impairments at 18 months of age

(Bauer, Ketteler et al. 2004, Slater, Cornelissen et al. 2010, Stevens, Yamada et al. 2016,Taddio, Shah et al. 2009) .(Johnston, Filion et al. 2002) .(Schneider, Duerden et al. 2018)

Sucrose- Dose Matters

Repeated exposure to sucrose in the first week of life (ten times daily) prior to handling or needle-prick as compared to placebo results in long-term alterations in white and gray matter volumes in mice

(Tremblay, Ranger et al. 2017)

Increased sucrose exposure (greater than ten doses per day) was associated with poorer motor development and attention/orientation scores, an association not observed in the placebo group

(Johnston, Filion et al. 2002, Ranger, Johnston et al. 2007)

Pharmacologic Management- Acute Pain

• Appropriate anesthesia prior to major surgery decreases post-operative physiologic instability and the incidence of acute brain injury.

(Anand, Sippell et al. 1987)

• Pre-medication prior to non-emergent endotracheal intubation significantly decreases the time and number of attempts needed to complete the procedure and minimizes the risk of airway trauma.

(Kumar, Denson et al. 2010)

Fentanyl and acute pain

-1

-0.5

0

0.5

1

1.5

2

2.5

nm

ol/

L

Adrenaline

Fentanyl Non-fentanyl

0

1

2

3

4

5

6

7

8

9

mm

ol/

L

Blood glucose

Fentanyl Non-fentanyl

*

*

*

*

*p < 0.025(Anand et al.,1987)

**

16 babies PDA lig randomized 8 PDA anesthesia +Fentanyl8 PDA anesthesia Non-fentanylVery significant less:- Hormonal Stress - Clinical complications

Pharmacologic Management- Continuous Analgesia-Sedation

• Not clear value

• Indicated only when the infant’s physiology demands strict ventilator synchrony and minimization of oxygen consumption

(Ancora, Lago et al. 2019)

• Approaches vary dramatically

(Zimmerman, Smith et al. 2017)

Benzodiazepines

• Bind to the γ-aminobutyric acidA (GABAA) receptor complex

• Sedation and anxiolysis.

24

32

4

0

5

10

15

20

25

30

35

Poor neurologic outcome

Placebo (N = 21) Midazolam (N = 21) Morphine (N = 24)

(Anand, et al., 1999)

*p = 0.03

*

Midazolam- NOPAIN Trial

67 neonates9 centersIntubated less than 8 hLess than 72 hMorphine or Midazolam or D10%PIPPS used Death/IVH III-IV or PVLNo difference in Neurobehavior 36 wGA

0.08

0.11

0.14

0.17

0.2

0.23

0 10 20 30 40 50 60 70

MC

BFV

(m

/s)

Midazolam Vecuronium

30

35

40

45

MA

P (

mm

Hg)

(Van Straaten et al. 1992)

∆, p < 0.001

∆, p = 0.06

Midazolam- Premature infants- GA 26-36 w- randomized - 0.1 mg/kg midazolam (n = 7)- 0.05 mg/kg vecuronium (n = 8)- MAP (arterial catheter)- MCBFV (Doppler MCA every 5

min)

- No Long term follow up

- Preclinical studies shows neuroapoptosis and long term functional and behavioral deficits

(Durrmeyer, Vutskits et al. 2010)

Midazolam

Opioids

Binds G-protein coupled mu opioid receptorsProduces analgesia and sedation

• 898 randomized to preemptive morphine infusion vs placebo. failed to document benefit with regard to acute brain injury.

• Loading dose: (100 mcg/kg), Infusions (23–26 W= 10 mcg/kg/h)(27-29 W=20)(30-32 W=30)

• Continued as long as clinically justified (maximum 14 days).

• Adverse effects :

• prolongation of mechanical ventilation

• delayed tolerance of enteral feedings

• Subtle tone abnormalities at 36 w PMA

• Limited Long-term follow-up

Morphine-NEOPAIN Trial

(Anand, Barton et al. 1999, Anand, Hall et al. 2004)

Steinhorn et al. J Pediatr 2015

r2=0.007

Median cumulative morphine dose 0.79 mg/kgCorrelations between morphine and brain morphology and behavioral dysregulation in infancy No correlation with cognitive or motor outcome at 2 years of age, No correlation with brain morphology or developmental outcome at 7 years of age

Morphine- Dose Matters

Zwicker et al. J Pediatr 2016; 172: 81-7.

Median cumulative dose = 1.905 mg/kg) Strong correlation between morphine exposure and reduced cerebellar volume, poorer cognitive and motor outcomes, and behavioral problems in infancy

Fentanyl

A randomized controlled trial suggests both acute and long-term adverse effects from fentanyl infusion, including:• prolonged duration of mechanical ventilation• association with neurodevelopmental adverse effects at 24

months corrected age(Ancora, Lago et al. 2013, Ancora, Lago et al. 2017)

r2 = 0.531p < 0.001

(McPherson et al, 2015)

Fentanyl – Dose Matters

• Retrospective• 103 preterm (mean GA26.9 ± 1.8

weeks) TE MRI• Cumulative fentanyl in the first week

of life associated with cerebellar hemorrhage (OR 2.1, 1.1-4.1).

• Cumulative fentanyl dose correlated with reductions in transverse cerebellar diameter after correction for covariates, including the presence of cerebellar hemorrhage (r = 0.461, P = 0.002).

• No correlation with development at 2 years of age.

Dexmedetomidine

• Highly selective α2-adrenergic receptor agonist • Provides analgesia, anxiolysis, and sedation• Promising to provide sedation with minimal side effects. (Resp

and GI)• Potentially provides neuroprotection of the immature brain

(Laudenbach, Mantz et al. 2002)

• Clinical data in preterm infants are limited (O'Mara, Gal et al. 2012, Chrysostomou, Schulman et al. 2014)

Agent Advantages Disadvantages

Morphine Increased ventilator synchrony

Decreased adrenaline concentrations

No impact on incidence of severe IVH, PVL, or death

Tachyphylaxis

Hypotension

Prolongation of mechanical ventilation

Prolongation of time to full enteral feedings

Reduced cerebellar growth at high doses

Fentanyl Decreased adrenaline and cortisol concentrations

Less impact on gastrointestinal motility compared to

morphine

Rapid tachyphylaxis

Prolongation of mechanical ventilation

Delayed meconium passage

Reduced cerebellar growth at high doses

Midazolam Decreased sedation scores Increased severe IVH, PVL, or death

Hypotension

Myoclonus

Frequent delirium

Potential for neuroapoptosis and delayed

motor development

Dexmedetomidine Decreased adjunctive sedation compared to fentanyl

Decreased incidence of delirium compared to benzo

Minimal respiratory depression

Minimal impact on gastrointestinal motility

Potential for neuroprotection after PVL, hypoxia-

ischemia, or concurrent neurotoxic drug exposure

Potential hypotension

McPherson, Miller, El-Dib, Massaro and Inder, Pediatric Research- In Print

Take Home Messages

• Pain should be avoided • A systematic scoring system should be adopted after proper

training• Pain should be treated with a stepwise algorithm- Non

pharmacological then pharmacologic • Sucrose could be administered in lowest effective dose less than

ten times /day• Rapidly-acting opioid agents with a relatively short duration of

action (e.g. fentanyl) should be provided prior to moderate painful procedures, including intubations

Take Home Messages

• Stress should be minimized during invasive mechanical ventilation by providing appropriate environment.

• Non pharmacologic therapy has demonstrated safety and effectiveness for preterm infants requiring prolonged, invasive mechanical ventilation

• Low-dose morphine (≤ 10 mcg/kg/hour) may be utilized selectively• In the setting of insufficient sedation from morphine,

dexmedetomidine infusion may be considered