Effect of sedative and analgesic on neonatal outcome

1. Balancing the Use of Sedatives andBalancing the Use of Sedatives and
Analgesics in Neonates: Risks andAnalgesics in Neonates: Risks and
Associated NeurodevelopmentalAssociated Neurodevelopmental
OutcomesOutcomes
BYBY
DR. Magdy ShafikDR. Magdy Shafik
Senior Pediatric ConsultantSenior Pediatric Consultant
Diploma, M.S ,Ph.D of PediatricDiploma, M.S ,Ph.D of Pediatric

2. ObjectivesObjectives
 Describe the impact of pain experiences and theDescribe the impact of pain experiences and the
developing braindeveloping brain
 Summarize pain assessment tools used withSummarize pain assessment tools used with
newbornsnewborns
 Discuss sedation analgesia strategies‐Discuss sedation analgesia strategies‐
 –– Non pharmacologic pain control in newborns‐Non pharmacologic pain control in newborns‐
 –– Review of frequently used medications in the NICUReview of frequently used medications in the NICU
 Examine the short and long term effects anesthesia‐Examine the short and long term effects anesthesia‐
exposureexposure
 Identify recommendations to guide provisionIdentify recommendations to guide provision
sedation analgesia in the NICU‐sedation analgesia in the NICU‐

3.  Stress is defined as a physical, chemical, orStress is defined as a physical, chemical, or
emotional factor that causes bodily or mentalemotional factor that causes bodily or mental
tension and may be a factor in disease causation.tension and may be a factor in disease causation.
 Pain is always stressful, but stress is notPain is always stressful, but stress is not
necessarily painfulnecessarily painful..

4. Pain and the Developing BrainPain and the Developing Brain
•• Newborn periodNewborn period is a time ofis a time of rapid brain growthrapid brain growth,,
development and particular vulnerabilitydevelopment and particular vulnerability
••
On average a preterm neonate experiencesOn average a preterm neonate experiences ~ 5 15‐~ 5 15‐ painfulpainful
proceduresprocedures per day (~ 7/d from admissionper day (~ 7/d from admission to termeto terme
quivalent age or discharge)quivalent age or discharge)
 Exposure to pain in preterm infants isExposure to pain in preterm infants is multifactorialmultifactorial
 Increased stress associated withIncreased stress associated with decreased frontal lobedecreased frontal lobe
width,width, abnormal temporalabnormal temporal lobe diffusion and neurallobe diffusion and neural
networksnetworks

5.  Preterm infants thought to have diminished painPreterm infants thought to have diminished pain
perceptionperception
due to CNS immaturitydue to CNS immaturity
 –– Sensory receptors and nerve fibers appear in the perioralSensory receptors and nerve fibers appear in the perioral
area by 7area by 7thth
week of gestation and spread to:week of gestation and spread to:
 •• Face, palms and soles by week 11Face, palms and soles by week 11
 •• Trunk, arms and legs by week 15Trunk, arms and legs by week 15
 •• All cutaneous surfaces by week 20All cutaneous surfaces by week 20
 •• Integrated nociceptive pathways are functional by 24 to 28Integrated nociceptive pathways are functional by 24 to 28
weeks’ gestationweeks’ gestation

6. How Pain is Transmitted to theHow Pain is Transmitted to the
BrainBrain

7. Neonatal pain and developmental outcomes inNeonatal pain and developmental outcomes in
children born pretermchildren born preterm
 Greater number of painful procedures in infantsGreater number of painful procedures in infants
born extremely preterm (< 29 w GA) associatedborn extremely preterm (< 29 w GA) associated
withwith
 –– Delayed postnatal growthDelayed postnatal growth
 –– Poor early developmentPoor early development
 –– High cortical activationHigh cortical activation
 –– Altered brain developmentAltered brain development
 –– Poor quality cognitive and motor development atPoor quality cognitive and motor development at
1 y age1 y age
 –– Changes in cortical rhythmicity and corticalChanges in cortical rhythmicity and cortical
thickness in children at age 7thickness in children at age 7

8. OUTLINEOUTLINE
 Pain and the developing brainPain and the developing brain
 –– Effects of pain on the developing brainEffects of pain on the developing brain
 •• Assessment of pain in newbornsAssessment of pain in newborns
 •• Pain ManagementPain Management
 –– Non pharmacologic pain control in newborns‐Non pharmacologic pain control in newborns‐
 –– Review of frequently used medications in the NICReview of frequently used medications in the NIC
 •• Review of Weiler NICU practicesReview of Weiler NICU practices
 •• SummarySummary
 •• RecommendationsRecommendations

9. Effect of Pain and Inadequate Pain Control on theEffect of Pain and Inadequate Pain Control on the
Developing BrainDeveloping Brain
 Immaturity of dorsal horn synaptic connectivityImmaturity of dorsal horn synaptic connectivity andand
descending inhibitory circuits in neonates results in:descending inhibitory circuits in neonates results in:
–– Poor localization and discrimination of sensory inputPoor localization and discrimination of sensory input
and poor noxious inhibitory modulationand poor noxious inhibitory modulation
 •• Repetitive noxious stimuli canRepetitive noxious stimuli can lead to acutelead to acute
physiologic and biochemical markers of stress that canphysiologic and biochemical markers of stress that can
lead to:lead to:
–– Impaired ventilation, changes in intra thoracic &Impaired ventilation, changes in intra thoracic &
arterial pressures, IVH, PVLarterial pressures, IVH, PVL
–– Emotional/behavioral problems in childhood such asEmotional/behavioral problems in childhood such as
anxiety, depression, and suicidal tendenciesanxiety, depression, and suicidal tendencies

11.  Exposure to procedural pain has been associatedExposure to procedural pain has been associated
with poorer cognitive & motor outcomes, reducedwith poorer cognitive & motor outcomes, reduced
white matter & subcortical grey matter maturation,white matter & subcortical grey matter maturation,
altered corticospinal tract structure & growthaltered corticospinal tract structure & growth
impairment.impairment.
 Functional brain MRI of former preterm neonatesFunctional brain MRI of former preterm neonates
showed greater activation of sensory areas inshowed greater activation of sensory areas in
response to pain compared to former full termresponse to pain compared to former full term
controls.controls.
 Early neonatal pain related stress are associated with‐Early neonatal pain related stress are associated with‐
reduced white matter and subcortical grey matterreduced white matter and subcortical grey matter
maturation on MRImaturation on MRI

12. Painful Procedures in the NICUPainful Procedures in the NICU
  DiagnosticDiagnostic (e.g., arterial puncture,(e.g., arterial puncture,
 venipuncture,venipuncture,
 heel prick,heel prick,
 lumbar puncture)lumbar puncture)
  TherapeuticTherapeutic (e.g., umbilical catheterization,(e.g., umbilical catheterization,
chest physiotherapy,chest physiotherapy,
dressing change,dressing change,
removal of adhesive tape,removal of adhesive tape,
nasogastric tube insertion,nasogastric tube insertion,
peripheral venous catheterization,peripheral venous catheterization,
tracheal intubation/extubation and tracheal suctioning)tracheal intubation/extubation and tracheal suctioning)

13. ASSESSMENT OF PAIN IN NEONATESASSESSMENT OF PAIN IN NEONATES
 Physiologic parameter changesPhysiologic parameter changes::
–– Changes in HR, RR, BP, SaO2Changes in HR, RR, BP, SaO2
–– Vagal toneVagal tone
–– Breathing patternBreathing pattern
–– Palmar sweatingPalmar sweating
–– Skin colorSkin color
–– Pupillary sizePupillary size
 Behavioral responses:Behavioral responses:
–– Crying patternsCrying patterns
–– Facial expressionsFacial expressions
–– Hand and body movements – Muscle toneHand and body movements – Muscle tone
–– Sleep patterns, behavioral state changesSleep patterns, behavioral state changes
–– ConsolabilityConsolability

14. Multidimensional Pain Assessment ToolsMultidimensional Pain Assessment Tools

15. Recommended assessment toolsRecommended assessment tools::
►► Premature Infant Pain profile (PIPP):Premature Infant Pain profile (PIPP): the onlythe only
validated method for pain assessment among pretermvalidated method for pain assessment among preterm
infantsinfants
►► Behavioral Pain Score (BPS)Behavioral Pain Score (BPS)
►► Neonatal Infant Pain Scale (NIPSNeonatal Infant Pain Scale (NIPS))

19. N PASS (Neonatal Pain, Agitation and Sedation‐N PASS (Neonatal Pain, Agitation and Sedation‐
Scale)Scale)
N PASS score < 4 = mild pain (non pharm rx); > 5 = mod‐ ‐
severe pain (non pharm + pharmacologic measures‐

20. Non pharmacological Pain Control in‐Non pharmacological Pain Control in‐
NewbornsNewborns
 BreastfeedingBreastfeeding in combination w/in combination w/ skin to skin‐ ‐skin to skin‐ ‐ (STS)(STS)
contactcontact
 Non nutritive sucking‐Non nutritive sucking‐ : oral sucrose or glucose solution: oral sucrose or glucose solution
 Swaddling or facilitated tuckingSwaddling or facilitated tucking (defined as gently(defined as gently
maintaining the arms and legs in a flexed position)maintaining the arms and legs in a flexed position)
 Skin to skin contact‐ ‐Skin to skin contact‐ ‐ (e.g., kangaroo care)(e.g., kangaroo care)
 SensorialSensorial saturationsaturation (use of touch, massage, voice, and(use of touch, massage, voice, and
smell)smell)
•• Combinations of non pharmacologic‐Combinations of non pharmacologic‐ measures (sucrose andmeasures (sucrose and
skin to skin contact) have additive‐ ‐skin to skin contact) have additive‐ ‐ or synergistic effectsor synergistic effects..
SucroseSucrose : 24-50%, 0.1-2 ml orally; 2 minutes before: 24-50%, 0.1-2 ml orally; 2 minutes before
procedure via syringe or pacifierprocedure via syringe or pacifier
GlucoseGlucose : 30%, 0.3-1 ml orally; 1-2 minutes before procedure: 30%, 0.3-1 ml orally; 1-2 minutes before procedure

21. Stepwise approach for the management ofStepwise approach for the management of
acute pain in neonatesacute pain in neonates

22.  •• Local Analgesia:Local Analgesia:
–– EMLAEMLA creamcream or tetracaine gel in addition to theor tetracaine gel in addition to the
administration of oral glucose to reduce pain associatedadministration of oral glucose to reduce pain associated
with venous, arterial, or lumbar punctures, andwith venous, arterial, or lumbar punctures, and
peripheral venous or arterial catheter insertion.peripheral venous or arterial catheter insertion.
–– Lidocaine infiltrationLidocaine infiltration is used during surgicalis used during surgical
operations including circumcision to reduce theoperations including circumcision to reduce the
postoperative hyperalgesia.postoperative hyperalgesia.

23.  Systemic AnalgesiaSystemic Analgesia
 NSAID:NSAID:
–– Not generally usedNot generally used for neonatal analgesia becausefor neonatal analgesia because
effective and safer agents are availableeffective and safer agents are available
–– Use of NSAIDs wasUse of NSAIDs was associateassociated with gastrointestinald with gastrointestinal
bleedingbleeding, platelet, platelet dysfunctiondysfunction, and decreased, and decreased
glomerular filtration rateglomerular filtration rate
–– Increased risk of bleeding in newborns < 21 days oldIncreased risk of bleeding in newborns < 21 days old
or < 37 weeks’ corrected GAor < 37 weeks’ corrected GA

24.  MorphineMorphine
Most commonly used opioid for analgesia inMost commonly used opioid for analgesia in
neonatesneonates
•• Morphine is metabolized in the liver to morphine 3‐ ‐Morphine is metabolized in the liver to morphine 3‐ ‐
glucoronide (antagonist) and morphine 6‐ ‐glucoronide (antagonist) and morphine 6‐ ‐
glucuronide (agonist)glucuronide (agonist)
•• Morphine associated respiratory depression is greaterMorphine associated respiratory depression is greater
in premature infants b/o immaturity of respiratoryin premature infants b/o immaturity of respiratory
center responses to hypoxia and hypercarbiacenter responses to hypoxia and hypercarbia

25. Effect of Morphine During DevelopmentEffect of Morphine During Development
 •• Chronic morphine exposure during prenatal andChronic morphine exposure during prenatal and
early postnatal periods – Inducesearly postnatal periods – Induces significantsignificant
reduction in brain volume,reduction in brain volume, neuronal packingneuronal packing
density, and dendritic growthdensity, and dendritic growth
 –– Leads toLeads to long term alterations in pain threshold‐long term alterations in pain threshold‐ ,,
impairments in learning abilities, and locomotorimpairments in learning abilities, and locomotor
activityactivity
 Repeated morphine exposure leads to:Repeated morphine exposure leads to:
–– Persistent effects on the reorganization of synapticPersistent effects on the reorganization of synaptic
connectionconnectionss in areas that regulate motivation,in areas that regulate motivation,
reward, and learningreward, and learning throughout adult lifethroughout adult life

26. FentanylFentanyl
 Continuous infusions in ventilated PT neonates areContinuous infusions in ventilated PT neonates are
not routinely usednot routinely used
 •• In ventilated very PT infants continuous fentanylIn ventilated very PT infants continuous fentanyl
infusion plus openlabel boluses of fentanyl does notinfusion plus openlabel boluses of fentanyl does not
reduce prolonged painreduce prolonged pain
 ResultingResulting respiratory depressionrespiratory depression prolongs the initialprolongs the initial
ventilatory course.ventilatory course.
 HigherHigher cumulativecumulative fentanylfentanyl dose in PTIdose in PTI correlatedcorrelated
withwith higher incidence cerebellar injuryhigher incidence cerebellar injury and lowerand lower
cerebellar diameter at term equivalent.cerebellar diameter at term equivalent.

27. MidazolamMidazolam
 Continuous midazolam infusion associated with anContinuous midazolam infusion associated with an
increase in IVHincrease in IVH
 –– Decreases cerebral blood flow velocityDecreases cerebral blood flow velocity
 –– Prolongs length of stay in the NICUProlongs length of stay in the NICU

30. AcetaminophenAcetaminophen
 Acetaminophen alone isAcetaminophen alone is notnot effective enough to reduceeffective enough to reduce
acute pain.acute pain.
 •• Acetaminophen with other analgesicAcetaminophen with other analgesic agentsagents reducesreduces
the overall amount of administered opioidthe overall amount of administered opioid
 •• Intravenous IV acetaminophenIntravenous IV acetaminophen reduced thereduced the
cumulative morphine dose followingcumulative morphine dose following majormajor
thoracicthoracic (non cardiac) or abdominal surgery.‐(non cardiac) or abdominal surgery.‐

31. Short term and long term outcome effects of untreated‐ ‐Short term and long term outcome effects of untreated‐ ‐
neonatal pain/stress, or exposure to opioids or paracetamolneonatal pain/stress, or exposure to opioids or paracetamol
in (pre)term neonates (Smits, et al.,in (pre)term neonates (Smits, et al., J Pharm PharmacolJ Pharm Pharmacol 20162016

32. SummarySummary
 •• ResearchResearch in nociception developmental physiologyin nociception developmental physiology
demonstratesdemonstrates the ability of preterm infants to perceive painthe ability of preterm infants to perceive pain
 •• Preclinical and clinicalPreclinical and clinical studiesstudies confirmed the adverseconfirmed the adverse
consequences of untreated pain and stress on brainconsequences of untreated pain and stress on brain
developmentdevelopment
 •• Based on the availableBased on the available evidence, treatmentevidence, treatment isis indicated forindicated for
acute eventsacute events ranging from minor procedural pain to majorranging from minor procedural pain to major
surgery as well as chronic stressful experiencessurgery as well as chronic stressful experiences includingincluding
mechanical ventilationmechanical ventilation
 •• Sedation & analgesicsSedation & analgesics are indicated for amelioratingare indicated for ameliorating
moderate severe pai‐moderate severe pai‐ nn •• Concerning preclinical and clinicalConcerning preclinical and clinical
data suggest these agents may promotedata suggest these agents may promote apoptosisapoptosis andand
impact neurodevelopmentimpact neurodevelopment

33. Analgesia for procedural pain inAnalgesia for procedural pain in
neonatesneonates
Procedures Management
Heel prick Sucrose with pacifier, swaddling, containment, skin-to-skin
contact with mother and use of mechanical lancet
Venipuncture Sucrose with pacifier, swaddling, containment facilitated
Tucking, EMLA cream at the site
Arterial puncture Sucrose with pacifier, swaddling, containment, facilitated
tucking, EMLA cream at the site, consider local subcutaneous
lidocaine locally
Lumbar puncture Sucrose with pacifier, EMLA cream at the site, consider
subcutaneous
lidocaine locally
Intubation Combination of opioid analgesics, sedatives, and muscle
relaxants, consider topical lidocaine spray (if not urgent(

34. Injection Avoid subcutaneous/intramuscular injections, prefer intravenous
route, sucrose with pacifier, swaddling, containment,
EMLA cream
Chest tube Sucrose with pacifier, subcutaneous lidocaine, consider opioid
analgesics or short-acting anesthetic agents
Umbilical catheter Sucrose with pacifier, swaddling, containment, facilitated
tucking, avoid sutures or hemostat clamps on the skin around
the umbilicus
Central line Sucrose with pacifier, swaddling, containment, facilitated
tucking, EMLA to the site, subcutaneous lidocaine,
opioid analgesics
Endotracheal suction Sucrose with pacifier, swaddling, containment, facilitated
tucking, consider opioid analgesics
Nasogastric tube Sucrose with pacifier, swaddling, containment, facilitated
tucking, gentle technique, apply lubrication
Circumcision Sucrose with pacifier, EMLA cream to the site, dorsal nerve block
or penile ring block using lidocaine, consider acetaminophen for
postoperative pain

35. Eye examination Sucrose with pacifier, local anesthetic eye
drops
Mechanical
ventilation
 First 24 hrs
)unless extubation is
anticipated in 4 hrs(
 >24
Fentanyl or morphine IV/4 hrs and as needed,
or fentanyl
infusion 0.2-2 μg/kg/hr (start at low rate(

36. RecommendationsRecommendations
 Stepwise approach in the management of neonatalStepwise approach in the management of neonatal
pain depending on the clinical setting ispain depending on the clinical setting is
recommendedrecommended
 •• Consider changing assessment tools to moreConsider changing assessment tools to more
effectively assess the degree of pain/agitateffectively assess the degree of pain/agitation versusion versus
level of sedation/sedation needslevel of sedation/sedation needs
 •• Using non pharmacologic measures‐Using non pharmacologic measures‐ (e.g., facilitated(e.g., facilitated
tucking or skin to skin contact)‐tucking or skin to skin contact)‐ to improve analgesiato improve analgesia
for any painful procedure, when feasiblefor any painful procedure, when feasible
 •• Oral sucrose with non pharmacological measures‐Oral sucrose with non pharmacological measures‐
for painful skin break proceduresfor painful skin break procedures

37.  Invasive procedures require local anesthesiaInvasive procedures require local anesthesia
& systemic analgesia& systemic analgesia
 •• Postoperative painPostoperative pain management can bemanagement can be
achieved by usingachieved by using acetaminophenacetaminophen as anas an
adjunctadjunct to opioid therapyto opioid therapy
 •• Morphine or fentanyl infusion for routineMorphine or fentanyl infusion for routine
sedationsedation or pain control in ventilatedor pain control in ventilated
neonatesneonates is not recommendedis not recommended