lecture

1. Balancing the Use of Sedatives and
Analgesics in Neonates: Risks and
Associated Neurodevelopmental
Outcomes
BY
DR. Magdy Shafik
Senior Pediatric Consultant
Diploma, M.S ,Ph.D of Pediatric

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

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

4. Pain and the Developing Brain
• Newborn period is a time of rapid brain growth,
development and particular vulnerability
•
On average a preterm neonate experiences ~ 5‐15 painful
procedures per day (~ 7/d from admission to terme
quivalent age or discharge)
 Exposure to pain in preterm infants is multifactorial
 Increased stress associated with decreased frontal lobe
width, abnormal temporal lobe diffusion and neural
networks

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

6. How Pain is Transmitted to the
Brain

7. Neonatal pain and developmental outcomes in
children born preterm
 Greater number of painful procedures in infants
born extremely preterm (< 29 w GA) associated
with
 – Delayed postnatal growth
 – Poor early development
 – High cortical activation
 – Altered brain development
 – Poor quality cognitive and motor development at
1 y age
 – Changes in cortical rhythmicity and cortical
thickness in children at age 7

8. OUTLINE
 Pain and the developing brain
 – Effects of pain on the developing brain
 • Assessment of pain in newborns
 • Pain Management
 – Non‐pharmacologic pain control in newborns
 – Review of frequently used medications in the NIC
 • Review of Weiler NICU practices
 • Summary
 • Recommendations

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

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

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

13. ASSESSMENT OF PAIN IN NEONATES
 Physiologic parameter changes:
– Changes in HR, RR, BP, SaO2
– Vagal tone
– Breathing pattern
– Palmar sweating
– Skin color
– Pupillary size
 Behavioral responses:
– Crying patterns
– Facial expressions
– Hand and body movements – Muscle tone
– Sleep patterns, behavioral state changes
– Consolability

14. Multidimensional Pain Assessment Tools

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

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

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

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

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

23.  Systemic Analgesia
 NSAID:
– Not generally used for neonatal analgesia because
effective and safer agents are available
– Use of NSAIDs was associated with gastrointestinal
bleeding, platelet dysfunction, and decreased
glomerular filtration rate
– Increased risk of bleeding in newborns < 21 days old
or < 37 weeks’ corrected GA

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

25. Effect of Morphine During Development
 • Chronic morphine exposure during prenatal and
early postnatal periods – Induces significant
reduction in brain volume, neuronal packing
density, and dendritic growth
 – Leads to long‐term alterations in pain threshold,
impairments in learning abilities, and locomotor
activity
 Repeated morphine exposure leads to:
– Persistent effects on the reorganization of synaptic
connections in areas that regulate motivation, reward,
and learning throughout adult life

26. Fentanyl
 Continuous infusions in ventilated PT neonates are
not routinely used
 • In ventilated very PT infants continuous fentanyl
infusion plus openlabel boluses of fentanyl does
not reduce prolonged pain
 Resulting respiratory depression prolongs the initial
ventilatory course.
 Higher cumulative fentanyl dose in PTI correlated
with higher incidence cerebellar injury and lower
cerebellar diameter at term equivalent.

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

30. Acetaminophen
 Acetaminophen alone is not effective enough to reduce
acute pain.
 • Acetaminophen with other analgesic agents reduces
the overall amount of administered opioid
 • Intravenous IV acetaminophen reduced the
cumulative morphine dose following major
thoracic (non‐cardiac) or abdominal surgery.

31. Short‐term and long‐term outcome effects of untreated
neonatal pain/stress, or exposure to opioids or paracetamol
in (pre)term neonates (Smits, et al., J Pharm Pharmacol 2016

32. Summary
 • Research in nociception developmental physiology
demonstrates the ability of preterm infants to perceive pain
 • Preclinical and clinical studies confirmed the adverse
consequences of untreated pain and stress on brain
development
 • Based on the available evidence, treatment is indicated for
acute events ranging from minor procedural pain to major
surgery as well as chronic stressful experiences including
mechanical ventilation
 • Sedation & analgesics are indicated for ameliorating
moderate‐severe pain • Concerning preclinical and clinical
data suggest these agents may promote apoptosis and impact
neurodevelopment

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

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

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

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

37.  Invasive procedures require local anesthesia
& systemic analgesia
 • Postoperative pain management can be
achieved by using acetaminophen as an
adjunct to opioid therapy
 • Morphine or fentanyl infusion for routine
sedation or pain control in ventilated
neonates is not recommended