Christopher C. McPherson, PharmD St. Louis Children’s Hospital, St. Louis, MO

1. Sedation, Analgesia, and the
Newborn Brain: Providing Comfort
and Protecting the Growing Brain
Christopher McPherson, PharmD
mcphersonc@wustl.edu

2. Disclosure Statements
Christopher McPherson, PharmD
• I have no relevant financial relationships with the
manufacturer(s) and/or provider(s) of commercial services
discussed in this CME activity.
• I do intend to discuss an unapproved/investigative use of
a commercial product/device in my presentation.

3. Objectives
• Define the impact of neonatal pain on the developing
brain
• Identify strategies to address common indications for
analgesia in neonates
• Evaluate strategies for controlling chronic neonatal
agitation and their impact on the developing brain

4. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain
Acute brain injury Neonatal brain growth 2,4,6,8 year follow-up

5. Premature neonates feel pain

6. Peripheral sensory neuron
Stimulus
Dorsal root ganglion
Dorsal horn
interneuron
Ventral horn
motor neuron
Spinothalamic
neuron
Muscle contraction Thalamocortical axon
Nociception
Spinothalamic tract
8 – 20 weeks
gestation
8 weeks
gestation
19 weeks gestation
23 – 24 weeks
gestation
Noxious
Thalamus
Anand and Hickey. N Engl J Med 1987; 317: 1321-9.

7. Peripheral sensory neuron
Stimulus
Dorsal root ganglion
Dorsal horn
interneuron
Ventral horn
motor neuron
Muscle contraction Thalamocortical axon
Nociception
Spinothalamic tract
8 – 20 weeks
gestation
8 weeks
gestation
19 weeks gestation
23 – 24 weeks
gestation
Noxious
Thalamus
Spinothalamic
neuron
34 – 38 weeks
gestation
Anand and Hickey. N Engl J Med 1987; 317: 1321-9.

8. Premature neonates feel pain
Acute pain worsens outcome

9. Nociception in the neonate
0
0.5
1
1.5
2
2.5
Pre-op End-op 6 hrs 12 hrs 24 hrs
nmol/L
Adrenaline
0
1
2
3
4
5
6
7
8
9
Pre-op End-op 6 hrs 12 hrs 24 hrs
mmol/L
Blood glucose
Anand et al. Lancet 1987; 1: 243-8.

10. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain

11. Nociception in the neonate
-1
-0.5
0
0.5
1
1.5
2
2.5
Pre-op End-op 6 hrs 12 hrs 24 hrs
nmol/L
Adrenaline
Fentanyl Non-fentanyl
0
1
2
3
4
5
6
7
8
9
Pre-op End-op 6 hrs 12 hrs 24 hrs
mmol/L
Blood glucose
Fentanyl Non-fentanyl
*
*
*
*
*p < 0.025
*
*
Anand et al. Lancet 1987; 1: 243-8.

12. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Pharmacotherapy improves
short-term outcome

13. Pain control improves outcome
• PDA ligation with fentanyl…
– Decreased ventilator requirements
– Decreased spontaneous bradycardia
– Improved perfusion
– Less metabolic acidosis
– Decreased incidence of IVH
Anand et al. Lancet 1987; 1: 243-8.

14. ATP
cAMP
AC
K+
Ca++
Presynaptic neurons
of the brain stem,
medial thalamus,
cerebral cortex,
amygdala,
caudate, putamen
Postsynaptic
K+
Ca++
G
G
µ1
µ1
GABA Cl-

15. ATP
cAMP
AC
K+
Ca++
Presynaptic neurons
of the brain stem,
medial thalamus,
cerebral cortex,
amygdala,
caudate, putamen
Postsynaptic
K+
G
G
µ1
µ1
GABA Cl-
Opioid
Opioid
-
+
Reduced neuronal metabolic rate
Reduced excitotoxicity
Reduced neuronal injury

16. • “Except for emergent intubation during resuscitation…,
premedication should be used for all endotracheal intubations in
newborns.”
• Analgesic agents or anesthetic dose of a hypnotic drug should be
given.
• Vagolytic agents and muscle relaxants should be considered.
Kumar et al. Pediatrics 2010; 125: 608-15.
Premedication for nonemergency
endotracheal intubation

17. • UK survey of 239 neonatal units in 2000
– 37% of units gave any sedation
– 14% had a written policy
• UK survey of 50 neonatal units in 2009
– 90% of units gave routine sedation
– 77% had a written policy
Whyte et al. Arch Dis Child Fetal Neonatal Ed 2000; 82: F38-41.
Chaudhary et al. Pediatric Anesthesia 2009; 19: 653-8.
Premedication for nonemergency
endotracheal intubation

18. Choice of agents
Durrmeyer et al. Pediatr Crit Care Med 2013; 14: e169-75.
Not described
- Fentanyl and morphine
- Sufentanil ± NMB ± midazolam
- Nalbuphine ± midazolam ± sucrose
Preferred drug
- Fentanyl
Acceptable
- Morphine
- Propofol
Not recommended
- Midazolam only
- Midazolam and fentanyl in a preterm

19. Morphine
Outcome Morphine Control p
value
Duration of hypoxemia,
seconds
235 (82.5 – 340) 90 (20 – 187.5) 0.04
Bradycardia during
procedure, n
16 12 0.175
Increase in MAP from
baseline, mm Hg
18 (9 – 24.25) 20 (11.75 – 28) 0.65
Intubation achieved at
first attempt, n
7 9 0.49
Lemyre et al. BMC Pediatr 2004; 4: 20.

20. Remifentanil vs. morphine
• Required second intubation attempt (0% vs. 40%)
Pereira e Silva et al. Arch Dis Child Fetal Neonatal Ed 2007; 92: F293-4.

21. The devil is in the details,

22. your pharmacist is in the weeds.

23. 4
McPherson. Neonatal Netw 2018; 37: 238-247.

24. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
short-term outcome

25. Smith et al. Ann Neurol 2011; 70: 541-9.
Neonatal pain and brain growth

26. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain

27. Impacts of pharmacotherapy
0
1
2
3
4
5
Morphine Placebo Morphine Placebo
Quinn et al. Lancet 1993; 342: 324-7.
Adrenaline Noradrenaline
*
*p < 0.001

28. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain

29. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain
Acute brain injury

30. Anand KJS. Biol Neonate 1998; 73: 1-9. Anand KJS et al. Lancet 2004; 363: 1673-82.
Acute
painful
stimuli
Diaphragmatic
splinting
Crying
Increased cerebral
blood volume
Chronic pain
and stress
Increased
cerebral blood
flow
Early IVH
Late IVH or
IVH extension
PVL
↑Heart rate
↑Blood pressure
↑Variability
↑Spinal cord
excitability
Handling
Stimulation
of HPA axis
Hyperglycemia
Lactic acidosis
Catabolism
↓Vagal
tone
Cerebral ischemia
Reperfusion injury
Hypoxia
Hypercarbia

31. NOPAIN
• Randomized, controlled trial of infants born between 24 and 32
weeks GA
• < 72 hours postnatal age and requiring mechanical ventilation for
< 8 hours at trial entry
• Placebo versus midazolam versus morphine
• Open label morphine allowed for breakthrough pain
• N = 67
Anand, et al. Arch Pediatr Adolesc Med 1999; 153: 331-8.

32. Morphine
Midazolam
Gestational
age (wks)
Loading dose
(mcg/kg)
Maintenance dose
(mcg/kg/hr)
24 – 26 200 20
27 – 29 200 40
30 - 32 200 60
Burtin et al. Clin Pharmacol Ther 1994; 56: 615-25.
Gestational
age (wks)
Loading dose
(mcg/kg)
Maintenance dose
(mcg/kg/hr)
24 – 26 100 10
27 – 29 100 20
30 - 32 100 30
Chay et al. Clin Pharmacol Ther 1992; 51: 334-42.
Hartley et al. Arch Dis Child 1993; 69: 55-58.

33. 0
5
10
15
20
25
30
35
Poor neurologic outcome
Placebo (N = 21) Midazolam (N = 21) Morphine (N = 24)
NOPAIN
*p = 0.03
Poor neurologic outcome = grade III or IV IVH, PVL, or death at ≤ 28 days
*
Anand, et al. Arch Pediatr Adolesc Med 1999; 153: 331-8.

34. Midazolam and hypotension
• Initial PK study in term infants showed no impact on blood
pressure
• Subsequent PK study in preterm infants showed a 20%
occurrence of clinically significant hypotension after 0.2 mg/kg
midazolam bolus
– Variable rate of clinically significant hypotension described in studies of
0.1 mg/kg bolus dose (0–29%)
Jacqz-Aigrain et al. Eur J Clin Pharmacol 1990; 39: 191-2.
Jacqz-Aigrain et al. Eur J Clin Pharmacol 1992; 42: 329-32.
Van Straaten et al. Dev Pharmacol Ther 1992; 19: 191-5.
Harte et al. J Paediatr Child Health 1997; 33: 335-8.

35. 0.08
0.11
0.14
0.17
0.2
0.23
0 10 20 30 40 50 60 70
MCBFV(m/s)
Midazolam Vecuronium
30
35
40
45
MAP(mmHg)
Van Straaten et al. Dev Pharmacol Ther 1992; 19: 191-5.
∆, p < 0.001
∆, p = 0.06

36. Benzodiazepines and neuroapoptosis
0
10
20
30
40
50
60
0 1 2 3
C3Aprofiledensity(/mm2)
Caudate-Putamen
0
5
10
15
20
25
0 0.5 1 1.5 2 2.5
Cortex
Young et al. Br J Pharmacol 2005; 146: 189-97.
Stefovska et al. Ann Neurol 2008; 64: 434-45.
Kellogg et al. Neurobehav Toxicol Teratol 1985; 7: 483-8.
Simmons et al. Brain Res 1984; 307: 39-46.
Kellogg et al. Science 1980; 207: 205-7.
Saline Midazolam Saline Midazolam
• Long-term functional deficits and
atypical behavioral patterns

37. Reactive oxygen
species
Lipid peroxidation
cytochrome c
caspase-3
caspase-9
cleaved
caspase-8
pro caspase-3
Apoptosis
MitochondriaCa2+
blc-2 bax bid
Intrinsic pathway Extrinsic pathway
F
a
s
Yon et al. Neuroscience 2005;
135: 815-27.

38. 0
5
10
15
20
25
30
35
Poor neurologic outcome
Placebo (N = 21) Midazolam (N = 21) Morphine (N = 24)
NOPAIN
*p = 0.03
Poor neurologic outcome = grade III or IV IVH, PVL, or death at ≤ 28 days
*
Anand, et al. Arch Pediatr Adolesc Med 1999; 153: 331-8.

39. NEOPAIN
• Randomized, controlled trial of infants born between 23 and 32
weeks GA
• < 72 hours postnatal age, and requiring mechanical ventilation for
< 8 hours at trial entry
• Morphine versus placebo
• Open label morphine allowed for breakthrough pain
• N = 898
Anand KJS et al. Lancet 2004; 363: 1673-82.

40. NEOPAIN
Poor neurologic outcome = grade III or IV IVH, PVL, or death at ≤ 28 days
0
5
10
15
20
25
30
35
Poor neurologic outcome
%
Placebo (N = 408) Morphine (N = 419)
Anand KJS et al. Lancet 2004; 363: 1673-82.

41. 0
5
10
15
20
25
30
Poor neurologic outcome Severe IVH
%
Placebo (N = 179) Morphine (N = 225)
NEOPAIN
Infants not receiving additional analgesia
p = 0.0338
p = 0.0209
Poor neurologic outcome = grade III or IV IVH, PVL, or death at ≤ 28 days
Anand KJS et al. Lancet 2004; 363: 1673-82.

42. 0
5
10
15
20
25
30
35
Before study initiation After loading dose Drug infusion
1 - 24 hours
Drug infusion
24 - 72 hours
%ofpatientswithhypotension
Placebo (N = 449) Morphine (N = 449)
Morphine and hypotension
Anand KJS et al. Lancet 2004; 363: 1673-82.
p = 0.1672
p = 0.0085
p < 0.0006
p = 0.7364

43. Time to extubation
Anand KJS et al. Lancet 2004; 363: 1673-82.
Bhandari et al. Pediatrics 2005; 116: 352-9.
P < 0.01

44. Time to full enteral feeds
Anand KJS et al. Lancet 2004; 363: 1673-82.
Menon et al. Arch Dis Child Fetal Neonatal Ed 2008; 93: F362-7.

45. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain
Acute brain injury 2,4,6,8 year follow-up

46. G-protein-receptor
coupled kinaseProtein Kinase C
P P
Extracellular
regulated
kinase
Cell cycle
progression
+
Apoptosis
signal-regulating
kinase
Apoptosis
+
Opioid Opioid
Opioid
Opioid
Opioid
G
µ1

47. β-arrestin
G-protein-receptor
coupled kinaseProtein Kinase C
Extracellular
regulated
kinase
Cell cycle
progression
+
Apoptosis
signal-regulating
kinase
Apoptosis
+
Opioid Opioid
Opioid
Opioid
Opioid
G
µ1
P P

48. β-arrestin
G-protein-receptor
coupled kinaseProtein Kinase C
Extracellular
regulated
kinase
Cell cycle
progression
+
Apoptosis
signal-regulating
kinase
Apoptosis
+
Opioid Opioid
Opioid
Opioid
Opioidµ1
+
GP P

49. NEOPAIN 5-7 year follow up
• N = 19
• Impaired short-term
memory
• More social problems
40
42
44
46
48
50
52
54
56
0 1 2 3
cm
Head circumference
Placebo Morphine
Ferguson et al. Neurotoxicol Teratol 2012; 34: 47-55.

50. Morphine
Gestational
age (wks)
Loading dose
(mcg/kg)
Maintenance dose
(mcg/kg/hr)
24 – 26 100 10
27 – 29 100 20
30 - 32 100 30
Chay et al. Clin Pharmacol Ther 1992; 51: 334-42.
Hartley et al. Arch Dis Child 1993; 69: 55-58.
10 mcg/kg/hr
Simons et al. JAMA 2003; 290: 2419-27.

51. European morphine trial
• No impact on severe IVH, PVL, or death
– N = 150
• Lower IQ in morphine group at 5 years
– N=90
– Subscale of visual analysis
• Better executive function at 8-9 years
– N=84
– Subscales of inhibition, organization, and monitoring
Simons et al. JAMA 2003; 290: 2419-27.
de Graaf et al. Pain 2011; 152: 1391-7.
de Graaf et al. Pain 2013; 154: 449-58.

52. Practice recommendations
• The role of continuous sedation/analgesia to treat chronic
agitation/discomfort is unclear
– Not indicated when short duration of mechanical ventilation
expected
– Clearly indicated in physiologies that require strict ventilator
synchrony (PPHN, CDH, air leak, etc.)
– For long duration of mechanical ventilation in premature infants,
• Avoid routine use (AAP/CPS 2006, 2016)
AAP and CPS. Pediatrics 2006; 118: 2231-41.
AAP. Pediatrics 2016; 137: e20154271.

53. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain
Acute brain injury Neonatal brain growth 2,4,6,8 year follow-up

54. Morphine and brain growth at term
Zwicker et al. J Pediatr 2016; 172: 81-7.
Median morphine dose = 1.905 mg/kg, p=0.04
Morphine exposure significantly associated with poorer motor scores (p<0.001) and
cognitive outcomes (p=0.006) at 18 months CA

55. Morphine and brain growth at term
Characteristic Morphine
N = 56
No Morphine
N = 136
Mean difference
(95% CI)
Whole Brain 383.3 ± 62.9 400.2 ± 63.3 -16.9 (-36.7, 2.9)
Cortical Gray Matter 151.3 ± 40.3 161.7 ± 41.6 -10.4 (-23.3, 2.5)
White Matter 208.3 ± 32.5 215.1 ± 32.5 -6.8 (-16.9, 3.4)
Deep nuclear gray matter 14.3 ± 4.1 13.4 ± 3.8 0.9 (-0.3, 2.1)
Cerebellum 20.6 ± 4.5 21.7 ± 4.5 -1.1 (-2.4, 0.3)
Steinhorn et al. J Pediatr 2015; 166: 1200-7.
Median morphine dose 0.79 mg/kg, interquartile range 0.12-0.95 mg/kg

56. Characteristic Morphine
N = 51
No Morphine
N = 160
Mean difference
(95% CI)
Bayley Mental 84.2 (19.2) 83.5 (19.4) 0.7 (-5.2, 6.6)
Bayley Psychomotor 87.6 (19.0) 88.4 (16.3) -0.8 (-6.0, 4.3)
ITSEA Externalizing 49.5 (8.1) 49.3 (9.7) 0.2 (-3.3, 3.6)
ITSEA Internalizing 50.1 (12.1) 48.7 (11.9) 1.4 (-3.0, 5.8)
ITSEA Dysregulation 58.0 (11.2) 52.0 (11.8) 6.0 (1.8, 10.2)*
ITSEA Competence 45.6 (9.5) 46.4 (10.6) -0.8 (-4.5, 2.9)
CSBS Social 21.5 (3.9) 21.1 (3.6) 0.4 (-0.8, 1.7)
CSBS Speech 11.1 (3.7) 11.4 (2.8) 0.3 (-1.4, 0.6)
Delayed alternation 19 (49%) 36 (25%) p < 0.01*
Morphine and development at 2 years
ITSEA = Infant Toddler Social Emotional Assessment
CSBS = Communication Symbolic Behavioral Scale
Delayed alternation = test of executive function Steinhorn et al. J Pediatr 2015; 166: 1200-7.

57. Morphine and brain growth at 7 years
Characteristic Morphine
N = 30
No Morphine
N = 87
Mean difference
(95% CI)
Total Brain Volume 557.5 (55.0) 561.8 (50.7) -4.3 (-25.3, 16.7)
Cortical Gray Matter 285.3 (27.1) 284.2 (24.6) 1.1 (-9.3, 11.5)
White Matter 201.7 (25.0) 201.1 (22.6) 0.4 (-9.0, 10.0)
Cerebellar Cortex 59.9 (5.4) 61.9 (5.9) -2.0 (-4.5, 0.3)
Cerebellar WM 12.9 (2.2) 12.9 (1.8) 0 (-0.8, 0.8)
Steinhorn et al. J Pediatr 2015; 166: 1200-7.

58. Morphine and development at 7 years
Characteristic Morphine
N = 46
No Morphine
N = 142
Mean difference
(95% CI)
Intelligence Quotient 98.0 (13.2) 96.6 (13.7) 1.4 (-3.1, 5.8)
Motor function 8.6 (3.1) 8.6 (3.6) 0 (-1.3, 1.2)
Strength and difficulties 10.1 (5.1) 10.7 (6.8) -0.6 (-3.0, 1.8)
Core language 97.7 (14.8) 90.6 (18.3) 7.1 (1.1, 13.1)
WRAT reading 106.4 (18.7) 96.6 (18.6) 9.8 (3.6, 16.0)
WRAT spelling 107.1 (17.6) 96.4 (18.2) 10.7 (4.6, 16.7)
WRAT computation 95.2 (16.1) 87.9 (18.3) 7.3 (1.2, 13.4)
Executive function 55.4 (10.2) 56.4 (13.6) -1.0 (-5.6, 3.7)
Steinhorn et al. J Pediatr 2015; 166: 1200-7.

59. Morphine and brain growth at term
Zwicker et al. J Pediatr 2016; 172: 81-7.
Median morphine dose = 1.905 mg/kg, p=0.04
Morphine exposure significantly associated with poorer motor scores (p<0.001) and
cognitive outcomes (p=0.006) at 18 months CA

60. Data from Steinhorn et al. J Pediatr 2015; 166: 1200-7.
Morphine and brain growth at term
r2=0.007

61. Dose and metabolism matters
Chau et al. EBioMedicine 2019; 40: 655-62.
Mitigates
association with
anxiety/depression
Mitigates
association with
acting out

62. Fentanyl in premature neonates
• Faster onset and shorter duration of action
• Minimal cardiovascular and gastrointestinal impact?
• Commonly utilized despite limited data in spite of
mounting negative data

63. Morphine
Gestational age
(wks)
Loading dose (mcg/kg) Maintenance dose
(mcg/kg/hr)
24 – 26 100 10
27 – 29 100 20
30 - 32 100 30
Chay et al. Clin Pharmacol Ther 1992; 51: 334-42.
Hartley et al. Arch Dis Child 1993; 69: 55-58.
Gestational age
(wks)
Loading dose (mcg/kg) Maintenance dose
(mcg/kg/hr)
24 – 26 1 1
27 – 29 1 1
30 - 32 1 1
Fentanyl
Beelzebub et al. Devil’s in the Details 2015; 666: 666-70.

64. Saarenmaa et al. J Pediatr 2000; 136: 767-770.
10.5 mcg/kg
t1/2 = 4-6 hrs
1.5 mcg/kg/hr

65. Ancora et al. J Pediatr 2013; 163: 645-51.
Ancora et al. Pain 2017; 158: 840-5.
Fentanyl versus placebo
Fentanyl (N=64) Placebo (N=67) p value
Open-label boluses per day 0.31 ± 0.67 0.31 ± 0.67 0.893
Duration of mechanical ventilation,
hours
152 110 0.019
Time to full enteral feeds 41 32 0.089
Fentanyl (N=39) Placebo (N=39) p value
Griffiths DQ 90 97 0.024
Eye-hand coordination SQ 89 99 0.002
Performance skills SQ 80 90 0.009
*Fentanyl infants smaller with higher CRIB score

66. Adjusted for gestational age, z-score for weight at MRI scan, the presence of CBH, 5-minute APGAR score,
CRIB score, duration of mechanical ventilation, duration of TPN, PDA requiring treatment, NEC, inotrope
exposure, hydrocortisone exposure, morphine exposure, and midazolam exposure (r = 0.461, p = 0.002)
r = 0.531
p < 0.001
McPherson et al. Ann Pharmacother 2015; 49: 1291-7.

67. Dose and metabolism matters
Voller et al. Arch Dis Child Fetal Neonatal Ed 2019; in press.

68. Practice recommendations
• The role of continuous sedation/analgesia to treat chronic
agitation/discomfort is unclear
– Not indicated when short duration of mechanical ventilation
expected
– Clearly indicated in physiologies that require strict ventilator
synchrony (PPHN, CDH, air leak, etc.)
– For long duration of mechanical ventilation in premature infants,
• Avoid routine use (AAP/CPS 2006, 2016)
• Fentanyl or morphine titrated to scores (ISN 2019)
AAP and CPS. Pediatrics 2006; 118: 2231-41.
AAP. Pediatrics 2016; 137: e20154271.
Ancora et al. Acta Paediatr 2019; 108: 208-17.

69. Premature neonates feel pain
Acute pain worsens outcome
Pharmacotherapy decreases
the physiologic markers of
acute pain
Chronic pain and agitation
worsen outcome
Pharmacotherapy improves
long-term outcome
Pharmacotherapy improves
short-term outcome
Pharmacotherapy decreases
the physiologic markers of
chronic pain
Acute brain injury Neonatal brain growth 2,4,6,8 year follow-up

70. ATP
cAMP
AC
K+
Ca++
Presynaptic neurons
of the brain stem,
medial thalamus,
cerebral cortex,
amygdala,
caudate, putamen
Postsynaptic
K+
G
G
µ1
µ1
GABA Cl-
Opioid
Opioid
-
+
Reduced neuronal metabolic rate
Reduced excitotoxicity
Reduced neuronal injury
Presynaptic neurons
of the locus coeruleus
α2-receptor agonist
α2-receptor
agonist
α2r
α2r

71. Efficacy
O’Mara K et al. J Pediatr Pharmacol Ther 2012; 17: 252-62.
P < 0.001

72. Time to extubation
P < 0.001
O’Mara K et al. J Pediatr Pharmacol Ther 2012; 17: 252-62.

73. Time to full enteral feeds
P < 0.001
O’Mara K et al. J Pediatr Pharmacol Ther 2012; 17: 252-62.

74. Impact on blood pressure
Petroz et al. Anesthesiology 2006; 105: 1098-1110.

75. Neuroprotection?
• Reduces lesion size after experimentally induced PVL
• Protects against brain matter loss and improves neurologic
function after hypoxia-ischemia
• Attenuates neuroapoptosis and prevents long-term memory
impairment from isoflurane
Laudenbach et al. Anesthesiology 2002; 96: 134-41.
Ma et al. Eur J Pharmacol 2004; 87-97.
Sanders et al. Anesthesiology 2009; 110: 1077-85.
Sanders et al. Acta Anaesthesiol Scand 2010; 54: 710-6.

76. Reactive oxygen
species
Lipid peroxidation
cytochrome c
caspase-3
caspase-9
cleaved
caspase-8
pro caspase-3
Apoptosis
MitochondriaCa2+
blc-2 bax bid
Intrinsic pathway Extrinsic pathway
F
a
s
Engelhard et al. Anesth Analg 2003;
96: 524-31.

77. Extracellular
regulated
kinase
Cell cycle
progression
+
Apoptosis
signal-regulating
kinase
Apoptosis
+
G
α2
α2 agonist
α2 agonist
α2 agonist
α2 agonist
α2 agonist
Dahmani et al. Anesthesiology 2008; 108: 457-66.
+

78. Summary
• Analgesia for major, acute painful stimuli improves neonatal
outcomes
• The role of long-term sedation/analgesia is less clear
– Midazolam increases risk of brain injury and likely produces
significant neuroapoptosis
– Morphine has adverse effects; dose and metabolism matter
– Fentanyl has adverse effects; dose and metabolism matter
– In this setting, dexmedetomidine deserves careful investigation
McPherson, Grunau. Clin Perinatol 2014; 41: 209-27.

79. Christopher McPherson, PharmD
mcphersonc@wustl.edu
Sedation, Analgesia, and the
Newborn Brain: Providing Comfort
and Protecting the Growing Brain