The Impact of Sedation and Analgesia on the Developing Preterm Brain. Christopher McPherson, PharmD

The Impact of Sedation and Analgesia on the Developing Preterm Brain Christopher McPherson, PharmD

Disclosures I have no conflicts of interest to disclose. I will be discussing off-label or unapproved use of drugs.

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

Premature neonates feel pain

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

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

Acute pain worsens outcome Premature neonates feel pain

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

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

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

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

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.

Presynaptic neurons of the brain stem, medial thalamus, cerebral cortex, amygdala, caudate, putamen ATP AC G i Ca++ µ 1 µ 1 G 0 Ca++ camp K+ G i µ 1 K+ Postsynaptic

Presynaptic neurons of the brain stem, medial thalamus, cerebral cortex, amygdala, caudate, putamen ATP AC G i µ 1 Ca++ G 0 Ca++ camp K+ G i µ 1 K+ Postsynaptic

Opioid Presynaptic neurons of the brain stem, medial thalamus, cerebral cortex, amygdala, caudate, putamen ATP AC camp µ 1 - G i µ 1 G 0 Ca++ G K+ i µ 1 Opioid Ca++ Opioid K+ Postsynaptic

Opioid Presynaptic neurons of the brain stem, medial thalamus, cerebral cortex, amygdala, caudate, putamen ATP AC camp Reduced neuronal metabolic rate Reduced excitotoxicity Reduced neuronal injury - µ 1 G i µ 1 G 0 Ca++ K+ G i µ 1 + Opioid Ca++ Opioid Postsynaptic

Premedication for nonemergency endotracheal intubation 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 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.

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

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

Remifentanil vs. morphine Possibly due to more rapid onset of action Pereira e Silva et al. Arch Dis Child Fetal Neonatal Ed 2007; 92: F293-4.

The devil is in the details,

your pharmacist is in the weeds.

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

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

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

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.

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 Midazolam 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 26 200 20 27 29 200 40 30-32 200 60 Burtin et al. Clin Pharmacol Ther 1994; 56: 615-25.

NOPAIN 35 30 25 20 15 10 5 * 0 Poor neurologic outcome Placebo (N = 21) Midazolam (N = 21) Morphine (N = 24) *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.

Midazolam and hypotension Initial PK study in term infants showed no impact on blood pressure Jacqz-Aigrain et al. Eur J Clin Pharmacol 1990; 39: 191-2. 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 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.

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

Benzodiazepines and neuroapoptosis 60 Caudate-Putamen 25 Cortex C3A profile density (/mm 2 ) 50 40 30 20 10 20 15 10 5 0 0 0 Saline 1 Midazolam 2 3 0 Saline 1 Midazolam 2 3 Long-term functional deficits and atypical behavioral patterns 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.

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

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.

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

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

Morphine and hypotension % of patients with hypotension 35 30 25 20 15 10 5 0 p = 0.1672 Before study initiation p = 0.0085 After loading dose p < 0.0006 Drug infusion 1-24 hours Placebo (N = 449) Morphine (N = 449) p = 0.7364 Drug infusion 24-72 hours Anand KJS et al. Lancet 2004; 363: 1673-82. Simons et al. Arch Dis Child Fetal Neonatal Ed 2006; 91: F46-51.

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

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.

Opioid Opioid Opioid Opioid P µ 1 G P Opioid Protein Kinase C G-protein-receptor coupled kinase Extracellular regulated kinase Apoptosis signal-regulating kinase + + Cell cycle progression Apoptosis

Opioid Opioid Protein Kinase C Extracellular regulated kinase + Cell cycle progression Opioid µ 1 P P β-arrestin G G-protein-receptor coupled kinase Apoptosis signal-regulating kinase + Apoptosis Opioid Opioid

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

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.

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.

AAP and CPS The routine use of continuous infusions of morphine, fentanyl, or midazolam in chronically ventilated preterm neonates is not recommended Despite this recommendation, use of opioids in clinical practice remains common AAP and CPS. Pediatrics 2006; 118: 2231-41.

Morphine and brain growth 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 Zwicker et al. J Pediatr 2016; 172: 81-7.

Global brain volume 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) Median morphine dose 0.79 mg/kg, interquartile range 0.12-0.95 mg/kg Steinhorn et al. J Pediatr 2015; 166: 1200-7.

Morphine and brain growth r 2 =0.002

Global brain volume 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.

Development at 2 years 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* 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.

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.

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

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

t 1/2 = 4-6 hrs 10.5 mcg/kg Saarenmaa et al. J Pediatr 2000; 136: 767-770.

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 Ancora et al. J Pediatr 2013; 163: 645-51. Ancora et al. Pain 2017; 158: 840-5.

r = 0.531 p < 0.001 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) McPherson et al. Ann Pharmacother 2015; 49: 1291-7.

Presynaptic neurons of the brain locus stem, coeruleus medial thalamus, cerebral cortex, amygdala, caudate, putamen ATP AC camp Reduced neuronal metabolic rate Reduced excitotoxicity Reduced neuronal injury - µ α 12 r G i µ α 12 r G 0 Ca++ K+ G i Opioid α 2 -receptor agonist + µ 1 α 2 r Opioid α 2 -receptor agonist Ca++ Opioid α 2 -receptor agonist Postsynaptic

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

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

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

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

Neuroprotection? Reduces lesion size after experimentally induced PVL Protects against brain matter loss and improves neurologic function after hypoxia-ischemia Attenuates neuroapoptosis and prevents longterm 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.

α 2 agonist α 2 agonist α 2 agonist α 2 G α 2 agonist α 2 agonist Extracellular regulated kinase + Cell cycle progression Apoptosis signal-regulating kinase + Apoptosis Dahmani et al. Anesthesiology 2008; 108: 457-66.

Contact information mcpherson_c@kids.wustl.edu