Neurobehavior of Preterm Infants at 36 Weeks Postconception as a Function of Morphine Analgesia

ABSTRACT

This study evaluated early neurobehavioral outcomes in ventilated preterm infants randomized to receive morphine analgesia or placebo in the Neurological Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial. Eight hundred and ninety-eight infants between 23 and 32 weeks of gestation were randomized to receive preemptive morphine analgesia (morphine) or placebo. Infants also received additional analgesia (AA) with open-label morphine. The Neurobehavioral Assessment of the Preterm Infant (NAPI) was used to evaluate 572 of 793 survivors (72.1%) at 36 weeks of postconceptual age. The Neonatal Medical Index (NMI) was used to evaluate the severity of medical complications. Regression analyses were used to determine the effect of covariates. Infants were equally distributed in morphine and placebo groups with similar neonatal and demographic characteristics. Infants assessed with the NAPI were more likely to have sepsis (p = 0.03), bronchopulmonary dysplasia (p = 0.02), and longer length of stay (p = 0.008). Infants randomized to the morphine group had higher NMI scores (odds ratio [OR]; 95% confidence interval [CI]: 1.75; 1.23 to 2.50; p = 0.002). Use of AA was associated with higher NMI scores (OR; 95% CI: 4.5; 2.9 to 5.9; p < 0.001). Of the NAPI subscales, the (mean ± standard deviation [SD]) popliteal angle cluster scores were significantly higher in the morphine group compared with placebo (51.2 ± 33.2 versus 45.0 ± 33.5; p = 0.03). AA use was associated with lower (mean ± SD) motor scores in the morphine group (48.2 ± 16.1 versus 52.7 ± 19.1; p = 0.03) and with lower popliteal angle cluster scores in both the morphine group (41.5 ± 34.0 versus 59.5 ± 30.1; p < 0.0001) and the placebo group (40.8 ± 36.8 versus 49.4 ± 28.0; p = 0.004). No differences were noted in the other NAPI subscales cluster scores in either subgroup. We conclude that morphine analgesia may result in subtle neurobehavioral differences in premature infants.

Morphine analgesia - Prematurity - Neurobehavioral - Neurobehavioral Assessment of the Preterm Infant (NAPI) - Neonatal Medical Index (NMI)

REFERENCES

• 1 Msall M E. Neurodevelopmental surveillance in the first 2 years after extremely preterm birth: Evidence, challenges, and guidelines.  Early Hum Dev. 2006;  82 157-166
• 2 Constantinou J C, Adamson-Macedo , Ariagno R L, Fleisher B E. Neurobehavioral assessment predicts differential outcome between VLBW and ELBW preterm infants.  J Perinatol. 2005;  12 788-793
• 3 Low J A, Galbraith R S, Muir D W, Broekhoven L H, Wilkinson J W, Karchmar E J. The contribution of fetal-newborn complications to motor and cognitive deficits.  Dev Med Child Neurol. 1985;  27 578-587
• 4 Ross G. Use of Bayley Scales to characterize abilities of premature infants.  Child Dev. 1985;  56 835-842
• 5 American Academy of Pediatrics Committee on Fetus and Newborn, Committee on Drugs . Section on Anesthesiology, Section on Surgery, Canadian Pediatric Society, Fetus and Newborn Committee. Prevention and management of pain and stress in the neonate.  Pediatrics. 2000;  105 454-461
• 6 Pokela M L. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures.  Pediatrics. 1994;  93 379-383
• 7 Goldstein R F, Brazy J E. Narcotic sedation stabilizes arterial blood pressure fluctuations in sick premature infants.  J Perinatol. 1991;  11 365-371
• 8 Orsini A J, Leef K H, Costarino A, Dettorre M D, Stefano J L. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome.  J Pediatr. 1996;  129 140-145
• 9 Anand K JS, McIntosh N, Lagercrantz H, Young T E, Vasa R K, Barton B A. Analgesia and sedation in ventilated preterm neonates: results from the pilot NOPAIN trial.  Arch Pediatr Adolesc Med. 1999;  153 331-338
• 10 Simons S HP, van Dijk M, van Lingen R A et al.. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial.  JAMA. 2003;  290 2419-2427
• 11 Taddio A. Opioid analgesia for infants in the neonatal intensive care unit.  Clin Perinatol. 2002;  29 493-509
• 12 Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation.  Pain. 1994;  56 95-101
• 13 Taddio A, Katz J, Ilersich A L, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination.  Lancet. 1997;  349 599-603
• 14 Grunau R E, Oberlander T F, Whitfield M F, Fitzgerald C, Lee S K. Demographic and Therapeutic Determinants of Pain Reactivity in Very Low Birth Weight Neonates at 32 Weeks Postconceptional Age.  Pediatrics. 2001;  107 105-112
• 15 Johnston C C, Stevens B J. Experience in a neonatal intensive care unit affects pain response.  Pediatrics. 1996;  98 925-930
• 16 Anand K J, Hall R W, Desai N for the NEOPAIN Trial Investigators Group et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.  Lancet. 2004;  363 1673-1682
• 17 Korner A F, Brown J V, Thom V A, Constantinou J C. The Neurobehavioral Assessment of the Preterm Infant: Manual, Revised 2nd edition. (2000) Van Nuys, CA; Child Development Media (distributor)
• 18 Korner A F, Constantinou J, Dimicili S, Brown Jr B W, Thom V A. Establishing the reliability and developmental validity of a neurobehavioral assessment for preterm infants: a methodological process.  Child Dev. 1991;  62 1200-1208
• 19 Schade J G, Joyce B A, Gerkensmeyer J, Keck J F. Comparison of three preverbal scales for postoperative pain assessment in a diverse pediatric sample.  J Pain Symptom Manage. 1996;  12 348-359
• 20 Snider L, Tremblay S, Limperopoulos C, Majnemer A, Filion F, Johnston C. Construct validity of the Neurobehavioral Assessment of Preterm Infants.  Phys Occup Ther Pediatr. 2005;  25 81-95
• 21 Senn T E, Espy K A. Effects of neurobehavioral assessment on feeding and weight gain in preterm neonates.  J Dev Behav Pediatr. 2003;  24 85-88
• 22 Korner A F. Reliable individual differences in preterm infants' excitation management.  Child Dev. 1996;  67 1793-1805
• 23 Korner A F, Brown B W, Dimiceli S et al.. Stable individual differences in developmentally changing preterm infants: a replicated study.  Child Dev. 1989;  60 502-513
• 24 Hyman C, Snider L M, Majnemer A, Mazer B. Concurrent validity of the Neurobehavioral Assessment for Pre-Term infants (NAPI) at term age.  Pediatric Rehabilitation. 2005;  8 225-234
• 25 Korner A F, Stevenson D K, Forrest T, Constantiou J, Dimiceli S, Brown B W. Preterm medical complications differentially affect neurobehavioral functions: Results from a new neonatal medical index.  Infant Behav Dev. 1994;  17 37-43
• 26 Korner A F, Stevenson D K, Kraemer H C et al.. Prediction of the development of low-birth weight preterm infants by a new neonatal medical index.  J Dev Behav Pediatr. 1993;  14 106-111
• 27 International Neonatal Network . CRIB Investigator's Group. The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units.  Lancet. 1993;  342 193-198
• 28 De Courcy-Wheeler R HB, Wolfe C DA, Fitzgerald M S, Goodman J DS, Gamsu H R. Use of the CRIB (Clinical Risk Index for Babies) score in prediction of neonatal mortality and morbidity.  Arch Dis Child. 1995;  73 F32-F36
• 29 Anand K JS, Coskun V, Thrivikraman V, Nemeroffs C B, Plotsky P M. Long-term behavioral effects of repetitive pain in neonatal rat pups.  Physiol Behav. 1999;  66 627-637
• 30 Bhutta A T, Rovnaghi C, Simpson P M, Gossett J M, Scalzo F M, Anand K JS. Interactions of inflammatory pain and morphine in infant rats: long term behavioral effects.  Physiol Behav. 2001;  73 51-58
• 31 Carbajal R, Lenclen R, Jugie M, Paupe A, Barton B A, Anand K JS. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.  Pediatrics. 2005;  115 1494-1500
• 32 Dyke M P, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants.  J Paediatr Child Health. 1995;  31 176-179
• 33 Anand K J. Consensus statement for the prevention and management of pain in the newborn.  Arch Pediatr Adolesc Med. 2001;  155 173-180
• 34 Grunau R. Early pain in preterm infants: a model of long-term effects.  Clin Perinatol. 2002;  29 373-394
• 35 Anand K JS, Aranda J V, Berde C B et al.. Summary proceedings from the Neonatal Pain-Control Group.  Pediatrics. 2006;  117 9-22
• 36 van Lingen R A, Simons S HP, Anderson B J, Tibboel D. The effects of analgesia in the vulnerable infant during the perinatal period.  Clin Perinatol. 2002;  29 511-534
• 37 Merritt T A, Pillers D, Prows S L. Early NICU discharge of very low birth weight infants: a criteria review and analysis.  Semin Neonatol. 2003;  8 95-115
• 38 Michael Cotten C, Oh W, McDonald S et al.. for NICHD Neonatal Research Network. Prolonged hospital stay for extremely premature infants: risk factors, center differences, and the impact of mortality on selecting a best-performing center.  J Perinatol. 2005;  25 650-655
• 39 Infant Mortality and low birth weight among black and white infants-United States, 1980-2000.  MMWR Morb Mortal Wkly Rep. 2002;  51(27) 589-592
• 40 Alexander G R, Kogan M, Bader D et al.. US birth weight/gestational age-specific neonatal mortality: 1995-1997 rates for whites, Hispanics, and blacks.  Pediatrics. 2003;  111 61-66
• 41 Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio; The Psychological Corporation 1993