Published online January 4, 2006
PEDIATRICS Vol. 117 No. 1 January 2006, pp. 250-252 (doi:10.1542/peds.2005-2250)
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Morphine, Hypotension, and Intraventricular Hemorrhage

K.J.S. Anand, MBBS, DPhil
R. Whit Hall, MD
Department of Pediatrics
University of Arkansas for Medical Sciences
College of Medicine
Little Rock, AR 72205

To the Editor.—

The commentary by Dr Perlman1 raises important questions about whether severe intraventricular hemorrhage (IVH) in ventilated premature infants is reduced, unaffected, or increased by morphine infusions to derive a balance between its beneficial and adverse effects. Although he agrees with the conclusions of our analysis on morphine and hypotension,2 he also raises several issues that require clarification. We address these issues to allow clinicians the opportunity to make their own judgments about the effects of morphine analgesia in ventilated preterm neonates.

First, Perlman asks at what postnatal age infants were enrolled and/or when they received the initial loading dose of morphine. These and other data regarding morphine therapy in the NEOPAIN trial are summarized in Table 1.


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  		TABLE 1 Morphine Therapy in the NEOPAIN Trial

 
Next, as we have pointed out in previous reports,2,3 Perlman echoes that "failure to obtain a cranial sonogram at study entry is a major weakness." This reflects the pragmatic choice of designing the NEOPAIN trial to include NICUs that did not have 24-hour access to cranial ultrasonography to allow greater generalization of the results. Because early morphine administration (within 8 hours of intubation) was important to investigate its effects on IVH, most centers were unable to get cranial ultrasonography within the brief intervening period. This choice was addressed in the discussion of our primary outcomes3(p1680) and need not be repeated here. We beg to differ with Perlman's statement, multiple times in his commentary, that "morphine administration may have contributed to severe IVH in a subset of the infants."1 First, our sample size (n = 898) provided sufficient power to support a lack of association between severe IVH and continuous morphine infusions.3 Second, although initial subgroup comparisons showed a higher incidence of IVH in 23- to 26-week neonates who were receiving morphine (P = .0472), logistic-regression analyses of the primary outcomes, while controlling for other clinical variables, showed no effect of morphine infusions on any of these outcomes (neonatal death [OR: 1.16; 95% confidence interval (CI): 0.72–1.88; P = .5459], severe IVH [OR: 1.33; 95% CI: 0.85–2.10; P = .2153], periventricular leukomalacia [PVL] [OR: 0.80; 95% CI: 0.47–1.36; P = .4080], or the composite outcome [OR: 1.07; 95% CI: 0.76–1.49; P = .7099]).3 Third, these results were further supported by the detailed logistic-regression analyses presented in our more recent article.2 We seek to be enlightened by Perlman's insight on which a subset of infants was exposed to increased risk of severe IVH by continuous morphine infusions (as opposed to intermittent morphine doses, which the NEOPAIN trial was not designed to examine2). Others have shown that morphine infusions do not increase severe IVH, reduce stress responses, and shorten NICU stays in ventilated preterm neonates.4,5

Perlman posits that cystic PVL grossly underrepresents white-matter injury in preterm infants. We agree but maintain that the NEOPAIN trial was designed at a time when there was minimal understanding of the definition or pathophysiology of PVL, and the current analyses were not intended to examine clinical factors related to PVL.2 We also agree with Perlman that the absence of longitudinal data are a major limitation, and we will continue our efforts to obtain funding for the collection of these follow-up data. As noted in Table 1, graded increases in the cumulative morphine dosage in the 4 neonatal groups (0, 0.71, 1.50, and 3.41 mg/kg) and the detailed perinatal data collected prospectively from the NEOPAIN trial provide us with a powerful cohort to examine the long-term effects of opioid therapy on brain development and behavior.

Further, Perlman calls for avoiding the use of ketamine, "because there are no data regarding the risks and/or benefits of using this medication in the sick premature infant." However, there is a significant body of data on the use of ketamine in neonates (summarized recently6,7), showing that it maintains hemodynamic stability with minimal effects on cerebral blood flow in ventilated preterm infants.8 We do not advocate its routine use in preterm neonates, because the effects of prolonged ketamine therapy have not been evaluated in large randomized trials (as with many other drugs used in the NICU).

Finally, we disagree with Perlman's suggestion that the doses of morphine used in the NEOPAIN trial may cause apoptosis in the preterm neonatal brain. Hu et al9 described apoptosis in neuronal cells at morphine concentrations of 10–12 M and in microglial cells at morphine concentrations of 10–8 M in vitro, which are orders of magnitude higher than the morphine concentrations measured in the NEOPAIN trial (see Table 1). Perinatal exposure of infant rats to morphine alters adult behavior, cognitive performance, and regulation of the hypothalamic-pituitary-adrenal axis,10–13 whereas morphine use in neonates may improve neurodevelopmental outcomes14–17 but does not alter regulation of the hypothalamic-pituitary-adrenal axis.18,19 We caution Dr Perlman that huge discrepancies between animal versus human data or in vitro versus in vivo data include many anesthetic and sedative drugs.20–22 In the past, muscle relaxants were used to achieve ventilator synchrony and reduce IVH in unsedated preterm neonates,23 but this practice may be untenable today.24–26

REFERENCES

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  2. Hall RW, Kronsberg SS, Barton BA, Kaiser JR, Anand KJ; NEOPAIN Trial Investigators Group. Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial. Pediatrics. 2005;115 :1351 –1359[Abstract/Free Full Text]
  3. Anand KJS, Hall RW, Desai NS, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363 :1673 –1682[CrossRef][ISI][Medline]
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  7. Berde CB, Jaksic T, Lynn AM, Maxwell LG, Soriano SG, Tibboel D. Anesthesia and analgesia during and after surgery in neonates. Clin Ther. 2005;27 :900 –921[CrossRef][ISI][Medline]
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  9. Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine induces apoptosis of human microglia and neurons. Neuropharmacology. 2002;42 :829 –836[CrossRef][ISI][Medline]
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  11. Bhutta AT, Rovnaghi CR, Simpson PM, Gosset JM, Scalzo FM, Anand KJS. Interactions of inflammatory pain and morphine treatment in infant rats: long-term behavioral effects. Physiol Behav. 2001;73 :51 –58[CrossRef][Medline]
  12. Spanagel B, Stohr T, Barden N, Holsboer F. Morphine-induced locomotor and neurochemical stimulation is enhanced in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol. 1996;8 :93 –97[CrossRef][ISI][Medline]
  13. D'Souza DN, Harlan RE, Garcia MM. Sexual dimorphism in the response to N-methyl-D-aspartate receptor antagonists and morphine on behavior and c-Fos induction in the rat brain. Neuroscience. 1999;93 :1539 –1547[CrossRef][ISI][Medline]
  14. MacGregor R, Evans D, Sugden D, Gaussen T, Levene M. Outcome at 5–6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F40 –F43[Abstract/Free Full Text]
  15. Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. Demographic and therapeutic determinants of pain reactivity in very low birth neonates at 32 weeks' postconceptional age. Pediatrics. 2001;107 :105 –112[Abstract/Free Full Text]
  16. Grunau RE, Whitfield MF, Davis C. Pattern of learning disabilities in children with extremely low birth weight and broadly average intelligence. Arch Pediatr Adolesc Med. 2002;156 :615 –620[Abstract/Free Full Text]
  17. Angeles DM, Wycliffe N, Michelson D, et al. Use of opioids in asphyxiated term neonates: effects on neuroimaging and clinical outcome. Pediatr Res. 2005;57 :873 –878[CrossRef][Medline]
  18. Grunau RE, Weinberg J, Whitfield MF. Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months. Pediatrics. 2004;114 (1). Available at: www.pediatrics.org/cgi/content/full/114/1/e77
  19. Grunau RE, Holsti L, Haley DW, et al. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain. 2005;113 :293 –300[Medline]
  20. SorianoSG, Anand KJS, Rovnaghi CR, Hickey PR. Of mice and men: should we extrapolate rodent experimental data to the care of human neonates? Anesthesiology. 2005;102 :866 –869[CrossRef][ISI][Medline]
  21. Anand KJS, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic agents? Anesthesiology. 2004;101 :527 –530[CrossRef][ISI][Medline]
  22. Todd MM. Anesthetic neurotoxicity: the collision between laboratory neuroscience and clinical medicine. Anesthesiology. 2004;101 :533 –534
  23. Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med. 1985;312 :1353 –1357[Abstract]
  24. Goldstein RF, Brazy JE. Narcotic sedation stabilizes arterial blood pressure fluctuations in sick premature infants. J Perinatol. 1991;11 :365 –371[Medline]
  25. Simons SHP, van Dijk M, van Lingen RA, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003;290 :2419 –2427[Abstract/Free Full Text]
  26. Aranda JV, Carlo WA, Thomas R, Hummel P, Anand KJS. Analgesia and sedation during mechanical ventilation in neonates. Clin Ther. 2005;27 :877 –899[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

Related articles in Pediatrics:

Morphine, Hypotension, and Intraventricular Hemorrhage: In Reply
Jeffrey M. Perlman
Pediatrics 2006 117: 252-253. [Extract] [Full Text]  




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