PEDIATRICS Vol. 117 No. 1 January 2006, pp. 250-252 (doi:10.1542/peds.2005-2250)
LETTER TO THE EDITOR |
Morphine, Hypotension, and Intraventricular Hemorrhage
K.J.S. Anand, MBBS, DPhilR. 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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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
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Pediatrics 2006 117: 252-253.
R. Carbajal and K. J. S. Anand
Prevention of Pain in Neonates--Reply
JAMA,
November 19, 2008;
300(19):
2248 - 2249.
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