PEDIATRICS Vol. 115 No. 5 May 2005, pp. 1416-1418 (doi:10.1542/peds.2005-0501)
COMMENTARY |
Morphine, Hypotension, and Intraventricular Hemorrhage in the Ventilated Premature Infant
Department of Pediatrics
Weill Cornell Medical Center
New York, NY 10021
Abbreviations: IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia • GA, gestational age
The article in this issue of Pediatrics entitled "Morphine, Hypotension, and Adverse Outcomes Among Preterm Neonates: Who’s to Blame?" is a reanalysis of a data set recently published.1,2 Before attributing blame and passing judgment, it is important to briefly review the data. Thus, the genesis of the study was based on pilot observations that suggest that morphine infusions decrease the frequency of early neurologic injury in ventilated infants.3 The authors extended these initial observations and conducted a multicenter, blinded, randomized trial to test the hypothesis that preemptive morphine, compared with a placebo group, would significantly reduce the frequency of early neurologic injury in ventilated preterm neonates. The primary outcome was neonatal death, severe intraventricular hemorrhage (IVH) (grade III/IV), or periventricular leukomalacia (PVL) defined as cystic echolucency adjacent to the lateral ventricles on cranial sonography obtained at 4 to 7 days and at 28 to 35 days of postnatal life. Ventilated infants were stratified by gestational age (GA) at birth as follows: 23 to 26, 27 to 29, and 30 to 32 weeks. The principal findings were that both groups had similar rates of composite outcome, severe IVH, and PVL. Because open-labeled morphine was an option for both groups, when the data were reanalyzed the morphine as well as the placebo group of infants, who received open-labeled morphine, had significantly worse rates of severe IVH or composite outcome, respectively.2 Regarding adverse effects, infants in the group receiving morphine had an increased incidence of hypotension (defined as the need for vasopressor support or intravenous fluid boluses 
20 mL/kg), particularly during the loading dose, and required a significantly longer duration of mechanical ventilation, as well as a significantly longer time to tolerate full-volume nasogastric feeds.2 Finally, the investigators found minor effects on pain scores. The data have now been reanalyzed by using a series of logistic-modeling strategies to identify clinical factors associated with hypotension at different time points in the study. Based on the additional analyses the authors now conclude: "Although morphine analgesia was associated with the increased occurrence of early hypotension, additional analyses revealed that morphine therapy had no significant effects on IVH or neonatal death, except that open-label morphine during 25 to 72 hours was associated with severe IVH." As one deliberates the combined analyses, there are 2 issues that require additional amplification. First, does continuous morphine administration reduce, have a neutral effect on, or even increase severe IVH in the ventilated premature infant? Second, do the adverse effects of morphine therapy outweigh potential benefits for this particular indication?
To briefly recall hemorrhagic-ischemic cerebral injury is a common problem, particularly in the very low birth weight infant of <1000 g birth weight or <28 weeks’ GA.4 The pathogenesis of IVH is complex and likely differs as a function of GA. Thus, the sonographic detection of hemorrhage is earlier (ie, in the first 24 hours in the smallest infants), whereas it is later (ie, between 48 and 72 hours) in the larger premature infant.5 Indeed, in a study that used indomethacin to prevent IVH, a large number of infants were excluded because of hemorrhage identified within the first 6 hours of age.6 In the current study it remains unclear at what postnatal age infants were enrolled and/or when they received the initial loading dose of morphine. This seems important, given the findings that pulmonary hemorrhage was a risk factor for severe IVH if present before the loading dose of morphine (see Table 3 in ref 1). This complication generally presents beyond the first postnatal day.7 Thus, it is conceivable that hemorrhage may have been present before morphine administration. The failure to obtain a cranial sonogram at study entry is a major weakness and limits any meaningful discussion as it relates to the potential prevention of IVH with morphine. The data suggest that morphine administration may have contributed to severe IVH in a subset of the infants. This unanticipated observation parallels that of Kuban et al,8 who demonstrated an increased risk for developing any IVH in premature infants administered phenobarbital, when the medication was used to prevent hemorrhage. Cystic PVL, the sonographic end point in this study, grossly underrepresents periventricular white-matter injury in the premature infant. Thus, both pathologic as well as magnetic resonance imaging studies demonstrate a more diffuse noncystic injury to periventricular white matter, a finding that is more common than a cystic lesion.9,10 The sonographic correlate of this injury is a nonhemorrhagic progressive dilatation of the lateral ventricles, often beyond 35 days.11
The absence of any longitudinal data is a major limitation. This would seem to be highly relevant, given the findings of Schmidt et al,12 who demonstrated a significant reduction in severe IVH in infants administered indomethacin to prevent this lesion versus a placebo group. However, at 18-month follow-up, there was no difference between groups in the rates of cerebral palsy and/or moderate to severe cognitive deficits.12 Thus, the potential impact of continuous morphine administration on long-term neurodevelopmental outcome remains unclear and, as noted by the authors, critical to determine.
Morphine administration was associated with several adverse effects. First, hypotension was a problem, particularly during the loading dose in the smallest infants but also during the first 24 hours, when preemptive as well as open-labeled morphine was administered. The authors appropriately caution against the use of morphine with hypotension but then suggest using intravenous ketamine as an alternative agent. This should be avoided, because there are no data regarding the risks and/or benefits of using this medication in the sick premature infant. Second, morphine administration resulted in a longer duration of ventilator support. It is unclear whether this translated into more chronic lung disease at 36 weeks’ corrected age, particularly in the smallest premature infants. The latter condition has been shown to be an independent risk factor for adverse neurodevelopmental outcome.13
The question of whether ventilated infants should be routinely administered narcotics such as morphine or fentanyl pain medication remains controversial.14 Despite the extensive reanalysis of the data, this study does little to guide the clinician through this controversy. Several questions linger. First, morphine failed to prevent IVH and/or cystic PVL and indeed may have contributed to hemorrhage in a subset of infants. However, as noted previously, flaws in the study design limit any definitive statement in this regard. Second, the hypotension associated with morphine administration in the smallest premature infants could increase the propensity for white-matter injury, which may have gone undetected based on the end points in this study. Third, in this report as well as another recent study, morphine administration had minimal effect on pain scores.2,15 In this regard, it is critical for the clinician to distinguish indicators of "perceived" pain (ie, tachycardia or perturbations in blood pressure) from other clinical or stressful events (ie, noise or frequent handling) that may produce the same physiologic responses.16 As an example of this point, the authors state: "Morphine blunts the physiologic responses to pain leading to the blood pressure fluctuations associated with IVH." One study that directly examined this relationship noted that the fluctuations in blood pressure were related to the infants breathing out of synchrony with the ventilator rather than as a consequence of pain.17 Indeed, as pointed out by the authors, such fluctuations may be minimized with appropriate ventilator support (ie, patient-triggered modes of ventilation). Fourth, recent in vitro experimental data indicate enhanced apoptosis of primary human fetal microglial and neuronal elements after morphine exposure, observations that should raise concerns regarding prolonged continuous infusions.18 Despite these overall concerns, we consider it essential that the potential for pain associated with medical management always be discussed frequently in any neonate requiring intensive care. Finally, we concur with the authors that narcotic infusions should be used judiciously, only in normotensive premature infants, and only if there are clinical indications of pain.
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FOOTNOTES |
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Accepted Mar 3, 2005.
Address correspondence to Jeffrey M. Perlman, MB, ChB, Department of Pediatrics, Weill Cornell Medical Center, New York, NY 10021. E-mail: jmp2007{at}med.cornell.edu
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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