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Rather than rehash a data set that has been extensively analyzed and reanalyzed in 2 recent articles, I would rather focus on a couple of points raised by the authors.1,2
First, Anand and Hall beg to differ with the statement in my commentary that "morphine administration may have contributed to severe IVH in a subset of patients."3 Yet, on page 1357 of their article, it is stated that "[t]he decision to use open-label morphine was a significant predictor of severe IVH [intraventricular hemorrhage] only if the open-label morphine was given during 25 to 72 hours of study drug infusion (OR: 1.86; P = .0161)."1 In addition, in the discussion on page 1358, the authors themselves comment that "open-label morphine during 25 to 72 hours after starting study drug infusion was associated with severe IVH." Thus, I consider my statement in the commentary appropriate.
Second, "a pragmatic design," while potentially understandable to complete a study, is flawed as it relates to answering the critical question of whether the intervention (ie, morphine) has any effect on the occurrence of IVH. The authors are referred once again to the study design of IVH prevention with indomethacin by Ment et al,4 who excluded a substantial number of infants with IVH who were diagnosed between 5 and 11 hours of age.
Third, long-term outcome is critical to any intervention study in sick preterm infants. Indeed, it should have been part of the original study design and the outcome data presented at that time. Regarding the use of ketamine, the authors state in their article that "[a]lternative approaches to analgesia and sedation (eg, synchronized ventilation or intravenous ketamine therapy) may be more appropriate for these patients"1 (not referenced). In support of this statement, Anand and Hall now refer the reader to a "significant body of literature" related to ketamine use in neonates in 2 recent review articles.5,6 In reality, there are very limited data regarding ketamine use in the premature infant; most of the reports include a small number of infants who received a single dose during a procedure. To quote from the Anand et al review article, "although ketamine is frequently used for surgical anesthesia during surgical procedures in neonates, further studies are needed to examine its physiologic and behavioral effect when used to treat procedural pain in preterm and term infants."5 The second review article by Berde et al6 raised important questions regarding potential neurodegeneration induced by N-methyl-D-aspartate (NMDA) receptor blockade. Thus, blockade of NMDA receptors for only a few hours during the late fetal and/or early neonatal period triggered widespread apoptotic neurodegeneration in the developing rat brain. One can argue the translational relevance of animal data; however, at a minimum, the experimental data should raise red flags. Thus, to summarize, the evidence demands careful prospective studies to evaluate the potential role of ketamine in controlling pain in the sick premature infant.
Finally, as concluded in my commentary, I consider it essential that the potential for pain associated with medical care be an integral part of any neonatal management strategy. However, any intervention to minimize pain should include agents that achieve the desired goal while at the same time minimizing potential adverse effects.
REFERENCES
Related articles in Pediatrics:
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