In a recently released issue of Pediatrics, Dr. Tetsuya Isayama and colleagues (10.1542/peds.2020-0586) describe a systematic review of both human and animal studies regarding dose, route, and interval of epinephrine administration for neonatal resuscitation. An accompanying commentary by Neonatologist Dr. Mark Hudak (10.1542/peds.2020-019968) provides an overview and clinical context for the study. Dr. Isayama and co-authors collaborated with ILCOR (the International Liaison Committee on Resuscitation), an international organization that aims to rigorously evaluate the best possible evidence on resuscitation in age groups across the spectrum. The most recent summary regarding epinephrine use in resuscitation was published in 2010, and hence this area was ripe for an update, with the hope that additional evidence had been published in the interim. Polled members of ILCOR identified route, dose and interval timing of epinephrine for neonatal resuscitation as key focus areas for this systematic review. The primary outcome for the review was in-hospital death, and secondary outcomes included achievement of, and time to achieve, audible sustained heart rate of >60 beats per minute.
The authors clearly describe their systematic search strategy for articles with randomized and non-randomized trials in neonates (infants <28 days of age), and explain how risk of bias and criteria for quality of evidence were assessed. Unfortunately, just four retrospective trials that included 117 infants were ultimately eligible for review, and hence the authors turned to studies in animals (which I find difficult to read about) in order to see if any of these provided relevant information. A narrative description of excluded human studies is included also. The authors also describe the design, methods and outcomes for included and excluded trials.
Although Dr. Isayama and colleagues were scientifically frustrated in their comprehensive efforts to achieve ironclad answers to the questions that drove this systematic review, there is great value in describing this work. They caution that due to the “very low certainty of the evidence,” even their findings of “no difference” between intravenous and endotracheal dosing, or between two endotracheal doses, are the best we have, yet not highly reliable “answers.” Dr. Hudak’s commentary beautifully discusses how clinicians can integrate this very unsatisfying “best evidence” into their practices. While we would all love a silver bullet study, and it certainly seems like with so much effort one should have emerged, this systematic review is a meaningful contribution to the quest for optimal clinical care in the resuscitation of critically ill newborns.