Epinephrine (from the Greek epi-nephros, “on top of the kidneys”), known across the Atlantic pond as adrenalin (from the Latin ad-renal, “near the kidneys”), has been an unquestioned staple in the neonatal resuscitation drug toolkit for many decades. First extracted from the adrenal medulla in 1895, purified in 1901, and synthesized in 1904, this drug has proven efficacy for the treatment of a number of acute conditions such as anaphylaxis and glaucoma.
In 2010, the International Liaison Committee on Resuscitation (ILCOR) published recommendations for using epinephrine to resuscitate newborns “derived largely from indirect evidence from pediatric studies of uncertain relevance to neonates or from animal studies.”1 Among newborns in whom effective lung ventilation and chest compressions fail to increase heart rate >60 beats per minute, the guidelines suggested administration of an intravenous dose of epinephrine (0.01–0.03 mg/kg) repeated every 3 to 5 minutes as needed. A higher dose (0.05–0.1 mg/kg) administered through an endotracheal tube was the fallback option in the absence of intravenous access. But what do we really know about the best dose, dosing interval, route of administration, and efficacy of epinephrine in neonatal resuscitation?
In this issue of Pediatrics, Isayama et al1 on the ILCOR Newborn Life Support Task Force present an exhaustive systematic review of the literature to answer this question. Specifically, they asked whether any nonstandard dose, interval, or route of administration of epinephrine administered to term or preterm neonates improved the primary outcome of survival to discharge or some secondary outcomes (eg, rate of achieving return of spontaneous circulation [ROSC], time until ROSC, need for a second dose of epinephrine, absence of major morbidities).1 They cast a wide net to capture both randomized and nonrandomized controlled studies, interrupted time series studies, controlled before-and-after studies, and observational cohort (but not case series) studies in the published literature that had English abstracts. De rigueur for systematic reviews, the authors assessed each study for risk of bias (using the Risk Of Bias In Non-Randomized Studies of Interventions tool2 ) and certainty of evidence (using the Grading of Recommendation Assessment, Development, and Evaluation methodology that considered risk of bias, inconsistency, and imprecision3,4 ).
Notably, authors of this review documented a striking paucity of evidence that speaks to their question. The authors deemed only 4 of 593 retrieved studies eligible for analysis. All 4 were single-center retrospective cohort studies of delivery room events that in total included 117 infants treated with epinephrine. Researchers of 3 studies reported on different time periods from the same institution. Of the 2 studies in which outcomes in infants treated with endotracheal and/or intravenous epinephrine were described, only 1 pertained to the primary outcome, 2 addressed return to ROSC, 1 assessed time to ROSC, and 1 included data on repeat dosing. Unfortunately, the quality of the studies was suboptimal. All 4 studies were judged to be biased because of confounding or because the threshold for treatment was less stringent than the 2010 ILCOR recommendation. In the end, no analysis found a difference between endotracheal and intravenous epinephrine with respect to the primary or any secondary outcome, but these findings are colored by a low certainty of evidence because of serious imprecision and serious risk of bias.
Having found insufficient guidance in the human literature, the authors turned next to a review of animal studies. Surprisingly, the referenced studies that detail different epinephrine regimens used in models of neonatal asphyxia in 2 animal species do not provide unambiguous assurance that epinephrine improves primary or secondary outcomes.
How should we as clinicians, who “know from experience” that epinephrine is effective, process this systematic review? I would suggest with large doses of honesty and humility! In this systematic review, it is made clear that the body of evidence pertaining to the outcome of infants resuscitated with epinephrine can neither validate nor refute current ILCOR recommendations. But it would be foolhardy to now abandon the use of epinephrine in newborns solely because we lack directly pertinent placebo-controlled trials of efficacy. We must also appreciate that better evidence of good quality is unlikely to emerge soon given that the rare (0.05% of all live births) and unexpected use of epinephrine in newborn infants frustrates the design and execution of controlled studies of sufficient power. The authors note that multicenter cluster-randomized trials might constitute a path forward. One has to question whether optimization of epinephrine administration is truly a priority area for study at the present time. Efforts to improve and maintain competencies in recognizing fetal asphyxia and performing efficient and effective neonatal resuscitation are likely to provide a much greater return on investment.
In the meantime, it seems self-evident to this simple clinician to continue to work to assure an effective team choreography of resuscitation and to administer epinephrine only when indicated via the first route available by using doses recommended by the current ILCOR guidelines.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/2020-0586.
POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.