Neonatal Resuscitation
Neonatal Resuscitation
Neonatal Resuscitation
a
National Center for Child Health and Development, Tokyo, Japan; bMiddlemore Hospital, Otahuhu, Auckland, New Zealand; cCentre for the Studies of Asphyxia and Resuscitation, Neonatal
Research Unit, Royal Alexandra Hospital, Edmonton, Alberta, Canada; dUniversity of Alberta, Edmonton, Alberta, Canada; eDepartment of Pediatrics, Seoul National University College of
Medicine, Seoul, Korea; fUniversity of Calgary, Calgary, Alberta, Canada; gSt Michael’s Hospital, Toronto, Ontario, Canada; and hMater Research Institute and Mater Clinical School, Faculty of
Medicine, The University of Queensland, Brisbane, Queensland, Australia
To cite: Isayama T, Mildenhall L, Schmölzer GM, et al. The Route, Dose, and Interval of Epinephrine for Neonatal Resuscitation: A Systematic Review. Pediatrics. 2020;
146(4):e20200586
studies (0.01 mg/kg per dose7 and infants in the first to 30 of 50 infants in outcomes of preterm infants receiving
0.03–0.05 mg/kg per dose8) the second study, indicating a practice endotracheal epinephrine for
were lower than those currently shift. In both studies, some infants who resuscitation (single-arm studies).19,20
recommended (0.05–0.1 mg/kg per initially received endotracheal Jankov et al19 included only infants
dose).2 Furthermore, the proportion of epinephrine subsequently received $1 #750 g birth weight. Although
infants receiving initial endotracheal doses of IV epinephrine. In the other Perlman et al20 included preterm and
epinephrine decreased from 44 of 47 two studies, authors reported the term infants, the subgroup of term
b The mean gestational age and time of initial endotracheal epinephrine of infants included in this review from Barber and Wyckoff8 (2006) was derived for 37 infants who responded to endotracheal or IV epinephrine. The gestational age and time
infants (with one group receiving IV
3 of 8 (38)
2 of 8 (25)
not reported by route of
NA
NA
administration. Therefore, gestation
8
NA
NA
12
Risk-of-Bias Assessment
Barber and Wyckoff8 2006a
NA
NA
NA
NA
NA
NA
NA
NA
3a
NA
NA
NA
44
16 of 20 (80)
prolonged shoulder dystocia). In each case, there was time to mobilize appropriate personnel and equipment.”8
20
of initial endotracheal epinephrine for 7 infants who failed to respond epinephrine were not reported.
21 of 30 (70)
Apgar 1 min
Birth wt, g
No. infants
Hoc Analysis)
Endotracheal Epinephrine
endotracheal versus initial IV
received subsequent doses of
very low certainty of evidence,
ISAYAMA et al
the second study, the proportion who
study, authors reported that mortality
serious imprecision).7 Post hoc analysis
Narrative Summary of Additional these points in Table 4. Data on the use to admission and time until ROSC with
Human Studies of high-dose IV epinephrine for high-dose epinephrine; however, the
neonatal resuscitation are meager quality of evidence was very low, the
No studies eligible for this systematic (Table 4). In adults and children, subgroup of pediatric studies revealed
review evaluated alternative doses of a systematic review of 15 RCTs in no difference, and the applicability to
IV epinephrine, routes other than IV which authors compared high-dose newborn infants is uncertain.21
and endotracheal (eg, intraosseous, versus standard-dose epinephrine for Although authors of a few case series
intramuscular [IM]) administration, or cardiac arrest (typical starting dose for reported high-dose IV or endotracheal
dosing intervals. We summarized children of 0.1 mg/kg vs 0.01 mg/kg) epinephrine in preterm infants, the
results of ineligible studies assessing reported a slight reduction in survival safety and effectiveness of high
doses remain unknown.22,23 Longer authors commented that intraosseous administering epinephrine (Table 4).
latency between doses was examined access was always accomplished within In a cohort of neonates who had a
in an observational cohort study of 2 minutes (although data were not 1-minute Apgar score of 0 (median
children with cardiac arrest and was shown) and incurred few major gestation of 36 weeks [range 27–41
associated with improved survival. complications.25 Nevertheless, in a few weeks]), among 23 for whom the time
However, the direction of effect had case reports, authors have described was documented, umbilical venous
reversed after adjustment for severe complications including catheter (UVC) placement was
confounders, suggesting a high risk amputation of an extremity due to accomplished at a median time of 9
of bias.24 extravasation and compartment (95% CI 7 to 14) minutes after birth,
syndrome attributable to intraosseous probably longer than ideal for
In a few studies, authors described lines in infants.26,27 In one case report, asystolic neonates, whereas
routes for epinephrine administration authors described severe skin lesions endotracheal tubes were placed much
other than via endotracheal or IV at the site of an IM epinephrine earlier at a median time of 3.8 (95%
during neonatal resuscitation. In injection.28 CI 2.0 to 7.5) minutes after birth.29
a cohort study of 27 neonates within Simulation studies in which authors
5 hours of birth (median gestation of In several studies, authors addressed used neonatal manikins suggest
31 weeks [range 25–41 weeks]), the the time to obtain access suitable for shorter times to intraosseous than
Dr Isayama drafted the protocol, screened studies, abstracted data, completed risk-of-bias evaluations and the Grading of Recommendations Assessment,
Development and Evaluation, completed the analysis, and prepared the first draft of the manuscript; Dr Mildenhall applied risk-of-bias assessment tools to articles
regarding human infants and drafted sections of the manuscript; Prof Schmölzer screened animal studies, extracted data, and drafted the section of the
manuscript in which the results of animal studies are reported; Dr Kim screened animal studies; Dr Rabi monitored the progress of this systematic review and
provided editorial and methodologic feedback at each step as a representative of the Scientific Advisory Committee of the International Liaison Committee of
Resuscitation; Ms Zeigler constructed the literature search strategies, obtained additional expert review of the search strategies and performed the database
searches, and drafted the part of the Methods section in which these processes are described; Prof Liley screened the human infant studies, extracted data, and
oversaw manuscript development; two reviewers provided suggestions to the manuscript; and all authors conceptualized and designed the study, including
preparing the protocol and critically reviewing and revising the manuscript for important intellectual content, approved the final manuscript as submitted, and
agree to be accountable for all aspects of the work.
DOI: https://doi.org/10.1542/peds.2020-0586
Accepted for publication Jun 16, 2020
Address correspondence to Tetsuya Isayama, MD, MSc, PhD, Division of Neonatology, Center for Maternal-Fetal Neonatal and Reproductive Medicine, National Center
for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. E-mail: isayama-t@ncchd.go.jp
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2020 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the American Heart Association, on behalf of the International Liaison Committee on Resuscitation for article submission to the editor. Dr
Isayama received payment from this funding source to complete this systematic review as expert systematic reviewer. The St Michael’s Hospital Health Sciences
Library received payment from this funding source for performing a literature search in this systematic review. Our information specialist, Ms Ziegler, did not
personally receive compensation. Dr Schmölzer is a recipient of the Heart and Stroke Foundation and University of Alberta Professorship in Neonatal Resuscitation,
is a National New Investigator of the Heart and Stroke Foundation Canada, and is an Alberta New Investigator of the Heart and Stroke Foundation Alberta; the other
authors have indicated they have no financial relationships relevant to this article to disclose.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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