Video Abstract

Video Abstract

CONTEXT:

Current International Liaison Committee on Resuscitation recommendations on epinephrine administration during neonatal resuscitation were derived in 2010 from indirect evidence in animal or pediatric studies.

OBJECTIVE:

Systematic review of human infant and relevant animal studies comparing other doses, routes, and intervals of epinephrine administration in neonatal resuscitation with (currently recommended) administration of 0.01 to 0.03 mg/kg doses given intravenously (IV) every 3 to 5 minutes.

DATA SOURCES:

Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, and trial registry databases.

STUDY SELECTION:

Predefined criteria were used for selection.

DATA EXTRACTION:

Risk of bias was assessed by using published tools appropriate for the study type. Certainty of evidence was assessed by using Grading of Recommendations Assessment, Development and Evaluation.

RESULTS:

Only 2 of 4 eligible cohort studies among 593 unique retrieved records yielded data allowing comparisons. There were no differences between IV and endotracheal epinephrine for the primary outcome of death at hospital discharge (risk ratio = 1.03 [95% confidence interval 0.62 to 1.71]) or for failure to achieve return of spontaneous circulation, time to return of spontaneous circulation (1 study; 50 infants), or proportion receiving additional epinephrine (2 studies; 97 infants). There were no differences in outcomes between 2 endotracheal doses (1 study). No human infant studies were found in which authors addressed IV dose or dosing interval.

LIMITATIONS:

The search yielded sparse human evidence of very low certainty (downgraded for serious risk of bias and imprecision).

CONCLUSIONS:

Administration of epinephrine by endotracheal versus IV routes resulted in similar survival and other outcomes. However, in animal studies, researchers continue to suggest benefit of IV administration using currently recommended doses.

Asphyxia is a leading cause of neonatal death and disability worldwide, and some of these deaths may be preventable by improvements in neonatal resuscitation.1  Epinephrine (adrenaline) is recommended as a key medication in neonates who have not responded to previous resuscitation measures, including lung ventilation and chest compressions2 ; however, the evidence for its use is limited. The International Liaison Committee on Resuscitation (ILCOR) evaluates and promotes the best available evidence on resuscitation in all age groups using rigorous review processes to generate an international consensus on science with treatment recommendations (CoSTR), which can be used to develop national and multinational resuscitation guidelines and algorithms.3  The most recent ILCOR treatment recommendations on epinephrine for neonatal resuscitation were derived largely from indirect evidence from pediatric studies of uncertain relevance to neonates or from animal studies.2  These recommendations are for epinephrine at a dose of 0.01 to 0.03 mg/kg intravenously (IV) (with repeated doses each 3–5 minutes if needed) if adequate assisted ventilation of the lungs and chest compressions have failed to increase the heart rate >60 beats per minute. Endotracheal epinephrine administration at a higher dose (0.05–0.1 mg/kg) is suggested but only if IV access is unavailable. These 2010 recommendations still stand because for the 2015 CoSTR, ILCOR did not rereview epinephrine for neonatal resuscitation.4 

Since 2015, ILCOR has used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process to appraise evidence.5  The need to assess evidence for epinephrine use during neonatal resuscitation by using GRADE, together with the possibility that relevant human or animal evidence had been published since the 2010 ILCOR review, led to a decision to conduct a new systematic review. Polling of the ILCOR Neonatal Life Support Task Force prioritized 3 areas of focus. In collaboration with the ILCOR Neonatal Life Support Task Force, we use this systematic review and meta-analysis to assess the following areas: the doses, routes, and intervals of epinephrine administration in neonatal resuscitation.

The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019132219).

With this systematic review, we assessed the question, “Among neonates (of any gestation) at ≤28 days of age who have no detectable cardiac output, have asystole, or have a heart rate <60 beats per minute despite ventilation and chest compressions, does any nonstandard dose, interval, or route of epinephrine (adrenaline) improve the primary outcome (death at discharge) or any secondary outcomes compared to standard-dose IV epinephrine (0.01–0.03 mg/kg at intervals of every 3–5 minutes)?”

Eligible participants were neonates of any gestational age within 28 days of birth who had either no detected cardiac output or asystole or heart rate <60 beats per minute despite ventilation and chest compressions and had received epinephrine for resuscitation. In eligible studies, authors either compared predefined outcomes between infants receiving epinephrine by using standard or nonstandard routes, doses, or intervals of administration or they reported predefined outcomes of infants receiving nonstandard administration of epinephrine. For this review (reflecting the ILCOR 2010 CoSTR), the standard administration of epinephrine was defined as IV administration of 0.01 to 0.03 mg/kg per dose, and if return of spontaneous circulation (ROSC) did not occur in response, it was defined as repeated administration at 3- to 5-minute intervals.2 

Randomized controlled trials (RCTs) and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Unpublished studies (eg, conference abstracts, trial protocols), case series in which authors could not provide an estimate of incidence of outcomes, and animal studies were excluded. In cohort studies, authors may compare different interventions or report outcomes for a single arm receiving one intervention. For this review, observational studies were considered to be cohort studies eligible for inclusion if the authors used a defined strategy to ensure that the participants were either all of those who received an exposure of interest in a defined population (eg, infants born at a hospital between specified dates) or were sampled in such a way as to be representative of such a population.6  Otherwise, the study was considered to be an ineligible case series. All languages were eligible if there was an English abstract.

The prespecified primary outcome was death at hospital discharge, and secondary outcomes were rate of failure to achieve ROSC (defined as a sustained audible heart rate >60 beats per minute),7,8  time until ROSC, moderate or severe hypoxic ischemic encephalopathy (only for term infants), intraventricular hemorrhage grade III or IV, other morbidities in early infancy (eg, necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia [only for preterm infants]), and neurodevelopmental outcomes. The need for repeat doses of epinephrine was evaluated as a post hoc secondary outcome.

An information specialist (C.Z.) conducted database searches on March 6, 2019, from Ovid Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Cumulative Index to Nursing and Allied Health Literature. The search strategies, adapted for each database, used a comprehensive combination of subject headings and keywords for neonates, cardiac arrest, and epinephrine, combined by using the Boolean operator “AND.” The Medline search strategy is found in the Supplemental Information. The databases were searched from inception, and no language limits were applied. The Medline search strategy was peer reviewed by another information specialist using the Peer Review of Electronic Search Strategies checklist.9  References from included studies and review articles were also hand searched, and ILCOR Neonatal Life Support Task Force and Working Group members were consulted. Trial registries in the United States, Europe, and Australia and/or New Zealand were searched.1012 

Titles and abstracts were independently screened by two authors (T.I. and H.G.L.) who then screened full-text articles selected by either reviewer. Discrepancies were resolved by consensus of all investigators. Cohen’s κ statistic for agreement was calculated. The same two authors independently extracted the data on study designs, study population, interventions, and outcomes. Study authors were contacted to obtain missing data or for clarification.

Two authors (T.I. and L.M.) assessed the risk of bias of each included study as low, moderate, serious, or critical using the Risk of Bias in Nonrandomized Studies - of Interventions (ROBINS-I) tool for comparative cohort studies.13  For single-arm (uncontrolled) cohort studies, a modification of a tool proposed by Murad et al14  was used.

For studies in which authors compared either primary or secondary outcomes between two interventions, meta-analyses were performed with random-effect models because heterogeneity was anticipated. Review Manager version 5.3 (Nordic Cochrane Centre, Copenhagen, Denmark) was used for the analyses.15  The results are shown with risk ratio (RR) for binary outcomes and mean differences (MDs) for continuous variables along with their 95% confidence intervals (CIs). For studies in which authors assessed one intervention (single arm), the proportions of outcomes were calculated. Statistical significance was determined by using two-sided P values <.05. No adjustment was conducted for multiple outcomes, which is typical of systematic reviews. Heterogeneity was evaluated among included studies by examining forest plots, the I2 statistic, and χ2 tests for heterogeneity.16 

The GRADEpro Guideline Development Tool (software) was used to assess the certainty of evidence as high, moderate, low, or very low for each outcome.5,17  For nonrandomized studies assessed by using ROBINS-I, in accord with recent recommendations of GRADE methodologists, an initial assumption of high certainty of evidence was applied.18  Ratings were downgraded on the basis of the assessment of risk of bias, inconsistency, indirectness, imprecision, and other considerations where applicable.18 

Because there were so few eligible studies during screening, articles in which outcomes for nonstandard doses, routes, or dosing intervals were reported but did not meet inclusion criteria for the systematic review were set aside to include in a table and narrative summary.

Because there were few eligible human studies, the searches were subsequently rerun to include animal studies. They were expected to contribute information regarding mechanisms, pharmacokinetics or pharmacodynamics, or toxicity and adverse effects. Animal studies were not submitted to GRADE analysis, combined with human studies, or used for estimates of magnitude of effect.

Among 593 unique articles retrieved, 98 articles were selected for full-text screening, and 4 studies were considered eligible (Supplemental Fig 2, Table 1).7,8,19,20  Initial agreement between the two reviewers was fair (κ = 0.34), but differences were resolved by discussion. All 4 included studies were single-center, retrospective cohort studies and included only newly born infants. Three studies were from the same institution, although the study populations did not overlap.7,8,20  In two sequential studies from one institution, authors reported outcomes of infants receiving chest compressions for resuscitation, some of whom received epinephrine initially via endotracheal and some via IV administration (referred to hereafter as two-arm studies).7,8  Of note, the endotracheal epinephrine doses used in both studies (0.01 mg/kg per dose7  and 0.03–0.05 mg/kg per dose8 ) were lower than those currently recommended (0.05–0.1 mg/kg per dose).2  Furthermore, the proportion of infants receiving initial endotracheal epinephrine decreased from 44 of 47 infants in the first to 30 of 50 infants in the second study, indicating a practice shift. In both studies, some infants who initially received endotracheal epinephrine subsequently received ≥1 doses of IV epinephrine. In the other two studies, authors reported the outcomes of preterm infants receiving endotracheal epinephrine for resuscitation (single-arm studies).19,20  Jankov et al19  included only infants ≤750 g birth weight. Although Perlman et al20  included preterm and term infants, the subgroup of term infants (with one group receiving IV epinephrine) were excluded from this review because their outcomes were not reported by route of administration. Therefore, gestation and birth weight characteristics were lower for included infants from these two studies than for the two-arm studies (Table 2). None of the included studies were specifically designed to address the question for this systematic review, so we extracted such data that did allow any comparison of review outcomes (Table 2). Reasons for exclusion of other studies are summarized in Supplemental Table 5.

TABLE 1

Included Studies

Halling et al7  2017Barber and Wyckoff8  2006Jankov et al19  2000Perlman and Risser20  1995
Study design Cohort study (2 arms) Cohort study (2 arms) Cohort study (1 arm) Cohort study (1 arm) 
Setting Single center (level 3 NICU), Texas, United States Single center (level 3 NICU), Texas, United States Single center (level 3 NICU), Ontario, Canada Single center (level 3 NICU), Texas, United States 
Years of recruitment 2006‒2014 1999‒2004 1990‒1996 1991‒1993 
Infants included in this review Newborns who received epinephrine in DR Newborns who received epinephrine in DR Newborns with birth wt ≤750 g who received epinephrine in DR Preterm infants who received epinephrine in DR 
Authors’ exclusion criteria Lethal anomalies (n = 5); infants born outside of the hospital (n = 1) Lethal congenital anomalies (n = 3); infants born outside the hospital (n = 1); missing charts (n = 1) Major congenital anomalies; infants not intubated in DR Not specified 
No. infants receiving epinephrine included in this reviewa 50 47 12 
Proportion of infants receiving epinephrine among all infants in the cohort, % (n of N0.05 (56 of 114 367) 0.06 (52 of 93 656) 6.06 (12 of 198) 0.13 (39 of 30 839) for all term and preterm infantsa 
Interventions Initial endotracheal epinephrine (0.03–0.05 mg/kg) Initial endotracheal epinephrine (0.01 mg/kg) Endotracheal epinephrine (median total dose of 0.1 mg) without IV epinephrine Endotracheal epinephrine (0.01–0.03 mg/kg) 
Controls Initial IV epinephrine (0.01 mg/kg) Initial IV epinephrine (0.01 mg/kg) None None 
Indication for epinephrine NRP guidelines (ie, HR <60 beats per minute) NRP guidelines (ie, HR <60 beats per minute) HR <100 beats per minute after intubation and chest compressions HR <80 beats per minute after 30 s of CPR 
Intervals between epinephrine doses 3–5 min 3–5 min Not applicable 3–5 min 
Outcomes reported Death in DR, death at discharge, time of first epinephrine-dose ROSC, and time to ROSC Apgar 10 min, death at discharge, ROSC, and time to ROSC Death in DR, death before discharge, and neurologic impairment at median 24 mo of age Death, neurodevelopmental impairment, IVH, PVL, and seizure 
Notes Initial endotracheal epinephrine dose changed from 0.03 to 0.05 mg/kg from 2006–2008 (June) to 2008 (July)–2014. The authors provided additional data for this systematic review. The original study was focused on 37 infants who received initial endotracheal epinephrine and responded (n = 14) or responded to subsequent IV epinephrine (n = 23). The authors provided additional data for this systematic review. Of 16 epinephrine-treated infants, 5 term infants received epinephrine, (4 endotracheal and 1 IV), but their results were not presented by route of administration and 4 additional preterm infants received epinephrine without chest compressions. Only the 8 preterm infants who received epinephrine by a known route (endotracheal) are included in subsequent tables. 
Halling et al7  2017Barber and Wyckoff8  2006Jankov et al19  2000Perlman and Risser20  1995
Study design Cohort study (2 arms) Cohort study (2 arms) Cohort study (1 arm) Cohort study (1 arm) 
Setting Single center (level 3 NICU), Texas, United States Single center (level 3 NICU), Texas, United States Single center (level 3 NICU), Ontario, Canada Single center (level 3 NICU), Texas, United States 
Years of recruitment 2006‒2014 1999‒2004 1990‒1996 1991‒1993 
Infants included in this review Newborns who received epinephrine in DR Newborns who received epinephrine in DR Newborns with birth wt ≤750 g who received epinephrine in DR Preterm infants who received epinephrine in DR 
Authors’ exclusion criteria Lethal anomalies (n = 5); infants born outside of the hospital (n = 1) Lethal congenital anomalies (n = 3); infants born outside the hospital (n = 1); missing charts (n = 1) Major congenital anomalies; infants not intubated in DR Not specified 
No. infants receiving epinephrine included in this reviewa 50 47 12 
Proportion of infants receiving epinephrine among all infants in the cohort, % (n of N0.05 (56 of 114 367) 0.06 (52 of 93 656) 6.06 (12 of 198) 0.13 (39 of 30 839) for all term and preterm infantsa 
Interventions Initial endotracheal epinephrine (0.03–0.05 mg/kg) Initial endotracheal epinephrine (0.01 mg/kg) Endotracheal epinephrine (median total dose of 0.1 mg) without IV epinephrine Endotracheal epinephrine (0.01–0.03 mg/kg) 
Controls Initial IV epinephrine (0.01 mg/kg) Initial IV epinephrine (0.01 mg/kg) None None 
Indication for epinephrine NRP guidelines (ie, HR <60 beats per minute) NRP guidelines (ie, HR <60 beats per minute) HR <100 beats per minute after intubation and chest compressions HR <80 beats per minute after 30 s of CPR 
Intervals between epinephrine doses 3–5 min 3–5 min Not applicable 3–5 min 
Outcomes reported Death in DR, death at discharge, time of first epinephrine-dose ROSC, and time to ROSC Apgar 10 min, death at discharge, ROSC, and time to ROSC Death in DR, death before discharge, and neurologic impairment at median 24 mo of age Death, neurodevelopmental impairment, IVH, PVL, and seizure 
Notes Initial endotracheal epinephrine dose changed from 0.03 to 0.05 mg/kg from 2006–2008 (June) to 2008 (July)–2014. The authors provided additional data for this systematic review. The original study was focused on 37 infants who received initial endotracheal epinephrine and responded (n = 14) or responded to subsequent IV epinephrine (n = 23). The authors provided additional data for this systematic review. Of 16 epinephrine-treated infants, 5 term infants received epinephrine, (4 endotracheal and 1 IV), but their results were not presented by route of administration and 4 additional preterm infants received epinephrine without chest compressions. Only the 8 preterm infants who received epinephrine by a known route (endotracheal) are included in subsequent tables. 

CPR, cardiopulmonary resuscitation; DR, delivery room (birth location as used by authors; may have included operating theater); HR, heart rate; IVH, intraventricular hemorrhage; NRP, Neonatal Resuscitation Program; PVL, periventricular leukomalacia.

a

Proportion of preterm infants who received epinephrine not reported.

TABLE 2

Infants’ Baseline Characteristics in Included Studies

Halling et al7  2017Barber and Wyckoff8  2006aJankov et al19  2000Perlman and Risser20  1995
Route (dose of initial epinephrine treatment), mg/kg Endotracheal (0.03–0.05) IV (0.01) Endotracheal (0.01) IV (0.01) Endotracheal (median dose 0.1) Endotracheal (0.01–0.03) 
No. infants 30 20 44 3a 12 
Gestation, wks Mean ± SD: 36 ± 6 Mean ± SD: 35 ± 5 Mean: 36b NA Median (range): 25 (24–28) Median (range): 29 (25–33) 
Birth wt, g Mean ± SD: 2559 ± 1073 Mean ± SD: 2868 ± 1487 NA NA Median (range): 672 (575–750) Median (range): 1186 (626–1785) 
Emergency cesarean delivery, n of N (%) 17 of 30 (57) 13 of 20 (65) NA NA NA 3 of 8 (38) 
Apgar 1 min Median 0 (IQR 0–1) Median 0 (IQR 0–0) NA NA Median (range): 1 (1–5) Median (range:) 1 (0–6) 
Time to first epinephrine, min Mean ± SD: 5.1 ± 2.7 Mean ± SD: 5.4 ± 2.2 Mean: 4.2–5.2b NA Median (range): 3 (1–15) NA 
Asystole, n of N (%) 21 of 30 (70) 16 of 20 (80) NA NA 0 of 12 (0) 2 of 8 (25) 
Cord pH Mean ± SD: 6.98 ± 0.2 Mean ± SD: 6.97 ± 0.17 NA NA NA Median (range): 7.22 (6.60–7.33) 
Cord blood base excess Mean ± SD: −19 ± 9 Mean ± SD: −20 ± 8 NA NA NA NA 
Halling et al7  2017Barber and Wyckoff8  2006aJankov et al19  2000Perlman and Risser20  1995
Route (dose of initial epinephrine treatment), mg/kg Endotracheal (0.03–0.05) IV (0.01) Endotracheal (0.01) IV (0.01) Endotracheal (median dose 0.1) Endotracheal (0.01–0.03) 
No. infants 30 20 44 3a 12 
Gestation, wks Mean ± SD: 36 ± 6 Mean ± SD: 35 ± 5 Mean: 36b NA Median (range): 25 (24–28) Median (range): 29 (25–33) 
Birth wt, g Mean ± SD: 2559 ± 1073 Mean ± SD: 2868 ± 1487 NA NA Median (range): 672 (575–750) Median (range): 1186 (626–1785) 
Emergency cesarean delivery, n of N (%) 17 of 30 (57) 13 of 20 (65) NA NA NA 3 of 8 (38) 
Apgar 1 min Median 0 (IQR 0–1) Median 0 (IQR 0–0) NA NA Median (range): 1 (1–5) Median (range:) 1 (0–6) 
Time to first epinephrine, min Mean ± SD: 5.1 ± 2.7 Mean ± SD: 5.4 ± 2.2 Mean: 4.2–5.2b NA Median (range): 3 (1–15) NA 
Asystole, n of N (%) 21 of 30 (70) 16 of 20 (80) NA NA 0 of 12 (0) 2 of 8 (25) 
Cord pH Mean ± SD: 6.98 ± 0.2 Mean ± SD: 6.97 ± 0.17 NA NA NA Median (range): 7.22 (6.60–7.33) 
Cord blood base excess Mean ± SD: −19 ± 9 Mean ± SD: −20 ± 8 NA NA NA NA 

IQR, interquartile range; NA, not available.

a

Stated in the article that, “As might be expected, for infants who received the first dose of epinephrine IV, there was sufficient time to anticipate that IV access would be needed (early recognized abruption, maternal motor vehicle crash, and prolonged shoulder dystocia). In each case, there was time to mobilize appropriate personnel and equipment.”8 

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 of initial endotracheal epinephrine for 7 infants who failed to respond epinephrine were not reported.

On the basis of the ROBINS-I, both two-arm studies had very serious risk of bias because of the risk of confounding (Supplemental Table 6).7,8  On the basis of the modified Murad’s tool,14  both single-arm studies had serious risk of bias (or indirectness) because the thresholds for administering epinephrine appeared to be lower than those of current ILCOR recommendations (Supplemental Table 7).19,20 

In only one study did authors provided data used to address the primary outcome of the systematic review. This study (reporting 50 infants treated with epinephrine) revealed no difference in death at hospital discharge between initial endotracheal and IV epinephrine (RR = 1.03 [95% CI 0.62 to 1.71]; absolute risk difference [ARD] = 17 more [209 fewer, 391 more] per 1000 infants; very low certainty of evidence, downgraded for very serious risk of bias and very serious imprecision) (Table 3, Fig 1).7  For the secondary outcome of failure to achieve ROSC, meta-analysis of two studies (97 infants treated with epinephrine) revealed no difference between initial endotracheal and initial IV administration (RR = 0.97 [95% CI 0.38 to 2.48]; ARD = 7 fewer [135 fewer, 322 more] per 1000 infants; very low certainty of evidence, downgraded for very serious risk of bias and very serious imprecision).7,8  For time to ROSC, one study (50 infants treated with epinephrine) revealed no difference between initial endotracheal and initial IV epinephrine (MD = 2.00 [95% CI −0.60 to 4.60] minutes; very low certainty of evidence, downgraded for very serious risk of bias and very serious imprecision).7  Post hoc analysis of the proportion of infants who received subsequent doses of epinephrine (two studies; 97 infants) revealed no difference after initial endotracheal versus initial IV administration (RR = 1.94 [95% CI 0.18 to 20.96]; ARD = 654 more [570 fewer, 1000 more] per 1000 infants; very low certainty of evidence, downgraded for very serious risk of bias and very serious imprecision).7,8 

TABLE 3

GRADE Evidence Profile Table Comparing the Outcomes After Initial Endotracheal Versus Initial IV Epinephrine Administration

No. StudiesCertainty AssessmentNo. PatientsEffectCertaintyImportancea
Study DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsInitial Endotracheal EpinephrineInitial IV EpinephrineRelative RR (95% CI)Absolute RR (95% CI)
Death at hospital discharge             
 N = 17  Observational studies Very seriousb Not serious Not serious Very seriousc None 17 of 30 (57%) 11 of 20 (55%) 1.03 (0.62 to 1.71) 17 more per 1000 (from 209 fewer to 391 more) infants Very low Critical 
Failure to achieve ROSC             
 N = 27,8  Observational studies Very seriousb Not serious Not serious Very seriousc None 14 of 74 (19%) 5 of 23 (22%) 0.97 (0.38 to 2.48) 7 fewer per 1000 (from 135 fewer to 322 more) infants Very low Critical 
Time to ROSC (in min)             
 N = 17  Observational studies Very seriousb Not serious Not serious Seriousd None 11 — MD 2 more (0.6 fewer to 4.6 more) min Very low Important 
Receiving additional doses after initial epinephrine administration (post hoc)             
 N = 27,8  Observational studies Very seriousb Not serious Not serious Very seriousc None 58 of 74 (78%) 16 of 23 (70%) 1.94 (0.18 to 20.96) 654 more per 1000 (from 570 fewer to 1000 more) infants Very low Important 
No. StudiesCertainty AssessmentNo. PatientsEffectCertaintyImportancea
Study DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsInitial Endotracheal EpinephrineInitial IV EpinephrineRelative RR (95% CI)Absolute RR (95% CI)
Death at hospital discharge             
 N = 17  Observational studies Very seriousb Not serious Not serious Very seriousc None 17 of 30 (57%) 11 of 20 (55%) 1.03 (0.62 to 1.71) 17 more per 1000 (from 209 fewer to 391 more) infants Very low Critical 
Failure to achieve ROSC             
 N = 27,8  Observational studies Very seriousb Not serious Not serious Very seriousc None 14 of 74 (19%) 5 of 23 (22%) 0.97 (0.38 to 2.48) 7 fewer per 1000 (from 135 fewer to 322 more) infants Very low Critical 
Time to ROSC (in min)             
 N = 17  Observational studies Very seriousb Not serious Not serious Seriousd None 11 — MD 2 more (0.6 fewer to 4.6 more) min Very low Important 
Receiving additional doses after initial epinephrine administration (post hoc)             
 N = 27,8  Observational studies Very seriousb Not serious Not serious Very seriousc None 58 of 74 (78%) 16 of 23 (70%) 1.94 (0.18 to 20.96) 654 more per 1000 (from 570 fewer to 1000 more) infants Very low Important 

On the basis of GRADE,18  serious risk of bias in ROBINS-I corresponds to very serious risk-of-bias GRADE (downgrade 2 levels). —, not applicable.

a

Importance was assigned by the consensus of the ILCOR Neonatal Life Support Task Force.

b

In the included studies, no adjustment for potential confounders (gestational age, Apgar score, asystole, cord blood pH, or base excess, etc) was conducted. Furthermore, there was a high risk of indication bias.

c

The relative risk included both the benefit (RR = 0.75) and harm (RR = 1.25) as well as the null effect (RR = 1.00).

d

The relative risk included the null effect (RR = 1.00).

FIGURE 1

Forest plots comparing the primary and secondary outcomes between initial endotracheal epinephrine and IV epinephrine. Meta-analyses were performed with random-effect models by using Review Manager version 5.3. A, Death at hospital discharge. B, Failure to achieve ROSC. C, Time to ROSC (in minutes). D, Receiving additional epinephrine after initial dose (post hoc). df, degree of freedom; I2, I2 statistic; M-H, Mantel-Haenszel.

FIGURE 1

Forest plots comparing the primary and secondary outcomes between initial endotracheal epinephrine and IV epinephrine. Meta-analyses were performed with random-effect models by using Review Manager version 5.3. A, Death at hospital discharge. B, Failure to achieve ROSC. C, Time to ROSC (in minutes). D, Receiving additional epinephrine after initial dose (post hoc). df, degree of freedom; I2, I2 statistic; M-H, Mantel-Haenszel.

In two studies, authors provided data for infants only exposed to initial endotracheal epinephrine.19,20  In one study, authors reported that mortality to hospital discharge among these infants was 0.38 (3 of 8 infants born at a mean gestation of 30 weeks)20  In the second study, the proportion who died or had severe neurodevelopmental impairment at a median assessment age of 2 years was 0.58 (7 of 12 infants born at a mean gestation of 25 weeks).19 

The rates of death at discharge and failure to achieve ROSC were similar for infants treated with each of these two doses (30 infants in one study with very serious risk of bias; Supplemental Fig 3).7 

No studies eligible for this systematic review evaluated alternative doses of IV epinephrine, routes other than IV and endotracheal (eg, intraosseous, intramuscular [IM]) administration, or dosing intervals. We summarized results of ineligible studies assessing these points in Table 4. Data on the use of high-dose IV epinephrine for neonatal resuscitation are meager (Table 4). In adults and children, a systematic review of 15 RCTs in which authors compared high-dose versus standard-dose epinephrine for cardiac arrest (typical starting dose for children of 0.1 mg/kg vs 0.01 mg/kg) reported a slight reduction in survival to admission and time until ROSC with high-dose epinephrine; however, the quality of evidence was very low, the subgroup of pediatric studies revealed no difference, and the applicability to newborn infants is uncertain.21  Although authors of a few case series reported high-dose IV or endotracheal epinephrine in preterm infants, the safety and effectiveness of high doses remain unknown.22,23  Longer latency between doses was examined in an observational cohort study of children with cardiac arrest and was associated with improved survival. However, the direction of effect had reversed after adjustment for confounders, suggesting a high risk of bias.24 

TABLE 4

Additional Referenced Studies

StudyStudy DesignPopulation and InterventionsaResultsaConclusionsa
High dose of epinephrine     
 Finn et al21  2019 SR of RCTs Fifteen RCTs were included comparing a high dose versus standard dose of epinephrine (mostly administered IV) for cardiac arrest in adults (12 RCTs; n = 6697) or children (3 RCTs; n = 317). Standard dose in children was mostly 0.01 mg/kg per dose, and the high dose was 0.1 mg/kg per dose. High-dose epinephrine slightly increased survival to admission (n = 5764; RR 1.13 [95% CI 1.03 to 1.24]) and ROSC in adults (n = 7014; RR 1.15 [95% CI 1.02 to 1.29]) (very low quality of evidence). No significant differences in survival at discharge were noted. No significant difference in ROSC in children was noted. There is uncertainty about the effect of high-dose epinephrine versus standard dose because of very low quality of evidence and uncertain applicability to neonates because they were excluded from most studies. 
 Schwab and von Stockhausen23  1994 Case series (N = 9) Preterm infants (median gestation 29 wk; birth wt 1225 g) received a high dose of endotracheal epinephrine (0.25 mg/kg per dose). Free plasma epinephrine was increased to 28.6 (7.4–1283) nmol/L in ∼30 min and reduced to 5.07 (1.2–44.4) nmol/L at ∼100 min after endotracheal epinephrine. Free epinephrine is degraded over 1–2 h in preterm infants after high-dose endotracheal epinephrine. 
 Goetting and Oaradis22  1989 Case series (N = 7) (3 preterm infants) Consecutive children in cardiac arrest given a high dose of epinephrine (0.2 mg/kg) after failure to respond to 2 doses of 0.01 mg/kg. A high dose of epinephrine (0.2 mg/kg per dose) was given via umbilical arterial catheter in 3 preterm infants (28, 29, and 34 wk’ gestation) on day 2–3 after birth. All 3 preterm infants responded to the high dose of epinephrine and had an ROSC within 2–3 min after the dose. All survived. In these 3 infants given epinephrine via umbilical arterial catheter, adverse effects were not reported. All 3 were also given atropine before high-dose epinephrine. 
Epinephrine intervals     
 Hoyme et al24  2017 Cohort study (N = 1133) Children ≤18 y old with in-hospital cardiac arrest who received >2 epinephrine doses at intervals of 1–5, >5–<8, and 8–<10 min (1630 events) (the average interval was calculated by dividing the time between the first dose and end of resuscitation by the total No. doses) The survival to discharge was lower for longer intervals (crude OR 0.62 [95% CI 0.49 to 0.79], 0.56 [0.39 to 0.81]) but higher after adjusting for several variables. (adjusted OR 1.71 [1.27 to 2.31] and 1.93 [95% CI 1.23 to 3.03]) comparing 1–5 min to between 5–8 and 8–10 min, respectively. The study raises the possibility that more frequent exposure to epinephrine impairs survival. The change in direction of effect after adjustment and uncertainty about applicability to newborns limit the conclusions that can be drawn. 
Intraosseous route     
 Ellemunter et al25  1999 Cohort study with 1 arm (N = 27) Preterm and term infants of median (range) gestation = 31 (25–41) wk and birth wt = 1560 (515–4050) g received intraosseous line for resuscitation after birth. (Not all infants received intraosseous epinephrine.) All intraosseous line insertion was successful with a procedure time of ≤2 min with no major complications. Complications included 1 hematoma, 1 subcutaneous necrosis, and 3 dislocations of intraosseous lines. The authors concluded that intraosseous line is quick, safe, and effective in neonatal resuscitation even for extremely preterm or low birth wt infants. 
 Suominen26  2015 Case report (N = 1) A 24-day-old infant received continuous epinephrine and norepinephrine infusion via intraosseous line after cardiopulmonary resuscitation and hypothermia treatment of 24 h. The neonate had dislodgement of intraosseous line twice and developed compartment syndrome 24 h after intraosseous line insertion that resulted in the below-knee amputation of lower limb. — 
 Oesterlie et al27  2014 Case report (N = 1) A neonate received volume and ionized calcium infusion via intraosseous line to manage septic shock. The neonate developed white demarcation likely because of extravasation of calcium that progressed to tissue necrosis resulting in transtibial amputation. — 
IM route     
 Doglioni et al28  2015 Case report Case report of a term infant who received IM epinephrine (0.02 mg/kg; concentration 1:10 000) in the right thigh The infant developed a “circumscribed, irregular, edematous, red-violet, 3 cm × 2 cm plaque surrounded by an ischemic line” at the injection site. — 
Time for securing epinephrine routes     
 Heathcote et al29  2018 Cohort study with 1 arm (N = 27) Infants with 1-min Apgar score of 0 received full resuscitation (median [range] gestation 36 wk [27–41 wk]; birth wt 2774 g [980–4778 g]). Median postnatal age of intubation, central IV access, and IV epinephrine were 3.8 (95% CI 2.0 to 7.5), 9.0 (95% CI 7.0 to 14.0), and 10.0 (95% CI 8.0 to 14.0) min after birth. The real-life times for UVC placement and IV epinephrine were longer than those reported in previous simulated studies. 
 McKinsey and Perlamn30  2016 Simulation cohort study with 1 arm Time for intubation, UVC placement, and IV epinephrine administration were measured in simulation of neonatal resuscitation of simulated asystole neonates performed by 10 neonatal fellows. Mean postnatal age of intubation, UVC placement, and IV epinephrine injection were ∼2, 6, and 6.5 min after birth, respectively. Applicability to infants is uncertain. 
 Rajani et al31  2011 Simulation crossover RCT A total of 40 health care personnel (16 residents, 6 fellows, 5 hospitalists, 5 neonatal nurse practitioners, and 8 neonatologists) performed intraosseous and UVC placement on neonatal manikins in simulated neonatal resuscitation scenarios after practice of intraosseous and UVC procedures. Mean procedure time (from time that the relevant vascular access kit was opened to time that lines were inserted and flushed) was significantly shorter for intraosseous than UVC by a mean of 46 s (59 vs 105 s; P < .001). The time difference was larger for residents than for other groups. No differences were found in the No. errors or ease of use between intraosseous and UVC, although residents considered UVC significantly more difficult than intraosseous. Applicability to infants is uncertain. 
 Abe et al32  2000 Simulation First- and second-year medical students (n = 42) without previous experience with intraosseous and UVC performed intraosseous and UVC procedures on task training models (twice for each procedure). The mean procedure time was significantly shorter for intraosseous than for UVC (52 and 134 s in the first attempt and 45 and 95 s in the second attempt for intraosseous and UVC, respectively). The intraosseous procedure was considered to be less difficult than the UVC procedure. Applicability to infants is uncertain. 
StudyStudy DesignPopulation and InterventionsaResultsaConclusionsa
High dose of epinephrine     
 Finn et al21  2019 SR of RCTs Fifteen RCTs were included comparing a high dose versus standard dose of epinephrine (mostly administered IV) for cardiac arrest in adults (12 RCTs; n = 6697) or children (3 RCTs; n = 317). Standard dose in children was mostly 0.01 mg/kg per dose, and the high dose was 0.1 mg/kg per dose. High-dose epinephrine slightly increased survival to admission (n = 5764; RR 1.13 [95% CI 1.03 to 1.24]) and ROSC in adults (n = 7014; RR 1.15 [95% CI 1.02 to 1.29]) (very low quality of evidence). No significant differences in survival at discharge were noted. No significant difference in ROSC in children was noted. There is uncertainty about the effect of high-dose epinephrine versus standard dose because of very low quality of evidence and uncertain applicability to neonates because they were excluded from most studies. 
 Schwab and von Stockhausen23  1994 Case series (N = 9) Preterm infants (median gestation 29 wk; birth wt 1225 g) received a high dose of endotracheal epinephrine (0.25 mg/kg per dose). Free plasma epinephrine was increased to 28.6 (7.4–1283) nmol/L in ∼30 min and reduced to 5.07 (1.2–44.4) nmol/L at ∼100 min after endotracheal epinephrine. Free epinephrine is degraded over 1–2 h in preterm infants after high-dose endotracheal epinephrine. 
 Goetting and Oaradis22  1989 Case series (N = 7) (3 preterm infants) Consecutive children in cardiac arrest given a high dose of epinephrine (0.2 mg/kg) after failure to respond to 2 doses of 0.01 mg/kg. A high dose of epinephrine (0.2 mg/kg per dose) was given via umbilical arterial catheter in 3 preterm infants (28, 29, and 34 wk’ gestation) on day 2–3 after birth. All 3 preterm infants responded to the high dose of epinephrine and had an ROSC within 2–3 min after the dose. All survived. In these 3 infants given epinephrine via umbilical arterial catheter, adverse effects were not reported. All 3 were also given atropine before high-dose epinephrine. 
Epinephrine intervals     
 Hoyme et al24  2017 Cohort study (N = 1133) Children ≤18 y old with in-hospital cardiac arrest who received >2 epinephrine doses at intervals of 1–5, >5–<8, and 8–<10 min (1630 events) (the average interval was calculated by dividing the time between the first dose and end of resuscitation by the total No. doses) The survival to discharge was lower for longer intervals (crude OR 0.62 [95% CI 0.49 to 0.79], 0.56 [0.39 to 0.81]) but higher after adjusting for several variables. (adjusted OR 1.71 [1.27 to 2.31] and 1.93 [95% CI 1.23 to 3.03]) comparing 1–5 min to between 5–8 and 8–10 min, respectively. The study raises the possibility that more frequent exposure to epinephrine impairs survival. The change in direction of effect after adjustment and uncertainty about applicability to newborns limit the conclusions that can be drawn. 
Intraosseous route     
 Ellemunter et al25  1999 Cohort study with 1 arm (N = 27) Preterm and term infants of median (range) gestation = 31 (25–41) wk and birth wt = 1560 (515–4050) g received intraosseous line for resuscitation after birth. (Not all infants received intraosseous epinephrine.) All intraosseous line insertion was successful with a procedure time of ≤2 min with no major complications. Complications included 1 hematoma, 1 subcutaneous necrosis, and 3 dislocations of intraosseous lines. The authors concluded that intraosseous line is quick, safe, and effective in neonatal resuscitation even for extremely preterm or low birth wt infants. 
 Suominen26  2015 Case report (N = 1) A 24-day-old infant received continuous epinephrine and norepinephrine infusion via intraosseous line after cardiopulmonary resuscitation and hypothermia treatment of 24 h. The neonate had dislodgement of intraosseous line twice and developed compartment syndrome 24 h after intraosseous line insertion that resulted in the below-knee amputation of lower limb. — 
 Oesterlie et al27  2014 Case report (N = 1) A neonate received volume and ionized calcium infusion via intraosseous line to manage septic shock. The neonate developed white demarcation likely because of extravasation of calcium that progressed to tissue necrosis resulting in transtibial amputation. — 
IM route     
 Doglioni et al28  2015 Case report Case report of a term infant who received IM epinephrine (0.02 mg/kg; concentration 1:10 000) in the right thigh The infant developed a “circumscribed, irregular, edematous, red-violet, 3 cm × 2 cm plaque surrounded by an ischemic line” at the injection site. — 
Time for securing epinephrine routes     
 Heathcote et al29  2018 Cohort study with 1 arm (N = 27) Infants with 1-min Apgar score of 0 received full resuscitation (median [range] gestation 36 wk [27–41 wk]; birth wt 2774 g [980–4778 g]). Median postnatal age of intubation, central IV access, and IV epinephrine were 3.8 (95% CI 2.0 to 7.5), 9.0 (95% CI 7.0 to 14.0), and 10.0 (95% CI 8.0 to 14.0) min after birth. The real-life times for UVC placement and IV epinephrine were longer than those reported in previous simulated studies. 
 McKinsey and Perlamn30  2016 Simulation cohort study with 1 arm Time for intubation, UVC placement, and IV epinephrine administration were measured in simulation of neonatal resuscitation of simulated asystole neonates performed by 10 neonatal fellows. Mean postnatal age of intubation, UVC placement, and IV epinephrine injection were ∼2, 6, and 6.5 min after birth, respectively. Applicability to infants is uncertain. 
 Rajani et al31  2011 Simulation crossover RCT A total of 40 health care personnel (16 residents, 6 fellows, 5 hospitalists, 5 neonatal nurse practitioners, and 8 neonatologists) performed intraosseous and UVC placement on neonatal manikins in simulated neonatal resuscitation scenarios after practice of intraosseous and UVC procedures. Mean procedure time (from time that the relevant vascular access kit was opened to time that lines were inserted and flushed) was significantly shorter for intraosseous than UVC by a mean of 46 s (59 vs 105 s; P < .001). The time difference was larger for residents than for other groups. No differences were found in the No. errors or ease of use between intraosseous and UVC, although residents considered UVC significantly more difficult than intraosseous. Applicability to infants is uncertain. 
 Abe et al32  2000 Simulation First- and second-year medical students (n = 42) without previous experience with intraosseous and UVC performed intraosseous and UVC procedures on task training models (twice for each procedure). The mean procedure time was significantly shorter for intraosseous than for UVC (52 and 134 s in the first attempt and 45 and 95 s in the second attempt for intraosseous and UVC, respectively). The intraosseous procedure was considered to be less difficult than the UVC procedure. Applicability to infants is uncertain. 

OR, odds ratio; SR, systematic review; —, not applicable.

a

Information most pertinent to our systematic review is summarized in this table.

In a few studies, authors described routes for epinephrine administration other than via endotracheal or IV during neonatal resuscitation. In a cohort study of 27 neonates within 5 hours of birth (median gestation of 31 weeks [range 25–41 weeks]), the authors commented that intraosseous access was always accomplished within 2 minutes (although data were not shown) and incurred few major complications.25  Nevertheless, in a few case reports, authors have described severe complications including amputation of an extremity due to extravasation and compartment syndrome attributable to intraosseous lines in infants.26,27  In one case report, authors described severe skin lesions at the site of an IM epinephrine injection.28 

In several studies, authors addressed the time to obtain access suitable for administering epinephrine (Table 4). In a cohort of neonates who had a 1-minute Apgar score of 0 (median gestation of 36 weeks [range 27–41 weeks]), among 23 for whom the time was documented, umbilical venous catheter (UVC) placement was accomplished at a median time of 9 (95% CI 7 to 14) minutes after birth, probably longer than ideal for asystolic neonates, whereas endotracheal tubes were placed much earlier at a median time of 3.8 (95% CI 2.0 to 7.5) minutes after birth.29  Simulation studies in which authors used neonatal manikins suggest shorter times to intraosseous than UVC placement, but variation in study design, participants, and models makes it difficult to know whether these results would correspond to clinically meaningful time differences in practice.31,32  Furthermore, selection of participants in some of these studies may have been weighted to those who had greater previous familiarity with intraosseous insertion than UVC placement.

Several animal studies provided relevant information, although there were variations in animal models and interventions (Supplemental Table 8). This systematic review was based on the presumption that epinephrine is efficacious, but this is based on expert opinion because there are no adequate human newborn infant trials.2  Animal studies are used to address this question. In near-term lambs undergoing perinatal transition with asphyxia-induced cardiac arrest, administration of IV epinephrine (0.01–0.015 mg/kg) was critical for increasing carotid arterial pressure and carotid blood flow and thereby achieving ROSC.33  However, authors of other animal models after the perinatal transition (porcine asphyxial cardiac arrest) found no benefit of epinephrine.34,35  Wagner et al35  reported that 50% of animals achieving ROSC did so without epinephrine, whereas Linner et al34  revealed that 80% of saline controls achieved ROSC. Both reported that epinephrine did not improve the rate of ROSC.34,35  Furthermore, early epinephrine (0.01 mg/kg administered before closed-chest cardiac massage) did not reduce the time to achieve ROSC, improve the rate of ROSC, or improve postresuscitation survival compared with saline controls.34 

A neonatal lamb study (asphyxial cardiac arrest) revealed that epinephrine doses administered into the right atrium at 0.05 or 0.1 mg/kg resulted in a greater increase in heart rate and systemic vascular resistance than lower doses (0.001 and 0.01 mg/kg).36  However, the higher dose (0.1 mg/kg) blunted the rise in cardiac output and stroke volume, probably because of a dose-dependent rise in peripheral vascular resistance.36  Vali et al37  examined asphyxiated term lambs in cardiac arrest with transitioning fetal circulation and fluid-filled lungs to compare IV versus endotracheal epinephrine. In this study, epinephrine administered via the right atrium or UVC (0.03 mg/kg every 3 minutes; maximum 4 doses) achieved higher and faster peak plasma concentrations than epinephrine administered via endotracheal (0.1 mg/kg) and resulted in a shorter time to ROSC with fewer doses.37 

The human infant data on which to base guidelines for epinephrine treatment during neonatal resuscitation are sparse. In this systematic review, we included 4 retrospective cohort studies in which authors reported outcomes for 117 eligible neonates. Only two studies reporting 97 neonates allowed comparison of endotracheal and IV epinephrine administration, and only one of these allowed analysis of the primary outcome for this systematic review: death at hospital discharge.7,8  The combined results revealed no difference in the primary outcome or the other critical and important outcomes that were reported: failure to achieve ROSC, time to ROSC, or the proportion of infants receiving additional epinephrine doses (post hoc analysis). The very low certainty of the evidence indicates that the findings of “no difference” should be interpreted cautiously; the wide CIs mean that the data could still be consistent with large, clinically meaningful differences between IV and endotracheal epinephrine for neonatal resuscitation.

The 2010 ILCOR recommendations were informed by indirect evidence from animal or pediatric studies of uncertain applicability to newborns.2  The human studies provided evidence against using doses >0.03 mg/kg IV. A pediatric case series suggested some improvement in ROSC if a higher dose was used after two lower doses had failed to achieve ROSC,22  authors of another study that included children found no associated benefit,38  and the only pediatric RCT suggested harm.39  Of note, the “high” epinephrine doses of these pediatric studies (0.1–0.2 mg/kg per dose) were 3 to 6 times higher than the maximum dose currently recommended for newborns (0.03 mg/kg per dose). Taken together, the evidence at that time was assessed as suggesting that endotracheal might be less effective than IV epinephrine, with the possibility that lower response rates could be mitigated by using a higher endotracheal dose.2  The evidence from the current systematic review is insufficient to confirm or refute these recommendations, and the available studies highlight the difficulties of studying, in vulnerable patients, rare events (eg, 0.05%–0.06% of all births) that are difficult to predict.7,8  Even if multihospital databases were used to increase the sample size, the high risk of bias seems inescapable in retrospective studies of routine practice for rare events. The reasons for choice of route of epinephrine administration were not predefined in either of the two studies that allowed comparison of routes. The choice was likely to have been influenced by factors such as the extent of forewarning and the characteristics of the resuscitation team available at the time.7,8  Because the use of epinephrine in newborn resuscitation is rare and unpredictable and the decision to use it must be made rapidly, it is difficult to design and perform adequate, ethical randomized trials in human infants, especially if previous parental informed consent is required. Prospective, multicenter cluster-randomized trials could offer a way forward.

We justified the decision to include single-arm cohort studies that did not allow any comparison between our predefined “intervention” and “control” by the extreme paucity of any evidence from comparative studies, but these studies did not alter the direction or strength of evidence. They provided data on preterm infants, but no robust conclusion about the efficacy or safety of endotracheal epinephrine in preterm infants can be drawn.19,20  In the cohort studied by Jankov et al,19  as many as 6% of all infants ≤750 g received epinephrine, raising the possibility that not all the infants were asphyxiated. A proportion of those receiving chest compressions and epinephrine might have responded to better lung ventilation alone, leading to overestimation of survival and quality of survival after epinephrine.

The lack of studies in which authors evaluated high doses, administration routes other than endotracheal or IV, and nonstandard intervals of administration of epinephrine precluded any conclusions about efficacy and risks. The narrative summary of human studies that did not meet the inclusion criteria of this systematic review yielded little more. The applicability of very low certainty evidence from a recent systematic review of adults and children in cardiac arrest to newborns is uncertain.21  There are major differences in the conditions that necessitate chest compressions and epinephrine in adults (predominance of asystole due to cardiac causes), in children (mixed causes), and in neonates (mostly intrapartum hypoxia or asphyxia related, against the background of the perinatal cardiorespiratory transition). Therefore, the extrapolation of study findings from adults and children to neonates requires caution. In the study by Halling et al,7  most of the infants (11 of 15 [73%]) who achieved ROSC after IV epinephrine required a cumulative dose of 0.03 mg/kg or more (median of ≥2 doses). This raises the possibility that the initial IV dose of 0.01 mg/kg per dose was too low for most infants. However, considering all the evidence, the balance of benefits and harms of higher doses epinephrine for neonates remains unresolved.

The best route of administration for epinephrine is also uncertain. Although in their study, Halling et al7  reported similar median time for first epinephrine administration via endotracheal and IV (median 5.1 and 5.4 minutes after birth, respectively), further research is needed to determine if this is achievable in other institutions. It is suggested in other evidence that there may be potential for endotracheal administration to be achieved faster, but the impact on efficacy is unknown.29,30  Although simulation studies (also of uncertain external validity with respect to resuscitation of newborn infants) indicated faster time for insertion of intraosseous than umbilical venous lines,31,32  caution is needed because severe complications of intraosseous lines in neonates have been reported.26,27  There is a need for future research to investigate any advantages and the safety of intraosseous lines in neonatal resuscitation.

For the key questions of this systematic review, animal studies reveal mixed results, which might be because of the variation in models. These include term or near-term lambs or piglets either during the perinatal transition or at a few days of age. The studies reflecting transitional physiology, that is, before closure of fetal shunts and before establishment of sustained lung aeration,34,38  might provide more valid evidence for newly born infants than studies in which authors use older animals. These transitional model studies revealed benefit of IV epinephrine treatment compared to no epinephrine or endotracheal epinephrine.33,37 

Strengths of our study include rigorous literature searching and systematic review by using a preregistered protocol, assessment of certainty of evidence by using GRADE,18  and input from experts from the ILCOR Neonatal Life Support Task Force. Limitations include the absence of RCTs and the small number of eligible studies and infants. Because all eligible studies included only newly born infants, the findings may not be applicable later in the neonatal period. Furthermore, no eligible studies examined alternative doses of IV epinephrine, nonstandard intervals of repeated epinephrine, and routes other than IV and endotracheal.

We found evidence that administration of epinephrine by endotracheal versus IV routes was associated with similar rates of death at discharge, failure to achieve ROSC, time to ROSC, and the proportion of patients receiving additional doses of epinephrine, but the evidence is of very low certainty. However, indirect evidence from animal studies supports IV administration over endotracheal administration at the 0.01 to 0.03 mg/kg dose that has been recommended by ILCOR. Although epinephrine can be administered via intraosseous instead of IV routes, further human infant data are needed.

Several of the authors of this study were ILCOR Neonatal Life Support Task Force members (T.I., L.M., G.M.S., H.-S.K., Y.R., and H.G.L.). The following additional task force members provided input to the review protocol, interpretation of the results, and on the article as experts in neonatal resuscitation: Dr Myra Wyckoff (The University of Texas Southwestern Medical Center, Dallas, TX); Dr Jonathan Wyllie (James Cook University Hospital, Middlesbrough, Cleveland, United Kingdom); Dr Khalid Aziz (Royal Alexandra Hospital, Edmonton, Alberta, Canada); Dr Maria Fernanda de Almeida (Federal University of Sao Paulo, Sao Paulo, Brazil); Dr Ruth Guinsburg (Federal University of Sao Paulo, Sao Paulo, Brazil); Dr Shigeharu Hosono (Jichi Medical University Saitama Medical Center, Saitama, Japan); Dr Vishal Kapadia (The University of Texas Southwestern Medical Center, Dallas, TX); Dr Jeffrey Perlman (Weill Medical College, Weill Cornell Medicine, New York, NY); Dr Charles Roehr (University of Oxford and John Radcliffe Hospital, Oxford, United Kingdom); Dr Edgardo Szyld (University of Oklahoma, Oklahoma City, OK); Dr Daniele Trevisanuto (University of Padua, Padua, Veneto, Italy); and Dr Sithembiso Velaphi (Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa).

We thank the authors of two included studies (Dr Cecilie Halling, The University of Texas Southwestern Medical Center, Dallas, TX; Dr Robert P. Jankov, Children’s Hospital of Eastern Ontario and the Ottawa Hospital, Ontario, Canada) for providing additional data for this systematic review. We also thank Dr Monica Kleinman (Boston Children’s Hospital, Boston, MA) for overseeing and monitoring the progress of our review as an ILCOR domain lead.

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.

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.

     
  • ARD

    absolute risk difference

  •  
  • CI

    confidence interval

  •  
  • CoSTR

    consensus on science with treatment recommendations

  •  
  • GRADE

    Grading of Recommendations Assessment, Development and Evaluation

  •  
  • ILCOR

    International Liaison Committee on Resuscitation

  •  
  • IM

    intramuscular

  •  
  • IV

    intravenous(ly)

  •  
  • MD

    mean difference

  •  
  • RCT

    randomized controlled trial

  •  
  • ROBINS-I

    Risk of Bias in Nonrandomized Studies - of Interventions

  •  
  • ROSC

    return of spontaneous circulation

  •  
  • RR

    risk ratio

  •  
  • UVC

    umbilical venous catheter

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data