Dose, route and interval of epinephrine (adrenaline) for neonatal resuscitation (NLS #593): Systematic Review

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This Review is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final Review will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Myra Wyckoff

CoSTR Citation

Liley HG, Kim H-S, Mildenhall L, Schmölzer GM, Rabi Y, Ziegler C, Aziz K, Guinsburg R, de Almeida MF, Kapadia VS, Hosono S, Perlman JM, Roehr CC, Szyld E, Trevisanuto D, Velaphi S, Wyckoff MH, Wyllie J, Isayama T. Dose, route and interval of epinephrine (adrenaline) for neonatal resuscitation; Consensus on Science with Treatment Recommendations [URL]: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, December 23, 2020. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of epinephrine dose, route of administration and interval (Isayama, 2019, CRD42019132219 – PROSPERO citation) conducted by the Knowledge Synthesis Unit at St Michael’s Hospital, Toronto, Canada with involvement of clinical content experts. Evidence for neonatal literature was sought and considered by the Newborn Life Support Task Force. Because of the paucity of human infant trials, scientific literature reporting relevant newborn animal studies were also systematically searched. Consideration of these studies is described within the evidence to decision highlights section of this CoSTR. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

To be submitted for publication

PICOST

Population: Among neonates (of any gestation) < 28 days of age who have no detected cardiac output or who have asystole or heart rate < 60 bpm despite ventilation and chest compressions

Intervention: Any non-standard dose, interval or route of epinephrine (adrenaline)

Comparators: Epinephrine (adrenaline) doses of 0.01-0.03 mg/kg intravenously at intervals of every 3-5 minutes

Outcomes: Mortality before hospital discharge (critical outcome); survival to neonatal unit admission (critical outcome); return of spontaneous circulation (ROSC - incidence and time until) (critical outcome); HIE Stage moderate-severe (term infants only); intraventricular hemorrhage grades III-IV (preterm infants only); other morbidities in early infancy (e.g., necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia); neurodevelopmental outcomes (important outcomes)

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Cohort studies may compare different interventions or include only one arm receiving one intervention. They were eligible for this review if they were considered representative of a defined population (e.g. infants born at a hospital between specified dates). Otherwise, they were considered to be (ineligible) case series. All languages were eligible if there was an English abstract. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded.

Timeframe: From inception of the searched databases to March 6, 2019

PROSPERO Registration CRD42019132219

RISK OF BIAS:

Bias was assessed per outcome (using the ROBINS-I tool for observational cohort studies), although there were no meaningful differences in bias between different outcomes.

Consensus on Science

Only two observational studies (both in term and preterm infants) were found that addressed any of the comparisons for the PICOST question. They were from a single neonatal unit, although the participants were from different epochs. The overall certainty of evidence was rated as very low for all outcomes primarily due to a very serious risk of bias and very serious imprecision. The individual studies were at a critical risk of bias due to confounding.

For the critical outcome of mortality before hospital discharge (O), we have identified very-low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from one observational study {Halling 2017 232} in which 50 neonates were treated with epinephrine (P), that showed no significant difference between the initial administration via the endotracheal tube (I) compared to initial intravenous administration (C) (relative risk [RR], 1.03; 95%CI, 0.62, 1.71; Absolute Risk Difference [ARD]; 17 more, 95%CI, 209 fewer to 391 more deaths per 1000 infants). This was despite larger doses given via the endotracheal route (0.03-0.05 vs. 0.01 mg/kg/dose).

For the critical outcome of failure to achieve ROSC (O), we have identified very-low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from two observational studies {Halling 2017 232; Barber 2006 1028} in which 97 neonates (P) were treated with epinephrine, that showed no significant difference between the initial administration of epinephrine via the endotracheal tube (I) compared to initial intravenous administration (C) (RR, 0.97; 95%CI, 0.38, 2.48; P=0.96; ARD; 7 fewer, 95%CI, 135 fewer to 322 more per 1000 neonates failed to achieve ROSC). This was despite the infants in one of the studies {Halling 2017 232} receiving larger doses given via the endotracheal route.

For the important outcome of time to ROSC (O), we have identified very-low-certainty evidence (downgraded for very serious risk of bias and serious imprecision) from one observational study {Halling 2017 232} in which 50 neonates were treated with epinephrine (P), that showed no significant difference in the time to ROSC after initial administration of epinephrine via the endotracheal tube (I) when compared to initial intravenous administration (C) (mean difference 2.00 minutes later, 95%CI, 0.60 minutes earlier to 4.60 minutes later). This was despite larger doses given via the endotracheal route (0.03-0.05 vs. 0.01 mg/kg/dose).

In a post-hoc analysis , we have identified very-low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from two observational studies {Halling 2017 232; Barber 2006 1028} in which 97 neonates were treated with epinephrine (P), that showed no significant difference in the receipt of an additional dose after the initial administration of epinephrine via endotracheal tube (I) when compared to intravenous administration (C) (RR, 1.94; 95%CI, 0.18, 20.96; P=0.59; ARD, 654 more neonates, 95%CI, 570 fewer to 1000 more per 1000 infants would receive additional epinephrine dose or doses after the first). This was despite infants having receiving larger doses given via the endotracheal route in one of the studies {Halling 2017 232}.

No studies specifically reported the critical outcome of survival to neonatal unit admission, but this is likely to have been similar to the inverse of the outcome ‘failure to achieve ROSC’ which was reported. We did not find any eligible studies comparing different doses of intravenous epinephrine, but one study {Halling 2017 232} in which 30 neonates received initial ET epinephrine allowed a post hoc comparison of 30 infants who received two different doses of endotracheal epinephrine (0.03 vs 0.05 mg/kg/dose) in different epochs of the study. Although no statistically significant difference was found there is such serious imprecision as to prevent any conclusion.

Except for the comparison between intravenous vs. endotracheal epinephrine, we did not find any eligible studies comparing different routes of administration.

We did not find any eligible studies comparing different intervals of epinephrine administration.

We did not find any eligible studies that allowed comparison of any other pre-specified important outcomes (HIE Stage moderate-severe (term infants only); intraventricular hemorrhage grades III-IV (preterm infants only); other morbidities in early infancy (e.g., necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia) or neurodevelopmental outcomes)

Treatment Recommendations

If the heart rate has not increased to > 60 beats per minute after optimizing ventilation and chest compressions, we suggest the administration of intravascular epinephrine (0.01 to 0.03 mg/kg). (Weak recommendation, very low certainty of evidence).

If intravascular access is not yet available, we suggest administering endotracheal epinephrine at a larger dose (0.05 to 0.1 mg/kg). (Weak recommendation, very low certainty of evidence). The administration of endotracheal epinephrine should not delay attempts to establish vascular access. (Weak recommendation, very low certainty of evidence).

We suggest the administration of further doses of epinephrine every 3-5 minutes, preferably intravascularly, if the heart rate remains less than 60 beats per minute. (Weak recommendation, very low certainty of evidence).

If the response to endotracheal epinephrine is inadequate, we suggest that an intravascular dose be given as soon as vascular access is obtained, regardless of the interval. (Weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the NLS Task Force because epinephrine administration is considered to have a key role in infants who have not responded to all previous steps in resuscitation, and the last ILCOR systematic review of epinephrine treatment was conducted for the 2010 CoSTR (Perlman 2010 S516). New cohort studies have been reported since then. The evidence had not been subjected to a contemporary GRADE assessment.

In making these recommendations, the NLS Task Force considered the following: The very limited human infant evidence does not demonstrate greater efficacy of endotracheal vs. intravenous epinephrine. However, in a randomized trial of term lambs undergoing perinatal transition with asphyxia-induced cardiopulmonary arrest, peak plasma epinephrine concentrations were higher and were achieved sooner after central venous epinephrine [right atrium 470±250ng/mL or low umbilical venous cord 450±190ng/mL at one minute] than after endotracheal epinephrine of 130±60 ng/mL at 5 minutes (p=0.03), despite lower central venous doses (0.03 mg/kg IV vs. 0.1 mg/kg endotracheal). In the same study, central venous epinephrine compared to endotracheal epinephrine resulted in a shorter median time (interquartile range) to achieve ROSC with 2 (1.9-3) versus 4.5 (2.9-7.4) minutes, p=0.02, using the same lower central venous doses. In addition, central venous epinephrine compared to endotracheal epinephrine resulted in higher rates of ROSC with 19/22 (86%) versus 12/22 (54%) p=0.02, respectively, using the same lower central venous doses. {Vali 2017, pii: e004402}.

SUBGROUP CONSIDERATIONS

There was no evidence on which to base any variation in recommendations for subgroups of infants (e.g. term vs preterm).

IMPLEMENTATION CONSIDERATIONS

This recommendation is similar to the previous ILCOR treatment recommendation in 2010 (Route and Dose of Epinephrine NRP-008A, NRP-008B, NRP-009A, NRP-009B); “If adequate ventilation and chest compressions have failed to increase the heart rate to > 60 beats per minute, then it is reasonable to use epinephrine despite the lack of human neonatal data. If epinephrine is indicated, a dose of 0.01 to 0.03 mg/kg should be administered intravenously as soon as possible. If adequate ventilation and chest compressions have failed to increase the heart rate to 60 beats per minute and intravenous access is not available, then it is reasonable to administer endotracheal epinephrine. If epinephrine is administered by the endotracheal route, it is likely that a larger dose (0.05 mg/kg to 0.1 mg/kg) will be required to achieve an effect similar to that of the 0.01 mg/kg intravenous dose. Higher intravenous doses cannot be recommended and may be harmful.” Therefore, there are no new implications for implementation.

MONITORING AND IMPLEMENTATION

We recommend that health services should monitor the rate of use of epinephrine for newborn resuscitation, together with the outcomes of epinephrine treatment reported in this review. Wherever possible, this monitoring should include the characteristics of the infants, the resuscitation measures they have received before epinephrine, the dose(s), route(s) and treatment intervals and any adverse effects of treatment. The reasons are that there is unlikely to be high certainty evidence from clinical trials on which to base treatment recommendations about epinephrine doses, administration time intervals and delivery routes in the near future. Meanwhile, increasing the number of good quality, published observational studies could offer an opportunity to validate or improve treatment recommendations. Also, rates of epinephrine administration may reflect the quality of earlier steps in intrapartum management and resuscitation and could therefore be a valuable benchmark.

Knowledge Gaps

The following specific gaps in knowledge were identified:

  • Optimal (heart rate) thresholds for administration of epinephrine
  • Doses or intervals specific to gestational age groups
  • Potential harms of epinephrine (single or multiple doses)
  • Optimal dose and interval of epinephrine.
  • Optimal route and method of administration of epinephrine.
  • Effect of vasoactive drugs other than epinephrine.
  • Human Factors approach to achieve the timely administration of epinephrine
  • Neurodevelopmental outcomes after epinephrine use

Since the decision to administer epinephrine needs to be rapid in newborn resuscitation, and the event is rare and unpredictable, adequate ethical randomized trials of human infants with prior parental informed consent may be difficult. Prospective, multicentre cluster-randomised trials could be a good option.

Newborn animal studies that address pharmacokinetics and pharmacodynamics to determine the optimal dose and route of epinephrine are also needed, in order to inform the optimal design of human infant studies.

Attachments

Evidence-to-Decision Table: NLS-593-Et D-_Adrenaline-for-Neonatal-Resuscitation

References

Barber CA, Wyckoff MH. Use and efficacy of endotracheal versus intravenous epinephrine during neonatal cardiopulmonary resuscitation in the delivery room. Pediatrics. 2006;118(3):1028-1034. PubMed PMID: 16950994

Halling C, Sparks JE, Christie L, Wyckoff MH. Efficacy of Intravenous and Endotracheal Epinephrine during Neonatal Cardiopulmonary Resuscitation in the Delivery Room. J Pediatr. 2017;185:232-236. PubMed PMID: 28285754.

Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N, Szyld E, Tamura M, Velaphi S; Neonatal Resuscitation Chapter Collaborators. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010 Oct 19;122(16 Suppl 2):S516-38. doi: 10.1161/CIRCULATIONAHA.110.971127.

Vali P, Chandrasekharan P, Rawat M, Gugino S, Koenigsknecht C, Helman J, Jusko WJ, Mathew B, Berkelhamer S, Nair J, Wyckoff MH, Lakshminrusimha S. Evaluation of Timing and Route of Epinephrine in a Neonatal Model of Asphyxial Arrest. J Am Heart Assoc. 2017 Feb 18;6(2). pii: e004402. doi: 10.1161/JAHA.116.004402.


Systematic Review

Discussion

GUEST
Aurimery Chermont (307 posts)
In our unit we use epinefrin 0,01 mg/kg first dose IV e second dose on 0,03mg/kg IV
Reply
GUEST
Colin Morley (307 posts)
I appreciate it is not exactly the question of this review however, The first question that needs to be addressed is, "should epinephrine be used at all during neonatal resuscitation". There are increasing number of areas where it has been realised that neonatal treatments that have used for ever, without good evidence, are not effective and are possibly harmful. It would be a pity to recommend epinephrine to later realise it was harming the infants. Of course outcome data is hard to collect but with large well organised collaborative randomised studies it should be possible to get some answers. I suggest this point should be strongly made in this review.
Reply
GUEST
Rob Tinnion (307 posts)
I agree wholeheartedly with this statement. There have been some studies in adults regarding adrenaline administration which suggest this area (whether adrenaline should be used) requires study urgently in the neonatal population.
GUEST
Fabio Cardoso (307 posts)
The use of adrenaline in our hospital (in Rio de Janeiro / Brazil) is preferably done intravenously, in full dose (0.03mg / kg) every 5 minutes. When venous route is not available, we do it through the tracheal route, also at the maximum dose (0.1 mg / kg). However, in practically all situations where tracheal adrenaline was administered, a new dose was necessary (usually by the intravenous route). We use a maximum of 3 doses of adrenaline, with an interval of 5 minutes between each dose, regardless of the route of administration. In particular, many case outcomes are unfavorable because of the severity of asphyxia and myocardial injury suffered by newborns.
Reply
GUEST
rob tinnion (307 posts)
Thank you for updating this work. My only comment would be that in the treatment recommendations, before the clear advice to not delay getting intravenous access by giving intratracheal adrenaline, I would ask the group to consider adding that where you have said "we suggest administering endotracheal epinephrine at a larger dose" the rider 'where an endotracheal tube has already been placed' is added so that then treatment recommendation is not interpreted as 'we have no IV access and therefore need to place an ETT before IV access'.
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