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Vasopressors in Adult Cardiac Arrest ALS 3208 TF SR

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This CoSTR 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 COSTR 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: Shannon Fernando was an author of a network meta-analysis that was discussed in the evidence-to-decision process, although as a systematic review it did not meet inclusion criteria to be considered in the consensus on science.

CoSTR Citation

Holmberg MJ, Fernando S, Elshaer A, Leong C, Drennan I, on behalf of the International Liaison Committee on Resuscitation Advanced Life Support Task Force. Vasopressors in Adult Cardiac Arrest, Consensus on Science with Treatment Recommendations. 1 Nov 2024. Available from www.costr.ilcor.org.

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of the Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review 1and an updated systematic review (Prospero CRD42024534331) with involvement of clinical content experts. Evidence for adult literature was sought and considered by the Advanced Life Support Adult Task Force. These data were considered when formulating the Treatment Recommendations.

Systematic Review

Webmaster to insert the Systematic Review citation and link to PubMed using this format when it is available if published

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adult individuals with cardiac arrest in any setting (out-of-hospital or in-hospital).

Intervention: Vasopressor or a combination of vasopressors provided intravenously or intraosseously during cardiopulmonary resuscitation.

Comparators: No vasopressor, a different vasopressor, a different combination of vasopressors, a different vasopressor dose, or a different timing of vasopressors provided intravenously or intraosseously during cardiopulmonary resuscitation.

Outcomes: Clinical outcome including survival, favorable neurological outcome, and health-related quality of life at hospital discharge, 30 days, 90 days, 180 days, and 1 year.

Study Designs: Human randomized controlled trials were included. Observational studies, animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, and unpublished studies were not included. All years and all languages were included if there was an English abstract or full-text article.

Timeframe: This was an update of the systematic review published by ILCOR in 2019.1 Controlled trials already included in the previous review and new controlled trials published between November 23, 2018, and May 9, 2024, were included.

PROSPERO Registration CRD42024534331

Consensus on Science

The updated systematic review identified 4 studies in adult patients: 1 randomized clinical trial comparing epinephrine plus vasopressin to epinephrine alone2, 2 sub-studies from a prior randomized clinical trial reporting long-term outcomes3 and time to epinephrine administration4, and 1 cost-effectiveness study5. These studies add to the previous systematic review1 that identified 22 randomized clinical trials and 67 observational studies in adult patients.

Given that evidence was available from 23 randomized clinical trials (or sub-studies of randomized clinical trials) and because the observational studies identified in the previous systematic review were limited by a serious or critical risk of bias, only randomized clinical trials were considered for the updated consensus on science. The comparison of high-dose vs standard-dose epinephrine was not re-analyzed as no new trials were identified since the 2015 ILCOR review.6

Epinephrine compared to no epinephrine – Any rhythm

For the critical outcome of favorable neurological outcome at 6 months, we identified low certainty evidence (downgraded one level for risk of bias from loss to follow-up and one level for imprecision) from 1 sub-study of a randomized clinical trial3 enrolling 7963 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.34 [95% CI, 0.96 to 1.88]; 5 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 1 fewer to 13 more]).

For the critical outcome of favorable neurological outcome at 3 months, we identified low certainty evidence (downgraded one level for risk of bias from loss to follow-up and one level for imprecision) from 1 randomized clinical trial7 enrolling 7965 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.30 [95% CI, 0.94 to 1.80]; 5 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 1 fewer to 13 more]).

For the critical outcome of favorable neurological outcome at hospital discharge, we identified moderate certainty evidence (downgraded one level for imprecision) from 2 randomized clinical trials7,8 enrolling 8535 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.21 [95% CI, 0.90 to 1.62]; 4 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 2 fewer to 12 more]).

For the critical outcome of survival at 12 months, we identified moderate certainty evidence (downgraded one level for imprecision) from 1 sub-study of a randomized clinical trial3 enrolling 7997 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with the use of placebo (RR, 1.33 [95% CI, 1.00 to 1.77]; 7 more survivors per 1000 patients [95% CI, from 0 fewer to 15 more]).

For the critical outcome of survival at 6 months, we identified moderate certainty evidence (downgraded one level for imprecision) from 1 sub-study of a randomized clinical trial3 enrolling 7997 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 1.37 [95% CI, 1.04 to 1.81]; 8 more survivors per 1000 patients [95% CI, from 1 more to 17 more]).

For the critical outcome of survival at 3 months, we identified moderate certainty evidence (downgraded one level for imprecision) from 1 randomized clinical trial7 enrolling 8000 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 1.40 [95% CI, 1.07 to 1.84]; 9 more survivors per 1000 patients [95% CI, from 2 more to 18 more]).

For the critical outcome of survival at hospital discharge, we identified moderate certainty evidence (downgraded one level for imprecision) from 2 randomized clinical trials7,8 enrolling 8538 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 1.44 [95% CI, 1.11 to 1.86]; 10 more survivors per 1000 patients [95% CI, from 2 more to 19 more]).

For the important outcome of survival at hospital admission, we identified high certainty evidence from 2 randomized clinical trials7,8 enrolling 8469 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 2.88 [95% CI, 2.57 to 3.22]; 156 more survivors per 1000 patients [95% CI, from 131 more to 185 more]).

For the important outcome of return of spontaneous circulation, we identified high certainty evidence from 2 randomized clinical trials7,8 enrolling 8469 out-of-hospital cardiac arrest patients with any initial rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 3.09 [95% CI, 2.82 to 3.39]; 243 more patients with return of spontaneous circulation per 1000 patients [95% CI, from 211 more to 277 more]).

Epinephrine compared to no epinephrine – Shockable rhythms

For the critical outcome of favorable neurological outcome at 3 months, we identified very low certainty evidence (downgraded one level for risk of bias from loss to follow-up and two levels for imprecision) from 1 randomized clinical trial7 enrolling 1482 out-of-hospital cardiac arrest patients with an initial shockable rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.16 [95% CI, 0.83 to 1.63]; 13 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 13 fewer to 49 more]).

For the critical outcome of favorable neurological outcome at hospital discharge, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial7 enrolling 1505 out-of-hospital cardiac arrest patients with an initial shockable rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.05 [95% CI, 0.76 to 1.45]; 4 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 21 fewer to 39 more]).

For the critical outcome of survival at hospital discharge, we identified moderate certainty evidence (downgraded one level for imprecision) from 2 randomized clinical trials7,8 enrolling 1753 out-of-hospital cardiac arrest patients with an initial shockable rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.23 [95% CI, 0.94 to 1.62]; 22 more survivors per 1000 patients [95% CI, from 6 fewer to 58 more]).

For the important outcome of return of spontaneous circulation, we identified moderate certainty evidence (downgraded one level for imprecision) from 2 randomized clinical trials7,8 enrolling 1741 out-of-hospital cardiac arrest patients with an initial shockable rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 1.68 [95% CI, 1.48 to 1.92]; 185 more patients with return of spontaneous circulation per 1000 patients [95% CI, from 130 more to 250 more]).

Epinephrine compared to no epinephrine – Non-shockable rhythms

For the critical outcome of favorable neurological outcome at 3 months, we identified very low certainty evidence (downgraded one level for risk of bias from loss to follow-up and two levels for imprecision) from 1 randomized clinical trial7 enrolling 6318 out-of-hospital cardiac arrest patients with an initial non-shockable rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 3.03 [95% CI, 0.98 to 9.38]; 3 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 0 fewer to 11 more]).

For the critical outcome of favorable neurological outcome at hospital discharge, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial7 enrolling 6330 out-of-hospital cardiac arrest patients with an initial non-shockable rhythm, which showed no benefit from the use of epinephrine compared with placebo (RR, 1.80 [95% CI, 0.80 to 4.07]; 2 more survivors with favorable neurological outcome per 1000 patients [95% CI, from 1 fewer to 9 more]).

For the critical outcome of survival at hospital discharge, we identified moderate certainty evidence (downgraded one level for imprecision) from 2 randomized clinical trials7,8 enrolling 6619 out-of-hospital cardiac arrest patients with an initial non-shockable rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 2.56 [95% CI, 1.37 to 4.80]; 6 more survivors per 1000 patients [95% CI, from 1 more to 15 more]).

For the important outcome of return of spontaneous circulation, we identified high certainty evidence from 2 randomized clinical trials7,8 enrolling 6579 out-of-hospital cardiac arrest patients with an initial non-shockable rhythm, which showed benefit from the use of epinephrine compared with placebo (RR, 4.45 [95% CI, 3.91 to 5.08]; 254 more patients with return of spontaneous circulation per 1000 patients [95% CI, from 214 more to 301 more]).

Initial vasopressin compared to epinephrine for out-of-hospital cardiac arrest – Any rhythm

For the critical outcome of favorable neurological outcome at hospital discharge, we identified very low certainty evidence (downgraded one level for risk of bias, one level for indirectness, and one level for imprecision) from 2 randomized clinical trials9,10 enrolling 1479 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 0.93 [95% CI, 0.58 to 1.49]; 3 fewer survivors with favorable neurological outcome per 1000 patients [95% CI, from 19 fewer to 23 more]).

For the critical outcome of survival at hospital discharge, we identified very low certainty evidence (downgraded one level for indirectness and two levels for imprecision) from 3 randomized clinical trials9-11 enrolling 1542 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 1.26 [95% CI, 0.76 to 2.07]; 23 more survivors per 1000 patients [95% CI, from 21 fewer to 94 more]).

For the important outcome of survival at hospital admission, we identified low certainty evidence (downgraded one level for indirectness and one level for imprecision) from 3 randomized clinical trials9-11 enrolling 1562 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 1.17 [95% CI, 0.82 to 1.66]; 49 more survivors per 1000 patients [95% CI, from 52 fewer to 192 more]).

For the important outcome of return of spontaneous circulation, we identified low certainty evidence (downgraded one level for indirectness and one level for imprecision) from 3 randomized clinical trials9-11 enrolling 1562 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 1.05 [95% CI, 0.80 to 1.39]; 14 more patients with return of spontaneous circulation per 1000 patients [95% CI, from 57 fewer to 111 more]).

There was no benefit from the use of initial vasopressin compared with epinephrine on any of the outcomes when separated by initial rhythm.

Initial vasopressin compared to epinephrine for in-hospital cardiac arrest – Any rhythm

For the critical outcome of favorable neurological outcome at hospital discharge, we identified low certainty evidence (downgraded one level for imprecision) from 1 randomized clinical trial12 enrolling 200 in-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 0.71 [95% CI, 0.33 to 1.54]; 39 fewer survivors with favorable neurological outcome per 1000 patients [95% CI, from 91 fewer to 73 more]).

For the critical outcome of survival at hospital discharge, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial12 enrolling 200 in-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with epinephrine (RR, 0.85 [95% CI, 0.41 to 1.77]; 20 fewer survivors per 1000 patients [95% CI, from 80 fewer to 104 more]).

For the important outcome of return of spontaneous circulation, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial12 enrolling 200 in-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of initial vasopressin compared with the epinephrine (RR, 1.09 [95% CI, 0.78 to 1.52]; 36 more patients with return of spontaneous circulation per 1000 patients [95% CI, from 87 fewer to 206 more]).

There was no benefit from the use of initial vasopressin compared with epinephrine on any of the outcomes when separated by initial rhythm.

Epinephrine plus vasopressin compared to epinephrine only – Any rhythm

For the critical outcome of favorable neurological outcome at hospital discharge, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial13 enrolling 2887 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin compared with epinephrine only (RR, 0.53 [95% CI, 0.24 to 1.19]; 6 fewer survivors with favorable neurological outcome per 1000 patients [95% CI, from 9 fewer to 2 more]).

For the critical outcome of survival at 12 months, we identified low certainty evidence (downgraded two levels for imprecision) from 1 randomized clinical trial13 enrolling 2884 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin compared with epinephrine only (RR, 0.60 [95% CI, 0.34 to 1.07]; 8 fewer survivors per 1000 patients [95% CI, from 14 fewer to 1 more]).

For the critical outcome of survival at hospital discharge, we identified very low certainty evidence (downgraded one level for inconsistency, one level for indirectness, and one level for imprecision) from 4 randomized clinical trials2,13-15 enrolling 3390 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin compared with epinephrine only (RR, 0.76 [95% CI, 0.47 to 1.22]; 6 fewer survivors per 1000 patients [95% CI, from 13 fewer to 5 more]).

For the important outcome of survival at hospital admission, we identified low certainty evidence (downgraded one level for indirectness and one level for imprecision) from 3 randomized clinical trials13-15 enrolling 3249 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin compared with epinephrine only (RR, 0.95 [95% CI, 0.83 to 1.08]; 11 fewer survivors per 1000 patients [95% CI, from 37 fewer to 17 more]).

For the important outcome of return of spontaneous circulation, we identified very low certainty evidence (downgraded one level for inconsistency, one level for indirectness, and one level for imprecision) from 4 randomized clinical trials2,13-15 enrolling 3397 out-of-hospital cardiac arrest patients with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin compared with epinephrine only (RR, 0.98 [95% CI, 0.88 to 1.08]; 6 fewer patients with return of spontaneous circulation per 1000 patients [95% CI, from 36 fewer to 24 more]).

There was no benefit from the use of epinephrine plus vasopressin compared with epinephrine only on any of the outcomes when separated by initial rhythm.

Treatment Recommendations

We recommend administration of epinephrine during cardiopulmonary resuscitation (strong recommendation, low certainty of evidence).

For patients with non-shockable rhythms (PEA/asystole), we recommend administration of epinephrine as soon as feasible during cardiopulmonary resuscitation (strong recommendation, very low certainty of evidence).

For patients with shockable rhythms (VF or pulseless VT), we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).

We suggest against the routine use of high-dose epinephrine in cardiac arrest (weak recommendation, very low certainty of evidence).

We suggest against the administration of vasopressin in place of epinephrine during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).

We suggest against the addition of vasopressin to epinephrine during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

The task force carefully considered the evidence from the updated systematic review in formulating the treatment recommendations. Recent evidence included 1 randomized clinical trial comparing epinephrine plus vasopressin to epinephrine alone2, 2 sub-studies from a prior randomized clinical trial reporting long-term outcomes3 and time to epinephrine administration4, and 1 cost-effectiveness study5. The results of these studies were consistent with the prior CoSTR. The task force concluded that the evidence did not warrant changes to the current treatment recommendations.

We recommend the administration of epinephrine during cardiopulmonary resuscitation. Standard-dose epinephrine compared to high-dose epinephrine was evaluated in the 2015 ILCOR review, with the recommendation that high-dose epinephrine is not used.6 The suggestion against routine use of high-dose epinephrine is based on trials from the 1990s comparing doses of 5-15 mg to 1 mg, showing a benefit in short-term outcomes, but no improvement in survival or neurological outcome. The task force notes the very low certainty of this evidence and that significant changes in cardiac arrest care and outcomes since these trials were conducted may limit their relevance to current practice. This treatment recommendation remains unchanged as there is no new evidence to support the use of high-dose epinephrine. The task force maintained the 1 mg dose used in the evaluated trials, acknowledging that this dosage is based on historical precedent rather than dose-finding studies. The potential for titrating epinephrine doses based on individual patient characteristics or physiological parameters was also discussed, but current evidence is insufficient to guide such practices. Epinephrine plus vasopressin or vasopressin only showed no statistical advantage over epinephrine. The task force suggests the use of epinephrine only, as compared to vasopressin only or a combination of these vasopressors, in order to minimize the complexity of the treatment algorithms. A recent network meta-analysis conducted on this topic, considering both direct comparisons between interventions within trials and indirect comparisons across trials, supports these recommendations.16

In recommending epinephrine during cardiopulmonary resuscitation, we considered the findings that epinephrine substantially improves return of spontaneous circulation, mid-term survival, and long-term survival compared to placebo. The task force made a strong recommendation, recognizing that epinephrine may reduce mortality in a life-threatening situation and adverse events are not prohibitive. A very high value is placed on an uncertain but potentially life preserving benefit.

The task force acknowledged the complexity of interpreting neurological outcome data in cardiac arrest research. Epinephrine likely increases the number of survivors with both favorable and unfavorable neurological outcomes, as observed in the PARAMEDIC2 trial3,7. This apparent increase in survivors with unfavorable neurological outcome should not be interpreted as epinephrine directly causing unfavorable neurological outcomes, but rather reflects its efficacy in restoring circulation in patients who may already have sustained significant cerebral injury due to prolonged cardiac arrest. There is no evidence in clinical trials that epinephrine specifically contributes to cerebral injury beyond its effect of increasing overall survival, including in patients who may have sustained neurological damage. This dilemma of balancing survival benefits against potential neurological outcomes is not unique to epinephrine, but a common consideration among cardiac arrest interventions. The task force considered the beneficial effect of epinephrine on survival to outweigh the uncertainties surrounding long-term neurological outcomes.

There appears to be a more pronounced effect of epinephrine on return of spontaneous circulation and survival to hospital discharge in patients with non-shockable rhythms compared to shockable rhythms, but assessment of these sub-groups should be taken with caution. There is also very limited data to guide the specific timing of epinephrine administration during cardiopulmonary resuscitation. For patients with non-shockable rhythms, we recommend administering epinephrine as soon as feasible, given limited alternative interventions in most cases and chances of survival decreasing rapidly over time.4 Exceptions may exist where a clear reversible cause can be rapidly addressed. For patients with shockable rhythms, the studies evaluating administration of epinephrine included protocols for provision after the third defibrillation. While the optimal timing in relation to defibrillations remains unknown, we suggest administering epinephrine after initial defibrillation attempts have been unsuccessful. This approach prioritizes early defibrillation, which has proven benefits in patients with shockable rhythms.

There were 2 randomized clinical trials comparing norepinephrine to epinephrine17,18 and 1 trial comparing phenylephrine to epinephrine19 during cardiac arrest. Due to the lack of any recent data on these comparisons, and as the above studies were all neutral, the treatment recommendations do not address norepinephrine or phenylephrine.

Epinephrine use was associated with increased donation rates in a recent cost-effectiveness analysis of the PARAMEDIC2 trial (99 recipients from 40 donors in the epinephrine group vs 67 recipients from 24 donors in the placebo group).5 The analysis, incorporating both direct economic effects of survivors and indirect economic benefits of organ donation, yielded an incremental cost-effectiveness ratio for epinephrine of GBP 16,086 per quality-adjusted life year gained. Costs are likely to be healthcare system specific.

Knowledge Gaps

  • What is the optimal timing of epinephrine administration in relation to defibrillations?
  • What is the optimal dose of epinephrine?
  • What is the optimal dosing interval for epinephrine?
  • The impact on favorable and unfavorable neurological outcomes remains uncertain
  • There are no randomized clinical trials evaluating epinephrine for in-hospital cardiac arrest

ETD summary table: ALS 3208 Et D Epinephrine 20241018; ALS 3208 Et D Vasopressin 20241018

References

1. Holmberg MJ, Issa MS, Moskowitz A, Morley P, Welsford M, Neumar RW, Paiva EF, Coker A, Hansen CK, Andersen LW, et al. Vasopressors during adult cardiac arrest: A systematic review and meta-analysis. Resuscitation. 2019;139:106-121. doi: 10.1016/j.resuscitation.2019.04.008

2. Kim JS, Ryoo SM, Kim YJ, Sohn CH, Ahn S, Seo DW, Hong SI, Kim SM, Chae B, Kim WY. Augmented-Medication CardioPulmonary Resuscitation Trials in out-of-hospital cardiac arrest: a pilot randomized controlled trial. Crit Care. 2022;26:378. doi: 10.1186/s13054-022-04248-x

3. Haywood KL, Ji C, Quinn T, Nolan JP, Deakin CD, Scomparin C, Lall R, Gates S, Long J, Regan S, et al. Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest. Resuscitation. 2021;160:84-93. doi: 10.1016/j.resuscitation.2021.01.019

4. Perkins GD, Kenna C, Ji C, Deakin CD, Nolan JP, Quinn T, Scomparin C, Fothergill R, Gunson I, Pocock H, et al. The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial. Intensive Care Med. 2020;46:426-436. doi: 10.1007/s00134-019-05836-2

5. Achana F, Petrou S, Madan J, Khan K, Ji C, Hossain A, Lall R, Slowther AM, Deakin CD, Quinn T, et al. Cost-effectiveness of adrenaline for out-of-hospital cardiac arrest. Crit Care. 2020;24:579. doi: 10.1186/s13054-020-03271-0

6. Soar J, Callaway CW, Aibiki M, Böttiger BW, Brooks SC, Deakin CD, Donnino MW, Drajer S, Kloeck W, Morley PT, et al. Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015;95:e71-120. doi: 10.1016/j.resuscitation.2015.07.042

7. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379:711-721. doi: 10.1056/NEJMoa1806842

8. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011;82:1138-1143. doi: 10.1016/j.resuscitation.2011.06.029

9. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH, Group ERCVdCRS. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105-113. doi: 10.1056/NEJMoa025431

10. Mukoyama T, Kinoshita K, Nagao K, Tanjoh K. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation. 2009;80:755-761. doi: 10.1016/j.resuscitation.2009.04.005

11. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535-537. doi: 10.1016/S0140-6736(97)80087-6

12. Stiell IG, Hébert PC, Wells GA, Vandemheen KL, Tang AS, Higginson LA, Dreyer JF, Clement C, Battram E, Watpool I, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001;358:105-109. doi: 10.1016/S0140-6736(01)05328-4

13. Gueugniaud PY, David JS, Chanzy E, Hubert H, Dubien PY, Mauriaucourt P, Bragança C, Billères X, Clotteau-Lambert MP, Fuster P, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359:21-30. doi: 10.1056/NEJMoa0706873

14. Callaway CW, Hostler D, Doshi AA, Pinchalk M, Roth RN, Lubin J, Newman DH, Kelly LJ. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol. 2006;98:1316-1321. doi: 10.1016/j.amjcard.2006.06.022

15. Ducros L, Vicaut E, Soleil C, Le Guen M, Gueye P, Poussant T, Mebazaa A, Payen D, Plaisance P. Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans. J Emerg Med. 2011;41:453-459. doi: 10.1016/j.jemermed.2010.02.030

16. Fernando SM, Mathew R, Sadeghirad B, Rochwerg B, Hibbert B, Munshi L, Fan E, Brodie D, Di Santo P, Tran A, et al. Epinephrine in Out-of-Hospital Cardiac Arrest: A Network Meta-analysis and Subgroup Analyses of Shockable and Nonshockable Rhythms. Chest. 2023;164:381-393. doi: 10.1016/j.chest.2023.01.033

17. Lindner KH, Ahnefeld FW, Grünert A. Epinephrine versus norepinephrine in prehospital ventricular fibrillation. Am J Cardiol. 1991;67:427-428. doi: 10.1016/0002-9149(91)90055-p

18. Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA. 1992;268:2667-2672.

19. Silfvast T, Saarnivaara L, Kinnunen A, Erosuo J, Nick L, Pesonen P, Luomanmäki K. Comparison of adrenaline and phenylephrine in out-of-hospital cardiopulmonary resuscitation. A double-blind study. Acta Anaesthesiol Scand. 1985;29:610-613. doi: 10.1111/j.1399-6576.1985.tb02265.x


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