Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials

doi:10.1016/j.resuscitation.2011.07.015

Resuscitation

Volume 83, Issue 1, January 2012, Pages 32-39

https://doi.org/10.1016/j.resuscitation.2011.07.015 Get rights and content

Abstract

Background

Prior meta-analyses-reported results of randomised controlled trials (RCTs) published between 1997 and 2004 failed to show any vasopressin-related benefit in cardiac arrest. Based on new RCT-data and a hypothesis of a potentially increased vasoconstricting efficacy of vasopressin, we sought to determine whether the cumulative, current evidence supports or refutes an overall and/or selective benefit for vasopressin regarding sustained restoration of spontaneous circulation (ROSC), long-term survival, and neurological outcome.

Methods

Two reviewers independently searched PubMed, EMBASE, and Cochrane Database for RCTs assigning adults with cardiac arrest to treatment with a vasopressin-containing regimen (vasopressin-group) vs adrenaline (epinephrine) alone (control-group) and reporting on long-term outcomes. Data from 4475 patients in 6 high-methodological quality RCTs were analyzed. Subgroup analyses were conducted according to initial cardiac rhythm and time from collapse to drug administration (T_DRUG) < 20 min.

Results

Vasopressin vs. control did not improve overall rates of sustained ROSC, long-term survival, or favourable neurological outcome. However, in asystole, vasopressin vs. control was associated with higher long-term survival {odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.04–3.12, P = 0.04}. In asystolic patients of RCTs with average T_DRUG < 20 min, vasopressin vs. control increased the rates of sustained ROSC (data available from 2 RCTs; OR = 1.70, 95% CI = 1.17–2.47, P = 0.005) and long-term survival (data available from 3 RCTs; OR = 2.84, 95% CI = 1.19–6.79, P = 0.02).

Conclusions

Vasopressin use in the resuscitation of cardiac arrest patients is not associated with any overall benefit or harm. However, vasopressin may improve the long-term survival of asystolic patients, especially when average T_DRUG is <20 min.

Introduction

Each year, more than 600,000 people in North America and Europe experience sudden death.¹ Cardiac arrest is a major public health problem with a very poor prognosis, especially in patients requiring vasopressors.1, 2, 3 Recently reported survival rates for vasopressor-treated cardiac arrest are within 2–20%.1, 2, 4, 5, 6

Adrenaline (epinephrine) remains the vasopressor drug of choice in cardiac arrest.³ Epinephrine increases myocardial oxygen consumption during cardiopulmonary resuscitation (CPR) and causes myocardial dysfunction after restoration of spontaneous circulation (ROSC).7, 8, 9 Vasopressin has been suggested as an alternative, potent vasopressor. Vasopressin causes contraction of vascular smooth muscle through stimulation of the V1a receptors and increases smooth muscle responsiveness to catecholamines.¹⁰ Endogenous vasopressin levels are higher in patients achieving ROSC.¹¹ Furthermore, prior experimental data suggest that vasopressin improves vital organ perfusion during CPR, post-ROSC survival, and neurological recovery.12, 13, 14, 15, 16, 17

Despite the promising laboratory and preliminary clinical data,12, 13, 14, 15, 16, 17, 18 prior, large, randomised, controlled trials (RCTs) comparing vasopressin and epinephrine failed to show any clear, overall advantage for vasopressin.4, 19 Accordingly, preceding meta-analyses of RCTs published between 1997 and 2004 concluded that “available evidence cannot support the inclusion of vasopressin in CPR protocols”.20, 21 However, the enrollment of patients with virtually no chance of survival may affect RCT results.22, 23 Besides previously meta-analyzed and inconclusive data,20, 21 4 RCTs assessing vasopressin efficacy in 100–2894 patients have been published between 2006 and 2009.1, 2, 24, 25 Results were either neutral,1, 24, 25 or favored vasopressin use.²

In the presence of new RCT-data and a hypothesis of an increased vasoconstricting efficacy of vasopressin-containing regimens during CPR,2, 26 we undertook the present meta-analysis. We sought to determine whether the cumulative, current evidence supports or refutes a possible, overall and/or selective benefit for vasopressin with respect to sustained ROSC, long-term survival, and neurological outcome.

Section snippets

Data sources

We searched PubMed (articles archived until June 2010), EMBASE and Cochrane Central Register of Controlled Trials. Our search strategy is detailed in the electronic supplement (eSupplement).

Study selection

Literature search and study selection were performed independently by 2 reviewers (IS and SDM). An RCT was potentially eligible if it compared a vasopressin-containing regimen (vasopressin group) to epinephrine alone (control group) for adult, out-of-hospital or in-hospital cardiac arrest, and reported on

Characteristics of the included studies

Table 1 displays the main characteristics of the 6 included RCTs, and of 2 RCTs excluded due to high risk of bias. The kappa statistic for included RCTs was 1.0. Four RCTs took place in Europe1, 2, 4, 19 and 2 in North America.19, 25 Four RCTs (3 multi-centre and 1 single-centre) reported on out-of-hospital cardiac arrest1, 4, 18, 25 and 2 (1 multi-centre and 1 single-centre) on in-hospital cardiac arrest.2, 19 Included RCT methodological quality was high, with low probability of bias (for

Discussion

According to overall, pooled results from 4475 adult patients with cardiac arrest, vasopressin with/without epinephrine vs. epinephrine alone during CPR did not improve the rates of sustained ROSC, long-term survival, and long-term survival with CPC score ≤ 2. Nevertheless, the novel finding of the current meta-analysis was that in the large asystole subgroup (n = 3210), vasopressin use was associated with an increased probability of long-term survival (absolute % increase–1.0%, corresponding to 10

Conclusions

According to the pooled results of 6 RCTs with high methodological quality, vasopressin use in the resuscitation of cardiac arrest patients is not associated with any overall benefit or harm. However, vasopressin may improve the long-term survival of asystolic patients, especially when average T_DRUG is <20 min. New RCTs specifically assessing vasopressin effects on subgroup neurological outcome are warranted.

Conflict of interest statement

Dr. Mentzelopoulos has acted as principal investigator and Dr. Zakynthinos as study director in 2 trials (Clinicaltrials.gov identifiers NCT00411879 and NCT00729794). The first trial has been published in the Archives of Internal Medicine and is included in the present meta-analysis and the other trial has been recently completed. Both trials have been funded by the Thorax Research Foundation, Athens, Greece. The first trial has also been funded in part by the Greek Society of Intensive Care

Acknowledgement

Funding/support: This meta-analysis did not receive any external funding. We wish to thank Dr. Clifton W. Callaway for the kind provision of additional data.

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Cited by (47)

Meta-Analysis of Efficacy of Vasopressin During Cardiopulmonary Resuscitation
2022, American Journal of Cardiology
Randomized controlled trials evaluating the efficacy of vasopressin versus standard of care during cardiopulmonary resuscitation (CPR) have yielded conflicting results. An electronic search of MEDLINE, Cochrane, and Embase databases was conducted through February 2022 for randomized controlled trials that evaluated the outcomes of vasopressin versus standard of care during CPR among patients with cardiac arrest. The primary outcome was the likelihood of spontaneous circulation (ROSC) return. Data were pooled using the random-effects model. The final analysis included 11 trials with 6,609 patients. The weighted mean age was 65.5 years, and 68.2% were men. There was no significant difference between the vasopressin and control groups in the likelihood of ROSC (33.1% vs 31.9%, odds ratio [OR] 1.23, 95% confidence interval [CI] 0.98 to 1.55). Subgroup analyses suggested that the use of vasopressin versus control increased the likelihood of ROSC when used in combination with steroids (p_interaction = 0.01) and in cases of in-hospital cardiac arrest (p_interaction = 0.01). There was no significant difference between the vasopressin and control groups in the likelihood of favorable neurological outcome (OR 1.14, 95% CI 0.75 to 1.71), in-hospital mortality (OR 0.89, 95% CI 0.60 to 1.31), or ventricular arrhythmias (OR 0.93, 95% CI 0.44 to 1.97). In conclusion, compared with the standard of care, the use of vasopressin during CPR did not increase the likelihood of ROSC among patients with cardiac arrest. There was no difference between the vasopressin and control groups in the likelihood of the favorable neurological outcome, in-hospital mortality, or ventricular arrhythmias.
Drug use during adult advanced cardiac life support: An overview of reviews
2021, Resuscitation Plus
To conduct an overview of systematic reviews and meta-analyses to summarize the ever-growing evidence on drug use during advanced life support.
We searched Embase, Medline, Cochrane central register of controlled trials and Web of science for systematic reviews and meta-analyses reporting on drug use during advanced life support from inception to March, 2020. Two reviewers independently assessed all abstracts for eligibility, extracted data and assessed risk of bias using the AMSTAR-2 tool. Corrected covered areas were calculated from publication citation matrices to account for potential risk of bias. Data were graphically represented using forest plots.
Twenty-two head-to-head drug comparisons from 47 included articles were analysed. Adrenaline significantly increases the incidence of return of spontaneous circulation and survival to hospital discharge, but not the incidence of neurological intact survival. Vasopressin alone or in combination with adrenaline is not superior to adrenaline alone. There is a trend favouring lidocaine over amiodarone in shockable cardiac arrest. The risk of bias assessment of included studies ranged from very low to very high and the overlap between articles was moderate to high.
In line with the guidelines, we currently suggest that a standard dose of adrenaline should be administered during resuscitation, however, studies assessing lower doses of adrenaline are pressing. There is no rationale for the combination of vasopressin and adrenaline or vasopressin alone instead of adrenaline. In addition, lidocaine is a valuable alternative for amiodarone and maybe even preferable for shockable cardiac arrest. However more research is necessary.
Vasopressin and methylprednisolone for in-hospital cardiac arrest — Protocol for a randomized, double-blind, placebo-controlled trial
2021, Resuscitation Plus
Citation Excerpt :
Only one relatively small trial (n = 200) included in-hospital cardiac arrest patients.37 In a meta-analysis of six randomized clinical trials, there was no overall benefit of vasopressin administration during cardiac arrest.34 Methylprednisolone is a synthetic glucocorticoid, which is a class of corticosteroids that is part of the larger group of steroid hormones.
To describe the clinical trial “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest” (VAM-IHCA).
The VAM-IHCA trial is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. The study drugs consist of 40 mg methylprednisolone and 20 IU of vasopressin given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU).
The primary outcome is return of spontaneous circulation and key secondary outcomes include survival and survival with a favorable neurological outcome at 30 days. 492 patients will be enrolled. The trial was registered at the EU Clinical Trials Register (EudraCT Number: 2017-004773-13) on Jan. 25, 2018 and ClinicalTrials.gov (Identifier: NCT03640949) on Aug. 21, 2018.
The trial started in October 2018 and the last patient is anticipated to be included in January 2021. The primary results will be reported after 3-months follow-up and are, therefore, anticipated in mid-2021.
The current article describes the design of the VAM-IHCA trial. The results from this trial will help clarify whether the combination of vasopressin and methylprednisolone when administered during in-hospital cardiac arrest improves outcomes.
The physiologic response to rescue therapy with vasopressin versus epinephrine during experimental pediatric cardiac arrest
2020, Resuscitation Plus
Compare vasopressin to a second dose of epinephrine as rescue therapy after ineffective initial doses of epinephrine in diverse models of pediatric in-hospital cardiac arrest.
67 one- to three-month old female swine (10−30 kg) in six experimental cohorts from one laboratory received hemodynamic-directed CPR, a resuscitation method where high quality chest compressions are provided and vasopressor administration is titrated to coronary perfusion pressure (CoPP) ≥20 mmHg. Vasopressors are given when CoPP is <20 mmHg, in sequences of two doses of 0.02 mg/kg epinephrine separated by minimum one-minute, then a rescue dose of 0.4 U/kg vasopressin followed by minimum two-minutes. Invasive measurements were used to evaluate and compare the hemodynamic and neurologic effects of each vasopressor dose.
Increases in CoPP and cerebral blood flow (CBF) were greater with vasopressin rescue than epinephrine rescue (CoPP: +8.16 [4.35, 12.06] mmHg vs. + 5.43 [1.56, 9.82] mmHg, p = 0.02; CBF: +14.58 [-0.05, 38.12] vs. + 0.00 [-0.77, 18.24] perfusion units (PFU), p = 0.005). Twenty animals (30%) failed to achieve CoPP ≥20 mmHg after two doses of epinephrine; 9/20 (45%) non-responders achieved CoPP ≥20 mmHg after vasopressin. Among all animals, the increase in CBF was greater with vasopressin (+14.58 [-0.58, 38.12] vs. 0.00 [-0.77, 18.24] PFU, p = 0.005).
CoPP and CBF rose significantly more after rescue vasopressin than after rescue epinephrine. Importantly, CBF increased after vasopressin rescue, but not after epinephrine rescue. In the 30% that failed to meet CoPP of 20 mmHg after two doses of epinephrine, 45% achieved target CoPP with a single rescue vasopressin dose.
Cardiopulmonary Resuscitation
2019, A Practice of Anesthesia for Infants and Children
Despite the increasing safety of anesthesia, perioperative cardiopulmonary resuscitation in infants and children remains a relatively common event. Successful resuscitation to spontaneous circulation requires early recognition and coordination of a team of practitioners to function effectively to deliver best practice CPR. Additionally, the perioperative and operative environment adds further challenges to delivery of effective CPR. Vigilance and following best evidence practice remain critical in the prevention and mitigation of critical events in the perioperative setting.
Drugs in Out-of-Hospital Cardiac Arrest
2018, Cardiology Clinics
Citation Excerpt :
Two additional RCTs of OHCA patients found no significant difference in ROSC, 24-hour survival, or survival to discharge.29,30 Two subsequent systematic reviews and metaanalyses in 2012 and 2014 also failed to find improvement in rates of sustained ROSC, long-term survival, or survival with favorable neurologic outcomes.12,31 A metaanalysis by Mentzelopoulos and colleagues31 did note an increased probability of long-term survival among those patients in asystole, especially when looking at patients with an average time to drug of less than 20 minutes.

View all citing articles on Scopus

^☆: A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.07.015.

^a: The contributions of the first 3 authors were equally important for this article.

View full text

Clinical paperVasopressin for cardiac arrest: Meta-analysis of randomized controlled trials☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Data sources

Study selection

Characteristics of the included studies

Discussion

Conclusions

Conflict of interest statement

Acknowledgement

J Surg Res

J Am Coll Cardiol

Lancet

Lancet

Ann Emerg Med

Resuscitation

Resuscitation

Am J Cardiol

Resuscitation

Control Clin Trials

Chest

Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation

N Engl J Med

Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest

Arch Intern Med

Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care

Circulation

European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation

N Engl J Med

In-hospital cardiac arrest: incidence, prognosis and possible measures to improve survival

Intensive Care Med

Rhythms and outcomes of adult in-hospital cardiac arrest

Crit Care Med

Epinephrine increases the severity of postresuscitation myocardial dysfunction

Circulation

Vasopressor agents: old and new components

Curr Opin Crit Care

Postresuscitation myocardial dysfunction: correlated factors and prognostic implications

Intensive Care Med

Stress hormone response during and after cardiopulmonary resuscitation

Anesthesiology

Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs

Circulation

Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary resuscitation in pigs

Circulation

Effects of combined administration of vasopressin, epinephrine, and norepinephrine during cardiopulmonary resuscitation in pigs

Crit Care Med

Developing a vasopressor combination in a pig model of adult asphyxial cardiac arrest

Circulation

Survival with full neurologic recovery after prolonged cardiopulmonary resuscitation with a combination of vasopressin and epinephrine in pigs

Anesth Analg

Clinical paper
Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials☆