Do Vasopressors Improve Outcomes in Patients With Cardiac Arrest?

Abstract

Take-Home MessageResearch evidence is currently inadequate to either support or reject the use of vasopressors in cardiac arrest.MethodsData SourcesThe authors searched PubMed, EMBASE, and the Cochrane Library through October 2011. Additionally, they reviewed bibliographies of selected articles and the American Heart Association Emergency Cardiovascular Care master library and the C2005 International Liaison Committee of Resuscitation worksheets.Study SelectionControlled trials, meta-analyses, and case series assessing the use of vasopressors in human cardiac arrest were reviewed by 2 authors. Studies without abstracts, in abstract only, without human subjects, and involving trauma, as well as case reports, narrative reviews, and non-English articles, were excluded.Data Extraction and SynthesisArticles were classified by level of evidence 1 to 5 for therapy and scored “poor” to “good,” using International Liaison Committee of Resuscitation design-specific criteria.ResultsThe authors addressed 5 different categories: 1 to 4 reflect adult data and 5 reflects pediatric data: (1) any vasopressor versus placebo, (2) vasopressin versus epinephrine, (3) high-dose epinephrine versus standard-dose epinephrine, (4) alternative vasopressor (other than vasopressin) versus epinephrine, and (5) the use of vasopressors in pediatric cardiac arrest. This snapshot will highlight patient-important outcomes among the highest-quality trials (International Liaison Committee of Resuscitation=1; randomized control trials (RCTs) and meta-analyses of RCTs) that are of good quality (have most/all of the relevant quality items).The use of epinephrine versus placebo was directly addressed in one fair-quality RCT that was ended early. A meta-analysis of 3 RCTs comparing vasopressin versus epinephrine showed no difference in survival to discharge even when subanalyzed by presenting rhythm (relative risk 0.96; 95% confidence interval [CI] 0.87 to 1.05). A meta-analysis of 5 RCTs comparing high-dose epinephrine with standard-dose epinephrine showed significantly improved rates of return of spontaneous circulation (odds ratio [OR] 1.14; 95% CI 1.02 to 1.27) but no benefit in survival to hospital discharge (OR 0.74; 95% CI 0.53 to 1.03). Alternative vasopressors, including methoxamine, norepinephrine, dopamine, and phenylephrine, showed no benefit over the use of epinephrine. In the pediatric population, there are limited data on the use of vasopressors in cardiac arrest and the discussion is largely focused on the comparison of high-dose epinephrine with standard-dose epinephrine; in the one good-quality RCT, there was no benefit to high-dose epinephrine compared with standard-dose epinephrine (OR 7.9; 97.5% CI 0.9 to 72.5).CommentaryRecent Institute of Medicine standards mandate systematic reviews as a routine aspect of clinical practice guidelines.1Committee on Standards for Developing Trustworthy Clinical Practice GuidelinesClinical Practice Guidelines We Can Trust. Institute of Medicine Report. National Academies Press, Washington, DC2011Google Scholar The qualitative systematic review by Larabee et al is largely derived from worksheets developed as part of the 2010 update of American Heart Association/International Liaison Committee of Resuscitation resuscitation guidelines and reflects other aspects of that effort. The review has some limitations in that studies published only in abstract or those without an abstract were not pursued and authors did not address other methodological issues such as independent data abstraction or reporting of interrater reliability of eligibility or quality assessments. However, it does reflect concern for increasing transparency on the part of developers of guidelines relevant to emergency care.Vasopressors have constituted a mainstay in resuscitation protocols for patients with cardiac arrest since the dawn of emergency medicine. Larabee et al find that research evidence is currently inadequate to either support or reject the use of these agents in that setting when survival beyond admission to the hospital is taken as the primary outcome. Systematic reviews cited by the authors suggest a consistent pattern. Both vasopressin2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar and high-dose epinephrine3Vandycke C. Martens P. High dose versus standard dose epinephrine—a meta-analysis.Resuscitation. 2000; 45: 161-166Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar compared with standard-dose epinephrine trend toward increasing return of spontaneous circulation and admission to intensive care with no increased chance of survival to hospital discharge among people with out-of-hospital cardiac arrest. Trials that assessed survival efficacy of the combination of vasopressin and epinephrine compared with epinephrine alone also yielded no increase in survival to hospital discharge.4Gueugniaud P. David J. Chanzy E. et al.Vasopressin and epinephrine vs epinephrine alone in cardiopulmonary resuscitation.N Engl J Med. 2008; 359: 21-30Crossref PubMed Scopus (234) Google Scholar, 5Callaway C.W. Hostler D. Doshi A.A. et al.Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest.Am J Cardiol. 2006; 98: 1316-1321Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar A suggestion that vasopressin is more effective than epinephrine for patients presenting with asystole, as opposed to ventricular fibrillation or pulseless electrical activity, failed scrutiny by rigorous analytic methods.2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar, 6Wyer P.C. Perera P. Jin Z. et al.Vasopressin or epinephrine for out-of-hospital cardiac arrest.Ann Emerg Med. 2006; 48: 86-97Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Finally, a recent placebo controlled trial, cited by Larabee et al, failed to find a statistically significant benefit of standard-dose epinephrine in increasing long-term survival in out-of-hospital cardiac arrest victims, although the trend potentially favored epinephrine (OR 2.2; 95% CI 0.7 to 6.3).7Jacobs I.G. Finn J.C. Jelinek G.A. et al.Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo controlled trial.Resuscitation. 2011; 82: 1138-1143Abstract Full Text Full Text PDF PubMed Scopus (318) Google ScholarHow should providers of emergency care interpret the evidence of lack of efficacy of vasopressors and other cardioactive agents for improving clinically important outcomes in patients with cardiac arrest? A potential tipping point in resuscitation research has been the advent of the “new cardiopulmonary resuscitation,” a simplified technique emphasizing uninterrupted chest compressions without ventilator support in patients with primary cardiac arrest, ie, arrest events not a result of respiratory or metabolic derangements. Implementation of the protocol in emergency medical services (EMS) systems in 3 states has double survival among this subgroup of patients8Ewy G.A. Kern K.B. Recent advances in cardiopulmonary resuscitation: cardiocerebral resuscitation.J Am Coll Cardiol. 2009; 53: 149-157Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and also improved outcomes in patients treated by laypeople by telephone instruction from EMS dispatch.9Bobrow B.J. Spaite D.W. Berg R.A. et al.Chest compression only CPR by lay rescuers and survival from out-of-hospital cardiac arrest.JAMA. 2010; 304: 1447-1454Crossref PubMed Scopus (352) Google Scholar Practitioners attending to patients experiencing primary cardiac arrest should adhere meticulously to the principles that have emerged from these trials rather than to nuances of pharmacologic adjuncts that have not been found to be clinically effective. They should not, however, curtail their attentiveness to ongoing resuscitation research. Published trials of efficacy of drugs for cardiac arrest heretofore have not distinguished between patients with primary versus secondary cardiac arrest and have not been systematically premised on approaches to basic resuscitation that maximize clinical outcomes among such patients. Preliminary research suggests the results might be different should those requisites be met.10Zuercher M. Kern K.B. Indik J.H. et al.Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration.Anesth Analg. 2011; 112: 884-890Crossref PubMed Scopus (37) Google Scholar Take-Home MessageResearch evidence is currently inadequate to either support or reject the use of vasopressors in cardiac arrest. Research evidence is currently inadequate to either support or reject the use of vasopressors in cardiac arrest. MethodsData SourcesThe authors searched PubMed, EMBASE, and the Cochrane Library through October 2011. Additionally, they reviewed bibliographies of selected articles and the American Heart Association Emergency Cardiovascular Care master library and the C2005 International Liaison Committee of Resuscitation worksheets.Study SelectionControlled trials, meta-analyses, and case series assessing the use of vasopressors in human cardiac arrest were reviewed by 2 authors. Studies without abstracts, in abstract only, without human subjects, and involving trauma, as well as case reports, narrative reviews, and non-English articles, were excluded.Data Extraction and SynthesisArticles were classified by level of evidence 1 to 5 for therapy and scored “poor” to “good,” using International Liaison Committee of Resuscitation design-specific criteria. Data SourcesThe authors searched PubMed, EMBASE, and the Cochrane Library through October 2011. Additionally, they reviewed bibliographies of selected articles and the American Heart Association Emergency Cardiovascular Care master library and the C2005 International Liaison Committee of Resuscitation worksheets. The authors searched PubMed, EMBASE, and the Cochrane Library through October 2011. Additionally, they reviewed bibliographies of selected articles and the American Heart Association Emergency Cardiovascular Care master library and the C2005 International Liaison Committee of Resuscitation worksheets. Study SelectionControlled trials, meta-analyses, and case series assessing the use of vasopressors in human cardiac arrest were reviewed by 2 authors. Studies without abstracts, in abstract only, without human subjects, and involving trauma, as well as case reports, narrative reviews, and non-English articles, were excluded. Controlled trials, meta-analyses, and case series assessing the use of vasopressors in human cardiac arrest were reviewed by 2 authors. Studies without abstracts, in abstract only, without human subjects, and involving trauma, as well as case reports, narrative reviews, and non-English articles, were excluded. Data Extraction and SynthesisArticles were classified by level of evidence 1 to 5 for therapy and scored “poor” to “good,” using International Liaison Committee of Resuscitation design-specific criteria. Articles were classified by level of evidence 1 to 5 for therapy and scored “poor” to “good,” using International Liaison Committee of Resuscitation design-specific criteria. ResultsThe authors addressed 5 different categories: 1 to 4 reflect adult data and 5 reflects pediatric data: (1) any vasopressor versus placebo, (2) vasopressin versus epinephrine, (3) high-dose epinephrine versus standard-dose epinephrine, (4) alternative vasopressor (other than vasopressin) versus epinephrine, and (5) the use of vasopressors in pediatric cardiac arrest. This snapshot will highlight patient-important outcomes among the highest-quality trials (International Liaison Committee of Resuscitation=1; randomized control trials (RCTs) and meta-analyses of RCTs) that are of good quality (have most/all of the relevant quality items).The use of epinephrine versus placebo was directly addressed in one fair-quality RCT that was ended early. A meta-analysis of 3 RCTs comparing vasopressin versus epinephrine showed no difference in survival to discharge even when subanalyzed by presenting rhythm (relative risk 0.96; 95% confidence interval [CI] 0.87 to 1.05). A meta-analysis of 5 RCTs comparing high-dose epinephrine with standard-dose epinephrine showed significantly improved rates of return of spontaneous circulation (odds ratio [OR] 1.14; 95% CI 1.02 to 1.27) but no benefit in survival to hospital discharge (OR 0.74; 95% CI 0.53 to 1.03). Alternative vasopressors, including methoxamine, norepinephrine, dopamine, and phenylephrine, showed no benefit over the use of epinephrine. In the pediatric population, there are limited data on the use of vasopressors in cardiac arrest and the discussion is largely focused on the comparison of high-dose epinephrine with standard-dose epinephrine; in the one good-quality RCT, there was no benefit to high-dose epinephrine compared with standard-dose epinephrine (OR 7.9; 97.5% CI 0.9 to 72.5). The authors addressed 5 different categories: 1 to 4 reflect adult data and 5 reflects pediatric data: (1) any vasopressor versus placebo, (2) vasopressin versus epinephrine, (3) high-dose epinephrine versus standard-dose epinephrine, (4) alternative vasopressor (other than vasopressin) versus epinephrine, and (5) the use of vasopressors in pediatric cardiac arrest. This snapshot will highlight patient-important outcomes among the highest-quality trials (International Liaison Committee of Resuscitation=1; randomized control trials (RCTs) and meta-analyses of RCTs) that are of good quality (have most/all of the relevant quality items). The use of epinephrine versus placebo was directly addressed in one fair-quality RCT that was ended early. A meta-analysis of 3 RCTs comparing vasopressin versus epinephrine showed no difference in survival to discharge even when subanalyzed by presenting rhythm (relative risk 0.96; 95% confidence interval [CI] 0.87 to 1.05). A meta-analysis of 5 RCTs comparing high-dose epinephrine with standard-dose epinephrine showed significantly improved rates of return of spontaneous circulation (odds ratio [OR] 1.14; 95% CI 1.02 to 1.27) but no benefit in survival to hospital discharge (OR 0.74; 95% CI 0.53 to 1.03). Alternative vasopressors, including methoxamine, norepinephrine, dopamine, and phenylephrine, showed no benefit over the use of epinephrine. In the pediatric population, there are limited data on the use of vasopressors in cardiac arrest and the discussion is largely focused on the comparison of high-dose epinephrine with standard-dose epinephrine; in the one good-quality RCT, there was no benefit to high-dose epinephrine compared with standard-dose epinephrine (OR 7.9; 97.5% CI 0.9 to 72.5). CommentaryRecent Institute of Medicine standards mandate systematic reviews as a routine aspect of clinical practice guidelines.1Committee on Standards for Developing Trustworthy Clinical Practice GuidelinesClinical Practice Guidelines We Can Trust. Institute of Medicine Report. National Academies Press, Washington, DC2011Google Scholar The qualitative systematic review by Larabee et al is largely derived from worksheets developed as part of the 2010 update of American Heart Association/International Liaison Committee of Resuscitation resuscitation guidelines and reflects other aspects of that effort. The review has some limitations in that studies published only in abstract or those without an abstract were not pursued and authors did not address other methodological issues such as independent data abstraction or reporting of interrater reliability of eligibility or quality assessments. However, it does reflect concern for increasing transparency on the part of developers of guidelines relevant to emergency care.Vasopressors have constituted a mainstay in resuscitation protocols for patients with cardiac arrest since the dawn of emergency medicine. Larabee et al find that research evidence is currently inadequate to either support or reject the use of these agents in that setting when survival beyond admission to the hospital is taken as the primary outcome. Systematic reviews cited by the authors suggest a consistent pattern. Both vasopressin2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar and high-dose epinephrine3Vandycke C. Martens P. High dose versus standard dose epinephrine—a meta-analysis.Resuscitation. 2000; 45: 161-166Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar compared with standard-dose epinephrine trend toward increasing return of spontaneous circulation and admission to intensive care with no increased chance of survival to hospital discharge among people with out-of-hospital cardiac arrest. Trials that assessed survival efficacy of the combination of vasopressin and epinephrine compared with epinephrine alone also yielded no increase in survival to hospital discharge.4Gueugniaud P. David J. Chanzy E. et al.Vasopressin and epinephrine vs epinephrine alone in cardiopulmonary resuscitation.N Engl J Med. 2008; 359: 21-30Crossref PubMed Scopus (234) Google Scholar, 5Callaway C.W. Hostler D. Doshi A.A. et al.Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest.Am J Cardiol. 2006; 98: 1316-1321Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar A suggestion that vasopressin is more effective than epinephrine for patients presenting with asystole, as opposed to ventricular fibrillation or pulseless electrical activity, failed scrutiny by rigorous analytic methods.2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar, 6Wyer P.C. Perera P. Jin Z. et al.Vasopressin or epinephrine for out-of-hospital cardiac arrest.Ann Emerg Med. 2006; 48: 86-97Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Finally, a recent placebo controlled trial, cited by Larabee et al, failed to find a statistically significant benefit of standard-dose epinephrine in increasing long-term survival in out-of-hospital cardiac arrest victims, although the trend potentially favored epinephrine (OR 2.2; 95% CI 0.7 to 6.3).7Jacobs I.G. Finn J.C. Jelinek G.A. et al.Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo controlled trial.Resuscitation. 2011; 82: 1138-1143Abstract Full Text Full Text PDF PubMed Scopus (318) Google ScholarHow should providers of emergency care interpret the evidence of lack of efficacy of vasopressors and other cardioactive agents for improving clinically important outcomes in patients with cardiac arrest? A potential tipping point in resuscitation research has been the advent of the “new cardiopulmonary resuscitation,” a simplified technique emphasizing uninterrupted chest compressions without ventilator support in patients with primary cardiac arrest, ie, arrest events not a result of respiratory or metabolic derangements. Implementation of the protocol in emergency medical services (EMS) systems in 3 states has double survival among this subgroup of patients8Ewy G.A. Kern K.B. Recent advances in cardiopulmonary resuscitation: cardiocerebral resuscitation.J Am Coll Cardiol. 2009; 53: 149-157Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and also improved outcomes in patients treated by laypeople by telephone instruction from EMS dispatch.9Bobrow B.J. Spaite D.W. Berg R.A. et al.Chest compression only CPR by lay rescuers and survival from out-of-hospital cardiac arrest.JAMA. 2010; 304: 1447-1454Crossref PubMed Scopus (352) Google Scholar Practitioners attending to patients experiencing primary cardiac arrest should adhere meticulously to the principles that have emerged from these trials rather than to nuances of pharmacologic adjuncts that have not been found to be clinically effective. They should not, however, curtail their attentiveness to ongoing resuscitation research. Published trials of efficacy of drugs for cardiac arrest heretofore have not distinguished between patients with primary versus secondary cardiac arrest and have not been systematically premised on approaches to basic resuscitation that maximize clinical outcomes among such patients. Preliminary research suggests the results might be different should those requisites be met.10Zuercher M. Kern K.B. Indik J.H. et al.Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration.Anesth Analg. 2011; 112: 884-890Crossref PubMed Scopus (37) Google Scholar Recent Institute of Medicine standards mandate systematic reviews as a routine aspect of clinical practice guidelines.1Committee on Standards for Developing Trustworthy Clinical Practice GuidelinesClinical Practice Guidelines We Can Trust. Institute of Medicine Report. National Academies Press, Washington, DC2011Google Scholar The qualitative systematic review by Larabee et al is largely derived from worksheets developed as part of the 2010 update of American Heart Association/International Liaison Committee of Resuscitation resuscitation guidelines and reflects other aspects of that effort. The review has some limitations in that studies published only in abstract or those without an abstract were not pursued and authors did not address other methodological issues such as independent data abstraction or reporting of interrater reliability of eligibility or quality assessments. However, it does reflect concern for increasing transparency on the part of developers of guidelines relevant to emergency care. Vasopressors have constituted a mainstay in resuscitation protocols for patients with cardiac arrest since the dawn of emergency medicine. Larabee et al find that research evidence is currently inadequate to either support or reject the use of these agents in that setting when survival beyond admission to the hospital is taken as the primary outcome. Systematic reviews cited by the authors suggest a consistent pattern. Both vasopressin2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar and high-dose epinephrine3Vandycke C. Martens P. High dose versus standard dose epinephrine—a meta-analysis.Resuscitation. 2000; 45: 161-166Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar compared with standard-dose epinephrine trend toward increasing return of spontaneous circulation and admission to intensive care with no increased chance of survival to hospital discharge among people with out-of-hospital cardiac arrest. Trials that assessed survival efficacy of the combination of vasopressin and epinephrine compared with epinephrine alone also yielded no increase in survival to hospital discharge.4Gueugniaud P. David J. Chanzy E. et al.Vasopressin and epinephrine vs epinephrine alone in cardiopulmonary resuscitation.N Engl J Med. 2008; 359: 21-30Crossref PubMed Scopus (234) Google Scholar, 5Callaway C.W. Hostler D. Doshi A.A. et al.Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest.Am J Cardiol. 2006; 98: 1316-1321Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar A suggestion that vasopressin is more effective than epinephrine for patients presenting with asystole, as opposed to ventricular fibrillation or pulseless electrical activity, failed scrutiny by rigorous analytic methods.2Aung K. Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis.Arch Intern Med. 2005; 165: 17-24Crossref PubMed Scopus (149) Google Scholar, 6Wyer P.C. Perera P. Jin Z. et al.Vasopressin or epinephrine for out-of-hospital cardiac arrest.Ann Emerg Med. 2006; 48: 86-97Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Finally, a recent placebo controlled trial, cited by Larabee et al, failed to find a statistically significant benefit of standard-dose epinephrine in increasing long-term survival in out-of-hospital cardiac arrest victims, although the trend potentially favored epinephrine (OR 2.2; 95% CI 0.7 to 6.3).7Jacobs I.G. Finn J.C. Jelinek G.A. et al.Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo controlled trial.Resuscitation. 2011; 82: 1138-1143Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar How should providers of emergency care interpret the evidence of lack of efficacy of vasopressors and other cardioactive agents for improving clinically important outcomes in patients with cardiac arrest? A potential tipping point in resuscitation research has been the advent of the “new cardiopulmonary resuscitation,” a simplified technique emphasizing uninterrupted chest compressions without ventilator support in patients with primary cardiac arrest, ie, arrest events not a result of respiratory or metabolic derangements. Implementation of the protocol in emergency medical services (EMS) systems in 3 states has double survival among this subgroup of patients8Ewy G.A. Kern K.B. Recent advances in cardiopulmonary resuscitation: cardiocerebral resuscitation.J Am Coll Cardiol. 2009; 53: 149-157Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and also improved outcomes in patients treated by laypeople by telephone instruction from EMS dispatch.9Bobrow B.J. Spaite D.W. Berg R.A. et al.Chest compression only CPR by lay rescuers and survival from out-of-hospital cardiac arrest.JAMA. 2010; 304: 1447-1454Crossref PubMed Scopus (352) Google Scholar Practitioners attending to patients experiencing primary cardiac arrest should adhere meticulously to the principles that have emerged from these trials rather than to nuances of pharmacologic adjuncts that have not been found to be clinically effective. They should not, however, curtail their attentiveness to ongoing resuscitation research. Published trials of efficacy of drugs for cardiac arrest heretofore have not distinguished between patients with primary versus secondary cardiac arrest and have not been systematically premised on approaches to basic resuscitation that maximize clinical outcomes among such patients. Preliminary research suggests the results might be different should those requisites be met.10Zuercher M. Kern K.B. Indik J.H. et al.Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration.Anesth Analg. 2011; 112: 884-890Crossref PubMed Scopus (37) Google Scholar