This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and

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1 This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier s archiving and manuscript policies are encouraged to visit:

2 Resuscitation (2008) 79, available at journal homepage: REVIEW Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone in the treatment of cardiac arrest A systematic review Victoria A.H. Sillberg a, Jeffrey J. Perry b,, Ian G. Stiell b, George A. Wells c a Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada b Department of Emergency Medicine, University of Ottawa, Ottawa, Ontario, Canada c Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada Received 1 April 2008; received in revised form 25 July 2008; accepted 30 July 2008 KEYWORDS Heart arrest; Epinephrine; Vasopressin; Systematic review; Cardiopulmonary resuscitation Summary Objective: No evidence supports vasopressin over epinephrine in cardiac arrest; however animal and some clinical studies support their concurrent use. This systematic review compares the efficacy of vasopressin and epinephrine used together versus repeated doses of epinephrine alone in cardiac arrest. Methods: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. We included randomized controlled trials (RCTs) where vasopressin and epinephrine were administered concurrently to cardiac arrest patients within the half-life of vasopressin. Two reviewers assessed studies for eligibility, data extraction and quality. Appropriateness of studies for meta-analysis was assessed. The primary outcome was survival to hospital discharge and the secondary outcome was return of spontaneous circulation (ROSC). Results: From 235 titles identified, we reviewed 29 abstracts. Three cardiac arrest studies were included (N = 1226). Study 1 randomized vasopressin versus epinephrine then subsequent epinephrine. Study 2 randomized two doses of vasopressin versus epinephrine. Study 3 randomized vasopressin versus placebo, administered following initial epinephrine. All studies favored combination treatment for ROSC, but only study 2 was statistically significant (RR 1.42, 95% CI ). Studies 1 and 2 reported survival to discharge, only study 2 was significant (RR 3.69, 95% CI ). The methods for the three studies were too dissimilar to allow pooling of results. A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi: /j.resuscitation Corresponding author at: The Ottawa Hospital, Civic Campus, Clinical Epidemiology Program, F6, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada. Tel.: x18763; fax: address: jperry@ohri.ca (J.J. Perry) /$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.resuscitation

3 Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone 381 Conclusion: This systematic review of the combination of vasopressin and epinephrine found trends towards better ROSC but equivocal effects on survival. At the present time, there is inadequate evidence to advocate the sequential use of vasopressin and epinephrine for cardiac arrest Elsevier Ireland Ltd. All rights reserved. Contents Methods Data sources and searches Study selection Data extraction and quality assessment Data synthesis and analysis Results Discussion Limitations Strengths Impact on practice Implications for future research Conclusions Conflict of interest Acknowledgement References Cardiac arrest, the sudden cessation of spontaneous ventilation and circulation, remains a serious health concern in North America with an estimated 300,000 cases annually. 1 Despite the rigorous algorithms for CPR and ALCS, the reported survival rates following cardiac arrest remain low, ranging from 2 to 24%. 2 5 Vasopressors are a key component of the ACLS algorithm, despite the fact that no vasopressor has ever been shown during CPR. Historically, epinephrine has been the first-line pharmacologic agent in the treatment of cardiac arrest refractory to defibrillation; however, vasopressin has gained some popularity as a potential adjunct or alternative to epinephrine. Previous studies have not demonstrated a survival benefit of vasopressin over epinephrine. 6,7 Recent interested has shifted to the possibility of a benefit of using both vasopressin and epinephrine over repeated doses of epinephrine alone. 8 The combination of both vasopressin and epinephrine has been shown to improve outcomes in animal models of cardiac arrest. Specifically, the combination increases coronary perfusion pressure, improves return of spontaneous circulation, 9 increases survival, 10,11 improves cerebral blood flow, 12 increases diastolic aortic pressures and improves neurological outcomes 13 compared to epinephrine or vasopressin alone. This has important implications for the use of this combination in humans as coronary perfusion pressure has previously been found to correlate with return of spontaneous circulation in human cardiac arrest. 14 There have been several human studies in which some patients received both vasopressin and epinephrine. Given vasopressin s relatively long half-life (6 min), patients who receive vasopressin and are treated 3 5 min later with epinephrine, as per ACLS algorithms, have both medications having therapeutic effects simultaneously. Several small retrospective and case studies have reported more desirable outcomes with the administration of both drugs including increased rates of return of spontaneous circulation, 24 h survival, and survival to hospital discharge While there has been some evidence from both human and animal trials that the combination of vasopressin and epinephrine may be superior to repeated doses of epinephrine alone in the treatment of cardiac arrest, there is a significant degree of contradiction in the existing literature. No previous systematic review has compared the combination of vasopressin and epinephrine to repeated doses of epinephrine alone. The goal of our systematic review is to review the current body of knowledge regarding treatment with both vasopressin and epinephrine compared to repeated doses of epinephrine alone in the treatment of cardiac arrest patients and combine these studies in a meta-analysis, if possible. Methods Data sources and searches MEDLINE (1950 to April Week ), EMBASE ( Week 15), and the Cochrane Central Register of Controlled Trials (1st Quarter 2007), were searched to identify all studies relating to the use of vasopressin and epinephrine in cardiac arrest. The search strategy included using the keywords such as epinephrine, vasopressin, heart arrest, cardiac arrest, cardiopulmonary resuscitation, and advanced cardiac life support (Appendix A). We also searched for all known names for epinephrine and vasopressin. Randomized controlled trial filters were adapted from the Scottish Intercollegiate Guidelines Network for the Medline and EMBASE searches. 18 The search strategy was reviewed by library personnel to ensure that it was complete. We did not limit the search by language and

4 382 V.A.H. Sillberg et al. included articles published as abstracts only. The references of identified articles were searched for citations which may have been missed by the electronic search and authors were contacted for unpublished or in press data. Study selection Two independent assessors (VS, JJP) reviewed titles, selected studies for inclusion using specific criteria (including: only randomized controlled trials, administration of both vasopressin and epinephrine to some patients, and measurements of one, or more, of our outcome variables). Interrater agreement was calculated using kappa statistics. All disagreements were resolved by consensus. We included all randomized controlled trials and controlled clinical trials meeting the following criteria: (1) the study reported outcomes for return of spontaneous circulation, survival to hospital admission, or survival to hospital discharge; (2) some patients received both vasopressin and epinephrine; (3) the study examined patients with non-traumatic cardiac arrest requiring administration of vasopressors. Figure 1 Study flow diagram. Data extraction and quality assessment Two independent reviewers (VS, JJP) extracted data, using standardized data collection forms. The primary outcomes was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation, and survival to hospital admission. Two independent reviewers assessed the methodologic quality of the selected studies (VS, JJP). Both reviewers rated all studies using the Jadad scale. 19 This is a validated scale of five levels ranging from 0 for low-quality studies to 5 for high-quality studies that were well-blinded, wellrandomized, and accounted for all patients intended for the study. Studies were deemed to be high quality if they scored a Jadad score of 3 or more. In addition, allocation concealment for randomization group was assessed using the Cochrane Collaboration method of A, B, or C: A representing adequate, B inadequate, or C unable to assess levels of treatment group allocation. Interrater agreement was measured for both these study quality assessments using the kappa statistic (VS, JJP). Data synthesis and analysis Study data were entered into Review Manager and relative risk (RR) was calculated for all studies. The methodologies of the included studies were examined (VS, JJP) to determine if they would be compatible in a meta-analysis. Results Our search strategy (e.g. Appendix A) identified 235 titles. From these, the abstracts of 29 articles were examined. Twenty-three articles were excluded because they were reviews, did not study at least one of our outcomes of interest, or they were not randomized controlled trials. Six studies were identified in which trial arms had patients receiving vasopressin and another in which they received epinephrine. Three studies were eliminated because patients in the vasopressin group did not receive epinephrine as well or because the data for the vasopressin and epinephrine subgroup was not reported and the authors did not provide additional information (Figure 1). The kappa statistic for selection by title was 0.79 (95% CI ) and by abstract was 0.77 (95% CI ), while the kappa statistic for included studies was 1.0. The kappa for high quality studies (i.e. Jadad score 3) was 1.0. The characteristics of the three included studies are reported in Table 1. All three studies were double or triple blinded randomized controlled trials in which one treatment arm received vasopressin and epinephrine together and another received repeated doses of epinephrine alone. We received additional unpublished data from two of the authors. Survival to hospital discharge was significantly improved in the study by Wenzel et al. 7 for the combination of vasopressin and epinephrine (RR 3.69, 95% CI ). The study by Stiell et al. 6 did not demonstrate any significant differences (RR 0.88, 95% CI ) and the study by Callaway et al. 21 did not report data for this outcome. Only the paper by Wenzel et al. 7 showed significantly improved rates of return of spontaneous circulation with the combination of vasopressin and epinephrine versus epinephrine alone (RR 1.42, 95% CI ). The studies by Stiell et al. 6 (RR 1.10, 95% CI ) and Callaway et al. 21 (RR 1.02, 95% CI ) both showed no significant difference for this outcome. Survival to hospital admission was significantly improved in the study by Wenzel et al. 7 for the combination of vasopressin and epinephrine versus repeated doses of epinephrine alone (RR 1.57, 95% CI ). The study by Callaway et al. 21 found no significant difference (RR 0.79, 95% CI ), and the study by Stiell et al. 6 did not report data for this outcome. The study conducted by Callaway et al. 21 was a prehospital study in which patients who did not respond to one dose of epinephrine were randomized to receive either

5 Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone 383 Table 1 Characteristics of included studies. Study ID Methods Participants Interventions Jadad score Allocation concealment a Callaway et al. 26 Wenzel et al. 7 Stiell et al. 6 RCT b double blind (N = 325) RCT double blind (N = 732) RCT triple blind (N = 169) OOHCA c Following 1 mg epinephrine 5 A 18 years old IU vasopressin 2. Placebo OOHCA IU vasopressin, followed by 3 B 40 IU vasopressin (if needed) Adult 2. 1 mg epinephrine followed by epinephrine (if needed) IHCA d IU vasopressin 5 A 16 years old a A: adequate; B: inadequate or unclear; C: unable to assess. b Randomized controlled trial. c Out-of-hospital cardiac arrest. d In-hospital cardiac arrest mg IV epinephrine vasopressin or a placebo. The study by Wenzel et al. 7 was also prehospital and patients were randomized to receive either vasopressin or epinephrine. If the patient was unresponsive following two doses of the study drug, epinephrine was given as per ACLS guidelines. Finally, the study by Stiell et al. 6 was an in-hospital study in which patients were randomized to receive either vasopressin or epinephrine. Patients who did not respond to one dose of the study drug were given subsequent doses of epinephrine according to ACLS guidelines. The methodologies for the three studies were deemed too different to be compared and thus a meta-analysis was not attempted. Discussion The results of this systematic review demonstrated that there are very few studies which have examined the effect of the combination of vasopressin and epinephrine compared to repeated doses of epinephrine alone and that there is contradiction evident in the existing literature with one of three studies finding a significant benefit to the combination. The findings from the study by Wenzel et al. 7 are consistent with the animal research that has been conducted in this area. We would have liked to combine the results of the three studies in a meta-analysis, however, the methodologies of the three studies were too dissimilar to be meaningfully compared. The study by Stiell et al. 6 was conducted in hospitalized patients. Patients were randomized to either vasopressin or epinephrine, with nonresponders receiving additional rescue doses of epinephrine as per ACLS guidelines. As this study was conducted in hospital, time to initial drug administration was rapid (1.6 min to CPR, 2.8 min to ACLS). This study did not demonstrate any significant improvement in outcome with the combination compared to epinephrine alone, however, outcomes were good for patients who survived to hospital discharge with 80% scoring in the highest cerebral performance category at discharge. This positive outcome is likely attributable to the short lag between cardiac arrest (and therefore impaired cerebral blood supply) and initiation of resuscitation. In the Wenzel et al. study, 7 patients received either vasopressin or epinephrine (i.e. routine ACLS care). Patients not responding in the vasopressin group were given a second dose of vasopressin followed by epinephrine as needed. Although this was the only study to show significantly improved outcomes with the combination of vasopressin and epinephrine, the outcomes for the patients who survived to hospital discharge were poor with many patients suffering severe cognitive impairment. In the Callaway et al. study, 21 all patients were all given an initial dose of epinephrine, with nonresponders then randomized to either vasopressin 40 IU or placebo. This study is the best designed to assess the combination of both epinephrine and vasopressin of the three studies included in this paper; however the average time from initial dose of epinephrine to the administration of the randomized drug (either vasopressin or placebo) was 5.2 min in the vasopressin group and 4.4 min in the placebo group following the initial dose of epinephrine. Given that epinephrine has a half-life of 3 min, not much active epinephrine would be present at the time the patients were administered vasopressin which may have influenced their results. With all three included studies, any patients who responded to the initial drug would not be included in the analysis as neither treatment arm would not have received both drugs. Thus it is possible that many of the patients in these studies who received both drugs were going to have a bad outcome regardless of the drug(s) used. Unfortunately, none of these studies truly used a combination of vasopressin and epinephrine in which all patients receiving vasopressin and epinephrine were given both in a way in which an overlap of therapeutic activity could be confidently assumed. The closest design to testing for both treatments was by Callaway et al. 21, where the randomization took place only after the initial dose of epinephrine, however the min delay until the administration of

6 384 V.A.H. Sillberg et al. the second vasopressor (vasopressin or placebo) was too great to truly test the presence of both vasopressors simultaneously versus epinephrine alone. We are currently aware of three in-progress clinical trials comparing vasopressin and epinephrine in cardiac arrest in which some patients could receive the combination of vasopressin and epinephrine. One of these trials is being conducted in a pediatric population. We hope that the results of these trials, once completed, will help to clarify the roles and effectiveness of the combination of vasopressin and epinephrine compared to repeated doses of epinephrine alone. We are aware of five previous systematic reviews examining the use of vasopressin in cardiac arrest. 1,22 25 No previous meta-analysis has looked at the combination treatment of vasopressin and epinephrine versus epinephrine alone, but rather all have looked at head-to-head comparisons (i.e. vasopressin vs. epinephrine). The most recent meta-analysis was performed by Wyer et al. 22 who report no significant difference between vasopressin and epinephrine groups overall. Nor did they find any difference for the subgroup patients presenting with asystole compared to the subgroup presenting in ventricular fibrillation. A review by Koshman et al. 23 only identified three randomized controlled trials. The authors of this study concluded that the evidence for vasopressin is indeterminate and that more studies were need to evaluate survival to hospital discharge, evaluate vasopressin treatment combined with epinephrine and be powered to explore the asystole subgroup which has shown positive outcomes in preliminary studies of vasopressin. This review suffered from inadequate techniques to avoid publication bias and excluded non-english and abstract publications. The second review by Aung and Htay 24 was more rigorous and combined five human studies including non-english and abstract publications. This review found no difference in outcomes between vasopressin and epinephrine groups with respect to return of spontaneous circulation, hospital admission, survival at 24 h or survival to discharge, nor did they find any evidence of a significant subgroup interaction in patients presenting in asystole. The fourth systematic review by Biondi-Zoccai et al. 25 was unique in that results were stratified into human and animal studies. They conclude that vasopressin was superior to epinephrine in animal studies; however, there was no difference based on the two human studies included in their analysis. The final review conducted by Zhong and Dorian 1 missed several important studies and was not systematic in nature. Limitations The major limitation to our review is our inability to acquire additional information from some of the authors. We were unable to reach the authors of the Wenzel and Lindner studies for additional information and thus we were not able to include the patients in the small study (N = 40) conducted by Lindner who received both vasopressin and epinephrine into our analysis as they were not separately analyzed or reported. We were also therefore limited to published data from the Wenzel study. The authors of the two small studies comparing vasopressin to epinephrine by Lee et al. 26 (N = 10) and Li et al. 27 (N = 83) were also contacted for more information but did not respond. As a result, we were unable to adequately evaluate the quality and results of these studies so they were excluded as well. Finally, although the authors of the Callaway study shared their data with us so that we could include it in several more outcomes, they were unable to collect information on survival to discharge. Strengths We believe that our study has several strengths. Our analysis is unique in that we have examined the combination of vasopressin and epinephrine. We also used a very open search strategy to include all non-english and abstract publications that related to our topic in order to be as inclusive as possible. Our use of two independent reviewers also helped to insure that we included only appropriate and high quality studies. We contacted the authors of all identified studies directly in an attempt to obtain unpublished or in press data and to ask if they were aware of any groups with unpublished we data. The unpublished data that we received allowed us to examine more outcomes and improve our sample size. We also contacted the authors of two in-progress clinical trials in an attempt to gather more information. Impact on practice Current guidelines support the use of vasopressin as an alternative or adjunct to epinephrine but the use of the combination of agents of agents has not been discussed. This review does not support the use of the combination of vasopressin and epinephrine for cardiac arrest, thus practitioners should continue to follow the standard ACLS guidelines. Implications for future research In light of our findings and the small number of randomized controlled trials which have studied the impact of the combination of vasopressin and epinephrine, we believe that further investigation in this area is warranted. The optimal method for examining this issue may be upfront randomization to back-to-back treatment with epinephrine and vasopressin or repeated doses of epinephrine alone. We are currently aware of two in-progress clinical trials examining the use of vasopressin and epinephrine in cardiac arrest which we hope will further help to clarify the role of a combination of vasopressors for cardiac arrest management. Conclusions This systematic review of the combination of vasopressin and epinephrine found trends towards better ROSC but equivocal effects on survival. There is a need for RCTs to evaluate the simultaneous use of vasopressin and epinephrine in cardiac arrest. At the present time, there is inadequate evidence to advocate the sequential use of vasopressin and epinephrine for cardiac arrest at this time. Conflict of interest None.

7 Is the combination of vasopressin and epinephrine superior to repeated doses of epinephrine alone 385 Acknowledgement Funding sources: Department of Emergency Medicine, University of Ottawa. Appendix A See Table A.1. Table A.1 Search strategy: MEDLINE (1950 to April Week ). Set Term Results 1. epinephrine/ 45, epinephrine.tw 23, adrenalin$.tw 16, catecholamines/ 31, catecholamine$.tw 45, or/ , vasopressins/or arginine vasopressin/or deamino arginine vasopressin/ 29, vasopressin$.tw 24, pitressin.tw pressyn.tw hemopressin.tw vasopin.tw antidiuretic hormone$.tw 3, or/ , exp heart arrest/ 22, ((cardiac or heart) adj arrest).tw 12, ventricular fibrillation/ 11, ventricular fibrillation.tw 10, exp tachycardia, ventricular/ 8, ventricular tachycardia.tw 12, resuscitation/or cardiopulmonary resuscitation/or advanced cardiac life support 24, (advanced cardiac life support or acls).tw resuscitation.tw 23, asystol$.tw 2, pulseless electrical activity.tw cpr.tw 4, or/ , randomized controlled trials/ 48, randomized controlled trial.pt 233, random allocation/ 57, double blind method/ 90, single blind method/ 10, exp clinical trials/ 190, clinical trial.pt 434, or/ , (clinic$ adj trial$1).tw 105, ((singl$ or doubl$ or treb$ or trip$) adj (blind$3 or mask$3)).tw 87, placebos/ 26, placebo$.tw 101, randomly allocated.tw 9, (allocate$ adj2 random$).tw or/ , or , case report.tw 123, letter.pt 588, historical article.pt 238, or/ , not , and 14 and 27 and 48 66

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