Vasopressin or Epinephrine for Out-of-Hospital Cardiac Arrest

Article Outline

• Abstract
• Clinical scenario
• Formulating the question
• Searching for and selecting the best evidence
• Examining the evidence
• Description of the trials
• Primary results of the trials
• Subgroup analysis
• Was the subgroup difference suggested by comparisons within rather than between studies?
• Was the magnitude of the subgroup difference large?
• Was the subgroup difference consistent across studies?
• Was the subgroup difference statistically significant?
• Applying the evidence
• Critically Appraised Topic (CAT): Does vasopressin in place of epinephrine improve survival to discharge without worsening neurological function in patients with out-of-hospital cardiac arrest?
• References
• Copyright

Study objective

The use of vasopressin in patients with cardiac arrest presenting with specific rhythms is controversial. We performed an evidence-based emergency medicine review of evidence comparing vasopressin to epinephrine in structured cardiac arrest protocols.

Methods

We searched MEDLINE, EMBASE, the Cochrane Library, and other databases for randomized trials or systematic reviews comparing vasopressin to epinephrine for adults with cardiac arrest and measuring survival to hospital discharge and neurologic function in survivors. We used standard criteria to appraise the quality of published trials and systematic reviews. We used the random effects model in supplementary analyses to summarize results and to test for significant differences across subgroups of patients presenting with different arrest rhythms.

Results

We found 3 high-quality well-reported randomized trials and 1 rigorous meta-analysis. The evidence does not confirm a consistent benefit of vasopressin over epinephrine in increasing survival or improving neurologic outcome in survivors. Subgroup analysis reveals a large difference in effect of vasopressin over epinephrine in cardiac arrest patients with asystole, compared to other arrest rhythms, coming from within-trial comparisons. The difference is not consistent across otherwise similar trials, is not statistically significant, may reflect the application of multiple unplanned subgroup analyses, and is not supported by a plausible biological hypothesis.

Conclusion

Evidence from randomized trials does not establish a benefit of vasopressin over epinephrine in increasing survival to discharge or improving neurologic outcomes in adult patients with nontraumatic cardiac arrest.

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Clinical scenario 

You are the medical and education director of a regional emergency medical system with basic and advanced life support capabilities. Publicity about a recent trial of vasopressin as an alternative to epinephrine for patients with cardiac arrest leads several members of your training committee to ask when your system is shifting to that alternative. They point out that the American Heart Association guidelines for cardiac resuscitation that you use as the basis for your own advanced life support protocols already list vasopressin as an option. Your paramedic ambulances do not stock vasopressin, nor do your training and recertification programs include it. You decide to examine the evidence favoring vasopressin over epinephrine before making a major revision in your protocols.

The following evidence-based emergency medicine review¹ seeks an answer to the question posed by this scenario.

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Formulating the question 

Hospital inpatients receiving cardiac resuscitation might have a prognostic advantage over patients outside of the hospital by virtue of earlier recognition and more rapid initiation of basic and advanced life support interventions. On the other hand, inpatients’ prognosis may be adversely affected by their concomitant acute conditions. The magnitude and direction of difference in effect of vasopressin on cardiac arrest outcomes between patients inside and outside of the hospital are unpredictable. We therefore included inpatient studies.

We confined our review to survival to hospital discharge and good neurologic function, outcomes that we believe patients themselves most value. Patients and families might consider admission to an ICU with no increased chance of survival to discharge to constitute an undesirable consequence of a new resuscitation drug. For expediency, resuscitation trialists sometimes define “survival to admission” as their primary outcome measure.², ³ Unfortunately, an intervention’s impact on a surrogate outcome such as survival to hospital admission is no guarantee of patient-important benefit.⁴, ⁵ Several studies suggest that survival to ICU admission is not a good surrogate for survival to hospital discharge.², ³, ⁶

We formulated our question as: In patients with cardiac arrest not attributable to trauma or environmental exposures, what is the impact on survival to hospital discharge and survivor neurologic function of vasopressin compared to epinephrine, administered at the first point in a cardiac arrest protocol at which epinephrine would routinely be given?

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Searching for and selecting the best evidence 

We searched for randomized trials and systematic reviews comparing vasopressin to epinephrine for adults in cardiac arrest. We searched MEDLINE from 1966 to July 2004 and EMBASE from 1980 to January 2004 with the OVID interface, using search terms “vasopressin,” “epinephrine,” “cardiac arrest,” and “heart arrest,” with no language restrictions. We limited our MEDLINE search, but not our other searches, to randomized trials or systematic reviews using epinephrine as the comparison intervention. We included randomized trials or systematic reviews of randomized trials, with no other exclusion criteria. Our search yielded 271 results. We also searched all databases of the Cochrane Library⁷ through 2004 issue 1, Emergency Medical Abstracts (available online at http://ccme.org) from 1977 through December 2004,⁸ and online resources including BestBETS (available online at http://www.bestbets.org), using the single search term “vasopressin.” These databases yielded a total of 1,036 results. We reviewed the bibliographies of eligible trials and systematic reviews and of selected non–systematic reviews and commentaries for citations of additional eligible articles. Finally, we searched the bibliography of the relevant sections of the 2000 update of the American Heart Association Advanced Cardiac Life Support guideline.⁹

We found 3 trials comparing vasopressin to epinephrine in patients with cardiac arrest, 2 out-of-hospital¹⁰, ¹¹ and 1 limited to inpatients.¹² One published systematic review,¹³ 1 protocol in the Cochrane Database of Systematic Reviews,¹⁴ and 1 “shortcut review,”¹⁵ as well as our bibliographical reference review, revealed no additional trials. We found no placebo-controlled trials or other human randomized trials involving vasopressin for patients with cardiac arrest. The systematic review by Biondi-Zoccai et al¹³ was limited in its reporting, was not restricted to clinical trials, and did not include the most recent and largest randomized trial by Wenzel et al.¹¹ After the completion of our primary searches and after the initial submission of our review, a second, well-reported, systematic review appeared that used inclusion criteria identical to our own.¹⁶ Aung and Htay¹⁶ identified the same 3 trials identified by our searches, as well as 2 additional clinical trials.¹⁷, ¹⁸ We will focus the rest of this review on the Aung and Htay¹⁶ meta-analysis, supplemented by elements of our own analysis that either differ from or go beyond that of Aung and Htay.¹⁶

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Examining the evidence 

Aung and Htay¹⁶ restricted their review to randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest and reporting patient-important outcomes. They independently selected studies for inclusion.

Aung and Htay¹⁶ report a rigorous search of MEDLINE, EMBASE, the Cochrane Library, CINAHL, bibliographies of related articles, registries of conference proceedings, and unpublished trials. They found a statistical test for evidence of studies not identified by their search to be negative. In addition to the 5 trials mentioned previously,¹⁰, ¹¹, ¹², ¹⁷, ¹⁸ Aung and Htay¹⁶ also report the existence of a trial in progress, the Cardiac Arrest Research Project being conducted by the University of Pittsburgh (available online at http://newsbureau.upmc.com/emergency/vasopressin04.htm). This trial compares vasopressin to placebo as an addition to standard therapy including epinephrine and will not be eligible for inclusion in our review.

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Description of the trials 

Table 1 summarizes the key features of the 5 randomized trials identified by Aung and Htay¹⁶ and included in their analysis. Of the 2 trials not identified in our own independent search, one was limited to 10 patients and was published in abstract form only,¹⁷ and the other was published in a Chinese journal.¹⁸ The inclusion of non-English studies and abstracts in systematic reviews is controversial.¹⁹, ²⁰ Exclusion of unpublished studies may lead to underestimation of treatment effect.¹⁹, ²¹ On the other hand, inclusion of non-English and incompletely reported studies may have little impact on the results of most systematic reviews.²², ²³

Table 1. Summarizing the characteristics of 5 randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest.

ACLS, Advanced cardiac life support.

Two members of our own author team fluent in Chinese (QZ and ZJ) reviewed the full text of the study by Li et al.¹⁸ The reports by Lee¹⁷ and Li¹⁸ do not allow full assessment of their study populations, treatment protocols, or the susceptibility to bias, nor do they provide information about the distribution of presenting rhythms between their study groups. We are unclear about the relationship of the results reported by Lee et al¹⁷ to our own target outcomes. Aung and Htay¹⁶ report failed attempts to obtain more information from the authors of these 2 trials. We did not attempt to reproduce their inquiry. The inclusion of these studies in a pooled analysis might distort the estimates in ways that the parsimoniously reported data does not allow an investigator to anticipate or assess.

The 3 fully reported trials encompass a broad range of settings and variability within potentially important parameters, such as time from arrest to initiation of advanced life support. For example, in contrast to the patients studied by Wenzel et al¹¹ and Lindner et al,¹⁰ the patients studied by Stiell et al¹² had concomitant acute problems warranting emergency department or hospital admission. Twenty-two percent were in the ICU at arrest.¹² Aung and Htay¹⁶ did not perceive these factors to prohibit pooling of the results of their primary outcomes across the trials, nor do we perceive them to constitute a priori incompatibility of these studies.

The 2 largest trials¹¹, ¹² used a common measure of neurologic outcome, a previously published cerebral performance instrument characterized by clear and discrete gradations of functional recovery, ranging from death to full recovery.²⁴ Other investigators have used this instrument in cardiac resuscitation research.²⁵ A preliminary report by Nesbitt et al²⁶ indicates that this instrument correlates well with a highly validated measure of health-related quality of life²⁷ but may overestimate the extent of functional recovery in survivors.²⁶

Aung and Htay¹⁶ performed independent assessment of the quality of the trials included in their review, with particular attention to concealment of randomization, blinding, completeness of follow-up, and outcome assessment.¹⁶ They found uniformly high quality in the 3 assessable trials using these criteria,¹⁰, ¹¹, ¹² although the blinding of outcome assessment was not explicit in the study by Lindner et al.¹⁰ Aung and Htay¹⁶ report 80% agreement for their independent assessments (κ=.64).

Table 2 summarizes our own assessment of the likelihood of bias within the 3 fully reported trials, using criteria similar to those used by Aung and Htay.¹⁶, ²⁸ The loss of 76 patients to complete follow-up (6% of patients randomized) in the Wenzel et al¹¹ study is potentially problematic. If these patients and their outcomes were not randomly distributed between the treatment groups, the results of the trial might be substantially affected.

Table 2. Summarizing the assessment for susceptibility to important bias of the 3 fully reported trials.

CPR, Cardiopulmonary resuscitation; BLS, basic life support.

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Primary results of the trials 

Aung and Htay¹⁶ chose the random effects model to summarize data from the 5 trials they included.²⁹, ³⁰ The random effects model usually leads to wider confidence intervals (CIs) around the pooled result than does the fixed effects model and may be considered “more conservative” for this reason.³¹ Aung and Htay¹⁶ used standard methods to assess for statistical heterogeneity between the results of the included studies. They used the I² statistic to provide an estimate of the percentage of the variability between the results of studies being pooled that is due to true differences between the studies, as opposed to variability due to chance alone.³², ³³ When all 5 trials were included, Aung and Htay¹⁶ report a high degree of heterogeneity for the primary outcome of death before hospital discharge.¹⁶ The χ² test for heterogeneity yielded a P value of .09, which is less than the commonly preferred cutoff of .1. I² was 34%, suggesting a substantial portion of variability between the studies to be due to actual differences.

In our own analysis, using odds ratios for the same outcome and including only the 3 fully reported trials, the P value for heterogeneity was .21, and the I² value was 35%. Most of the heterogeneity is due to a trend in the direction of benefit of vasopressin in the study by Lindner et al,¹⁰ a trend not observed in the studies by Wenzel et al¹¹ and Stiell et al.¹², ¹⁶ A review of the characteristics of the Lindner et al¹⁰ study, compared to the analogous characteristics of the studies by Wenzel et al¹¹ and Stiell et al,¹² (Table 1) fails to reveal consistent differences that would explain this difference in trend. Under the circumstances, pooling of these 3 studies, as elected by Aung and Htay,¹⁶ may reasonably provide a more generalizable result.³⁴

Aung and Htay¹⁶ report a pooled relative risk of death before hospital discharge, vasopressin compared to epinephrine, across the 3 fully reported trials of 0.99 (95% CI 0.95 to 1.02). When the trials by Li et al¹⁸ and Lee et al¹⁷ were included, the relative risk was 0.96 (95% CI 0.87 to 1.05). Our own analysis also used the random effects model and preferred odds ratios to risk ratios because of important inconsistencies between the results when risk ratios were used. Such inconsistencies commonly occur when outcome rates are extremely high, as in cardiac arrest. Our pooled odds ratio for the outcome of predischarge mortality, vasopressin compared to epinephrine, was 0.91 (95% CI 0.52 to 1.57). In all analyses, the CI around the pooled effect included values favoring epinephrine.

Aung and Htay¹⁶ analyzed the effect of vasopressin on death before hospital discharge or neurologic impairment. They grouped patients with only moderate disability together with those who died or were in a persistent vegetative states and included the study by Lee et al¹⁷ with those by Stiell et al¹² and Wenzel et al.¹¹ The Lee et al¹⁷ study contributed substantial heterogeneity to this analysis (I² of 34%).¹⁶ Aung and Htay¹⁶ report a pooled relative risk of death or neurologic impairment, vasopressin compared to epinephrine, of 1.0 (95% CI 0.94 to 1.07).

A disadvantage of the Aung and Htay¹⁶ approach to assessment of neurologic outcome is that a patient with some residual neurologic deficit but still able to engage in part-time employment is grouped with patients who die or survive with major functional or cognitive impairment. To correct for this disadvantage, including data from the 2 trials that used a common measure of outcome, we classified patients in the 2 worst neurologic outcome categories by the cerebral performance instrument ²⁴, ²⁵ used by Stiell et al¹² and Wenzel et al¹¹ as “poor neurologic outcome.” Such patients may have some cognitive function but no independence in activities of daily living. A patient without poor neurologic function by these criteria is at least able to engage in part-time employment in a sheltered environment.²⁵ We believe that this definition of the outcome is more likely to cohere with the values of patients and their families than is that used by Aung and Htay.¹⁶

Using this revised composite outcome of death or major disability, the pooled odds ratio, vasopressin compared to epinephrine, is 1.32, 95% CI 0.82 to 2.14 (Figure 1). We found no important trends with respect to other measures of cognitive function used by Stiell et al¹² and Lindner et al.¹⁰

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• Figure 1. 

  Forest plot of outcome of death or severe disability in the 2 trials using a common measure of neurologic outcome. For each trial, the small square corresponds to the observed odds ratio for predischarge mortality, and the horizontal line defines the 95% CI. An odds ratio of 1, identified by the vertical line, would reflect an identical effect of the 2 drugs. The lowest plot provides the pooled random effects odds ratio and CI. Poor neurologic outcome is defined as a score of 3 or greater on the cerebral performance score.²⁵

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Subgroup analysis 

Wenzel et al¹¹ emphasized an apparent positive effect of vasopressin in decreasing hospital mortality among patients presenting with asystole when advanced life support interventions were initiated. Three trials report data on predischarge mortality in subgroups of patients defined by presenting rhythm at initiation of resuscitation.¹⁰, ¹¹, ¹² Lindner et al’s¹⁰ small trial was confined to patients presenting with ventricular dysrhythmias.

Wenzel et al¹¹ also reported apparent benefit of initial vasopressin over initial epinephrine among patients receiving additional doses of epinephrine after the 2 doses of the study drug provided for in the protocol failed to result in return of spontaneous circulation. Such patients are not prospectively identifiable, nor has this effect been reported in other trials.

Aung and Htay¹⁶ detected no statistically significant difference between subgroups defined by presenting rhythm. Their analysis does not, however, exhaust the issue raised by Wenzel et al¹¹ and others. We conducted a systematic subgroup analysis using published validity criteria (Table 3).³⁵, ³⁶ We confined our consideration of the effect of vasopressin in subgroups to the hypothesis that vasopressin is of benefit in patients with asystole but not in those with ventricular fibrillation. We present the criteria in suggested order of application.

Table 3. Summary of appraisal of presenting rhythm subgroups in 3 randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest based on criteria proposed for evaluation of subgroup analyses in randomized trials.³⁵, ³⁶ The hypothesis of a selective benefit of vasopressin over epinephrine in patients resenting with asystole fails with respect to several criteria.

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Was the subgroup difference suggested by comparisons within rather than between studies? 

When investigators conduct independent trials on different subgroups of patients (eg, one trial includes only patients with asystole, another only patients with ventricular fibrillation), apparent differences in effect between the studies may originate from differences in the study populations other than that hypothesized (differences in comorbidity rather than differences in cardiac rhythm) or in aspects of study design (blinding of clinicians or outcome assessors) rather than from differences in response between the subgroups on whom the investigators focus (ventricular fibrillation versus asystole). The apparently greater benefit of vasopressin in patients with asystole reported by Wenzel et al¹¹ is an example of a “within-study” comparison (both Wenzel et al¹¹ and Stiell et al¹² included patients with ventricular fibrillation and asystole), and this strengthens the hypothesis that the difference in effect may be real.

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Was the magnitude of the subgroup difference large? 

The larger the observed difference in effect between subgroups, the less likely it is to have arisen by chance alone. SDW and QZ performed an exact analysis using a logistic regression model to assess the magnitude and precision of subgroup effects. We believe this method to be more reliable in the setting at hand because exact models are generally preferable, and particularly so when, as here, the data are sparse.

The pooled odds ratio for predischarge mortality of patients treated with vasopressin compared to those treated with epinephrine from our exact inference analysis was 0.43 for the asystole subgroups reported by Wenzel et al¹¹ and Stiell et al,¹² contrasting with 1.00 for the ventricular fibrillation subgroups of all 3 trials. This large difference supports the subgroup hypothesis.

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Was the subgroup difference consistent across studies? 

Wenzel et al¹¹ observed a trend in the direction favoring vasopressin over epinephrine among patients presenting with asystole and a trend in the opposite direction among patients presenting with ventricular fibrillation (and with pulseless electrical activity). In the trial by Stiell et al,¹² the trends in both asystole and ventricular fibrillation subgroups favored epinephrine. The Lindner et al¹⁰ study of patients with ventricular fibrillation observed a trend in favor of vasopressin. Hence, a consistent pattern of subgroup effects does not emerge from the trials to date.

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Was the subgroup difference statistically significant? 

Investigators and authors sometimes contrast a statistically significant difference between treatment and control in one subgroup (such as those with asystole) with the lack of statistical significance in another subgroup (such as those with other presenting rhythms). This, however, misses the important question, can the difference between the apparent effects in different subgroups (asystole versus ventricular fibrillation) be explained by chance?³⁶

Aung and Htay¹⁶ applied a statistical test for heterogeneity to pooled results in each of the 3 rhythm subgroups. This approach is illustrated in simplified form in Figure 2. In both the Aung and Htay¹⁶ analysis and our own, the tests for significance yield P values well above .1 and low values of I², indicating that the observed effect of vasopressin compared to epinephrine in patients with asystole is consistent with a hypothesis of a uniform underlying effect across all rhythm subgroups. This falls short of a direct test of the difference in comparative effect of vasopressin between asystole and other rhythm subgroups. Our own analysis illustrates such a direct test.

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• Figure 2. 

  Forest plot illustrating an indirect approach to testing for statistical significance of differences in subgroup effect. See legend to Figure 1 for the explanation of the plot. Subgroup data are pooled across the 2 studies that included patients with all 3 presenting rhythm subtypes. A statistical test for heterogeneity is applied. The P value of .51 indicates that the effect of vasopressin compared to epinephrine on mortality within these 3 subgroups is consistent with an underlying effect. The I² value of 0 further suggests that all of the observed variation between the subgroups is attributable to chance.

We started our exact analysis by considering the possibility of an interaction between presenting rhythm subgroup and treatment effect. When we found no significant interaction, we repeated the analysis without the interaction term and computed exact tests of the subgroup and treatment main effects. The method was applied to all 3 trials (Figure 3)¹⁰, ¹¹, ¹² and—because this is restricted to within-study comparisons of ventricular fibrillation and asystole subgroups—to the studies by Wenzel et al¹¹ and Stiell et al.¹²

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• Figure 3. 

  Forest plot illustrating the pooled subgroup effects from the analysis. The analysis uses paired and unpaired data pertaining to the asystole and ventricular fibrillation subgroups from the trials by Wenzel et al,¹¹ Stiell et al,¹² and Lindner et al.¹⁰ See legend to Figure 1 for the explanation of the plot. Odds ratios for the effect on mortality of vasopressin compared to epinephrine are pooled within each subgroup. See text for further explanation.

Figure 3 displays the results of our statistical analysis of the subgroup effect. The question we are asking is, can the difference in the odds ratios in the asystole group (0.43) and the ventricular fibrillation group (1.00) be explained by chance? The ratio of these 2 odds ratios is 0.43, and the 95% CI is 0.12 to 1.37. The CI includes 1 and indicates that the difference between the original odds ratios of 0.43 and 1.00 is compatible with chance, ie, it is not statistically significant (P=.18).

The odds ratio for mortality for these 2 subgroups from the 3 trials is 0.87 (95% CI 0.58 to 1.29) favoring vasopressin. As a further control for study effect in the exact model, the ratio of odds ratios of effect on mortality of vasopressin in asystole compared to ventricular fibrillation subgroups in the strictly paired analysis is 0.38 (95% CI 0.11 to 1.22; P=.12), and the odds ratio for mortality in both subgroups combined is 0.95 (95% CI 0.62 to 1.44), both reflecting trends favoring vasopressin.

In summary, when a direct test of statistical significance is applied, the trend toward a mortality benefit of vasopressin compared to epinephrine in patients with asystole is not significantly different from the comparative effect in patients with ventricular fibrillation.

As summarized in Table 3, the remaining criteria for believability of the subgroup hypothesis about vasopressin compared to epinephrine in patients with asystole were not met.

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Applying the evidence 

Returning to our clinical scenario, as the director of emergency medical services and personnel in your region, you must consider a number of issues in deciding whether to upgrade the status of vasopressin in your protocols for patients in cardiac arrest. The recent trial of vasopressin compared to epinephrine received high publicity in the lay press. An editorial accompanying the Wenzel et al¹¹ trial report in the New England Journal of Medicine called for unscheduled conventions of the American Heart Association and the American College of Cardiology to incorporate a recommendation of vasopressin for patients presenting in asystole.³⁷ You consequently may be under some pressure to provide the perceived benefits of the new therapy to the region and may even be identified as the cause of any delay.

Changing regional emergency medical services protocols, however, entails considerable effort and expense, whether or not unscheduled meetings and conferences are required. Your regional emergency medical services committee would have to approve the new protocol, and you would have to administer a training update to all relevant care providers. To justify this effort, you need convincing evidence that a patient-important benefit of vasopressin exists.

We have summarized the data from a well-done meta-analysis and from the 3 fully reported randomized trials and have found no overall effect of vasopressin compared to epinephrine in reducing mortality before discharge. After systematically applying 7 published criteria for evaluation of subgroup analyses in randomized trials of effectiveness, we have concluded that the evidence of an important survival benefit of vasopressin over epinephrine for patients with asystole is not compelling. It also remains unclear whether vasopressin compared to epinephrine improves or worsens neurologic outcomes in survivors.

Our review is subject to the limitations inherent in shortcut reviews.¹ However, a well-done meta-analysis and our own independent analysis all suggest that you may reasonably decide not to change cardiac arrest protocols until new evidence becomes available.

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Critically Appraised Topic (CAT): Does vasopressin in place of epinephrine improve survival to discharge without worsening neurological function in patients with out-of-hospital cardiac arrest? 

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References 

1. Wyer PC , Rowe BH , Guyatt GH , et al.   The clinician and the medical literature (when can we take a shortcut?) . Ann Emerg Med . 2000;36:149–155
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (37 KB)
   • CrossRef
2. Dorian P , Cass D , Schwartz B , et al.   Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation . N Engl J Med . 2002;346:884–890
   • View In Article
   • CrossRef
3. Kudenchuk PJ , Cobb LA , Copass MK , et al.   Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation . N Engl J Med . 1999;341:871–878
   • View In Article
   • MEDLINE
   • CrossRef
4. Guyatt G , Montori V , Devereaux PJ , et al.   Patients at the center (in our practice, and in our use of language) . ACP J Club . 2004;140:A11–A12
   • View In Article
   • MEDLINE
5. Bucher H , Guyatt G , Cook D , et al.   Therapy and applying the results (surrogate outcomes) . In:  Guyatt G ,  Rennie D editor. Users’ Guides to the Medical Literature (A Manual for Evidence-Based Clinical Practice) . Chicago, IL: American Medical Association; 2002;p. 393–413
   • View In Article
6. Vandycke C , Martens P . High dose versus standard dose epinephrine in cardiac arrest (a meta-analysis) . Resuscitation . 2000;45:161–166
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (81 KB)
   • CrossRef
7. Wiley InterScience. The Cochrane library. Available at: http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME. Accessed June 1, 2005.
   • View In Article
8. The Center for Medical Education. Emergency medical abstracts. Available at: http://ccme.org. Accessed June 1, 2005.
   • View In Article
9. American Heart Association . Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care, part 6 (advanced cardiovascular life support) . Circulation . 2000;102(suppl):I86–I166
   • View In Article
   • MEDLINE
10. Lindner KH , Dirks B , Strohmenger HU , et al.   Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation . Lancet . 1997;349:535–537
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (389 KB)
    • CrossRef
11. Wenzel V , Krismer AC , Arntz HR , et al.   A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation . N Engl J Med . 2004;350:105–113
    • View In Article
    • CrossRef
12. Stiell IG , Hebert PC , Wells GA , et al.   Vasopressin versus epinephrine for inhospital cardiac arrest (a randomised controlled trial) . Lancet . 2001;358:105–109
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (86 KB)
    • CrossRef
13. Biondi-Zoccai GGL , Abbate A , Parisi Q , et al.   Is vasopressin superior to adrenaline or placebo in the management of cardiac arrest? a meta-analysis . Resuscitation . 2003;59:221–224
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (261 KB)
    • CrossRef
14. Jacobs I , Finn F . Adrenaline and Vasopressin for Cardiac Arrest (Protocol) (The Cochrane Library) . Chichester, UK: John Wiley & Sons; 2004;
    • View In Article
15. Hogg K. Vasopressin or adrenaline in cardiac resuscitation [BestBETs Web site]. Available at: http://www.bestbets.org/cgi-bin/bets.pl?record=00407. Accessed March 2, 2004.
    • View In Article
16. Aung K , Htay T . Vasopressin for cardiac arrest . Arch Intern Med . 2005;165:17–24
    • View In Article
    • MEDLINE
    • CrossRef
17. Lee CC , Jung YS , Yoon SK , et al.   Vasopressin administration in out-of-hospital cardiac arrest . [abstract] Ann Emerg Med . 2000;36:S91
    • View In Article
18. Li PJ , Chen TT , Zhang JM , et al.   Clinical study on administration of vasopressin during closed chest cardiopulmonary resuscitation . Chinese Crit Care Med . 1999;11:28–31
    • View In Article
19. Hopewell S , McDonald S , Clarke M , et al.   Grey literature in meta-analyses of randomized trials of health care interventions . The Cochrane Database of Methodology Reviews . 2002; Issue 4
    • View In Article
20. Cook DJ , Guyatt GH , Ryan G , et al.   Should unpublished data be included in meta-analyses? . JAMA . 1993;269:2749–2753
    • View In Article
    • MEDLINE
21. McAuley L , Pham B , Tugwell P , et al.   Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? . Lancet . 2000;356:1228–1231
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (78 KB)
    • CrossRef
22. Juni P , Holenstein F , Sterne J , et al.   Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? . Int J Epidemiol . 2002;31:115–123
    • View In Article
    • MEDLINE
    • CrossRef
23. Fergusson D , Laupacis A , Salmi LR , et al.   What should be included in meta-analyses? an exploration of methodological issues using the ISPOT meta-analyses . Int J Technol Assess Health Care . 2000;16:1109–1119
    • View In Article
    • MEDLINE
    • CrossRef
24. Jennett B , Bond M . Assessment of outcome after severe brain damage (a practical scale) . Lancet . 1973;1:480–484
    • View In Article
    • MEDLINE
25. The Brain Resuscitation Clinical Trial II Study Group . A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest (design, methods, and patient characteristics) . Control Clin Trials . 1991;12:525–545
    • View In Article
    • MEDLINE
    • CrossRef
26. Nesbitt LP , Stiell IG , Cousineau D , et al.   Is the cerebral performance category score a valid measure of functional outcome after out-of-hospital cardiac arrest? . Acad Emerg Med . 2005;12:71; [abstract]
    • View In Article
    • MEDLINE
    • CrossRef
27. Feeny D , Farris K , Cote I , et al.   A cohort study found the RAND-12 and Health Utilities Index Mark 3 demonstrated construct validity in high-risk primary care patients . J Clin Epidemiol . 2005;58:138–141
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (152 KB)
    • CrossRef
28. Guyatt G , Cook D , Devereaux PJ , et al.   Therapy . In:  Guyatt G ,  Rennie D editor. Users’ Guides to the Medical Literature (A Manual of Evidence-Based Clinical Practice) . Chicago, IL: American Medical Association; 2002;p. 55–79
    • View In Article
29. Fleiss JL . The statistical basis of meta-analysis . Stat Methods Med Res . 1993;2:121–145
    • View In Article
    • MEDLINE
    • CrossRef
30. DerSimonian R , Laird N . Meta-analysis in clinical trials . Control Clin Trials . 1986;7:177–188
    • View In Article
    • MEDLINE
    • CrossRef
31. Montori V , Guyatt G , Oxman A , et al.   Summarizing the evidence (fixed-effects and random-effects models) . In:  Guyatt G ,  Rennie D editor. Users’ Guides to the Medical Literature (A Manual for Evidence-Based Clinical Practice) . Chicago, IL: American Medical Association; 2002;p. 539–545
    • View In Article
32. Higgins JPT , Thompson SG . Quantifying heterogeneity in a meta-analysis . Stat Med . 2002;21:1539–1558
    • View In Article
    • MEDLINE
    • CrossRef
33. Higgins JPT , Thompson SG , Deeks JJ , et al.   Measuring inconsistency in meta-analyses . BMJ . 2003;327:557–560
    • View In Article
    • CrossRef
34. Montori V , Hatala R , Guyatt G . Summarizing the evidence (evaluating differences in study results) . In:  Guyatt G ,  Rennie D editor. Users’ Guides to the Medical Literature (A Manual for Evidence-Based Clinical Practice) . Chicago, IL: American Medical Association; 2002;p. 547–552
    • View In Article
35. Oxman AD , Guyatt GH . A consumer’s guide to subgroup analyses . Ann Intern Med . 1992;116:78–84
    • View In Article
    • MEDLINE
36. Oxman A , Guyatt G . Summarizing the evidence (when to believe a subgroup analysis) . In:  Guyatt G ,  Rennie D editor. Users’ Guides to the Medical Literature (A Manual for Evidence-Based Clinical Practice) . Chicago, IL: American Medical Association; 2002;p. 553–565
    • View In Article
37. McIntyre KM . Vasopressin in asystolic cardiac arrest . N Engl J Med . 2004;350:179–181
    • View In Article
    • CrossRef
38. Teng EL , Chui HC . The modified Mini-Mental State (3MS) examination . J Clin Psychiatry . 1987;48:314–318
    • View In Article
    • MEDLINE