Does Vasopressin Improve Survival?

The American Heart Association (AHA) has estimated that the probability of survival diminishes 7%-10% for each minute an individual is in a state of ventricular fibrillation (VF) sudden cardiac arrest (SCA).1 If ventricular fibrillation is not reversed, the heart progresses into a state of asystole.1 Survival from asystolic cardiac arrest is estimated to be approximately 2%.2 Historically, survival rates from SCA have been reported to range between 1% and 30%, depending on the circumstances of the event.3,4 Put into context, SCA claims approximately 250,000 lives per year in the United States.5 The poor outcome of SCA patients drives the continuous research, development and implementation of new therapeutic approaches in emergency cardiac care.

     In 2000, the AHA Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care incorporated the addition of vasopressin in conjunction with current acceptable therapeutic interventions.6 This systematic review and meta-analysis utilized an evidence-based medicine (EBM) methodology to evaluate the existing clinical evidence toward assessing whether vasopressin improved survival in the setting of adult SCA.

Background

     Victims of SCA present with two major categories of electrical heart activity observed on electrocardiogram: shockable and nonshockable rhythms. The shockable rhythm category includes ventricular fibrillation and pulseless ventricular tachycardia. These are classified as shockable because the definitive treatment is direct-current shock (defibrillation). Pharmacological interventions are initiated if defibrillation is not initially successful. The nonshockable rhythm category includes asystole and pulseless electrical activity (PEA). These rhythms are not shockable and are treated with pharmacological or other invasive interventions.

     The AHA has established treatment algorithms for each rhythm disturbance.6 The Comprehensive Emergency Care Algorithm outlines the treatment guidelines for patients in sudden cardiac arrest. There are specific treatment guidelines for subclassifications of rhythm disturbances of sudden cardiac arrest (pulseless ventricular fibrillation/ventricular tachycardia, asystole and PEA). Therapeutic interventions are classified based on the level of evidence and critical appraisal. The current scheme for the classification of therapeutic interventions includes Class I (excellent intervention), Class IIa (good to very good intervention), Class IIb (fair to good intervention), Class Indeterminate (preliminary research stage) and Class III (an unacceptable intervention).

     Prior to the publication of the AHA's Guidelines 2000, the first-line pharmacological intervention for cardiac arrest patients was epinephrine. With publication of the Guidelines 2000, the addition of vasopressin was incorporated into the ventricular fibrillation/ventricular tachycardia treatment algorithm (Class IIb) only. Insufficient evidence establishing the effectiveness of vasopressin versus epinephrine in asystolic and PEA categories of cardiac arrest resulted in the decision to exclude the drug in those treatment algorithms (Class Indeterminate). Additionally, epinephrine was reclassified as Class Indeterminate in all cardiac arrest treatment algorithms due to insufficient clinical data; however, it still remains incorporated in the treatment protocols.

     Epinephrine, a naturally occurring catecholamine, is a á1, â1, and â2 adrenergic agonist.7 In cardiac arrest, the á1 agonist action of epinephrine causes peripheral vasoconstriction,7 which is desirable during cardiopulmonary resuscitation because it improves cerebral perfusion, coronary perfusion and VF median frequency (increases response to defibrillation).7-11 The â1 effects include increased heart rate (chronotropic), contractility (inotropic) and conduction (dromotropic).7 The consequences of â1 stimulation include increased myocardial workload and reduced endocardial perfusion with a net increasing oxygen demand.7,10 The standard dosage of epinephrine is 1 mg intravenous push (IVP) every 3-5 minutes for patients in cardiac arrest.10,12 Epinephrine is conveniently packaged in a prefilled syringe of 1 mg per 10 ml normal saline, at an average price of $2.59.

     Vasopressin (also known as anti-diuretic hormone) is a naturally occurring peptide hormone released from the posterior pituitary.13 Laboratory and clinical studies have revealed increased concentrations of endogenous (arginine) vasopressin during and after sudden cardiac arrest.14-16 In higher dosages needed for its anti-diuretic effect, vasopressin stimulates smooth-muscle V1 receptors, resulting in peripheral vasoconstriction.14, 17 Lindner et al. demonstrated that endogenous (arginine) vasopressin raised arterial and coronary pressures, in addition to increasing both myocardial and cerebral blood flow when compared with the effects of the standard doses (1 mg IVP) of epinephrine in experimental porcine models.18 Experimental data imply that the vasoconstrictive results of vasopressin are similar to the á1 results of epinephrine and produce similar desirable effects. Unlike epinephrine, vasopressin does not have â-adrenergic activity and therefore does not cause an increase in myocardial oxygen consumption.14,17 The half-life of vasopressin is approximately 10-20 minutes, compared to the 3-5-minute half-life of epinephrine.14,17 The standard dosage of vasopressin is 40 units IVP, one-time dose, for patients in cardiac arrest.19 Vasopressin is packaged in single-dose vials with 20 units in 1 ml at an average price of $6.99.

Methodology

     A search of existing world literature for peer-reviewed clinical trials was conducted. Cochrane EBM, Medline, ACP Journal Club, CDSR, DARE and CCTR databases were searched for the period of January 1, 1996, through January 1, 2005, using text terms epinephrine or adrenaline and vasopressin and cardiac arrest or sudden cardiac arrest. Pertinent references from clinical and reference textbooks published after 2000 were also reviewed. The search resulted in a total of 24 studies.

     To be considered for inclusion, the studies had to compare the administration of vasopressin versus epinephrine against either return of spontaneous circulation (ROSC) or survival to admission (first end-point) and survival to discharge including neurological outcome (second end-point). The studies needed to be in the setting of adult (>16 years of age) medical cardiac arrest patients. The randomized groups were similar in age, medical history and SCA consequences and presentation. Classification of presenting ECG rhythm type and other interventions performed before and after administration of pharmacologic agents was compared to ensure homogeneity of each group. Exclusion factors included patients with terminal illness, the presence of a do-not-resuscitate (DNR) order, and nonmedical cardiac arrest (hemorrhagic shock and traumatic cardiac arrest). Animal studies and studies evaluating extended survival of vital organs for donation were additionally excluded.

     A meta-analysis was performed on the population from acceptable trials utilizing the statistical mean as the basis of comparison. Relative benefit increase (RBI), absolute benefit increase (ABI) and number needed to treat (NNT) parameters were chosen to describe the effects of treatment as endorsed by evidence-based medicine and the American College of Physicians' Journal Club.20 RBI, ABI and NNT measures including 95% confidence intervals (CI) were calculated in accordance with Sackett et al.19 The primary outcomes are defined as survival to discharge and survival to admission. Survival to admission is considered due to the relative importance of this indicator, especially in the out-of-hospital setting, where a large percentage of sudden cardiac arrests occur.

Results

     Three studies fulfilled the stated search criteria. Each study demonstrated a homogeneous group of patients as noted by comparing patient age, medical history and circumstances of SCA. Within each study, the patient groups were treated similarly as demonstrated by the time to treatment, length of treatment time and additional therapeutic intervention. There was no evidence of adverse outcomes in any of the studies.

     The first human study was conducted by Lindner et al.21 in response to animal data, research hypothesis and human experience that suggested vasopressin might have beneficial effects in humans. In this double-blinded, randomized prehospital study, 40 patients in ventricular fibrillation SCA were randomized into epinephrine (n=20) and vasopressin (n=20) groups. The epinephrine group received 1 mg boluses intravenously and the vasopressin group received 40-unit intravenous boluses. If the patient did not respond to the initial drug (return of spontaneous circulation), the patient was then given epinephrine, 1 mg every 3-5 minutes, until either resuscitation was successful or efforts were ceased. Of the 20 patients randomized to the vasopressin group, 14 (70%) survived to admission and eight (40%) survived to discharge with an average Glasgow Coma Scale (GCS) of 10.7 compared to the 20 patients randomized to the epinephrine group, of which seven (35%) survived to admission and three (15%) survived to discharge with an average GCS of 11.7. None of the 40 patients were lost to follow-up. The results of the study are summarized in Table I.

     The second study by Stiell et al. was larger in size, comprised of 200 patients.22 This study was a triple-blinded, randomized controlled study performed in-hospital (emergency department, critical care unit or general ward) on adult SCA patients. Patients were randomized to receive one of the two drugs as their initial vasopressor drug. The epinephrine group received 1 mg IV; the vasopressin group received 40 units IV. If the patient did not respond to the initial drug (ROSC), the patient was then given epinephrine, 1 mg every 3-5 minutes, until either resuscitation was successful or efforts were ceased.

     A total of 324 patients were assessed for inclusion in the study, of which 124 patients were excluded (predefined exclusion criteria were the same as the other study's), leaving a total of 200 patients included in the analysis. Of the 96 patients randomized to the vasopressin group, 40 (39%) survived to admission and 12 (12%) survived to discharge with an average Mini Mental Status (MMS) of 36, compared to the 104 patients randomized to the epinephrine group, of which 34 (35%) survived to admission and 13 (14%) survived to discharge with an average MMS of 35. None of the 200 patients were lost to follow-up. Results of the Stiell et al. study are summarized in Table I.

     The third and most recent study by Wenzel et al. was a multi-country, multi-center, double-blind, prospective, randomized, controlled study.23 For statistical significance, the required sample size was calculated to be a minimum of 571 patients in each treatment group.24 Patients included in the study were adult (>18 years of age) victims of out-of-hospital SCA. Patients with terminal illness, the presence of a do-not-resuscitate order, hemorrhagic shock, pregnancy, traumatic cardiac arrest or a lack of IV access were excluded, as were patients who converted by defibrillation without trial drug initiation. Patients were randomized to receive one of the two drugs as their initial vasopressor drug. The epinephrine group received 1 mg IVP; the vasopressin group received 40 units IVP. Patients who did not respond to the initial trial drug (ROSC) were then given a repeat dosage of the same trial drug. If the patient did not respond to the second dosage of the trial drug, he/she was then given epinephrine, 1 mg every 3-5 minutes, until either resuscitation was successful or efforts were ceased.

     A total of 1,219 patients were enrolled in the study, of which 33 patients were excluded due to missing data, leaving a total of 1,186 patients included in the analysis. Of the 589 patients randomized to the vasopressin group, 214 (36.3%) survived to admission and 57 (9.9%) survived to discharge, with 16 patients discharged with good cerebral performance, compared to the 597 patients randomized to the epinephrine group, of which 186 (31.2%) survived to admission and 58 (9.9%) survived to discharge, with 15 patients discharged with good cerebral performance. A total of 43 patients were lost to follow-up. The results of the Wenzel et al. study are summarized in Table I.

     A meta-analysis was performed on the data from the three trials. A combined total of 1,426 patients were included from the three studies. Of the total number of patients, 705 were randomized to the vasopressin group and 721 were randomized to the epinephrine group. The patient data as a whole demonstrate a homogeneous group of patient characteristics prior to the trial as noted by patient age, medical history and circumstances of SCA. Comparing each study to one another, each patient group was treated similarly, as demonstrated by the time to treatment, length of treatment time and additional therapeutic interventions. The statistical mean for survival to admissions between vasopressin and epinephrine is 38.0% versus 31.5%, respectively. The statistical mean for survival to discharge between vasopressin and epinephrine is 10.9% versus 10.3%, respectively (Table II). Relative benefit increase for survival to admissions between vasopressin and epinephrine is 20.6%, (95% CI 4.6% to 39.3%). Absolute benefit increase for survival to admissions between vasopressin and epinephrine is 5.5% (95% CI 0.6% to 10.4%). Number needed to treat to realize one benefit event, survival to admission, is 18 (95% CI 10 to 167). Relative Benefit Increase for survival to discharge between vasopressin and epinephrine is 5.8% (95% CI 21% to 43.9%). Absolute benefit increase for survival to discharge between vasopressin and epinephrine is 0.6% (95% CI 0.0% to 3.8%). Number needed to treat to realize one benefit event, survival to discharge, is 167 (95% CI 26 to infinity).

Discussion

     When considering the outcomes of cardiac arrest it is important to understand the ramifications of resuscitation. Survival to admission with subsequent death is a clinical failure. Survival to admission is an end-point for prehospital providers and may be viewed as an entry point for definitive care. Survival to discharge without neurological sequelae is the clinical goal. Survival to discharge with neurological impairment may be considered undesirable for many reasons, e.g., diminished quality of life, cost associated with long-term care, etc. Sudden cardiac arrest is a dire situation that historically has resulted in poor outcomes. Initiation of the best treatment options is critical, as the opportunity to treat is limited by the very nature of the patient's condition. Cerebral and myocardial hypoxia severely restrict the time interval the clinician has to effectively resuscitate the patient. Critical review of clinical trials is paramount in understanding the true effects of the therapy under investigation.

     The Lindner et al. study demonstrated a greater percentage of the vasopressin group survived to admission and discharge.21 Neurological outcome for the vasopressin group was comparable to the epinephrine group. Due to the study size, the results are inconclusive with regard to equivalency or superiority, but demonstrated the efficacy for larger-scale testing.

     In contrast to the Lindner study, the larger Stiell et al. study concluded that there was no difference between the vasopressin group and the epinephrine group with respect to either hospital admissions or hospital discharge (including neurological outcome).22 Additionally, there were no differences in subgroup analysis (initial ECG rhythm, cause of cardiac arrest or age). There were no differences in adverse outcomes between the two groups. Although this study was larger, 200 patients versus 40, a much larger sample size would be required for statistical significance.

     Similar to the Stiell study, the Wenzel et al. study concluded that, in general, there was no difference between the vasopressin group and the epinephrine group with respect to either hospital admissions or hospital discharge (including neurological outcome).23 There were no differences in adverse outcomes between the two groups. Unlike the Lindner and Stiell studies, based on Wenzel's sample size for each treatment group, the resulting data are considered statistically significant.

     The results of the meta-analysis do not support the position that vasopressin improves survival to admission or survival to discharge for adult patients in sudden cardiac arrest. Relative benefit increase (RBI) and Absolute benefit increase (ABI) figures are low, indicating nominal benefit. Number needed to treat (NNT) for survival to admission, although it appears promising, must be tempered with the fact that survival to discharge is the primary objective. NNT demonstrates nominal benefit to survival to discharge, especially when considering the 95% CI of 26 to infinity.

     Three findings identified by Wenzel et al. deserve additional discussion. An increase in hospital admission and discharge for patients who initially received vasopressin and subsequently received additional treatment with epinephrine was identified post-hoc (see Table III), and a subgroup analysis post-hoc identified an increase in hospital admission and discharge for asystolic patients who received vasopressin (Table IV) or vasopressin and epinephrine (Table V). RBI, ABI and NNT were calculated for each subgroup to evaluate the effects of treatment (Tables III, IV and V).23,25

     The first subgroup finding, an increase in hospital admission and discharge for patients who initially received vasopressin and subsequently received additional treatment with epinephrine, included a total of 732 patients, 373 randomized to the vasopressin plus epinephrine group and 359 randomized to the epinephrine group (Table III). The statistical mean for survival to admission between vasopressin plus epinephrine and epinephrine is 25.7% versus 16.4%, respectively. The statistical mean for survival to discharge between vasopressin plus epinephrine and epinephrine is 6.2% versus 1.7%, respectively. RBI, ABI and NNT values indicate potential benefit. A NNT of 22 (14 to 59) is optimistic when considering the number of SCA incidents per year in the U.S. and worldwide. In contrast to Wenzel et al., of the 200 patients in the Stiell et al. study, 87% of the vasopressin group and 81% of the epinephrine group received epinephrine (second drug or additional drug) with no difference in survival to admission or discharge.22

     The second subgroup finding, an increase in hospital admission and discharge for asystolic patients who received vasopressin versus epinephrine, included a total of 528 patients, 262 randomized to the vasopressin group and 266 randomized to the epinephrine group (Table IV). The statistical mean for survival to admission between vasopressin and epinephrine is 29.0% versus 20.3%, respectively. The statistical mean for survival to discharge between vasopressin plus epinephrine and epinephrine is 4.7% versus 1.5%, respectively. A 95% CI for RBI, ABI and NNT indicates the large variability of potential benefit. Of the 16 patients who survived to discharge, neurological outcome (ranging from no neurologic deficits to coma) was disappointing. Only one patient from the vasopressin group had excellent neurological outcome (no neurologic deficit), while no patients from the epinephrine group had excellent neurological outcome.23 Neurological outcome interpretations are difficult because the study was not designed specifically for this subgroup and end-point.26-28 Additional analysis is required to identify variables that might explain the disappointing neurological outcomes.28,29

     Within the first and second subgroups, a finding relative to asystolic cardiac arrest and patients who received vasopressin plus epinephrine was identified (Table V). An increase in hospital admission and discharge for asystolic patients who received vasopressin plus epinephrine versus epinephrine included a total of 371 patients, 187 randomized to the vasopressin plus epinephrine group and 184 randomized to the epinephrine group. The statistical mean for survival to admission between vasopressin and epinephrine is 22.5% versus 13.3%, respectively. The statistical mean for survival to discharge between vasopressin plus epinephrine versus epinephrine is 3.8% versus 0.0%, respectively. Although ABI is relatively small, NNT is again optimistic, considering the number of SCA incidents per year in the U.S. and worldwide. Again, neurological outcome interpretation is difficult because the study was not designed specifically for this subgroup and end-point.26-28 Additional analyses are required to identify variables that might explain the disappointing neurological outcomes.28, 29

     These findings have sparked controversy in the resuscitation community as to their implications and what future actions should be taken.25-30 Although promising, a large randomized, prospective controlled study specific to the above subgroups must be performed before any conclusions can be established.28,30

Conclusion

     Vasopressin does not improve survival outcomes in cardiac arrest. There is no difference between vasopressin and epinephrine with respect to either hospital admissions or hospital discharge (including neurological outcome) for victims of sudden cardiac arrest. Although vasopressin is not superior to epinephrine, vasopressin is a safe alternative vasopressor. AHA classification of vasopressin for ventricular fibrillation/ventricular tachycardia is appropriate at Class IIB (acceptable, safe and useful).

Recommendations

     AHA should add vasopressin to the asystolic and PEA treatment guidelines as an alternative with the classification of Class Indeterminate (no harm, possible benefit, insufficient data). Additional prospective studies are required to establish vasopressin's superior efficacy in the treatment of asystolic cardiac arrest and in combination with epinephrine for treatment of refractory cardiac arrest.

Postscript

     Research for this manuscript was conducted in November 2004, with the subsequent manuscript being generated in December 2004. On November 28, 2005, the American Heart Association released its 2005 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. One of several major changes in the guidelines is the consolidation of the ventricular fibrillation/pulseless ventricular tachycardia algorithm with the asystole and pulseless electrical activity algorithms into one concise pulseless arrest algorithm. This revised guideline and algorithm recommends the use of a single dose of vasopressin, either as an initial pharmacologic treatment or secondary to epinephrine in the management of VF or pulseless VT. Additionally, the guideline and algorithm recommends the use of a single dose of vasopressin, again as either an initial or secondary pharmacologic treatment in the management of asystole and PEA. The AHA has concluded that although the current data regarding vasopressin do not indicate an improved survival to discharge, vasopressin is an acceptable alternative to epinephrine in the treatment of VF, pulseless VT, asystole and PEA. The revisions to these guidelines and conclusions made by the AHA are consistent with the conclusions and recommendations of this manuscript.32,33

Glossary

     Relative benefit increase (RBI): The proportional increase in rates of good outcome between experimental and control patients in a trial, calculated as |EER-CER|/CER, and accompanied by a 95% confidence interval (CI).31

     Absolute benefit increase (ABI): The absolute arithmetic difference in rates of good outcome between experimental and control patients in a trial, calculated as |EER-CER|, and accompanied by a 95% confidence interval (CI).31

     Number needed to treat (NNT): The number of patients who need to be treated to achieve one additional good outcome, calculated as 1/ARR and accompanied by a 95% confidence interval (CI).31

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Acknowledgements: The author wishes to thank Louise Lee, PA-C, Physician Assistant Program Director; Gale Furey, MS, PA-C, Academic Coordinator and Assistant Professor, Physician Assistant Studies; and his advisor, Steve Steiner, PA-C, Instructor, Physician Assistant Studies, Massachusetts College of Pharmacy and Health Sciences, Physician Assistant program, Manchester, NH, for their guidance and support.

Tony Pellegrino, PA-S, NREMT-P, MBA, is currently a physician assistant student (MPAS) at the Massachusetts College of Pharmacy and Health Science (MCPHS) in Manchester, NH. Prior to MCPHS, he held various positions in the medical device industry as a program manager and product manager, as well as vice president of a regional ambulance company and paramedic. He works part-time as a field paramedic with the town of Billerica (MA) Emergency Medical Services. He is an American Heart Association ACLS, BCLS and PALS instructor and member of the FEMA MA-1 DMAT team based at Massachusetts General Hospital in Boston, MA. Contact him at anthony.pellegrino@stu.mcphs.edu.