Vasopressin as First-Line Therapy for Cardiac Arrest: A Review of the Guidelines and Clinical-Effectiveness
From CADTH Technology Overviews, Volume 1, Issue 2, June 2010
[Adapted from Tsakonas E, Spry C. Vasopressin as First-Line Therapy for Cardiac Arrest: A Review of the Guidelines and Clinical-Effectiveness. (Heath Technology Inquiry Service). Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.]
Introduction
Cardiac arrest occurs when mechanical activity of the heart ceases, confirmed by the absence of a detectable pulse, patient unresponsiveness, and apnea, and leads to death if untreated.1-3 An estimated 70% of cardiac arrests occur outside a hospital,1 and 75% of cardiac arrests are caused by electrical or mechanical cardiac dysfunction, primarily due to coronary artery disease.1 The reported incidence of cardiac arrest may vary because of differences in definition and ascertainment.2 A Canadian study of five geographic regions estimated the annual incidence of out-of-hospital cardiac arrest to range from 53 to 59 per 100,000 population.1 Based on this estimate and the relative proportion of cardiac arrests occurring out-of-hospital, there are approximately 27,000 cases of cardiac arrest in Canada each year.
Four types of arrhythmias that may produce pulseless cardiac arrest are ventricular fibrillation (VF), rapid ventricular tachycardia (VT), pulseless electrical activity (PEA), and asystole or cardiac standstill.4 Survival of these arrest rhythms is dependent on the provision of basic and advanced cardiovascular life support (ACLS).4 Vasopressors are pharmacologic interventions that are delivered to cardiac arrest patients intravenously during ACLS, with the objective of enhancing aortic diastolic and coronary perfusion pressure, as well as coronary and cerebral blood flow and oxygen delivery.5 Epinephrine (adrenaline) has been the preferred vasopressor used for resuscitating cardiac arrest patients for several decades; however, vasopressin, an antidiuretic hormone, has been evaluated and recommended as an alternative in recent years.6,7 While there has been some study of the relative effectiveness of these vasopressors (or their combination) in the treatment of the four types of arrhythmias, this issue was identified as a knowledge gap and clinical research priority during the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.8
The dosages of epinephrine and vasopressin that are commonly used in clinical studies are 1 mg/mL and 40 IU, respectively. The cost of a 40 IU dose of vasopressin in Canada is reported to be C$16.12;9 however, it is unclear if there has been a change in this cost in recent years, as there has been a change in the United States.10 The cost of a 1 mg/mL dose of epinephrine ranges from C$0.53 to C$2.61 on some Canadian provincial and territorial formularies.11-13
A review of the most recent clinical evidence on these drugs would be useful for informing decisions regarding their use. The objective of this report is to review current guidelines as well as the most recent clinical evidence for the use of vasopressin versus epinephrine as first-line therapy in the treatment of patients with cardiac arrest.
Objective
The objective of the report is to answer the following research question:
What is the clinical-effectiveness of vasopressin as a first-line therapy versus epinephrine for the treatment of adults in cardiac arrest?
Methods
A limited literature search was conducted on key health technology assessment resources, including Ovid MEDLINE, Ovid Embase, The Cochrane Library (Issue 2, 2009), the University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English- language articles published between 2004 and April 2009. No filters were applied to limit the retrieval by study type.
Results
The literature search yielded 209 citations, as well as 21 references from the grey literature. The initial screening process resulted in the retrieval of 34 reports for further evaluation. The final screening yielded 13 relevant reports including seven guidelines, three systematic reviews (one of which also performed a meta-analysis), two randomized control trials (RCTs), and one observational study. No health technology assessments were identified. The reasons for excluding reports were: the indication was not cardiac arrest; vasopressin was not assessed as a first-line agent; treatment with vasopressin included other agents (e.g., corticosteroids or hydroxyethyl starch) that were not provided similarly to the epinephrine group; not a systematic review; and duplicate report.
The Australian Resuscitation Council (ARC) published guidelines for advanced life support in 2006.14 Their protocol for advanced life support states that 1 mg/mL adrenaline should be administered every three minutes during CPR once intravenous access is obtained. This treatment is recommended for all rhythms and is to be carried out continuously for adult cardiorespiratory arrest or during each loop of the treatment algorithm. The guidelines state that other drugs should be considered depending on the individual circumstances. Vasopressin was listed among the drugs used in resuscitation, and the authors stated that while vasopressin is an alternative vasopressor to adrenaline, there is insufficient evidence to support or refute the use of vasopressin as an alternative to, or in combination with, adrenaline in any cardiac arrest rhythm.
In 2006, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) published guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.3 During ACLS, epinephrine 1 mg/mL intravenous (IV) is to be administered and followed by repeated defibrillation attempts at 360J, and administration may be repeated at three- to five-minute intervals with defibrillator shocks in-between doses. Only one dose of 40 IU IV vasopressin may replace either the first or second dose of epinephrine. This treatment is recommended for all rhythms. The authors note that high-dose epinephrine does not appear to provide added benefit, and evidence for superiority of vasopressin is not clearly established. A level of evidence and grade of recommendation for the use of epinephrine and vasopressin was not specified.
The AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care that were published in 20054 were also based on the evidence evaluation from the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care in collaboration with the International Liaison Committee on Resuscitation (ILCOR). Recommendations for use of vasopressors were the same as those in the ACC/AHA/ESC guidelines.3
The 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care published their evidence review and recommendations for advanced life support in 2005.15 As with the ARC guidelines,14 these guidelines state that no placebo-controlled study had shown that the routine use of any vasopressor at any stage during human cardiac arrest increases survival to hospital discharge. The guidelines also state that current evidence does not support the use of any drug or sequence of drugs, but continued routine use of vasopressors is reasonable. The treatment recommendation was that epinephrine is the standard vasopressor in cardiac arrest, despite the absence of placebo-controlled trials, and there is insufficient evidence to support or refute the use of vasopressin as an alternative to, or in combination with, epinephrine in any cardiac arrest rhythm. Specific recommendations regarding dose and frequency of use of either vasopressor were not provided; however, the dosages for vasopressin and epinephrine that were mentioned in the evidence review were 40 IU and 1 mg, respectively.
Both the European Resuscitation Council 2005 Guidelines for Resuscitation16 and the UK Resuscitation Council guidelines for advanced life support17 were in agreement with the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care15 and the ARC14 regarding evidence, and recommended epinephrine as the first vasopressor used in cardiac arrest of any etiology. One mg/mL adrenaline is to be used intravenously for every three to five minutes of CPR.
The ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (2004)18 recommended that clinicians follow the 2000 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care published by the AHA and ILCOR regarding resuscitation methodology. As in 2005,4 these guidelines recommend that vasopressin 40 IU IV may be substituted for epinephrine 1 mg/mL. In addition, both vasopressin and epinephrine were included among prompt resuscitative measures recommended for the treatment of ventricular asystole.
Systematic reviews and meta-analyses
A 2008 systematic review examined the evidence for the combination of vasopressin and epinephrine versus epinephrine alone for cardiac arrest,19 and included three RCTs. Only two of the studies address the question of using vasopressin first-line, as all patients in the third study received epinephrine first-line. The authors concluded that the combination of vasopressin and epinephrine showed trends toward better return of spontaneous circulation (ROSC) but uncertain effects on survival, and that there is inadequate evidence to advocate the sequential use of vasopressin and epinephrine for cardiac arrest.
A 2005 systematic review of RCTs of vasopressin for cardiac arrest in humans9 identified three RCTs, two of which were identified in the abovementioned 2008 systematic review. All three trials compared vasopressin with epinephrine. One reported better outcomes in patients administered with vasopressin, with survival at 24 hours being statistically significantly higher compared with patients administered with epinephrine. One of the other studies showed no difference in outcomes in patients randomized to receive vasopressin or epinephrine. Subgroup analyses (by cardiac rhythm) showed significantly better survival to hospital admission and survival to hospital discharge in patients administered with vasopressin among asystole patients compared with patients administered with epinephrine. The authors concluded that the evidence for the use of vasopressin in cardiac arrest is indeterminate; either drug could be considered the first-line agent in cardiac arrest, and further research was needed.
A 2005 systematic review and meta-analysis of vasopressin in cardiac arrest20 identified five RCTs of vasopressin versus epinephrine. Three of the trials compared 40 IU IV vasopressin with 1 mg/mL IV epinephrine, while one trial studied IV vasopressin 0.5 U/kg (low dose) or 1.0 U/kg (high dose), and in a fifth trial, the doses of vasopressin and epinephrine were 40 IU and 1 mg, respectively. The authors also conducted three subgroup meta-analyses based on cardiac rhythm (VF or VT, PEA, and asystole) on the outcome of death before hospital discharge and found no important differences between vasopressin and epinephrine groups in any of the three analyses. The authors concluded that their findings demonstrated no clear benefit or evidence of harm for the use of vasopressin versus epinephrine in cardiac arrest, and that guidelines for ACLS should not recommend vasopressin in resuscitation protocols until more solid human data on superiority are available.
A 2004 RCT21 examined vasopressin and epinephrine in out-of-hospital CPR randomized patients. The results of this study have been previously referred to in the three systematic reviews discussed in this report. The authors concluded that effects of vasopressin were similar to those of epinephrine in the management of VF and PEA, but that vasopressin was superior to epinephrine in patients with asystole, and that vasopressin followed by epinephrine may be more effective than epinephrine alone in the treatment of refractory cardiac arrest.
The authors of a 2008 RCT22 of vasopressin and epinephrine versus epinephrine alone in cardiac arrest patients concluded that the combination of vasopressin and epinephrine does not improve outcomes in cardiac arrest, compared with epinephrine alone.
An observational study of the effects of epinephrine and vasopressin on end-tidal carbon dioxide tension (petCO2) and mean arterial blood pressure (MAP) in out-of-hospital CPR in 200723 aimed to compare the values of petCO2 and MAP in patients with cardiac arrest, and to demonstrate that vasopressin contributes to higher petCO2 and MAP values, consequently leading to better patient outcomes.
Average petCO2 and MAP values were higher in the vasopressin group. Neurological outcome was better in the vasopressin group (72% of survivors) compared with the epinephrine group (52% of survivors). Vasopressin was an independent significant predictor of ROSC and hospital admission as well as survival at 24 hours, but not of hospital discharge alive. The authors concluded that petCO2 and MAP are strong predictors for the outcome of out-of-hospital cardiac arrest; that patients treated with vasopressin and epinephrine compared with epinephrine alone have higher petCO2 and MAP values on hospital admission; and that this treatment combination improves ROSC, short-term survival, and neurological outcome.
Limitations
There are a limited number of studies evaluating vasopressin compared with epinephrine alone as first-line therapy in cardiac arrest.
Very few new studies met the inclusion criteria for this report in the three years since guidelines were last updated. There appeared to be little new evidence to challenge the position of international guidelines on the relative effectiveness of vasopressors in cardiac arrest.
There is some question regarding the relevance of the clinical end points chosen in clinical trials,9,24 and better evaluation of more relevant end points such as survival to hospital discharge may require significantly larger sample sizes.
Conclusions
There does not appear to be additional evidence to support the use of a specific vasopressor as first-line therapy during human cardiac arrest. Most of the guidelines reviewed for this report considered the 2005 meta-analysis20 and RCT21 in making their recommendations. The more recent RCT published in 200822 did not provide evidence for the use of vasopressin first line. Information from ongoing and future trials25 may provide additional evidence about the clinical-effectiveness of vasopressin over epinephrine for cardiac arrest patients. In the interim, the decision to use one vasopressor over another may be dependent on clinical opinion and, possibly, cost.
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