Vasopressin, Epinephrine, and Corticosteroids for Inhospital Cardiac Arrest: A Multicenter Randomized Controlled Trial

Background and Rationale Inhospital cardiac arrest still constitutes an important clinical problem with survival to discharge ranging within 0-42% (most common range = 15-20%) (1). Survival after witnessed, pulseless ventricular fibrillation/tachycardia (VF/VT) that is responsive to one or two direct current countershock(s) may exceed 30%. However, survival after inhospital asystole, pulseless electrical activity, or refractory VF/VT (defined as not responsive to two countershocks) may be substantially lower (i.e., 5-10%) (2). As in nonsurvivors, both endogenous vasopressin and adrenocorticotrophin are reduced compared to survivors (3,4), the investigators hypothesize that the addition of exogenous vasopressin during cardiopulmonary resuscitation (CPR) (5) and of steroids during and after CPR may increase the rates of return of spontaneous circulation (ROSC) and improve post-arrest survival. This hypothesis is supported by the single-center results of NCT 00411879. Thus, the investigators intend to either refute or provide definitive evidence supporting this hypothesis (and its generalizability) by conducting the present multicenter, randomized, controlled clinical trial of inhospital cardiac arrest.

Methods Adult in-patients with cardiac arrest not responsive to two direct current countershocks (when applicable), or asystole, or pulseless electrical activity are randomized to receive either arginine vasopressin (20 IU/CPR cycle for the first 5 CPR-cycles in non-VF/VT and from the second to sixth CPR-cycle in VF/VT) plus epinephrine (1 mg/CPR-cycle) plus methylprednisolone (single dose = 40 mg during the first and second CPR-cycle in non-VF/VT and VF/VT, respectively) or normal saline-placebo plus epinephrine (1 mg/CPR-cycle) plus normal saline-placebo during the first 5 or second to sixth CPR-cycles. Further CPR-vasopressor treatment includes epinephrine (1 mg/CPR-cycle) for both groups. Apart from the initial, combined drug administration in the study group, CPR is conducted in full concordance with the 2005 Guidelines for Advanced Life Support (5). Following ROSC and in the presence of postresuscitation shock (defined as inability to maintain mean arterial pressure > 70 mm Hg without using exogenous catecholamines at infusion rates conferring vasopressor and/or inotropic activity), study group patients receive stress-dose hydrocortisone (300 mg/day for a maximum of 7 days and then gradual taper), whereas controls receive saline placebo. Patients with pre-arrest history and clinical features, and/or electrocardiographic, biochemical, and echocardiographic evidence of acute myocardial infarction receive the stress-dose hydrocortisone (study-group) or the saline-placebo (control-group) for a maximum of 3 days, followed by gradual taper.1 This time-limit has been chosen to prevent any potential retardation of infarct healing by glucocorticoid treatment (6).

Following ROSC, control group patients may receive stress dose steroid treatment if prescribed by the attending physician for indications such as septic shock or known adrenocortical insufficiency. This holds also for study group patients during the follow-up period. Any steroid prescription by attending physicians cancels any concomitant investigational interventions regarding steroid supplementation and results in patient exclusion, unless the prescribed corticosteroid regimen is in full concordance with the above-described, protocolized one.

The investigators involved in CPR drug administration are blinded to the use (or no-use) of vasopressin and methylprednisolone, and do not coordinate the CPR procedures. For the study group, steroid treatment is determined by the hospital pharmacies, which are also aware of the computer-based patient randomization and encoding, and prepare the study drugs for CPR.

Patient follow-up and data recording is conducted by associates who are unaware of CPR drug regimens. Daily follow-up to day 60 post-arrest includes physiological variables, medication and other treatment interventions, results of laboratory and diagnostic studies (including serum interleukins for days 1-10), and determination of the sequential organ dysfunction assessment (SOFA) score. For the first 10 days post-randomization, monitored/recorded physiological variables include hemodynamics (arterial and central venous pressure, and heart rate), gas exchange and respiratory mechanics, body temperature, urinary output and fluid balance. Patient neurological status will be assessed with the Glasgow Coma Score. Additional follow-up data will include hospital/intensive care unit (ICU)-related morbidity, length of ICU/hospital stay, and cerebral performance/residual disabilities (7) at hospital discharge.