Vasopressin, Epinephrine, and Steroids for Cardiac Arrest

Condition(s) targeted: Cardiac Arrest

Intervention: Vasopressin, Epinephrine, Methylprednisolone, Hydrocortisone (Drug); Standard CPR Protocol with Epinephrine and two Placebos (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Athens

Official(s) and/or principal investigator(s):
Spyros D Mentzelopoulos, MD, PhD, Principal Investigator, Affiliation: University of Athens Medical School, Athens, Greece
Spyros G Zakynthinos, MD, PhD, Study Director, Affiliation: University of Athens Medical School, Athens, Greece
Charis Roussos, MD, PhD, Study Chair, Affiliation: University of Athens Medical School, Athens, Greece

Overall contact:
Spyros D Mentzelopoulos, MD, PhD, Phone: (01130)-6977465832, Email: sdmentzelopoulos@yahoo.com

The simultaneous activation of adrenergic and vasopressin receptors, in conjunction with a potential steroid-mediated enhancement of the vascular reactivity to epinephrine may have beneficial effects in patients with cardiac arrest. This hypothesis is supported by the single-center results of NCT 00411879. 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 in hospital cardiac arrest.

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

Study design: Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Return of Spontaneous Circulation for at least 15 min and Survival to Hospital Discharge with or without neurological recovery

Secondary outcome:

Arterial pressure and gas exchange during CPR and at 15-20 min following return of spontaneous circulation; hemodynamic status during days 1 to 10 post-randomization

The number of organ failure-free days during follow-up

Complications related to the use of steroids

Detailed description: 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 patient is assigned to the study group and the prescribed corticosteroid regimen is in full concordance with the experimental 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. Following successful weaning from mechanical ventilation, cerebral performance is assessed with the cerebral performance scale (7). Additional follow-up data will include hospital/intensive care unit (ICU)-related morbidity, length of ICU/hospital stay, and cerebral performance/residual disabilities at hospital discharge.

Primary end-points are ROSC for ≥ 15 min, and survival to discharge either to home or to a rehabilitation facility. Secondary end-points include arterial pressure and gas exchange during CPR and at 15-20 min following ROSC, the number of organ failure-free days during follow-up, and neurological status and cerebral performance during follow up and at discharge from the hospital.

As in previous cardiac arrest trials, the requirement of informed consent for the drug combination during CPR has been waived. However, informed consent is actually requested for corticosteroid treatment of postresuscitation shock.

Randomization Technique Randomization will be conducted in blocks of four with the use of the Research Randomizer (www. randomizer. org).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adult patients with refractory inhospital cardiac arrest, defined as epinephrine

requirement for ventricular fibrillation/tachycardia or asystole/pulseless electrical activity according to guidelines for resuscitation 2005 (5).

Exclusion Criteria:

- Age < 18 years

- Terminal illness or do-not resuscitate status

- Cardiac arrest due to exsanguination

- Cardiac arrest before hospital admission

- Pre-arrest treatment with intravenous corticosteroids

- Previous enrollment in or exclusion from the current study

Spyros D Mentzelopoulos, MD, PhD, Phone: (01130)-6977465832, Email: sdmentzelopoulos@yahoo.com

Evaggelismos General Hospital, Athens, Attica GR-10675, Greece; Recruiting
Spyros D Mentzelopoulos, MD, PhD, Phone: (01130)-6977465832, Email: sdmentzelopoulos@yahoo.com
Spyros G Zakynthinos, MD, PhD, Phone: (01130)-210-7201911, Email: szakynthinos@yahoo.com
Sotiris Malachias, MD, Sub-Investigator
Elissavet Stamataki, MD, Sub-Investigator
Nikos Katsios, MD, Sub-Investigator
Anastasios Stathopoulos, MD, Sub-Investigator
Dimitris Kostantopoulos, MD, Sub-Investigator
Andreas Lomaka, MD, Sub-Investigator
Christos N Chamos, MD, Sub-Investigator
Maria Theodoridi, MD, Sub-Investigator
Lucilla Comi, MD, Sub-Investigator
Androula Papastylianou, MD, Sub-Investigator
Helen Ischaki, MD, Sub-Investigator

401 General Military Hospital of Athens, Athens, Attica GR-11526, Greece; Recruiting
Sotiris Sourlas, MD, Phone: (01130)-210-7494000, Ext: 4502, Email: stavrinavg@yahoo.gr
Sotiris Sourlas, MD, Principal Investigator
Aloizos Stavros, MD, Sub-Investigator

University General Hospital of Larissa, Larissa, Thessaly GR-41110, Greece; Recruiting
Epaminondas G Zakynthinos, MD, Phone: (01130)-2410-681264, Email: ezakynth@yahoo.com
Epaminondas G Zakynthinos, MD, PhD, Principal Investigator
Dimosthenis Makris, MD, PhD, Principal Investigator

Related publications:

Sandroni C, Nolan J, Cavallaro F, Antonelli M. In-hospital cardiac arrest: incidence, prognosis and possible measures to improve survival. Intensive Care Med. 2007 Feb;33(2):237-45. Epub 2006 Sep 22. Review.

Stiell IG, Hebert PC, Wells GA, Vandemheen KL, Tang AS, Higginson LA, Dreyer JF, Clement C, Battram E, Watpool I, Mason S, Klassen T, Weitzman BN. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001 Jul 14;358(9276):105-9.

Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care. 2004 Jun;10(3):208-12. Review.

Hékimian G, Baugnon T, Thuong M, Monchi M, Dabbane H, Jaby D, Rhaoui A, Laurent I, Moret G, Fraisse F, Adrie C. Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation. Shock. 2004 Aug;22(2):116-9.

Nolan JP, Deakin CD, Soar J, Böttiger BW, Smith G; European Resuscitation Council. European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support. Resuscitation. 2005 Dec;67 Suppl 1:S39-86. Review. No abstract available.

Shizukuda Y, Miura T, Ishimoto R, Itoya M, Iimura O. Effect of prednisolone on myocardial infarct healing: characteristics and comparison with indomethacin. Can J Cardiol. 1991 Dec;7(10):447-54.

[No authors listed] A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest. Design, methods, and patient characteristics. The Brain Resuscitation Clinical Trial II Study Group. Control Clin Trials. 1991 Aug;12(4):525-45.

Starting date: September 2008
Last updated: August 17, 2010