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Vasopressin, Epinephrine, and Steroids for Cardiac Arrest (VSE-2)

This study has been completed.
Sponsor:
Collaborator:
University of Thessaly
Information provided by (Responsible Party):
Spyros D. Mentzelopoulos, University of Athens
ClinicalTrials.gov Identifier:
NCT00729794
First received: July 31, 2008
Last updated: May 16, 2014
Last verified: May 2014

July 31, 2008
May 16, 2014
September 2008
November 2010   (final data collection date for primary outcome measure)
Return of Spontaneous Circulation for at least 15 min and Survival to Hospital Discharge with or without neurological recovery [ Time Frame: 60 days ] [ Designated as safety issue: No ]
Return of Spontaneous Circulation for at least 15 min and Survival to Hospital Discharge [ Time Frame: 60 days ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00729794 on ClinicalTrials.gov Archive Site
  • 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 [ Time Frame: 30 min to 10 days ] [ Designated as safety issue: No ]
  • The number of organ failure-free days during follow-up [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Complications related to the use of steroids [ Time Frame: 10 days ] [ Designated as safety issue: Yes ]
  • Arterial pressure and gas exchange during CPR and at 15-20 min following return of spontaneous circulation [ Time Frame: 90 min ] [ Designated as safety issue: No ]
  • The number of organ failure-free days during follow-up [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Neurological status and cerebral performance during follow up and at discharge from the hospital [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Complications related to the use of steroids [ Time Frame: 10 days ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Vasopressin, Epinephrine, and Steroids for Cardiac Arrest
Vasopressin, Epinephrine, and Corticosteroids for Inhospital Cardiac Arrest: A Multicenter Randomized Controlled Trial

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.

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.

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. Furthermore, the patients' families are always informed about the trial after the resuscitation procedures. Any next-of-kin objection regarding the trial will result in patient exclusion.

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

Pre-specified subgroup analyses included the effect of study center, and data from patient subgroups defined according to the need for >5mg or =<5 mg of epinephrine during CPR.

Post hoc analyses included within-group control group comparisons according to the actual use or no use of stress dose hydrocortisone (300 mg /day for a maximum of 7 days followed by gradual taper) by attending physicians. Also, patients without "crossover" of the control group were compared to patients of the VSE group. Lastly, following a relative suggestion by the Data Monitoring Committee, we attempted to determine the 1 year survival with good neurological recovery; for this purpose, survivors of both groups (and/or their families) were contacted / interviewed through telephone communication; this was followed by in-person interview/examination of the survivors.

After completion of three years from the last patient data collection on the primary outcomes, the study data will be maintained in de-identified electronic form.

In concordance with a suggestion of a recent Editorial (Intensive Care Med (2014) 40:743-745), the Original and (its minor revision to) the Final Form of the Study Protocol detailing the Pre-specified Study Planning (which explains the reason for any prior changes in the current registration data) can be found at the bottom of the following webpage: http://www.evaggelismos-hosp.gr/0010000688/%CE%B9%CF%83%CF%84%CE%BF%CF%81%CE%B9%CE%BA%CE%BF-%CE%B5%CE%B5%CF%80%CE%BD%CE%B5.html

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Cardiac Arrest
  • Drug: Vasopressin, Epinephrine, Methylprednisolone, Hydrocortisone

    Combination Treatment

    Administration of vasopressin, epinephrine, and methylprednisolone during CPR, and of stress dose hydrocortisone after CPR

  • Drug: Standard CPR Protocol with Epinephrine and two Placebos
    Patients receive advanced life support according to the Guidelines for Resuscitation 2005
  • Experimental: Study Group
    Patients with refractory, inhospital cardiac arrest, i.e., with asystole, pulseless electrical activity, or ventricular fibrillation/pulseless ventricular tachycardia not responsive to two attempts at defibrillation.
    Intervention: Drug: Vasopressin, Epinephrine, Methylprednisolone, Hydrocortisone
  • Placebo Comparator: Control Group
    Patients with refractory, inhospital cardiac arrest, i.e., with asystole, pulseless electrical activity, or ventricular fibrillation/pulseless ventricular tachycardia not responsive to two attempts at defibrillation.
    Intervention: Drug: Standard CPR Protocol with Epinephrine and two Placebos

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
300
November 2010
November 2010   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Greece
 
NCT00729794
VSE-226-2008
Yes
Spyros D. Mentzelopoulos, University of Athens
University of Athens
University of Thessaly
Principal Investigator: Spyros D Mentzelopoulos, MD, PhD University of Athens Medical School, Athens, Greece
Study Director: Spyros G Zakynthinos, MD, PhD University of Athens Medical School, Athens, Greece
Study Chair: Charis Roussos, MD, PhD University of Athens Medical School, Athens, Greece
University of Athens
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP