Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Combined Vasopressin, Methylprednisolone, and Epinephrine for Inhospital Cardiac Arrest

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00411879
Recruitment Status : Completed
First Posted : December 15, 2006
Last Update Posted : January 12, 2016
Sponsor:
Information provided by (Responsible Party):
Spyros D. Mentzelopoulos, University of Athens

Tracking Information
First Submitted Date  ICMJE December 14, 2006
First Posted Date  ICMJE December 15, 2006
Last Update Posted Date January 12, 2016
Study Start Date  ICMJE June 2006
Actual Primary Completion Date April 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 23, 2008)
1) Return of Spontaneous Circulation for > 15 min and 2) Survival to discharge either to home or to a rehabilitation facility. [ Time Frame: 60 days (actual) ]
Original Primary Outcome Measures  ICMJE
 (submitted: December 14, 2006)
  • Return of spontaneous circulation for ≥ 15 min.
  • Survival to discharge either to home or to a rehabilitation facility.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 26, 2007)
  • Sequential Organ Dysfunction Assessment Score during follow-up. Organ failure free days. [ Time Frame: 60 days (actual) ]
  • Neurological status during follow-up. [ Time Frame: 60 days (actual) ]
  • Cerebral performance during follow-up and at discharge. [ Time Frame: 60 days (actual) ]
  • Peri-arrest arterial pressure [ Time Frame: 30 minutes (actual) ]
  • Plasma cytokine concentration [ Time Frame: 7 days (actual) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2006)
  • Sequential Organ Dysfunction Assessment Score during follow-up.
  • Neurological status during follow-up.
  • Cerebral performance during follow-up and at discharge.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combined Vasopressin, Methylprednisolone, and Epinephrine for Inhospital Cardiac Arrest
Official Title  ICMJE Phase 2, Single-Center, Placebo-Controlled Study of the Effects of Combined Administration of Vasopressin, Methylprednisolone, and Epinephrine During Cardiopulmonary Resuscitation on Survival After Cardiac Arrest
Brief Summary A randomized controlled trial did not show benefit of vasopressin versus epinephrine in inhospital cardiac arrest. Preceding laboratory data suggest that combined vasopressin and epinephrine ensure long-term survival and neurologic recovery. Also, postresuscitation abnormalities mimic severe sepsis. The investigators hypothesized that combined vasopressin and epinephrine during cardiopulmonary resuscitation (CPR), and steroid supplementation during and after (when required) CPR may improve survival in cardiac arrest.
Detailed Description

Inhospital cardiac arrest still constitutes an important clinical problem with survival to discharge ranging within 0-42% (most common range = 15-20%). 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 (< 5-10%). As in nonsurvivors, both endogenous vasopressin and adrenocorticotrophin are reduced compared to survivors, we hypothesized that the addition of exogenous vasopressin and steroids to the standard CPR protocol may increase the rates of both the return of spontaneous circulation (ROSC) and of post-arrest survival. The mechanistic basis of this hypothesis comprises the simultaneous activation of adrenergic and vasopressin receptors, in conjunction with a potential steroid-mediated enhancement of the vascular reactivity to epinephrine.

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 (Pitressin, 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 European Resuscitation Council Guidelines. 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. 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.

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 director of the pharmacy of Evaggelismos hospital, who also performs the computer-based patient randomization and encoding, and supervises the preparation of study drugs for CPR.

Patient follow-up and data recording is being conducted by four associates who are unaware of the CPR interventions. Daily follow-up to day 28 post-arrest includes physiological variables, medication and other treatment interventions, results of laboratory and diagnostic studies (including serum interleukins), and determination of the sequential organ dysfunction assessment (SOFA) score. 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 is being assessed with the Glasgow Coma Score. Following successful weaning from mechanical ventilation, cerebral performance is being assessed with the cerebral performance scale. Additional follow-up data 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 during CPR and at 15-20 min following ROSC, the intensity of the post-arrest systemic inflammatory response, 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.

In patients who survived for more than 28 days after the occurrence of the cardiac arrest, it has been ultimately feasible to collect full data on organ failure free days and medication until 60 days following randomization. Consequently, the analysis of the data during April and May 2007, actually enabled the calculation of the organ failure free days, the comparison of the length of the use of various drugs between the two groups, and the construction of survival curves and conduct of Kaplan-Meier analysis and Cox regression analysis until day 60 following randomization.

As in previous cardiac arrest trials, the requirement of informed consent before the administration of the drug combination during CPR has been waived. Informed consent was actually obtained for corticosteroid treatment of postresuscitation shock and for the blood sampling required for determination of plasma cytokine concentration after ROSC.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Heart Arrest
Intervention  ICMJE
  • Drug: Vasopressin, Epinephrine, and Steroids
    During resuscitation, study group patients receive vasopresssin [20 IU IV maximum dose = 100 IU] and methylprednisolone (40 mg IV). Epinephrine is given to both groups according to guidelines for resuscitation 2005. In the study group, postresuscitation shock is treated with stress-dose hydrocortisone.
  • Drug: Placebo, Epinephrine, Placebo
    Epinephrine is given to both groups according to guidelines for resuscitation 2005. Control group patients receive placebo instead of vasopressin and steroids.
Study Arms  ICMJE
  • Placebo Comparator: Control Group
    Patients with refractory cardiac arrest (as defined in methods) treated according to the latest guidelines for resuscitation and receiving placebo instead of vasopressin and corticosteroids
    Intervention: Drug: Placebo, Epinephrine, Placebo
  • Experimental: Study Group
    Patients with refractory cardiac arrest treated with combined vasopressin, epinephrine, and methylprednisolone during resuscitation. Patients receive stress-dose hydrocortisone for postresuscitation shock
    Intervention: Drug: Vasopressin, Epinephrine, and Steroids
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 14, 2006)
100
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2007
Actual Primary Completion Date April 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult in-patients with cardiac arrest requiring epinephrine according to current guidelines.

Exclusion Criteria:

  • Age < 18 years.
  • Documented terminal illness (life expectancy < 6 weeks).
  • Do not resuscitate status.
  • Cardiac arrest before arrival at hospital.
  • Prior enrollment into the study (i.e. second or third inhospital arrest etc.).
  • Corticosteroid treatment before the cardiac arrest.
  • Any inaccurate documentation of CPR data such as medication, number of countershocks etc.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00411879
Other Study ID Numbers  ICMJE 10531-VMA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Spyros D. Mentzelopoulos, University of Athens
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE University of Athens
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Spyros D Mentzelopoulos, Lecturer First Department of Intensive Care Medicine, Univerisy of Athens Medical School
Study Chair: Charis Roussos, Professor First Department of Intensive Care Medicine, Univerisy of Athens Medical School
Study Director: Spyros G Zakynthinos, As Professor First Department of Intensive Care Medicine, Univerisy of Athens Medical School
PRS Account University of Athens
Verification Date January 2016

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