Vasopressin, Epinephrine, and Steroids for Cardiac Arrest
Information source: University of Athens
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cardiac Arrest
Intervention: Vasopressin, Epinephrine, Methylprednisolone, Hydrocortisone (Drug); Standard CPR Protocol with Epinephrine and two Placebos (Drug)
Phase: Phase 3
Status: Completed
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
Summary
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.
Clinical Details
Official title: Vasopressin, Epinephrine, and Corticosteroids for Inhospital Cardiac Arrest: A Multicenter Randomized Controlled Trial
Study design: Allocation: Randomized, 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-randomizationThe 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 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
Eligibility
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
Locations and Contacts
401 General Military Hospital of Athens, Athens, Attica GR-11526, Greece
Evaggelismos General Hospital, Athens, Attica GR-10675, Greece
University General Hospital of Larissa, Larissa, Thessaly GR-41110, Greece
Additional Information
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, Hébert 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. 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. 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: May 16, 2014
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