American Heart Journal
Volume 157, Issue 3 , Pages 488-494.e1, March 2009

Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: Rationale and design

  • Paul S. Myles, MPH, MD

      Affiliations

    • Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Victoria, Australia
    • Academic Board of Anaesthesia and Perioperative Medicine, Monash University, Melbourne, Victoria, Australia
    • Department of Epidemiology and Preventive Medicine, Monash University; Melbourne, Victoria, Australia
    • Australian National Health and Medical Research Council Centre for Clinical Research Excellence in Therapeutics, Melbourne, Victoria, Australia
    • Corresponding Author InformationReprint requests: Paul S. Myles, MPH, MD, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia.
    • ,
  • Kate Leslie, MEpi, MD

      Affiliations

    • Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Victoria, Australia
    • ,
  • Philip Peyton, MBBS, MD

      Affiliations

    • Department of Anaesthesia, Austin Hospital, Heidelberg, Victoria, Australia
    • ,
  • Michael Paech, MB.BS, DM

      Affiliations

    • The School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia
    • ,
  • Andrew Forbes, MSc, PhD

      Affiliations

    • Department of Epidemiology and Preventive Medicine, Monash University; Melbourne, Victoria, Australia
    • ,
  • Matthew T.V. Chan, MB.BS, FANZCA

      Affiliations

    • Department of Anaesthesia, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
    • ,
  • Daniel Sessler, MD

      Affiliations

    • Department of Outcomes Research, The Cleveland Clinic, Cleveland, OH
    • ,
  • Philip J. Devereaux, MD, PhD

      Affiliations

    • Departments of Clinical Epidemiology and Biostatististics and Medicine, McMaster University, Hamilton, Ontario, Canada
    • ,
  • Brendan S. Silbert, MBBS, FANZCA

      Affiliations

    • Department of Anaesthesia, St Vincent's Hospital, Fitzroy, Victoria, Australia
    • ,
  • Konrad Jamrozik, MB.BS, DPhil

      Affiliations

    • School of Population Health & Clinical Practice, University of Adelaide, SA, Australia
    • ,
  • Scott Beattie, MD, PhD

      Affiliations

    • Department of Anaesthesia, University Health Network, Toronto, Ontario, Canada
    • ,
  • Neal Badner, MD, FRCP(C)

      Affiliations

    • Department of Anesthesiology, University of Western Ontario, London, Ontario, Canada
    • ,
  • James Tomlinson, MB.BS, FRACP

      Affiliations

    • Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Victoria, Australia
    • Academic Board of Anaesthesia and Perioperative Medicine, Monash University, Melbourne, Victoria, Australia
    • ,
  • Sophia Wallace, BSc

      Affiliations

    • Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Victoria, Australia
    • ,
  • the ANZCA Trials Group

Received 30 September 2008; accepted 25 November 2008.

Background

Globally there are >200 million major surgical procedures undertaken annually, and about 20% of these involve patients who have coronary artery disease. Many receive nitrous oxide, which impairs methionine synthase, thus inhibiting folate synthesis and increasing postoperative homocysteine levels. Nitrous oxide anesthesia leads to postoperative endothelial dysfunction, and there is some evidence that it increases myocardial ischemia and, possibly, myocardial infarction. We have initiated the Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial to test the hypothesis that in inpatients undergoing anesthesia for major noncardiac surgery, avoidance of nitrous oxide will reduce the incidence of death and major cardiovascular events.

Methods

ENIGMA-II is a 7,000-patient, international randomized trial involving patients at risk of coronary artery disease undergoing noncardiac surgery. The patients, health care providers (except for the anesthesiologists), data collectors, and outcome adjudicators are blinded to whether patients receive nitrous oxide–containing or nitrous oxide–free anesthetic. The primary outcome is a composite of death and major nonfatal events (ie, myocardial infarction, cardiac arrest, pulmonary embolism, and stroke) at 30 days after surgery.

Results

At present, ENIGMA-II has randomized >1,000 patients in 22 hospitals in 5 countries. To date, patients' mean age is 70 years, 66% are men, 38% have a history of coronary artery disease, 19% have a history of cerebrovascular disease, and 84% have a history of hypertension. Most patients have undergone intra-abdominal 28%, vascular 32%, and orthopedic 16% surgery.

Conclusions

The ENIGMA-II Trial will be the largest study yet conducted to ascertain the benefits and risks of removing nitrous oxide from the gas mixture in anesthesia. The results of this large international trial will guide the clinical care of the hundreds of millions of adults undergoing noncardiac surgery annually.

 

 Trial Registration: www.clinicaltrials.gov CT00430989.

 For ENIGMA-II Trial Organization and a list of committees see Appendix A, available online.

PII: S0002-8703(08)01038-7

doi:10.1016/j.ahj.2008.11.015

American Heart Journal
Volume 157, Issue 3 , Pages 488-494.e1, March 2009

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