Clinical trial NCT00430989: The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial
Official title: Large, Randomised, Parallel-group, Controlled Trial, With Patients Randomly Allocated to Either N2O-containing (70% N2O in Oxygen [FiO2 0.3]) or N2O-free (70% Nitrogen in Oxygen [FiO2 0.3]).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Coronary Artery Disease
Keywords: Anaesthesia
Major Surgery
Coronary artery disease
Nitrous oxide
Effects of Nitrous Oxide following Anaesthesia
Anaesthesia and coronary artery disease
Lead sponsor: Bayside Health
Sponsor class: OTHER_GOV
Collaborators: name: National Health and Medical Research Council, Australia
First posted: 2007-02-02
Enrollment: 7112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery.
Primary purpose: TREATMENT

Brief summary: To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors for coronary artery disease undergoing major surgery.

Detailed description: Approximately 25% of patients undergoing major surgery have known coronary artery disease (CAD) or risk factors for CAD.

N2O interferes with vitamin B12 and folate metabolism. This impairs production of methionine (from homocysteine), used to form tetrahydrofolate and thymidine during DNA synthesis. It has been repeatedly demonstrated that N2O anaesthesia increases postoperative homocysteine levels. Chronic hyperhomocysteinaemia is associated with cardiovascular disease, and acute hyperhomocysteinaemia is known to cause endothelial dysfunction. One small trial has demonstrated an increased incidence of postoperative myocardial ischaemia in patients receiving N2O anaesthesia. Reducing postoperative myocardial infarction and death are important aims for those with CAD undergoing major surgery.

Our previous trial (ENIGMA) studied 2050 patients and identified some serious adverse effects, but most patients were not at risk of CAD and so we could not reliably assess serious cardiac complications. We propose a large simple randomized clinical trial of 7,000 patients to provide a definitive evaluation of the safety of N2O anaesthesia.

Updated statistical analysis plan can be found at www.enigma2.org.au.

Eligibility criteria: Inclusion Criteria

1. Adult males and females age ≥ 45 years, undergoing noncardiac surgery and general anaesthesia expected to exceed two hours.
2. At increased risk of cardiac events, defined as any of

   1. history of coronary artery disease as defined by a history of any one of the following: i. angina ii. MI iii. segmental wall motion abnormality on echocardiography or a fixed defect on radionuclide imaging iv. a positive exercise stress test for cardiac ischaemia v. a positive radionuclide exercise, echocardiographic exercise, or pharmacological cardiovascular stress test for cardiac ischaemia vi. coronary revascularization (CABG or PTCA) vii. angiographic evidence of atherosclerotic stenosis \> 50% of the diameter of any coronary artery viii. ECG with pathological Q waves in two contiguous leads
   2. heart failure
   3. cerebrovascular disease thought due to atherothrombotic disease
   4. aortic or peripheral vascular disease
   5. or three or more of the following risk factors:

      * age ≥70 years
      * any history of congestive heart failure
      * diabetes and currently on an oral hypoglycaemic agent or insulin therapy
      * current treatment for hypertension
      * preoperative serum creatinine \>175 micro mol/L (\> 2.0 mg/dl)
      * current or previous high cholesterol ≥6.2 mmol/L (\> 240 mg/dl)
      * history of a transient ischemic attack (TIA) (i.e. a transient focal neurological deficit that lasted less than 24 hours and thought to be vascular in origin)
      * emergency/urgent surgery (i.e. surgery which must be undertaken within 24 hours of acute presentation to hospital)
      * high-risk type of surgery (i.e. intrathoracic or intraperitoneal)

Exclusion Criteria

1. having cardiac surgery
2. marked impairment of gas-exchange expected to require Fi02\> 0.5 intraoperatively
3. specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure) or the anaesthetist plans to use supplemental oxygen (eg. colorectal surgery)
4. N2O unavailable for use.

Primary outcomes:
measure: The Primary Endpoint is a Composite of Death and Cardiovascular Events (Clinical and Silent MI, Cardiac Failure, Cardiac Arrest, Pulmonary Embolism, and Stroke) Measured at 30 Days After Surgery.
timeFrame: 30 days post op
Secondary outcomes:
measure: Myocardial Infarction (MI)
timeFrame: 30 days post op
measure: Cardiac Arrest
timeFrame: 30 days
measure: Pulmonary Embolism
timeFrame: 30 Days Post op
measure: Stroke
timeFrame: 30 Days Post op
measure: Wound Infection
timeFrame: 30 Days Post op
measure: Hospital Stay (Days)
timeFrame: 30 Days Post Op
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Alfred Hosptial
state: Victoria
Study officials:
affiliation: The Alfred
name: Paul S Myles, MBBS MPH MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beattie WS, Wijeysundera DN, Chan MTV, Peyton PJ, Leslie K, Paech MJ, Sessler DI, Wallace S, Myles PS, Galagher W, Farrington C, Ditoro A, Baulch S, Sidiropoulos S, Bulach R, Bryant D, O'Loughlin E, Mitteregger V, Bolsin S, Osborne C, McRae R, Backstrom M, Cotter R, March S, Silbert B, Said S, Halliwell R, Cope J, Fahlbusch D, Crump D, Thompson G, Jefferies A, Reeves M, Buckley N, Tidy T, Schricker T, Lattermann R, Iannuzzi D, Carroll J, Jacka M, Bryden C, Badner N, Tsang MWY, Cheng BCP, Fong ACM, Chu LCY, Koo EGY, Mohd N, Ming LE, Campbell D, McAllister D, Walker S, Olliff S, Kennedy R, Eldawlatly A, Alzahrani T, Chua N, Sneyd R, McMillan H, Parkinson I, Brennan A, Balaji P, Nightingale J, Kunst G, Dickinson M, Subramaniam B, Banner-Godspeed V, Liu J, Kurz A, Hesler B, Fu AY, Egan C, Fiffick AN, Hutcherson MT, Turan A, Naylor A, Obal D, Cooke E; ANZCA Clinical Trials Network for the ENIGMA-II Investigators. Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. Anesth Analg. 2018 Nov;127(5):1118-1126. doi: 10.1213/ANE.0000000000003310.
citation: Corcoran T, Kasza J, Short TG, O'Loughlin E, Chan MT, Leslie K, Forbes A, Paech M, Myles P; ENIGMA-II investigators. Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX). Br J Anaesth. 2017 Feb;118(2):190-199. doi: 10.1093/bja/aew446.
citation: Chan MT, Peyton PJ, Myles PS, Leslie K, Buckley N, Kasza J, Paech MJ, Beattie WS, Sessler DI, Forbes A, Wallace S, Chen Y, Tian Y, Wu WK; and the Australian and New Zealand College of Anaesthetists Clinical Trials Network for the ENIGMA-II investigators. Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial. Br J Anaesth. 2016 Dec;117(6):801-811. doi: 10.1093/bja/aew338.
citation: Myles PS, Leslie K, Chan MT, Forbes A, Peyton PJ, Paech MJ, Beattie WS, Sessler DI, Devereaux PJ, Silbert B, Schricker T, Wallace S; ANZCA Trials Group for the ENIGMA-II investigators. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014 Oct 18;384(9952):1446-54. doi: 10.1016/S0140-6736(14)60893-X.
citation: Myles PS, Leslie K, Peyton P, Paech M, Forbes A, Chan MT, Sessler D, Devereaux PJ, Silbert BS, Jamrozik K, Beattie S, Badner N, Tomlinson J, Wallace S; ANZCA Trials Group. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design. Am Heart J. 2009 Mar;157(3):488-494.e1. doi: 10.1016/j.ahj.2008.11.015.