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The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial

Primary Purpose

Coronary Artery Disease

Status

Completed

Phase

Phase 4

Locations

Australia

Study Type

Interventional

Intervention

Nitrous Oxide

No Nitrous Oxide

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring Anaesthesia, Major Surgery, Coronary artery disease, Nitrous oxide, Effects of Nitrous Oxide following Anaesthesia, Anaesthesia and coronary artery disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Adult males and females age ≥ 45 years, undergoing noncardiac surgery and general anaesthesia expected to exceed two hours.
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

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

Sites / Locations

Alfred Hosptial

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

70% Nitrous Oxide

No Nitrous Oxide

Arm Description

General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30%

General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Myocardial Infarction (MI)

Cardiac Arrest

Pulmonary Embolism

Stroke

Wound Infection

Hospital Stay (Days)

Full Information

NCT ID

NCT00430989

First Posted

January 31, 2007

Last Updated

November 24, 2019

Sponsor

Bayside Health

Collaborators

National Health and Medical Research Council, Australia

1. Study Identification

Unique Protocol Identification Number

NCT00430989

Brief Title

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

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

April 2007 (undefined)

Primary Completion Date

September 2013 (Actual)

Study Completion Date

September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bayside Health

Collaborators

National Health and Medical Research Council, Australia

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Coronary Artery Disease

Keywords

Anaesthesia, Major Surgery, Coronary artery disease, Nitrous oxide, Effects of Nitrous Oxide following Anaesthesia, Anaesthesia and coronary artery disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

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.

Masking

ParticipantCare ProviderOutcomes Assessor

Masking Description

The treating anaesthetist will be unblinded to the allocation. All other personnel (surgeon, participant and outcome assessor are all blinded to treatment.

Allocation

Randomized

Enrollment

7112 (Actual)

8. Arms, Groups, and Interventions

Arm Title

70% Nitrous Oxide

Arm Type

Other

Arm Description

General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30%

Arm Title

No Nitrous Oxide

Arm Type

Other

Arm Description

General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%

Intervention Type

Other

Intervention Name(s)

Nitrous Oxide

Intervention Description

General anaesthesia with the inclusion of Nitrous Oxide at 70%

Intervention Type

Other

Intervention Name(s)

No Nitrous Oxide

Intervention Description

General anaesthesia with no use of Nitrous Oxide

Primary Outcome Measure Information:

Title

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.

Time Frame

30 days post op

Secondary Outcome Measure Information:

Title

Myocardial Infarction (MI)

Time Frame

30 days post op

Title

Cardiac Arrest

Time Frame

30 days

Title

Pulmonary Embolism

Time Frame

30 Days Post op

Title

Stroke

Time Frame

30 Days Post op

Title

Wound Infection

Time Frame

30 Days Post op

Title

Hospital Stay (Days)

Time Frame

30 Days Post Op

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Adult males and females age ≥ 45 years, undergoing noncardiac surgery and general anaesthesia expected to exceed two hours. At increased risk of cardiac events, defined as any of 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 heart failure cerebrovascular disease thought due to atherothrombotic disease aortic or peripheral vascular disease 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 having cardiac surgery marked impairment of gas-exchange expected to require Fi02> 0.5 intraoperatively specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure) or the anaesthetist plans to use supplemental oxygen (eg. colorectal surgery) N2O unavailable for use.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paul S Myles, MBBS MPH MD

Organizational Affiliation

The Alfred

Official's Role

Principal Investigator

Facility Information:

Facility Name

Alfred Hosptial

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

29533264

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.

Results Reference

derived

PubMed Identifier

28100522

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.

Results Reference

derived

PubMed Identifier

27956679

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. Erratum In: Br J Anaesth. 2017 Oct 1;119(4):851.

Results Reference

derived

PubMed Identifier

25142708

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.

Results Reference

derived

PubMed Identifier

19249419

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.

Results Reference

derived

Links:

URL

http://www.enigma2.org.au

Description

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The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial

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