Coronary Artery Disease
Conditions
Keywords
Anaesthesia, Major Surgery, Coronary artery disease, Nitrous oxide, Effects of Nitrous Oxide following Anaesthesia, Anaesthesia and coronary artery disease
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.
Interventions
OTHERNitrous Oxide
General anaesthesia with the inclusion of Nitrous Oxide at 70%
OTHERNo Nitrous Oxide
General anaesthesia with no use of Nitrous Oxide
Sponsors
Bayside Health
National Health and Medical Research Council, Australia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes 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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. | 30 days post op |
Secondary
| Measure | Time frame |
|---|---|
| Myocardial Infarction (MI) | 30 days post op |
| Cardiac Arrest | 30 days |
| Pulmonary Embolism | 30 Days Post op |
| Stroke | 30 Days Post op |
| Wound Infection | 30 Days Post op |
| Hospital Stay (Days) | 30 Days Post Op |
Countries
Australia
Contacts
PRINCIPAL_INVESTIGATORPaul S Myles, MBBS MPH MD
The Alfred
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N2O Group (FiO2 0.3) Nitrous Oxide as an inspired concentration of 70% in 30% Oxygen | 3,495 |
| N2O Free Group (FiO2 0.3) Nitrous Oxide free air and inspired Oxygen concentration of 30% | 3,516 |
| Total | 7,011 |
Baseline characteristics
| Characteristic | N2O Free Group (FiO2 0.3) | Total | N2O Group (FiO2 0.3) |
|---|---|---|---|
| Age, Continuous Age | 69.5 years STANDARD_DEVIATION 9.7 | 69.3 years STANDARD_DEVIATION 9.7 | 69.2 years STANDARD_DEVIATION 9.8 |
| Race/Ethnicity, Customized Asian | 701 participants | 1407 participants | 706 participants |
| Race/Ethnicity, Customized Black or African American | 11 participants | 30 participants | 19 participants |
| Race/Ethnicity, Customized Indian/Pakistani | 57 participants | 120 participants | 63 participants |
| Race/Ethnicity, Customized Other | 50 participants | 63 participants | 13 participants |
| Race/Ethnicity, Customized Unknown | 67 participants | 174 participants | 107 participants |
| Race/Ethnicity, Customized White | 2630 participants | 5217 participants | 2587 participants |
| Sex: Female, Male Female | 1299 Participants | 2552 Participants | 1253 Participants |
| Sex: Female, Male Male | 2217 Participants | 4459 Participants | 2242 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 42 / 3,483 | 57 / 3,509 |
| other Total, other adverse events | 662 / 3,483 | 546 / 3,509 |
| serious Total, serious adverse events | 283 / 3,483 | 296 / 3,509 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | 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. | 283 participants |
| N2O Free Group (FiO2 0.3) | 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. | 296 participants |
Secondary
Cardiac Arrest
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Cardiac Arrest | 15 participants |
| N2O Free Group (FiO2 0.3) | Cardiac Arrest | 19 participants |
Secondary
Hospital Stay (Days)
Time frame: 30 Days Post Op
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Hospital Stay (Days) | 6.1 Days |
| N2O Free Group (FiO2 0.3) | Hospital Stay (Days) | 6.1 Days |
Secondary
Myocardial Infarction (MI)
Time frame: 30 days post op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Myocardial Infarction (MI) | 215 participants |
| N2O Free Group (FiO2 0.3) | Myocardial Infarction (MI) | 219 participants |
Secondary
Pulmonary Embolism
Time frame: 30 Days Post op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Pulmonary Embolism | 18 participants |
| N2O Free Group (FiO2 0.3) | Pulmonary Embolism | 22 participants |
Secondary
Stroke
Time frame: 30 Days Post op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Stroke | 26 participants |
| N2O Free Group (FiO2 0.3) | Stroke | 19 participants |
Secondary
Wound Infection
Time frame: 30 Days Post op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitrous Oxide: 70% N2O (FiO2 0.3) | Wound Infection | 321 participants |
| N2O Free Group (FiO2 0.3) | Wound Infection | 311 participants |