Trial Summary
Background Synopsis
There are about 20 million anaesthetics given each year in the US (1:10 of the population), with the majority receiving N2O. Approximately 25% of patients undergoing major surgery have known coronary artery disease (CAD) or risk factors for CAD. In 1990, approximately 1 million of the 25 million Americans who underwent noncardiac surgery suffered a perioperative cardiac event, resulting in $20 billion in costs.
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 hyper¬homo¬cysteinaemia 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 identified a non–significant increased risk of confirmed myocardial infarction in the N2O group, 1.3% vs. 0.7%; adjusted p = 0.19, and 10 postoperative deaths (1.0%) in the N2O group compared with 4 (0.4%) in the control group p = 0.26. We propose a large simple multicentre randomized controlled trial (RCT) to definitively evaluate the efficacy of removing N2O from the anaesthetic in moderate and high risk patients undergoing noncardiac surgery.
Research Plan Synopsis:
Design: Large, multi–centre, randomised, blinded, clinical trial. Patients will be randomly allocated to either a N2O–containing (70% N2O in oxygen) or N2O–free (nitrogen in oxygen) anaesthetic; both groups FiO2 0.3. Patients, surgeons, and nursing staff, and all individuals responsible for all outcome assessments will be blinded.
Primary End Point: The primary endpoint is a composite of death and cardiovascular events (clinical and silent MI, cardiac arrest, pulmonary embolism, and stroke) measured at 30 days after surgery.
Secondary End Points: Myocardial Infarction (MI), Cardiac arrest, Pulmonary embolism, Stroke, Wound infection, Severe PONV, ICU Stay, Hospital Stay.
Sample size: 7,000 patients (alpha 0.05, beta 0.10), to detect an absolute risk reduction of 2% (from 8 to 6%) in the primary endpoint
Randomisation: After stratification by centre, patients will be randomly allocated from a computer–generated list (1:1) to either 70% N2O in oxygen (FiO2 0.3) or 70% nitrogen in oxygen (FiO2 0.3).
Treatment of the patient postoperatively
1. Preoperative period: All patients will receive preoperative care and premedication as per usual practice. We will record preoperative cardiac medications, including beta–blockers, calcium antagonists, ACE inhibitors, AII–blockers, statins and anticoagulants. Medications will be continued to be administered peri–operatively unless or at the clinicians discretion. It is recommended to continue preoperative beta–blockers. Preoperative blood glucose and haemoglobin measurements will be recorded in the CRF, only if collected as routine clinical care.
2. Intraoperative period: If BIS or entropy monitoring is to be used, then anaesthesia can be adjusted to maintain a BIS (or equivalent) of 40–55 during surgery. Choice of anaesthetic agents, muscle relaxants, perioperative analgesia and prophylactic antibiotics will be left to the discretion of the anaesthetist. End–tidal volatile agent concentrations will be measured; alternatively, predicted propofol concentration will be recorded if available. Intraoperative thermal management will be guided by a recommendation to avoid hypothermia (<35.5oC), as it is known that hypothermia is a risk factor for myocardial ischaemia and arrhythmias. Efforts will be made to maintain core temperature at least 36ºC. All efforts will be used to maintain oxygenation, heart rate and blood pressure within the patient’s usual range at all times peri–operatively.
3. Postoperative period: While in hospital patients will be followed daily, and outcomes will be recorded, until discharge. Data on medications, temperature (excluding skin temperature), nausea and vomiting and wound infection will be recorded in the CRF. A 12–lead ECG will be ordered preoperatively and on day 1 and 3 after surgery, and at hospital discharge. Troponins will be taken 6–12 hours post–op and on the first three days following surgery. On day 1 all patients will complete a Quality of Recovery Score (QoR) Additional tests will be ordered if clinically indicated (eg. if patient experiences chest pain, serial ECGs and troponins, echocardiography, nuclear myocardial scanning or angiography may be clinically indicated.). Additionally, patients will be contacted by phone at 30 days to ascertain if they have experienced any outcomes, and, if detected, further testing will be arranged. If a patient indicates they have experienced an event, the documentation of the event (i.e. hospital records) will be obtained. Confirmation reports of all detected outcomes will be de–identified and re–labelled with study number.