Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design
Myles PS, ANZCA Trials Group.
Am Heart J. 2009 Mar;157:488-94.
Maryam Jowza, MD, Theodore A. Alston, MD, PhD
Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School
Nitrous oxide has an anti-vitamin B12 effect that, theoretically, is of particular concern in cardiovascular patients. For instance, B12 inactivation elevates levels of homocysteine, a toxic metabolite linked to endothelial dysfunction and hypercoagulability. Hoping to quantitate the potential problem, investigators from Australia, China, USA, and Canada have initiated a randomized clinical study planned to include 7,000 patients. The ENIGMA-II trial will delineate the contribution of nitrous oxide anesthesia in the development of complications in patients undergoing non-cardiac surgery.
Patients are over 45 years old, undergoing an anesthetic that is expected to exceed 2 h, and at increased risk for a cardiac event (history of CAD, heart failure, cerebrovascular or peripheral vascular disease or more than three risk factors for CAD). Patients requiring an FiO2 of greater that 0.5 are excluded.
Patients receive either 70% N2O or else 70% N2 together with isoflurane, sevoflurane, desflurane or propofol. Only the anesthesia provider has knowledge of the nitrous status. Blood samples from participants are collected at 6 to 72 h postoperatively for troponin and CK-MB levels, and a 12-lead EKG is performed on postoperative day 1 and 3. On postoperative day 30, patients are contacted and their charts are reviewed for adverse events. Analysis is on an intention to treat basis.
The primary endpoints for the trial are death or nonfatal cardiovascular event such as a myocardial infarction, cardiac arrest, pulmonary embolus or stroke within 30 days of surgery. Secondary endpoints include wound infection, nausea, and duration of hospital stay.
Inhaled nitrous oxide is a venerable drug. Humphry Davy proposed the gas as an aid to surgery in 1800. Horace Wells failed to convince MGH surgeons of that possibility in 1845, but Gardner Q. Colton soon thereafter incorporated nitrous into an influential painless dental practice. Early in the 20th century, George W. Crile was a particularly vocal champion of the safety of nitrous oxide for “shockless” anesthesia in major surgery. Despite considerable safety, an anti-vitamin B12 side-effect was inferred in 1956 when megaloblastic anemia occurred in a tetanus victim ventilated with 50% nitrous for days. By 1980, the nitrous-sensitive B12 enzyme was determined to be methionine synthase, also called methionine synthetase. The enzyme is irreversibly inactivated in a slow reaction with N2O, and recovery over days requires synthesis of new enzyme from fresh amino acids.
Methionine is an essential amino acid in the diet, but many of its metabolic functions require recycling via methionine synthase. Its methyl group is used in the construction of myelin lipid, so B12 deficiency or nitrous toxicity can cause demyelination of the spinal cord. When methionine is used as a methyl donor, the cardiovascularly toxic amino acid homocysteine is produced. This accumulates during nitrous anesthesia since methionine synthase is required to convert homocysteine back to methionine. Disruption of the methionine cycle also disrupts the supply of methyl groups for the conversion of uracil to thymine for DNA synthesis. Hence, megaloblastic anemia can ensue. (Megaloblasts are pathologically large erythrocyte precursor cells. They have uracil to make RNA and protein and can thus enlarge, but they lack thymine to make DNA for cell division.)
Patients with pre-existing defects in methyl group metabolism may be particularly sensitive to metabolic toxicity of nitrous. Examples include patients receiving methotrexate, those with genetic deficiency of methylenetetrahydrofolate reductase, and incipient cases of pernicious anemia.
If avoidance of nitrous oxide in patients at risk of coronary disease causes a reduction in perioperative cardiovascular complications, the impact on clinical practices will be substantial.