The Specialist Forum Volume 13 No 11 November 2013

ANAESTHIOLOGY N2O does not increase risk of MI, new study shows M ore than 200 million major surgeries are performed annually around the world. Many of these patients receive nitrous oxide (N2O), a general anaesthetic gas, which is typically used in combination with other inhalation or intravenous agents during these procedures. Over the past few years concerns have been raised about the safety of N2O during noncardiac surgery. Several studies, most notably the N2O and perioperative cardiac morbidity (Enigma) I trial, reported a small, but significant increase in myocardial infarction (MI) among patients who received N2O as part of anaesthesia for noncardiac surgery. This led to new concerns about the safety of N2O in patients with existing or the risk of developing coronary artery disease (CAD). The researchers of the Enigma I trial concluded that the administration of N2O was associated with increased long-term risk of myocardial infarction (MI), but not of death or stroke in patients enrolled in the trial. The exact relationship between N2O administration and serious longterm adverse outcomes will require confirmation by an appropriately designed large randomised controlled trial. The study has been criticised by a number of academics and resulted in the launch of the Enigma II trial in 2009. This is a five year international randomised trial involving 7000 patients at risk of CAD. The primary outcome is a composite of death and major nonfatal events (MI, cardiac arrest, pulmonary embolism, and stroke) at 30 days after surgery. New study A newer study by Nagelle et al, has shown that the use of N2O does in fact not increase the risk for postoperative myocardial injury and infarction and is safe to use in patients with the methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C gene variant - the most important genetic determinants of chronically elevated plasma homocysteine (chronic elevations are associated with cardiovascular disease). Methods A total of 625 patients undergoing elective noncardiac surgery were randomised into three arms: • N2O (60% N2O/40%O2 plus placebo [n=250]), • N2O plus B-vitamins (60% N2O/40%O2 plus 1mg of vitamin B12 and 5mg of folic acid IV before and after surgery [n=250]) • No N2O (control group, 40% O2 [n=125]) The use of N2O was open-label and the administration of B-vitamins was blinded and placebo-controlled. Any other aspect of perioperative management was at the discretion of the anaesthesia team. Patients were eligible if they had been diagnosed or were at risk for coronary artery disease and had no contraindication for the use of N2O. Serial blood draws and 12-lead electrocardiography were obtained at baseline, end of surgery and postoperative on days one to three. High-sensitive troponin T (hsTnT), 4th generation troponin I (TnI), and plasma total homocysteine were measured at all time-points. Vitamin B12 and folate were measured at baseline and postoperative on day one. MTHFR variants were genotyped on the Sequenom platform. The primary outcome was the change in hsTnT and the incidence of clinically relevant TnI elevations and MI related to the increase in plasma homocysteine. Results The three randomisation groups did not differ at baseline. The median increase in plasma homocysteine in the N2O group was 3.4 ?mol/L (IQR: 0.8, 6.7) and lower in the B-vitamin group (2.1 ?mol/L, IQR: 0, 5.3; p=0.002). Patients in the control group had no increase in plasma Hcy. Neither MTHFR C677T nor A1298C variant had a significant effect on the postoperative increase in plasma Hcy. No differences in cardiovascular outcomes were observed between the three groups. The median postoperative peak hsTnT was 10.7 pg/mL (IQR: 5.6, 21.8) in the B-vitamin group, 11.7 pg/mL (IQR: 5.6, 23.5) in the N2O group and 15.1 pg/mL (8.0, 23.8) in the control group (p=0.052). The median change (?) hsTnT was 3.1 pg/mL (IQR: 0, 7.0), 2.8 pg/mL (IQR 0, 7.5) and 3.9 pg/mL (IQR: 0.5, 8.9) for the B-vitamin, N2O- and control group, respectively (p=0.36). The rate of postoperative troponin I elevations > 99th percentile of the URL (? 0.07 ng/mL) was 33/249 (13.3%), 34/250 (13.6%), and 15/125 (12.0%) among the three groups (p=0.91). The incidence rate of postoperative MI was 2.8% (7/250) in the B-vitamin group, 6.0% (15/249) in the N2O-group and 6.4% (8/125) in the control group (p=0.15 between all groups and p= 0.89 between N2O and control group). The MTHFR genotype has no effect on cardiovascular outcomes within each group. The researchers concluded that the results provide strong evidence that N2O does not increase the risk for postoperative myocardial injury and infarction. In addition, they found that carriers of the MTHFR C677T and A1298C gene variants do not experience an increased cardio ascular risk after N2O anaesthesia. v References available on request.? SF Page 30 November 2013 | The Specialist Forum

The Specialist Forum Volume 13 No 11 November 2013 | Page 30