February 1, 2014 Volume 78, Number 2
SEE Question

You are planning the anesthetic for an upcoming carotid endarterectomy. Based on the equivocal results of the General Anaesthesia versus Local Anaesthesia for Carotid Surgery (GALA) trial, you decide to perform a general anesthetic. A colleague suggests always using nitrous oxide (N2O) for quicker emergence in these cases. Reflecting on a recent secondary analysis of the GALA trial, you respond:

(A) No, because N2O increases the risk of stroke.

(B) No, because N2O increases the risk of myocardial infarction (MI).

(C) No, because N2O increases the risk of death.

(D) Yes, as N2O does not significantly increase the risk of stroke, MI or death.

The question about general versus local anesthesia for carotid endarterectomy was addressed by the GALA trial. This trial looked at more than 3,000 patients and ultimately concluded that there were no differences in 30-day occurrences of stroke, MI, or death between the two techniques.

The use of N2O in general anesthesia has been addressed in studies such as the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA) trial and a secondary analysis of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST). The ENIGMA group reported that N2O was associated with an increased risk of myocardial ischemia. One criticism of this result is that the ENIGMA study population may have been at higher risk of myocardial ischemia after exposure to N2O because of the high percentage of Asian patients enrolled in the study. These patients are genetically predisposed to a higher rate of folate deficiency, which is postulated to lead to an exaggerated elevation of homocysteine levels upon exposure to N2O. Elevated homocysteine levels increase the risk of cardiac ischemia and may have influenced the ENIGMA results. The IHAST secondary analysis looked at patients undergoing cerebral aneurysm clipping and showed an increased likelihood of neurological deficits in patients receiving N2O.

The authors of a recent secondary analysis of the GALA trial wanted to evaluate the effect of N2O exposure on patients undergoing carotid endarterectomy. They used the same outcome variables as the original trial: 30-day occurrences of stroke, MI, and death. This analysis only looked at the general anesthesia arm of the GALA trial and separated out the anesthetics where N2O exposure or avoidance was clearly documented. Of the 1,773 patients who received general anesthesia in the GALA trial, 671 were definitely exposed to N2O and 944 were definitely not exposed to N2O. The decision to use N2O in the GALA trial was not randomized, but was determined at the discretion of the anesthesiologist. The patients in the N2O-exposed group were more likely to have underlying comorbid conditions such as coronary artery disease, peripheral vascular disease, and atrial fibrillation. Despite this statistically significant difference in underlying comorbidities in the N2O-exposed group, there was no difference between groups in the 30-day occurrence of stroke, MI, or death. The authors of this trial did not specifically address the presence of pulmonary disease in their decision processes or outcomes.


• Sanders RD, Graham C, Lewis SC, Bodenham A, Gough MJ, Warlow C; GALA Trial Investigators. Nitrous oxide exposure does not seem to be associated with increased mortality, stroke, and myocardial infarction: a non-randomized subgroup analysis of the General Anaesthesia compared with Local Anaesthesia for carotid surgery (GALA) trial. Br J Anaesth. 2012;109(3):361-367.

• GALA Trial Collaborative Group; Lewis SC, Warlow CP, Bodenham AR, et al. General anaesthesia versus local anaesthesia for carotid surgery (GALA): a mulitcentre, randomised controlled trial. Lancet. 2008;372(9656):2132-2142.

• Pasternak JJ, McGregor DG, Lanier WL, et al; IHAST Investigators. Effect of nitrous oxide use on long-term neurologic and neuropsychological outcome in patients who received temporary proximal artery occlusion during cerebral aneurysm clipping surgery. Anesthesiology. 2009;110(3):563-573.

• Leslie K, Myles PS, Chan MT, et al. Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial. Anesth Analg. 2011;112(2):387-393.

Answer: D

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