If you wish to respond to a paper or other item already published in the BJA, please go to the abstract/full text version of that item and click on the link "E-Letters: Submit a response to the article".
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E-letters: Electronic letters published:
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response
- Paul S. Myles (14 August 2008)
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Nitrous oxide and post-operative cardiovascular morbidity
- Dan Connor (11 August 2008)
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Re: Folate for high risk surgical patients
- Paul S. Myles, Matthew Chan, Kate Leslie, Philip Peyton, Michael Paech, Andrew Forbes (15 July 2008)
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Folate for high risk surgical patients
- Prashanth Sadhahalli (10 July 2008)
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Paul S. Myles Alfred Hospital and Monash University
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We thank Dr Connor for his letter. Random allocation to groups should result in comparable baseline characteristics, but it remains possible that small differences can still exist. In our study there were slightly more patients with some risk factors for coronary artery disease in the nitrous oxide group (as suggested by Dr Connors), yet there were slightly more patients with other risk factors in the control groups (older age, diabetes). These random differences are inevitable, and are unlikely to explain the differences in outcome that we observed. The prime purpose of presenting baseline characteristics – typically Table 1 of a clinical trial – is to demonstrate comparable groups in all respects except that of the intervention of interest (in our case, exposure to nitrous oxide). Although some choose to compare these factors with hypotheses testing, it is wrong and potentially misleading (1). If groups are randomly allocated, then significance tests only test the success of randomization. A significance level of 0.05 merely suggests that one in twenty comparisons will be significant purely by chance. Importantly, there may be a clinically significant difference between the groups which is not detected by significance testing, yet such an imbalance may have an important effect on the outcome of interest. We, also, await the results of ENIGMA-II with interest. 1. Myles PS, Gin T. Statistical methods for anaesthesia and intensive care. London: Butterworth Heinemann, 2000; 126-7. Paul S. Myles, on behalf of the ENIGMA study group. Conflict of Interest:None declared |
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Dan Connor, Consultant Anaesthetist Portsmouth Hospitals NHS Trust
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I read with interest Professor Myles' article on the effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery 1. I would like to query the conclusion with respect to cardiovascular morbidity in this cohort. In the demographic data in Table 1 the patients are well matched until the medical conditions are considered. However, smokers, patients with coronary artery disease, patients with heart failure and patients with previous stroke seem to be over-represented in the nitrous oxide group. There is no comment as to whether this reached statistical significance, or could have affected the cardiovascular morbidity experienced. I look forward to the results coming through from ENIGMA-II to determine the impact of nitrous oxide on patients with pre-existing cardiovascular morbidity, though this will not affect my practice as I ceased to use N2O many years ago. 1. P. S. Myles, M. T. V. Chan, K. Leslie, P. Peyton, M. Paech, and A. Forbes: Effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery; Br. J. Anaesth. 2008 100: 780-786 Conflict of Interest:None declared |
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Paul S. Myles Alfred Hospital and Monash University, Matthew Chan, Kate Leslie, Philip Peyton, Michael Paech, Andrew Forbes
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We thank Dr Sadhahalli for his letter, for which he raises some interesting points. We agree that nitrous oxide-induced hyperhomocysteinaemia could be a risk factor for postoperative cardiovascular morbidity. This problem may be exaggerated in patients with mutations in the methylenetetrahydrofolate reductase gene (1). However this proposition is based on evidence from nonsurgical populations and may not apply to the perioperative setting - witness the recent results from the POISE study (2). Nevertheless the circumstantial evidence is troubling. We are in fact testing this hypothesis in 7000 patients at- risk of coronary artery disease (www.enigma2.org.au). Similarly, to recommend preoperative folate supplementation in high risk surgical patients without evidence of its effectiveness or safety would be premature and could be misguided. For example, folate supplementation can precipitate severe neurological damage in patients with cobalamin deficiency (3). The points raised by Dr Sadhahalli are important and demand serious consideration from all anaesthetists. But we must await definitive evidence from large scale clinical trials before recommending changes in practice (4). 1. Nagele P, Zeugswetter B, Wiener C, et al. Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia. Anesthesiology 2008; 109:36 -43. 2. POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomized controlled trial. Lancet. 2008; 371: 1839-1847. 3. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev 2003;(4):CD004514. 4. Myles PS. Why we need large randomised studies in anaesthesia. Br J Anaesth 1999;83:833-4. Conflict of Interest:None declared |
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Prashanth Sadhahalli, Anaesthetic Registrar
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It has long been known that an association exists between serum homocysteine concentration and cardiovascular disease, and several studies have shown that the association is causal. The results from a metaanalysis1 of single gene mutations in methylenetetrahydrofolate reductase have shown that a decrease in serum homocysteine of 3 μmol/l (achievable by daily intake of about 0.8 mg folic acid) should reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24% .Given such a substantial benefit in cardiovascular outcome, as also shown by your study, there is a case not only for excluding nitrous oxide from regular anaesthetic practice but also for administering regular folic acid pre and post operatively for our high risk surgical patients. 1. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis, BMJ. 2002 November 23; 325(7374): 1202 Conflict of Interest:None declared |
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