ORIGINAL ARTICLEPreoperative folate and homocysteine status in patients undergoing major surgery
Introduction
Unrecognised folate and vitamin B12 deficiency is common in the community, particularly in the elderly and socially disadvantaged.1, 2, 3, 4 For those undergoing surgery, folate and vitamin B12 deficiency are associated with a variety of postoperative complications.5, 6, 7, 8, 9 In addition, folate deficiency is associated with elevated homocysteine (Hcy) in blood, which in turn is associated with cerebrovascular and cardiovascular disease.10, 11, 12, 13, 14
Folate and vitamin B12 deficiency have direct relevance for patients undergoing surgery and general anaesthesia. Nitrous oxide (N2O) interferes with folate metabolism, via a mechanism that inactivates the vitamin B12-dependent enzyme methionine synthetase.8, 15 This leads to an increase in Hcy, and impaired production of methionine, a substrate needed for thymidine and DNA synthesis.8, 10, 16 Prolonged or repeated exposure to N2O can cause megaloblastic anaemia and subacute combined degeneration of the spinal cord.5, 6, 7, 8, 9, 15
Some of the N2O-induced complications may be more common in patients with low folate status or elevated Hcy.5, 6, 7, 8, 9, 10, 17 Despite the widespread use of N2O in contemporary anaesthetic practice, patients with folate deficiency or elevated Hcy concentration are usually not identified preoperatively. Extensive dietary history, food frequency questionnaires and weighed-food records are recommended for this purpose,2, 3, 13, 18, 19, 20, 21, 22, 23 but require experienced staff and can be time-consuming. The purpose of this study was to assess the incidence of folate deficiency and hyperhomocysteinemia in patients presenting for major surgery. We also tested the ability of a brief medical and dietary questionnaire to identify patients at risk of nutritional deficiencies.
Section snippets
Materials and methods
The ENIGMA Trial (Effectiveness of Nitrous oxide In the Gas Mixture for Anaesthesia) is testing the safety and effectiveness of N2O in 2000 adult patients undergoing major noncardiac surgery expected to exceed 2 h duration. The protocol of this multi-centre, double-blind, randomised controlled trial has been described in detail elsewhere.8 In the present study, a sequential cohort of patients at two of the participating centres (Alfred Hospital, Melbourne; Prince of Wales Hospital, Hong Kong)
Statistical analysis
Our sample size was based on detecting a correlation between any numerical or ordered variable (e.g. patient age, ASA status, summed dietary factors) and plasma concentrations of 0.30 or better, using a one-sided α error of 0.05 and 80% power. The required number of patients was calculated at 68 patients. We increased this sample size because of additional funding for our biochemical testing, and to facilitate additional exploratory analyses. The final sample size of 390 patients provided >80%
Results
We recruited 390 surgical patients, who underwent a broad range of types of surgery (Table 1). The average duration of surgery was about 5 h. Only one patient had folate deficiency (< 7.0 nmol/l) preoperatively (incidence 0.3%), but there were 29 patients with elevated Hcy (>15 μmol/l) preoperatively (incidence 7.5%). The mean±SD folate and Hcy concentrations were 23.7±5.2 nmol/l and 9.4±4.2 μmol/l, respectively. The distributions of folate and Hcy concentrations are presented in Table 2. One
Discussion
We found that folate and vitamin B supplementation was associated with improved folate status and lower Hcy plasma concentrations in patients presenting for major surgery. In addition, male gender, age >65 year, cardiovascular disease (hypertension or coronary artery disease), and infection were associated with increased Hcy concentrations. Australian patients had higher Hcy concentrations compared with those in Hong Kong; although we did not collect ethnicity data, it is probable that this
Conclusion
We found hyperhomocysteinaemia occurs in about 7.5% of surgical patients, and both low folate status and elevated Hcy concentration are less likely in those taking folate or vitamin B supplements. This has implications for anaesthetists considering use of N2O, because of its inhibition of folate metabolism. More studies are required to evaluate possible adverse effects of low folate status and hyperhomocysteinaemia, and possible beneficial effects of folate and other nutritional supplementation
Acknowledgements
The authors would like to thank Ms. Aushra Saldukas, Project Officer, and all members of the ENIGMA Trial Group. Professor Myles is supported by an Australian National Health and Medical Research Council (NHMRC) Practitioner's Fellowship. The ENIGMA Trial is supported by project grants from the NHMRC (ID 236956), the Australian and New Zealand College of Anaesthetists, and Health and Health Services Research Fund, Hong Kong SAR (HHSRF 02030051).
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