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Clinical Trial of the Neuroprotectant Clomethiazole in Coronary Artery Bypass Graft Surgery a Randomized Controlled Trial Robert S

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Clinical Trial of the Neuroprotectant Clomethiazole in Coronary Artery Bypass Graft Surgery a Randomized Controlled Trial Robert S Anesthesiology 2002; 97:585–91 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Clinical Trial of the Neuroprotectant Clomethiazole in Coronary Artery Bypass Graft Surgery A Randomized Controlled Trial Robert S. Kong, F.R.C.A.,* John Butterworth, M.D.,† Wynne Aveling, F.R.C.A.,‡ David A. Stump, M.D.,† Michael J. G. Harrison, F.R.C.P.,§ John Hammon, M.D.,ʈ Jan Stygall, M.Sc.,# Kashemi D. Rorie, Ph.D.,** Stanton P. Newman, D.Phil.†† Background: The neuroprotective property of clomethiazole THE efficacy of coronary artery bypass surgery in the has been demonstrated in several animal models of global and relief of angina and in some circumstances in enhancing Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/3/585/335909/0000542-200209000-00011.pdf by guest on 29 September 2021 focal brain ischemia. In this study the authors investigated the life expectation is now accepted. It is a tribute to the low effect of clomethiazole on cerebral outcome in patients under- mortality of the procedure that interest is now focused going coronary artery bypass surgery. Methods: Two hundred forty-five patients scheduled for on the neurologic and neuropsychological complica- 1–3 coronary artery bypass surgery were recruited at two centers tions. Adverse neurologic outcomes have been found and prospectively randomized to clomethiazole edisilate to occur in 2–6% of patients and neuropsychological (0.8%), 225 ml (1.8 mg) loading dose followed by a maintenance deficits in 10–30%.4–6 These complications are consid- dose of 100 ml/h (0.8 mg/h) during surgery, or 0.9% NaCl ered to be ischemic in nature, being a consequence of (placebo) in a double-blind trial. Coronary artery grafting was macroembolism and microembolism or impaired cere- completed during moderate hypothermic (28–32°C) cardiopul- bral perfusion. Attempts to reduce the frequency or monary bypass. Plasma clomethiazole was measured at several intervals during and up to 24 h after the end of infusion. A severity of neuropsychological deficits have included 7 8,9 battery of eight neuropsychological tests was administered pre- modifications to surgical and anesthetic manage- operatively and repeated 4–7 weeks after surgery. Analysis of ment, equipment design,10 and pharmacologic neuro- the change in neuropsychological test scores from baseline was protection.11–13 Some of these interventions have been used to determine the effect of treatment. shown to be effective in demonstrating the sensitivity of Results: Neuropsychological assessments were completed in neuropsychological testing in this context.8–10,13 219 patients (110 clomethiazole; 109 placebo). The mean Clomethiazole enhances ␥-aminobutyric acid type A plasma concentration of clomethiazole during surgery was 66.2 ␮M. There was no difference between the clomethiazole receptor activity and has a long history of use as an and placebo group in the postoperative change in neuropsy- anticonvulsant and sedative, particularly in the treatment chological test scores. of ethanol withdrawal.14 In 1991, Cross et al.15 reported Conclusion: Clomethiazole did not improve cerebral outcome that clomethiazole was neuroprotective in a gerbil following coronary artery bypass surgery. model of forebrain ischemia, and further studies have since confirmed that this agent is protective in both focal and global models of cerebral ischemia.16–19 The first This article is featured in “This Month in Anesthesiology.” prospective randomized clinical trial of clomethiazole in 20 ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. acute stroke (CLASS) showed some promising results, and another large multicenter study has recently been completed. * Research Fellow, Royal Free and University College London Medical School; Coronary artery bypass surgery offers another oppor- current position: Consultant, Department of Anaesthesia and Intensive Care, Royal Sussex County Hospital, Brighton, United Kingdom. † Professor, ** Assis- tunity to investigate pharmacological neuroprotection in tant Professor, Department of Anesthesiology, ʈ Professor, Department of Car- a clinical context with a quantifiable outcome, but diothoracic Surgery, Wake Forest University School of Medicine. ‡ Consultant Anaesthetist, Middlesex Hospital. # Health Psychologist, § Emeritus Professor, where the timing of drug administration in relation to Department of Neurology, †† Professor of Health Psychology, Royal Free and the cerebral insult can be controlled. In this study we University College London Medical School. hypothesized that clomethiazole would be neuroprotec- Received from the Health Psychology Unit, Academic Department of Psychi- atry & Behavioural Sciences, Reta Lila Weston Institute of Neurological Studies, tive in patients undergoing coronary artery bypass graft- Royal Free and University College London Medical School, London, United ing (CABG) and that this effect would be verified by an Kingdom; Department of Anaesthesia, Middlesex Hospital, London, United King- dom; and the Department of Anesthesiology, Wake Forest University School of improvement in postoperative neuropsychological Medicine, Winston-Salem, North Carolina. Received for publication May 10, performance. 2001. Accepted for publication February 6, 2002. Supported by AstraZeneca, Sodertalje, Sweden. Presented at the autumn meeting of the Association of Cardiothoracic Anaesthetists, Glasgow, United Kingdom, November 19, 1999, and the Fifth International Brain and Cardiac Surgery Conference, London, Materials and Methods United Kingdom, September 9, 2000. Address reprint requests to Prof. Newman: Unit of Health Psychology, Depart- Study Design ment of Psychiatry & Behavioural Sciences, Royal Free and University College A prospective, randomized, placebo-controlled, dou- London Medical School, Wolfson Building, 48 Riding House Street, London W1N 8AA, United Kingdom. Address electronic mail to: [email protected]. Individ- ble-blind trial was designed to assess the efficacy of ual article reprints may be purchased through the Journal Web site, clomethiazole as a neuroprotectant in coronary artery www.anesthesiology.org. bypass surgery. To recruit an adequate number of pa- Anesthesiology, V 97, No 3, Sep 2002 585 586 KONG ET AL. tients within a reasonable study duration, the study was priate, were scored on the National Institutes of Health conducted at two cardiac surgical centers: Middlesex stroke scale. Serious adverse events were recorded pro- Hospital (London, United Kingdom) and Wake Forest spectively to the final follow-up assessment. University Medical Center (Winston-Salem, NC). Ap- proval for the study was obtained from the ethical re- Anesthesia, Surgery, and Postoperative view committees at both hospitals. Participants were Management given written and verbal information about the study A standardized anesthesia technique was used that before we obtained their written consent. All patients was similar to that used routinely by the cardiac anes- (age Ն 50 yr) listed for standard (not minimally invasive) thetists at the two centers. Patients were premedicated first-time or repeat coronary artery bypass were consid- with intramuscular morphine (7.5–10 mg) and hyoscine ered for the study. Patients were excluded if it was (0.2–0.3 mg) or oral diazepam (5 mg). Anesthesia was Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/3/585/335909/0000542-200209000-00011.pdf by guest on 29 September 2021 difficult to assess their preoperative neuropsychological induced with midazolam (0.1–0.2 mg/kg), fentanyl status and if they had a need for other concurrent vas- (10–15 ␮g/kg) or sufentanil (10–15 ␮g/kg), and pancu- cular and surgical procedures or emergency surgery on ronium (0.1–0.15 mg/kg). After tracheal intubation, the the day of admission, chronic hepatic disease, serum lungs were ventilated with nitrous oxide and oxygen. creatinine concentration greater than 200 ␮M, acute or Anesthesia was maintained throughout the procedure severe chronic respiratory insufficiency, known intoler- with 0.5–1.5% isoflurane. The cardiopulmonary bypass ance of clomethiazole, known alcohol or drug depen- (CPB) circuit was primed with a crystalloid solution and dence, or if they were breast feeding or pregnant included a membrane oxygenator and 40-␮m arterial line women or women of child-bearing potential. Patients filter. Hypothermic CPB was initiated after heparin (300 were also excluded if they received cimetidine within IU/kg) was given, and an activated clotting time of greater the last 7 days, as this inhibits metabolism of clomethia- than 400 s was confirmed. A roller pump maintained non- zole. No patient was rejected because of the clinician’s pulsatile systemic blood flow at 2–2.4 l · minϪ1 · mϪ2, perception of operative mortality or the risk of adverse and phenylephrine, isoflurane, or phentolamine was cardiac or neuropsychological and neurologic outcome. used as required to achieve target mean arterial pressure A computer-generated randomization sequence was in the 60–90-mmHg range. The patients were cooled to used to allocate patients to either clomethiazole or pla- a nasopharyngeal temperature between 28°C and 32°C cebo and also to balance the two treatment groups during CPB and rewarmed to 37°C before weaning. The within each center. All clinicians, investigators, and pa- technique of myocardial protection was according to the tients were blinded to treatment allocation. surgeon’s usual practice, which was intermittent aortic cross clamp and fibrillation or crystalloid
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