ISOFLURANE DOES NOT INCREASE THE INCIDENCE OF INTRAOPERATIVE MYOCARDIAL ISCHAEMIA COMPARED WITH HALOTHANE DURING VASCULAR SURGERY

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1 British Journal of Anaesthesia 1992; 69: ISOFLURANE DOES NOT INCREASE THE INCIDENCE OF INTRAOPERATIVE MYOCARDIAL ISCHAEMIA COMPARED WITH HALOTHANE DURING VASCULAR SURGERY K. D. STUHMEIER, B. MAINZER, W. SANDMANN AND J. TARNOW SUMMARY We have studied the incidence of new intraoperative myocardial ischaemia (IMI), myocardial infarction (Ml) and cardiac death (CD) in 5 consecutive patients undergoing elective major non-cardiac vascular surgery. Patients were allocated randomly to receive either halothane (n = 226) or isoflurane (n = 274) as principal anaesthetic agent. Using real-time ST segment trend analysis (leads V5 and II) IMI (halothane 39%, isoflurane 38%), Ml (halothane 1.3%, isoflurane 1.5%) and CD (halothane.4%, isoflurane.7%) did not differ significantly between the two groups. Twentythree per cent of IMI episodes were related to haemodynamic disturbances, but unrelated to the type of surgery: 148 supra-aortic (IMI = 39%), 244 abdominal aortic (IMI = 41%) and 18 lower extremity revascularizations (IMI = 33%). We conclude that the choice of volatile anaesthetic agent does not influence cardiac morbidity or mortality in this type of patient. (Br. J. Anaesth. 1992; 69: 62-66) KEY WORDS Anaesthetics, volatile: halothane, isoflurane. Complications: intraoperative myocardial ischaemia. Heart: myocardial infarction. Surgery: vascular. has been shown to have either beneficial or deleterious effects on myocardial oxygenation in animal and human studies [1 5]. Three large prospective outcome studies in patients undergoing coronary artery bypass grafting (CABG) [6-8] have shown conflicting results. Although the "CABGmodel" provides a relatively homogeneous patient population, cardiopulmonary bypass, the adequacy of cardioplegia and myocardial revascularization may have important but independent effects on new intraoperative myocardial ischaemia (IMI) and outcome. Moreover, these studies may not be applicable to the greater number of non-cardiac patients with suspected or proven ischaemic heart disease (IHD). In patients undergoing major non-coronary vascular procedures, IHD is the principal factor determining early and late cardiac morbidity and mortality [9]. Because a significant relationship has been demonstrated between the incidence of new ischaemic episodes and the occurrence of postoperative myocardial infarction (MI) [1, 11], we have examined the role of the primary anaesthetic agent on the incidence of new IMI in 5 vascular surgical patients who were prospectively allocated randomly to receive either isofiurane or halothane. PATIENTS AND METHODS After obtaining approval from our institutional board and informed consent from each patient, we studied 5 consecutive patients undergoing elective vascular procedures. These patients underwent one of dtree types of peripheral vascular surgical procedure: 244 abdominal aortic reconstructions (abdominal aortic aneurysmectomy using the graftinclusion technique, aorto-bifemoral or bi-iliac bypass, aortic or transaortic renal artery endarterectomy); 148 supra-aortic reconstructions (carotid, subclavian or vertebral artery endarterectomy and aorto-brachiocephalic trunk bypass); 18 lower extremity arterial revascularizations (iliac and femoral artery reconstruction, or femoro-femoral or femoro-crural saphenic vein bypass). Two staff anaesthetists (K.D.S. and B.M.) and five staff vascular surgeons participated in this study as part of their regular clinical duties between November 1, 1988 and July 31, 199. Assignment of an anaesthetist to a patient in this study was by chance alone. Preoperative patient characteristics, long-term medication and cardiac history are listed in table I. All patients were classified using the grading score for angina pectoris of the Canadian Cardiovascular Society [12]. The classification was modified by grouping patients without angina pectoris (AP) and asymptomatic patients (APA) with silent ischaemia, unknown previous MI, or both, but with signs present in the preoperative ECG. A standard 12-lead ECG (5mm.s~'; 1 mm = 1 mv) was recorded on the day before surgery. Each patient was visited before operation by the anaesthetist. Approximately 2 h before scheduled induction of anaesthesia, flunitrazepam 1-2 mg and the respective anti-anginal or antihypertensive medications, or both, were administered orally. K. D. STOHMEIER, M.D., B. MAINZER, M.D., J. TARNOW, M.D. (Abteilung fur Klinische Anaesthesiologie); W. SANDMANN, M.D. (Abteilung fur Gefasschirurgie und Nicrentransplantion); Heinrich-Heine Universitat Dusseldorf, Moorenstr. 5, D-4 Dflsseldorf 1, F.R. Germany. Accepted for Publication: July 6, 1992.

2 INTRAOPERATIVE MYOCARDIAL ISCHAEMIA 63 TABLE I. Preoperalive characteristics. ACBG = aorto-coronary bypass grafting; PTCA = percutaneous transluminar coronary angioplasly Age (yr) Age > 6 yr (%) Sex(M:F) Preoperative medication (%) Beta blocking agents Calcium antagonists Nitrates Annhypertensives Cardiac history (%) History of MI Previous ACBG/PTCA No angina pectoris (APO) Asymptomatic angina (APA) Typical angina pectoris API APII APIII APIV (n = 226) 61<38-83) : (n = 274) 58(43-83) : P Anaesthesia was induced with thiopentone 2-4 mg kg" 1 i.v. and neuromuscular block was produced with vecuronium.1 mg kg" 1 initially for tracheal intubation. Anaesthesia was maintained with halothane or isoflurane and 5 % nitrous oxide in oxygen and supplemented with small to moderate doses of fentanyl (less than 6 ug kg" 1 for the entire operation), depending on surgical requirements. was administered on even-numbered days and isoflurane on odd-numbered days during the first 1 yr and vice versa in the second half of the study. The inspired concentration of the volatile agent was adjusted to maintain the arterial pressure at a value determined by the anaesthetist. was not used in patients in whom liver enzyme concentrations were increased or where halothane had been given within the preceding 4 weeks [13]. Normoventilation was produced as assessed by capnography and blood-gas analysis. Neither anaesthetic nor surgical techniques changed during the 21-month period of the study. If, despite adequate anaesthesia, vasodilatators were needed, either nitroglycerin or nifedepine was used, depending on clinical circumstances. After arrival of the patient in the operating room, ECG leads were attached and a seven-lead ECG (I, II, III, avr, avl, avf, V5) was recorded with a standardization of 1 mv =1 mm. The ST segment trends of lead II and V5 were monitored continuously 8 ms after the J-point of the QRS complex (Sirecust 128, Siemens AG, Erlangen, Germany) from the beginning of the preanaesthetic preparation until the patient left the operating room. Leads II and V5 calibrated to 1 mm mv" 1 were recorded at 25 mm s~ x for 15 s when the ST segment trend analysis was suggestive of ischaemia. The recording system (Sirecust D 22, Siemens AG, Erlangen, Germany) complied with the recommendations of the American Heart Association (diagnostic quality,.5-1 Hz). The 12-lead ECG which had been recorded the day before surgery was used as a reference. Ischaemia was diagnosed by the observer using the continuous ST segment trend analysis as new reversible horizontal or downsloping ST segment depression of at least.1 mv or ST segment elevation of at least.2 mv at J point+ 8 ms lasting for at least 1 min. Arterial pressure and heart rate were noted when ischaemia was diagnosed and compared with values taken 2 min before the event. In addition, when a flow-directed pulmonary artery catheter was used (38 of 5 patients) myocardial ischaemia was considered present when wedge pressure recordings showed an abnormal AC wave > 15 mm Hg or V wave > 2 mm Hg [14]. All ECG recordings were reviewed after operation by one investigator who was unaware of the patient and of the principal anaesthetic used. In case of IMI, treatment was commenced immediately after ECG traces were recorded and according to the probable cause. Hypotension (systolic pressure < 9 mm Hg) in combination with blood loss was treated by fluid replacement and decrease of inspired volatile anaesthetic concentration; hypertension (systolic pressure > 18 mm Hg) by increase of anaesthetic depth (increasing inspired volatile anaesthetic concentration or administration of fentanyl followed by nitroglycerin or nifedepine); tachycardia (> 11 beat min" 1 ) (after excluding hypovolaemia) by increase of anaesthetic dose as above, followed by pindolol 8 ug i.v.; and ischaemia without haemodynamic disturbances by administration of nitroglycerin. In the postoperative period, serial 12-lead ECG recordings, serum creatine kinase (CK) and myoglobin fraction (CKMB) concentrations were measured in samples obtained immediately after surgery and 12 and 24 h later. MI was considered present if ECG changes (new persistent Q waves of at least.4 s duration in the absence of bundle branch blocks or major QRS axis changes) were found or CKMB concentrations were in excess of 1 % of CK concentrations or greater than 4 u litre" 1. Cardiac death (CD) was diagnosed if the patient died from arrhythmias or congestive heart failure. Statistics Data were collected, stored and analysed on an Intel 8386-based microcomputer using the Statistical Package for the Social Sciences (SPSS/PC). Chi-square analysis of significance was calculated for frequency data of the halothane and isoflurane groups (in case of MI and CD, Fisher's exact test because of the small number of patients). The data were expressed as mean (SD) for normally distributed variables (heart rate and mean arterial pressure using the Shapiro-Wilks and Lilliefors test). Data were compared by Student's t test for unpaired data between both groups in the three types of surgery. P <.5 was considered statistically significant. RESULTS At completion of our study, 274 patients had received isoflurane and 226 halothane as their primary anaesthetic agent. Both groups were comparable

3 64 BRITISH JOURNAL OF ANAESTHESIA TABLE II. Perioperative complications and outcome in 5 vascular patients (n = 226) New intraoperative ischaemia 88 (38.9%) associated with Tachycardia 25(11%) (> 11 beat min" 1 ) Hypertension 14(6%) (> 18 mm Hg) Hypotension 16(7%) (< 9 mm Hg) Myocardial infarction 3(1.3%) Cardiac death 1 (.4%) (n = 274) P 15(38.3%) (9 %).57 16(6%).87 22(8%).69 TABLE III. Perioperative myocardial ischaemia Myocardial ischaemia observed during Arrival Anaesthetic induction Surgical stimulation Tracheal extubation (%) (1.5%).9 2(.7%).68 (%) P with the exception of sex in preoperative cardiac assessment, medication and characteristics (table I). Before operation, more than 6 % of patients in both groups had ECG or clinical signs of IHD and were at risk of perioperative MI. The incidence of new IMI, MI and CD did not differ between the two groups (table II). About 23% of all ischaemic episodes in both groups were linked with haemodynamic disturbances such as tachycardia (heart rate > 11 beatmin" 1 ) (halothane 11 %, isoflurane 9%), hypertension (systolic arterial pressure > 18 mm Hg) (halothane 6%, isoflurane 6%) or hypotension (systolic arterial pressure < 9 mm Hg) (halothane 7%, isoflurane 8%). In the anaesthetic room, about 8% (halothane 8.4%, isoflurane 8.8%) of the patients had acute new ischaemia (ST segment depression or elevation, prominent V waves and increased pulmonary capillary wedge pressure without chest discomfort that is, silent angina), which were at least partly reversible during anaesthesia and surgery (table III). During induction of anaesthesia, about 6 % of the patients had new ischaemic episodes, with no difference between the halothane and isoflurane groups. Approximately 23 % of all patients had new reversible episodes of MI during surgery, while 8 % of the isoflurane group and 11 % of the halothane patients had ischaemic changes during and immediately after tracheal extubation. Abnormal A and V waves indicative of new myocardial ischaemia appeared in only two of 3 patients (6.7%) without ST segment changes. Table IV summarizes the haemodynamic changes (mean (SD)) during the occurrence of acute IMI in relation to the three types of vascular surgical interventions. The incidence of new myocardial ischaemia was similar in the three groups. There were no significant haemodynamic changes during the ischaemic episodes, and the extent of these changes was unrelated to the type of surgery. DISCUSSION We have found that the risk of myocardial ischaemia, perioperative myocardial infarction, and fatal cardiac outcome during anaesthesia was similar when either halothane or isoflurane was used as the primary anaesthetic for major non-cardiac vascular procedures. As the study was designed to mimic clinical practice, the effects of nitrous oxide and fentanyl were not analysed separately because the doses of these drugs did not differ between the groups. TABLE IV. Haemodynamic observations before and during new intraoperative myocardial ischaemia (/Af/) in three types of vascular surgery {mean (SD) or No. (%)) t Obtained 2 min before onset of new intraoperative myocardial ischaemia Control valuef Changes during IMI Control valuef Changes during IMI Supra-aortic surgery Aortic surgery Infra-aortic surgery (n = 73) 82 (2) 92 (15) 3(4.1) 4 (5.5) 1 (1-4) (/.= 112) 78 (2) 84 (2) 3 (2.7) 3 (2.7) 5 (4.5) (n = 41) 82 (16) 87 (21) 1 (2.4) 3 (3.7) (IMI =43.8%) 5(1) -1(1) 9 (12.3) 5 (6.8) 5 (6.8) (IMI = 36.6%) 3(2) 9(6) 11 (1.7) 7 (6.3) 8 (7.1) (IMI = 36.6%) 5(5) -1 (.4) 3 (7.3) 2 (4.9) 3 (7.3) («= 75) 84(23) 95 (21) 5 (6.7) 4 (5.8) (n = 132) 78 (18) 84(17) 5 (3.8) 7 (5.3) (n = 67) 77 (12) 88 (17) 1 (1-5) 1 (15) (IMI = 34.7%) 4(1) -2(5) 8 (1.7) 6(8) 6(8) (IMI =4.6%) 4(1) -2(2) 12 (9.1) 7 (5.3) 11 (8.3) (IMI = 31.3%) 5(4) -2(2) 5 (7.5) 3 (4.5) 5 (7.5)

4 INTRAOPERATIVE MYOCARDIAL ISCHAEMIA 65 There were no significant differences between the groups with respect to any factors known to influence IMI (patient age or preoperative ischaemia, arterial pressure and drug therapy, anaesthetic technique or anaesthetist). All cases were undertaken at one institution by two anaesthetists. The prevalence of spontaneous transient impairment of myocardial oxygen supply [15] in the groups could not be compared, but is unlikely to differ, as the groups were comparable for severity of myocardial ischaemia and were similar to those described previously [16-19]. However, the incidence of cardiac deaths and myocardial infarction was too small to reveal outcome differences between the primary anaesthetics but, assuming that the incidence of adverse and fatal outcome remained constant we would need more than 1 patients (i.e. 35 years) to observe statistically significant differences between patients having received halothane or isoflurane as a primary anaesthetic. The incidence of MI and fatal cardiac outcome was less than in previous studies [5, 11]. This may be attributable to the use of an on-line ST segment trend analyser and immediate provision of therapy. The poor correlation between IMI and haemodynamic disturbances confirms previous studies [7, 1, 15,2] and is the probable explanation for the similarity of IMI in the different operation groups. The haemodynamic changes associated with vascular cross-clamping and declamping are much greater for the aorta than for peripheral vessels, but other factors appear to be of greater importance. Previous studies have suggested that anaesthetic agents per se might cause or contribute to myocardial ischaemia under certain circumstances; controversy exists, however, on whether isoflurane alone or in combination with nitrous oxide or fentanyl has deleterious effects on the coronary circulation and outcome in IHD patients [2,4,8,21,22]. In particular, because isoflurane acts as a coronary arteriolar dilatator it may induce coronary steal [21, 22]. In contrast to prospective and retrospective clinical trials [5-7,23], halothane appeared preferable to isoflurane in pharmacological studies [4,21,22]. While the latter drug was thought to induce maldistribution (steal) in CABG patients [4], especially in the presence of hypotension [22], recently published data have failed to support this belief: Slogoff and colleagues [23] demonstrated that the incidence of IMI did not differ between halothane and isoflurane groups in more than 9 CABG patients with a steal-prone coronary anatomy. In contrast, Inoue and colleagues reported a causal relationship between the incidence of MI and the number of deaths and isoflurane anaesthesia compared with enflurane in 1178 CABG patients [8]. However, the incidence of fatal IMI was only 43 % (six of 14) of total mortality and the_ majority of adverse outcomes could not be attributed directly to the primary anaesthetic, as there were group differences in the requirement for antihypertensive drugs, the use of catecholamines or inotropic drugs and the need for intraoperative balloon pump assistance after cardiopulmonary bypass. Moreover, most perioperative MI occurred in the majority of studies h after operation, and factors such as unsuccessful weaning, early tracheal extubation, discontinuation of supplementary oxygen, inadequate analgesia and stress during postoperative intensive care may also be important [4, 5]. 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