COMPARISON OF SUFENTANIL-OXYGEN AND FENTANYL-OXYGEN ANAESTHESIA FOR CORONARY ARTERY BYPASS GRAFTING

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1 Br. J. Anaesth. (1988), 60, COMPARISON OF SUFENTANIL-OXYGEN AND FENTANYL-OXYGEN ANAESTHESIA FOR CORONARY ARTERY BYPASS GRAFTING H. M. L. MATHEWS, G. FURNESS, I. W. CARSON, I. A. ORR, S. M. LYONS AND R. S. J. CLARKE Sufentanil, a synthetic opioid five to 10 times more potent than fentanyl in humans [1] has been used to produce surgical anaesthesia in patients undergoing coronary artery bypass grafting. A study using 15 ug kg" 1 as a single loading dose at induction of anaesthesia reported that this did not totally prevent the hypertensive response relating to sternotomy [2]. In a further study comparing sufentanil and fentanyl for coronary artery surgery, de Lange and colleagues [3] found that a mean dose of sufentanil 4.2 ^g kg" 1 was required to induce anaesthesia. This study therefore assessed and compared the cardiovascular responses when anaesthesia was induced with sufentanil 5 jig kg" 1 and fentanyl 25 (xg kg" 1 in combination with pancuronium, with further supplementation with opioid before skin incision and before sternotomy. PATIENTS AND METHODS With the approval of the local University Medical Ethics Committee, 40 consenting adult patients were studied during coronary artery bypass surgery. All had symptomatic, angiographically proven ischaemic heart disease, with moderate to good left ventricular function (ejection fraction > 40%). Patients with left ventricular aneurysm, valvular disease, or hepatic or renal disorders were excluded from the study. H. M. L. MATHEWS, M.B., F.F.A.R.C.S.; G. FURNESS, M.B., F.F.A.R.C.S. ; R. S. J. CLARKE, M.D., PH.D., F.F.A.R.C.S. ; Department of Anaesthetics, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL. I. W. CARSON, M.D., F.F.A.R.C.S.; I. A. ORR, M.D., F.F.A.R.C.S.; S.M.LYONS, M.D., F.F.A.R.C.S.; Department of Clinical Anaesthesia and Cardiac Surgical Unit, Royal Victoria Hospital, Belfast. Accepted for Publication: October 9, Correspondence to R.S.J.C. SUMMARY Haemodynamic variables were compared in 40 adults undergoing coronary artery bypass grafting during anaesthesia induced with either sufentanil 5 fig kg'' or fentanyl 25 ug kg' 1 in combination with pancuronium 0.1 mg kg' 1. Further doses of sufentanil 2.5 ug kg' 1 or fentanyl 12.5 ug kg~ 1 were given before skin incision and again before sternotomy. All patients were receiving fi-adrenoceptor blocking therapy. Satisfactory induction of anaesthesia was produced with both drugs and opioid supplementation prevented any marked haemodynamic response to skin incision and to sternotomy. Following induction of anaesthesia, sufentanil produced the greater decrease in mean arterial pressure and left ventricular stroke work index which continued throughout the study. This suggests that, in the doses used in this study, sufentanil is preferable to fentanyl in patients with coronary artery disease. All patients were controlled on P-adrenergic blocking drugs which were continued until the evening before surgery. Premedication comprised lorazepam 4-6 mg by mouth 2 h before operation and their usual dose of calcium antagonist and nitrate if they were maintained on this therapy. They were allocated by means of a table of random numbers to receive either sufentanil or fentanyl. ECG monitoring was commenced when the patient arrived in the operating theatre. Peripheral venous, jugular venous and radial artery cannulation was performed under local anaesthesia. A quadruple-lumen thermodilution catheter was floated into the pulmonary artery for measure-

2 SUFENTANIL-O, OR FENTANYL-O, FOR BYPASS GRAFTING 531 ment of central venous (CVP), pulmonary artery (PAP) and wedge (PCWP) pressures. Cardiac output was determined using iced injectate (5% dextrose 10 ml), taking the arithmetic mean of three consecutive values within 10% of each other. All cardiac output measurements, pulmonary capillary wedge and central venous pressures were taken at the end of expiration. Preoxygenation was undertaken for a period of approximately 10 min, during which time baseline measurements of heart rate, systolic, diastolic and mean arterial pressure, central venous, pulmonary artery and pulmonary capillary wedge pressure and cardiac output were recorded. Samples of arterial blood were obtained for gas analysis. All patients received pancuronium 0.03 mg kg" 1 1 min before induction of anaesthesia (table I). The patients received either sufentanil 5 ug kg" 1 or fentanyl 25 ug kg" 1 injected over 1 min. All drugs were administered via the central catheter and flushed with 5% dextrose. Time to loss of eyelash reflex was noted, at which time a further dose of pancuronium 0.07 mg kg" 1 was given. Ventilation was assisted by hand to maintain normocapnia, checked by arterial blood-gas measurements. Cardiovascular measurements were recorded 5 min after the initial dose of pancuronium and intubation was performed at 7 min, with further haemodynamic variables recorded 1 min thereafter. The patient's lungs were 0 1 min Time Loss of eyelash reflex 5 min 7 min 8 min 1 min before skin incision 1 min after skin incision 1 min before sternotomy 1 min after sternotomy TABLE I. Time sequence of study Event Baseline haemodynamics Pancuronium 0.03 mg kg" 1 Sufentanil 5 ug kg" 1 or fentanyl 25 ug kg" 1 Pancuronium 0.07 mg kg" 1 INTUBATION 12.5 ug kg" 1 fentanyl or 2.5 ug kg" 1 sufentanil SKIN INCISION 12.5 ug kg" 1 fentanyl or 2.5 ig kg" 1 sufentanil STERNOTOMY ventilated with a 50 % air in oxygen mixture using an Engstrom ventilator to maintain normocapnia. A supplementary dose of sufentanil 2.5 ug kg" 1 or fentanyl 12.5 ug kg" 1 was given 1 min before skin incision and also 1 min before sternotomy, haemodynamic variables being recorded before and 1-2 min after both events at time of maximum increase in arterial pressure. Systemic vascular resistance (SVR), left ventricular stroke work index (LVSWI) and cardiac index (CI) were calculated using a standard computer program. No fluid was administered during the period of study other than the dextrose used for cardiac output determination. Any muscle rigidity during the study was noted. All patients were questioned the next day on recall of events in the anaesthetic room and during anaesthesia. The results were analysed using repeated measures analysis of variance, and, where statistically significant effects were observed in the analysis of variance, means were compared by Student's t test using the appropriate standard errors derived from the analysis. A significance level of less than 5 % was considered significant throughout. RESULTS Patients were comparable with respect to age, weight and preoperative drug therapy (table II). Loss of eyelash reflex occurred in a mean of 67 s (range 45-1 s) and 82 s (range s) in the sufentanil and fentanyl groups, respectively, although the difference was not significant. During the period of manual ventilation before intubation Pa co averaged 5.3 ±0.55 (SD)kPa in the sufentanil and kpa in the fentanyl Times to skin incision averaged 51 and 46 min and to sternotomy 62 and 58 mm in the sugroups, respectively. fentanil and fentanyl These TABLE II. Demographic data (mean±seat) Number Male/female Age (yr) Weight (kg) Drugs before op. P-Blocker Nitrates Ca 2+ blocker Sufentanil group 15/5 57± Fentanyl group 13/7 54± ±

3 532 BRITISH JOURNAL OF ANAESTHESIA TABLE III. Haemodynamic values (mean±sem) during study. S = Sufentanil; F = fentanyl. HR = heart rate; MAP = mean arterial pressure; CVP = central venous pressure; MPAP = mean pulmonary artery pressure; PCWP' = pulmonary capillary wedge pressure; CI= cardiac index; LVSWl = left ventricular stroke work index; SVR = systemic vascular resistance. *P < 0.05; **P < 0.01; ***P < HR (beat min" 1 ) MAP CVP MPAP PCWP CI (litre min" 1 m" 2 ) LVSWI (g m m" 2 ) SVR (dyn s cm" 5 ) Control S F 70 ±2.6 5 min S 74 ±2.9 F After intubation S 75±3.1 F 75±2.1 Before skin incision S F 73±3.1 After skin incision S 67 ±2.4 F Before sternotomy S F After S F 69 ± sternotomy ± ± ±3.5* 90 ±3.0 88±3.1* 98 ± ±2.9*** 96 ± ±3.4** 98 ± ±3.3* 102 ± * 104 ± ± ±0.48* 8.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±2.55* 44.8 ± ** 42.3± ±1.95* 43.8 ± ±1.91* 47.7 ± * 46.8± ± ± ± ± ± ± ± ± ± ± ± i, 100- E 0- < 50- Baseline 5 min Intub. Before After Skin incision FlG. 1. Mean arterial pressure (±SEM) during the study. A Intub. = intubation. i Before After Sternotomy Fentanyl; i sufentanil. differences were not significant. Two patients in the fentanyl and one in the sufentanil group had slight rigidity lasting approximately 30 s. No patient in either group had any recall of events during induction of anaesthesia or the operation. Haemodynamic values at all the times studied are shown in table III. Analysis of variance showed that the time-course of change in mean arterial pressure was significantly different (F = 2.49; P < 0.05) in the two groups, with sufentanil producing a greater decrease in pressure following induction which remained lower than with fentanyl

4 SUFENTANIL-O, OR FENTANYL-O, FOR BYPASS GRAFTING 533 throughout the period of study (fig. 1). For CVP and LVSWI the analysis of variance showed a difference in baseline between the groups, therefore analysis was repeated with baseline results used as a covariate in the analysis. The change with time was similar in both groups (F = 0.42; P > 0.05) but, after adjustment for differences in baseline, LVSWI was significantly smaller following intubation and during the remainder of the study in the sufentanil group (F=7.72; P<0.0l). CVP was significantly greater (P < 0.05) in the fentanyl group following intubation, but otherwise there was no significant difference between groups during the remainder of the study. Analysis of variance showed no difference between the groups in any of the other haemodynamic indices, although differences with time were noted. Heart rate increased significantly in both groups (P < 0.05) following induction and intubation, but returned to baseline values for the duration of the study. Mean pulmonary and pulmonary capillary wedge pressure showed no significant change during the period of study in either group. Systemic vascular resistance decreased significantly in both groups (P < 0.001) following induction and then increased progressively during the study, with an insignificant increase above baseline following sternotomy. Cardiac index remained stable during induction and intubation with a decrease from baseline before skin incision (P < 0.01). The mean data shown in table III obscure any particular change in cardiovascular dynamics occurring in individual patients. For this reason cardiovascular data have been reviewed from several individual patients in whom marked changes in mean arterial pressure occurred. One patient who received fentanyl had an increase in mean arterial pressure from a baseline of 106 mm Hg to 131 mm Hg following induction of anaesthesia, associated with an increase in heart rate from 57 to 75 beat min" 1 and in PCWP from 7 to 11 mm Hg, and a high LVSWI value of 59.1 gmm" 2. This high mean arterial pressure was maintained until skin incision with no decrease following further supplementation with fentanyl. Although there was no evidence of myocardial ischaemia as detected on ECG lead CM 6, it was felt necessary to supplement the anaesthetic with halothane after skin incision. This patient was included in the study. One other patient who received fentanyl had a marked increase in mean arterial pressure from 81 mm Hg to 124 mm Hg associated with an increased heart rate from 82 to 117 beat min" 1, PCWP 17 mm Hg and LVSWI of 65.2 g m m~ 2 at insertion of skin clips, but this responded to supplementation with fentanyl before skin incision. Both patients reported no recall of events during the operation. One patient in the sufentanil group had a high baseline mean arterial pressure (122 mm Hg) which decreased to 101 mm Hg before skin incision, but increased to baseline values after skin incision and during sternotomy. One sufentanil-treated patient had a mean arterial pressure which decreased from 115mmHg at baseline to 70 mm Hg following induction. The lowest mean arterial pressure in the sufentanil treated patients at any time was 62 mm Hg. None of these changes in mean arterial pressure was associated with any evidence of myocardial ischaemia on ECG at any time in either group. DISCUSSION In this study induction of anaesthesia was rapid in both groups, explained by the rapid administration of sufentanil and fentanyl over 1 min. Rapid administration of fentanyl produces higher peak blood concentrations and more rapid induction of anaesthesia. It has further been shown that there is little difference in onset of anaesthesia or cardiovascular effects between 15 and 60 ug kg" 1 of fentanyl when administered rapidly at 72 ug kg" 1 min" 1 [4]. De Lange [3] found that, by increasing the rate of administration of sufentanil to 300 ug min" 1, anaesthetic induction was faster; rates above this increased the overall frequency of rigidity without decreasing induction time. The induction time of 1.3 min for sufentanil in De Lange's study is similar to our figure of 62 s, although he found a slower induction time of 4.6 min when fentanyl was administered at 400 ug min" 1. In our study fentanyl was administered at approximately 1750 ug min" 1, which would explain the more rapid induction time of 82 s. With such rapid administration. of opioid, pretreatment with pancuronium 0.03 mg kg" 1 1 min before induction prevented any marked rigidity, and in fact only three patients had slight rigidity lasting 30 s. This study, therefore, used doses of opioids in the lower therapeutic range administered rapidly to produce induction of anaesthesia and lack of

5 534 BRITISH JOURNAL OF ANAESTHESIA cardiovascular response to intubation. Waller and his colleagues [5], however, found that a single induction dose of fentanyl 60 (ig kg" 1 was insufficient to block haemodynamic changes following sternotomy and Sebel and Bovill [2] found similar inadequacies with a single dose of sufentanil 15ugkg~ l. In our study, therefore, supplements of one-half the original dose of opioid were given before skin incision and before sternotomy in an attempt to ablate the haemodynamic response to surgical stimulus. Using this opioid regimen, mean arterial pressure was significantly less in the sufentanil group at all times following induction of anaesthesia and during the study, and did not increase above baseline values following sternotomy. The decrease in mean arterial pressure in both groups following induction was initially the result of a decrease in peripheral vascular resistance. In conjunction with this lower mean arterial pressure, the left ventricular stroke work index was also less in the sufentanil group, which is advantageous in patients with ischaemic heart disease. The transient increase in heart rate in both groups following induction of anaesthesia may be assumed to be an effect of the pancuronium, as this increase was not maintained during the remainder of the study and further supplements of opioids had no effect on the heart rate. Thomson and Putnins [6] found that patients given pancuronium, compared with those given dimethyltubocurarine, had significantly increased heart rates following induction and continuing through to sternotomy, despite the presence of 3- adrenergic blockade. However, Pinaud and Souron [7] found that P-adrenergic blockade attenuated the increase in heart rate associated with pancuronium, producing only a slight and transient increase for 5 min after administration of pancuronium, as in our study. Pancuronium increases heart rate by two mechanisms: release of noradrenaline and inhibition of re-uptake of noradrenaline effects which should be blocked by P-blockade. The second mechanism is by vagal blockade, and since our patients did not receive any vagolytic premedication, this mechanism may be the reason for the increase in heart rate associated with pancuronium in our study. No difference was found between groups with respect to systemic vascular resistance, unlike the study by Howie and colleagues [8], in which sufentanil produced a greater decrease in SVR than fentanyl when using twice the dose of opioid used in our study. These workers found no difference in mean arterial pressure between groups. However, if the potency ratio is incorrect, the lower doses used in this study may have given a false impression of the effectiveness of sufentanil. If the higher potency ratio of 10 times, rather than five times, had been taken and a larger dose of fentanyl given, there might have been no differences in cardiovascular stability between the groups. The degree of P-adrenergic blockade present at operation may influence changes in heart rate and arterial pressure during laryngoscopy, skin incision and sternotomy. Stanley, de Lange and Boscoe [9] found that a mean dose of sufentanil 11.4 ug kg" 1 was required in patients who received long term P-blocking therapy, compared with a mean dose requirement of sufentanil 14.8 ug kg" 1 in patients not subjected to P-blockade. All patients in this study were receiving P-blocking drugs, although they did not receive any medication on the morning of surgery. This may account for the adequate control of heart rate and arterial pressure obtained with these relatively low doses of sufentanil, although a further study is required to ascertain if this dose of sufentanil is adequate in patients not receiving P-blocking therapy. In conclusion, all patients in the sufentanil group were adequately anaesthetized. However, two patients in the fentanyl groups had a marked hypertensive response to surgical stimuli, although no awareness was reported, perhaps because of the amnesic properties of the lorazepam premedication. The suggestion that sufentanil was superior to fentanyl in these doses is confirmed by the lower mean arterial pressure and left ventricular stroke work index in the sufentanil group, with no profound hyper- or hypotensive episodes in this group. ACKNOWLEDGEMENTS We are indebted to Mrs Julie Harris and Mr John Meikleham for their skilful technical assistance and to Mr Chris Patterson for his help and guidance with statistics. REFERENCES 1. Rosow CE. Sufentanil citrate: a new opioid for use in anesthesia. Pharmacotherapy 1984; 4: Sebel PS, Bovill JG. Cardiovascular effects of sufentanil

6 SUFENTANIL-O, OR FENTANYL-O, FOR BYPASS GRAFTING 535 anesthesia; a study in patients undergoing cardiac surgery. Anesthesia and Analgesia 1982; 61: De Lange S, Boscoe MJ, Stanley TH, Pace N. Comparison of sufentanil-o 2 and fentanyl-o 2 for coronary artery surgery. Anesthesiology 1982; 56: Bazaral MG, Wagner R, Abi-Nader E, Estafanous FG. Comparison of the effects of 15 and 60 ug/kg fentanyl used for induction of anesthesia in patients with coronary artery disease. Anesthesia and Analgesia 1985; 64: Waller JL, Hug CC, Nagle DM, Craver JM. Heraodynamic changes during fentanyl-oxygen anesthesia for aortocoronary bypass operation. Anesthesiology 1981; 55: Thomson IR, Putnins CL. Adverse effects of pancuronium during high dose fentanyl anesthesia for coronary artery bypass grafting. Anesthesiology 1985; 62: Pinaud MLJ, Souron RJ. Beta-adrenergic effect of pancuronium bromide: fact or fallacy. Antsthesiology 1984; 60: Howie MB, McSweeney TD, Lingam RP, Maschke SP. A comparison of fentanyl-o 2 and sufentanil-o 2 for cardiac anesthesia. Anesthesia and Analgesia 1985; 64: Stanley TH, de Lange Si Boscoe MJ. The influence of chronic preoperative beta adrenergic blocker therapy on intraoperative cardiovascular dynamics and narcotic requirements in patients with coronary artery disease. Anesthesiology 1981; 55: A48.