Inhalation induction with sevoflurane: a double-blind comparison with propofol

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1 British Journal of Anaesthesia 1997; 78: Inhalation induction with sevoflurane: a double-blind comparison with propofol A. THWAITES, S. EDMENDS AND I. SMITH Summary We conducted a randomized, double-blind comparison of 8% sevoflurane and propofol as induction agents for day-case cystoscopy in 102 patients. All patients received an i.v. cannula and breathed oxygen 5 litre min 1. Anaesthesia was induced with propofol i.v. or inhalation of 8% sevoflurane and 10% Intralipid (as a placebo) i.v., delivered by a blinded observer. Anaesthesia was maintained in all patients with 2% sevoflurane via a face mask. Induction of anaesthesia with sevoflurane was significantly slower compared with propofol (mean 84 (SD 24) s vs 57 (11) s), but was associated with a lower incidence of apnoea (16% vs 65%) and a shorter time to establish spontaneous ventilation (94 (34) s vs 126 (79) s). Induction complications were uncommon in each group but the transition to maintenance was smoother with sevoflurane and was associated with less hypotension compared with propofol. Emergence from anaesthesia induced with sevoflurane occurred significantly earlier compared with propofol (5.2 (2.2) min vs 7.0 (3.2) min) and anaesthetic induction was also significantly cheaper with sevoflurane. According to a postoperative questionnaire, the majority of patients found both anaesthetic techniques acceptable. Nevertheless, significantly more patients (14%) rated induction with sevoflurane as unpleasant compared with propofol (0) and significantly more patients (24%) would not choose sevoflurane induction compared with propofol (6%). This phenomenon may have been related to the particular patient population studied, however. Inhalation induction with 8% sevoflurane would appear to offer several objective advantages compared with induction with propofol in day-case patients, although a significant minority may dislike this technique. (Br. J. Anaesth. 1997; 78: ). Key words Anaesthetics volatile, sevoflurane. Anaesthetics i.v., propofol. Anaesthesia, day case. Anaesthetic techniques, induction. One of the major objections to performing inhalation induction of anaesthesia is patients dislike of a black rubber face mask. Nevertheless, the widespread availability of modern clear plastic masks, combined with an increasing tendency to use face masks to perform preoxygenation before induction of anaesthesia have largely overcome this objection. With the availability of a non-pungent and rapidly acting volatile anaesthetic, it would seem logical to use a face mask both to provide oxygen and induce anaesthesia, thereby avoiding many of the problems associated with i.v. induction. Sevoflurane has a low blood:gas solubility coefficient (0.69) 1 and is the least respiratory irritant of the available volatile anaesthetics. 2 These properties make sevoflurane an ideal inhalation induction agent. 3 Previous investigations have shown sevoflurane to be an acceptable induction agent in adult patients. 4 5 However, these investigators used an earlier sevoflurane vaporizer which was limited to a maximum output of 5% (compared with 8% on current models). In addition, patients were pretreated with opioid analgesics. Finally, the earlier comparisons were not blinded and did not specifically examine the patient s experience of induction. We therefore conducted a randomized, double-blind comparison of induction of anaesthesia in unpremedicated patients with 8% sevoflurane ord propofol (the most commonly used induction agent). Patients and methods We studied 102 ASA I III patients undergoing daycase cystoscopy for follow-up of bladder carcinoma, haematuria or urinary tract infection, according to a design approved by the Ethics Committee of the North Staffordshire Hospital. After obtaining written, informed consent, patients were allocated randomly to one of two induction groups using computer-generated random numbers and sequentially numbered sealed envelopes. All patients were unpremedicated. Patients with a previous history of malignant hyperthermia or adverse reaction to inhalation anaesthetics or propofol were excluded. Patients receiving sedative medications chronically ALISON THWAITES, MB, BS, FRCA, SHIREEN EDMENDS, MB, BS, FRCA, IAN SMITH, BSC, MB, BS, FRCA, North Staffordshire Hospitals, Newcastle Road, Stoke-on-Trent, Staffordshire ST4 6QG. Correspondence to I. S. Presented in part at the American Society of Anesthesiologists Annual Meeting, October 1996.

2 Inhalation induction with sevoflurane 357 and those with serious, life-threatening respiratory or cardiovascular diseases were also excluded. Before induction of anaesthesia, one anaesthetist (A. T.) prepared a 20-ml syringe containing either propofol or 10% Intralipid as a placebo control. A 20-gauge i.v. cannula was inserted into the patient s non-dominant hand and 2 ml of 1% lignocaine were administered to all patients. Although lignocaine was injected as prophylaxis against pain on injection of propofol, it was administered to both groups of patients because of possible effects on haemodynamic variables. All patients received oxygen for 1 min from a clear plastic face mask at a flow rate of 5 litre min 1 and patients were given a weighted object to hold. 6 At the start of induction of anaesthesia, fresh gas flow was changed to nitrous oxide 4 litre min 1 and oxygen 2 litre min 1 in all patients. In the sevoflurane group, the non-blinded anaesthetist (A. T.) turned the sevoflurane vaporizer to 8% at the start of induction. A similar hand movement was made in the propofol group, but the vaporizer dial was not actually turned. The sevoflurane vaporizer was hidden from view of the blinded observer (I. S.) by an opaque curtain. Simultaneous with the start of induction, the observer began to inject the contents of the 20-ml syringe (propofol or placebo) at a constant rate of ml min 1 and continued until the patient dropped the weighted object. Spontaneous patient activities and comments were recorded by the observer. Arterial pressure, heart rate and haemoglobin oxygen saturation ( S p O ) 2 were recorded at 1-min intervals during induction. The observer judged anaesthesia to be induced when the patient dropped the weighted object. At this point, the volume of i.v. drug injected was recorded and anaesthesia was maintained with 2% sevoflurane in both groups of patients, subsequently adjusted up or down as necessary in order to maintain adequate anaesthesia as judged by the usual clinical signs. 7 Anaesthesia was maintained using a face mask. The observer recorded a guess as to which induction agent had been used, evaluated the occurrence of apnoea and recorded when spontaneous ventilation resumed. The occurrence of movements and coughing during the transition period from induction to maintenance was also recorded. All induction sequence events were timed using a palm top computer (Psion, London) and custom software. Oxygen and anaesthesia were delivered using a Humphrey ADE circuit used in its A setting. The system was flushed with oxygen 50 litre min 1 between patients until the investigators were unable to smell residual sevoflurane. The costs of induction (see appendix) were calculated on the current list price of the primary induction drug. Induction costs for sevoflurane were based on the list price of the anaesthetic liquid, the volume of vapour produced per ml of liquid (182.7 ml), 8 fresh gas flow and induction time. At the end of the procedure, sevoflurane and nitrous oxide were discontinued simultaneously and the time at which patients opened their eyes to command was recorded by the observer. Before discharge from the day-case unit, patients completed a questionnaire to evaluate their induction experience. Patients were asked about their recollection of the face mask, smells and tastes during induction of anaesthesia and whether or not these were unpleasant. Patients were also asked about pain on injection of the i.v. drug and were asked to guess if their anaesthesia had been induced by an injection or by breathing a gas. Induction of anaesthesia was rated as pleasant neither pleasant nor unpleasant or unpleasant. Finally, the patient s willingness to receive an identical anaesthetic induction in the future was determined. Data were analysed using the Statview statistical package. Continuous variables were analysed using non-paired t tests. Discrete data were analysed using chi-square tests or Fisher s exact test as appropriate. Data which were not distributed normally were analysed using an appropriate non-parametric test. In all cases P 0.05 was considered significant. Results The two induction groups were comparable in patient characteristics (table 1). Induction of anaesthesia with propofol was significantly more rapid compared with 8% sevoflurane (mean 57 (SD 11) s vs 84 (24) s, P 0.01). Induction of anaesthesia with propofol required an average of 167 (31) mg (2.3 (0.5) mg kg 1 ). Six patients spoke with slurred speech during induction with propofol compared with seven who received sevoflurane. Purposeful movements were made by three patients in the propofol group and by five in the sevoflurane group (P 0.46). In addition, one patient in the sevoflurane group exhibited mild coughing. The induction sequences were sufficiently similar that the observer could identify the induction technique correctly only 65% of the time with propofol and 61% of the time with sevoflurane. Apnoea occurred significantly more frequently in the propofol induction group (33 (65%)) compared with the sevoflurane group (eight (16%)) (P 0.01). As a consequence, the time from beginning induction until patients were breathing spontaneously with a regular ventilatory pattern was significantly shorter with sevoflurane compared with propofol (94 (34) s vs 126 (79) s, respectively). Coughing after induction of anaesthesia, during the transition to the maintenance phase, occurred in four patients (8%) in the sevoflurane group and in 12 patients (24%) in the propofol group (P 0.03). Mean arterial pressure (MAP) recorded immediately before induction of anaesthesia did not differ significantly between the two groups (fig. 1). Table 1 Patient characteristics in the two anaesthetic induction groups. Values are mean (SD or range) or number of occurrences Sevoflurane Number (n) Age (yr) 58 (20 81) 60 (18 85) Weight (kg) 73 (14) 73 (13) ASA (I/II/III) 18/32/1 23/26/2 Sex (M/F) 29/22 31/20 Smoking history Non-smoker Ex-smoker Current smoker 14 15

3 358 British Journal of Anaesthesia Table 2 Patient s perspective on induction of anaesthesia. Values are number (%) of responses. *P 0.05 compared with propofol Sevoflurane Figure 1 Mean arterial pressure (MAP) before induction of anaesthesia (Preop.) and at the indicated times after induction of anaesthesia with propofol (!) or 8% sevoflurane ("). Values are mean, SEM. *P 0.05 compared with propofol. Recall face mask 51 (100%) 50 (98%) Mask unpleasant 2 (4%) 10 (20%)* Recall smell 31 (61%) 47 (92%)* Smell unpleasant 4 (8%) 15 (29%)* Recall taste 14 (27%) 26 (51%)* Taste unpleasant 4 (8%) 11 (22%) Pain on injection 12 (24%) 5 (10%) Guess Correct 8 (16%) 34 (67%)* Incorrect 21 (41%) 2 (4%)* No guess attempted 22 (43%) 15 (29%) Induction Pleasant 35 (69%) 24 (47%)* Indifferent 13 (25%) 16 (31%) Unpleasant 0 7 (14%)* No recall 3 (6%) 4 (8%) Future preference Same technique 31 (61%) 22 (43%) No preference 17 (33%) 17 (33%) Different technique 3 (6%) 12 (24%)* Figure 2 Heart rate (HR) before induction of anaesthesia (Preop.) and at the indicated times after induction of anaesthesia with propofol (!) or 8% sevoflurane ("). Values are mean, SEM. Induction of anaesthesia with propofol was associated with a decrease of approximately 20 mm Hg in MAP which occurred within 2 min and persisted for at least the first 5 min of anaesthesia. In contrast, the decrease in MAP with sevoflurane was only 10 mm Hg and MAP had returned to baseline values within 5 min. As a consequence, MAP was significantly lower at 2 5 min after induction of anaesthesia with propofol compared with sevoflurane (fig. 1). Heart rate (HR) increased slightly compared with baseline after induction of anaesthesia with each agent. However, HR did not differ significantly between the groups at any time during induction (fig. 2). There was also no difference in Sp O between the two 2 groups at any time. Patient responses to the postoperative questionnaire are shown in table 2. Most patients recalled the presence of the face mask. While this was well tolerated by the majority of patients, significantly more patients in the sevoflurane group found the face mask unpleasant. Although a smell was reported most commonly by patients receiving sevoflurane (92%), 61% of patients recalled a smell in the propofol group. However, this smell was reported as unpleasant by significantly more patients in the sevoflurane group. A taste was also reported more commonly with sevoflurane, although there was no significant difference in the number of patients who described this as unpleasant. When patients attempted to guess which induction technique they had received, they were more inclined to choose the inhalation technique. As a result, significantly more patients guessed correctly in the sevoflurane induction group and incorrectly in the propofol induction group. Induction with propofol was rated as pleasant significantly more frequently compared with sevoflura ne, with most of the rema ining patients either having no recall of induction or providing an indifferent response (neither pleasant nor unpleasant). Induction was described as unpleasant by a minority of patients (seven (14%)) all of whom were in the sevoflurane group. There was a tendency for more patients receiving propofol to favour the same induction technique in the future, although this difference was not statistically significant. However, significantly more patients who received sevoflurane (24% vs 6%) were unwilling to receive the same induction again (P 0.02). Based on the actual amount of i.v. drug used, the cost of induction of anaesthesia with propofol was 3.23 (0.60). On the basis of one ampoule of propofol per patient, this cost increased to The cost of induction with 8% sevoflurane was 1.95 (0.56), which was significantly cheaper compared with propofol. The average time from the start of induction of anaesthesia to completion of surgery was 10.0 (3.9) min in the propofol group and 10.2 (3.2) min in the sevoflurane group. There were no significant differences between groups in terms of the highest or lowest anaesthetic concentrations required during maintenance or in the delivered anaesthetic concentration at the end of anaesthesia (2.3 (0.9) % and 2.3 (0.8) % in the propofol and sevoflurane groups, respectively). Emergence times in the sevoflurane induction group (5.2 (2.2) min) were significantly faster compared with the propofol group (7.0 (3.2) min). There were no differences in subsequent recovery events between the two groups. Postoperative nausea (two) and vomiting (two) occurred in

4 Inhalation induction with sevoflurane 359 four patients in the sevoflurane group compared with none in the propofol group. This difference was not statistically significant. Discussion This is the first double-blind comparison of induction of anaesthesia with sevoflurane and an i.v. agent. Our results suggest that sevoflurane is a practical induction agent for unpremedicated adult daycase patients. Although induction times with sevoflurane were slower compared with propofol, this difference was not of great clinical significance and was not obvious to the observer. Furthermore, the higher incidence of apnoea with propofol resulted in the end-point of anaesthesia accompanied by regular spontaneous ventilation being achieved significantly earlier with sevoflurane. Although this difference was also of limited clinical significance, the transition from induction to maintenance with sevoflurane was significantly smoother compared with propofol, with fewer patients coughing after induction. This difference is probably explained by the fact that when anaesthesia has been induced by inhalation, the inspired and alveolar anaesthetic concentrations are almost equilibrated, so that subsequent small changes in the depth of anaesthesia are readily achieved. In contrast, after induction of anaesthesia with an i.v. agent, the drug rapidly redistributes leading to a decrease in the depth of anaesthesia. During this period, it is necessary to introduce the maintenance agent rapidly in order to re-establish an adequate depth of anaesthesia. At the same time, stimulating events such as patient positioning, skin cleaning and surgical incision may be occurring, requiring a relatively greater depth of anaesthesia. The fact that our patients predominantly exhibited coughing during this period suggests that anaesthesia was sufficient to prevent purposeful movements, but inadequate to suppress reflex stimulation resulting from the presence of an oral airway or manipulation of the anatomical airway. It is possible that the transition from induction to maintenance would have been smoother had a concentration of sevoflurane greater than 2% been introduced in patients receiving propofol. However, the results of a pilot study suggested that this concentration was the best compromise to use in both groups of patients without unblinding the investigation. Induction of anaesthesia with sevoflurane was associated with several other advantages. MAP was better maintained with sevoflurane compared with propofol and while the difference may be of limited significance for healthy patients, the relative hypotension associated with propofol may be disadvantageous in the elderly and coronary artery disease. Emergence from sevoflurane anaesthesia also occurred significantly faster when sevoflurane was used for induction compared with propofol. This difference was presumably because of the residual sedative effect of propofol and would probably not have been detectable after longer operations. However, this difference of only 2 min is probably of little, if any, clinical significance. Induction of anaesthesia with 8% sevoflurane was also significantly cheaper compared with propofol. In practice, the cost of i.v. induction depends on how much induction agent is actually drawn up and whether the remainder of the ampoule is discarded or used for the next patient. Although the manufacturers of propofol state that their ampoules are for single patient use, ampoule sharing occurs commonly. We therefore calculated the cost of propofol induction using the two extremes, that is on the basis of the exact amount of propofol required and on the basis of one ampoule per patient. Sevoflurane induction was substantially cheaper by both methods of comparison. Our calculation did not include the cost of the plastic syringe or of lignocaine required to reduce pain on injection of propofol. Sevoflurane costs did not include the (small) cost of nitrous oxide or the cost of obtaining and servicing the sevoflurane vaporizer. Costs common to both techniques (e.g. face mask and breathing system) were also not included. Despite these advantages of sevoflurane over propofol, inhalation induction of anaesthesia was not as popular with our patients as the use of an i.v. induction agent. Although the majority of patients either had no preference or would choose the same anaesthetic again, a significant minority were unwilling to undergo further inhalation induction and several patients described this technique as unpleasant. The most likely explanation for this finding was the odour reported by most patients receiving sevoflurane, and which 29% of these patients described as unpleasant. In contrast, previous open (non-blinded) evaluations of sevoflurane have reported its odour to be pleasant 9 10 and have found inhalation induction popular with almost all patients Our patient population was chosen because cystoscopy is a short procedure without significant postoperative pain. It was therefore considered that these patients would have optimum postoperative recall of the induction period. More prolonged anaesthesia may have modified patients recall of the induction process in these previous investigations. Although this comparison was double-blind, the possibility of patient bias cannot be excluded. This is suggested by the fact that more than 60% of patients receiving propofol also reported a smell during induction and patients were more inclined to guess that they had received an inhalation induction irrespective of the technique used. Patients undergoing cystoscopy have usually received multiple previous anaesthetics, often with the same anaesthetist, and are accustomed to a particular routine. Furthermore, these relatively elderly patients often have had personal experience of inhalation induction with older, less satisfactory anaesthetic agents. As a result, these patients are suspicious of any changes in anaesthetic practice, as indicated by a relatively high rate of refusal to consent to participate in this clinical study compared with our previous experience with other studies. Patients receiving propofol for induction of anaesthesia may have detected a residual smell from previous use of the anaesthetic system. In an attempt to reduce this possibility, the breathing system was

5 360 British Journal of Anaesthesia flushed with oxygen between patients until the investigator could no longer smell sevoflurane. Previous investigations have also used lower concentrations of sevoflurane for induction of anaesthesia. A tidal breathing technique in which 5% sevoflurane was inspired from the outset induced anaesthesia in s and was tolerated well by adult patients pretreated with fentanyl. 4 5 Stepwise induction with 0.5% sevoflurane increased to a maximum of 4.5% also induced anaesthesia in a similar time, but was associated with excitatory activity in more than 30% of patients. 9 This level of excitement does not appear to be observed with more rapid induction of anaesthesia. 9 The use of 8% sevoflurane in a tidal breathing technique allowed more rapid induction of anaesthesia than reported in previous investigations with 5% sevoflurane and was also not associated with significant excitatory activity. The previous highest concentration of sevoflurane used for induction was 7.5%. 10 These authors reported coughing in 25% of patients receiving a tidal breathing induction technique with 7.5% sevoflurane, although coughing was reduced to 5% by a vital capacity breathing technique. 10 Interestingly, we observed coughing during induction in only one patient (2%) during tidal breathing with 8% sevoflurane. In the former study, the anaesthetic system was primed with 7.5% sevoflurane (in nitrous oxide) before being applied to the patients, whereas our patients initially breathed oxygen from a system to which sevoflurane and nitrous oxide were subsequently added. Because of mixing with oxygen within the breathing system, the concentration of sevoflurane at the mask would have reached a maximum more slowly and this may have minimized coughing. Nevertheless, the relatively high number of patients who described the smell of sevoflurane as unpleasant may have been as a consequence of using 8% sevoflurane rather than the lower doses used previously. Further work is needed to determine the optimum sevoflurane concentration and administration technique for induction of anaesthesia. Four patients experienced postoperative nausea and vomiting (PONV) when anaesthesia was induced and maintained with sevoflurane compared with none when propofol was the induction agent. Our study was not designed with sufficient power to detect such a small difference in PONV as statistically significant. Nevertheless, propofol is known to have antiemetic effects which may persist into the postoperative period even when it is used solely as an induction agent It is possible therefore that this small difference in PONV is genuine, although with the small numbers involved it is unlikely to be of great clinical importance. In summary, 8% sevoflurane was a practical induction agent for use in unpremedicated adult patients undergoing day-case cystoscopy. A slightly slower induction time with sevoflurane was offset by a reduced incidence of apnoea, earlier establishment of regular spontaneous ventilation, smoother transition to the maintenance phase, minimal depression of MAP during induction of anaesthesia, earlier emergence from anaesthesia and reduced induction costs. Although induction of anaesthesia with sevoflurane was acceptable to the majority of patients, a significant minority found it to be unpleasant and would prefer a different technique in the future. While it is possible that this finding was unique to the particular patient population chosen, inhalation induction may not prove as universally popular as i.v. induction. However, the technique may be particularly beneficial to patients with needle phobias or difficult venous access. Appendix CALCULATION OF INDUCTION COSTS Cost ( ) (List price of ampoule / 20)εinduction dose (ml) Sevoflurane Cost ( ) Induction time (min)εfresh gas flow (ml)εset %ε price of bottle / (100-set %) bottle size (ml) ml vapour per ml liquid anaesthetic (182.7) List prices used for this study 3.88 for a 20-ml ampoule Sevoflurane for a 100-ml bottle. Acknowledgements This project was supported, in part, by educational grants from Abbott Laboratories and Zeneca Pharma. References 1. Strum DP, Eger EI II. Partition coefficients for sevoflurane in human blood, saline, and olive oil. Anesthesia and Analgesia 1987; 66: Doi M, Ikeda K. Airway irritation produced by volatile anaesthetics during brief inhalation: Comparison of halothane, enflurane, isoflurane and sevoflurane. Canadian Journal of Anaesthesia 1993; 40: Smith I, Nathanson M, White PF. Sevoflurane A longawaited volatile anaesthetic. British Journal of Anaesthesia 1996; 76: Smith I, Ding Y, White PF. 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Induction of anesthesia with sevoflurane, nitrous oxide, and oxygen: A comparison of spontaneous ventilation and vital capacity rapid inhalation induction (VCRII) techniques. Anesthesia and Analgesia 1993; 76: Yurino M, Kimura H. A comparison of vital capacity breath and tidal breathing techniques for induction of anaesthesia with high sevoflurane concentrations in nitrous oxide and oxygen. Anaesthesia 1995; 50:

6 Inhalation induction with sevoflurane Yurino M, Kimura H. Vital capacity breath technique for rapid anaesthetic induction: Comparison of sevoflurane and isoflurane. Anaesthesia 1992; 47: Sloan MH, Conard PF, Karsunky PK, Gross JB. Sevoflurane versus isoflurane: Induction and recovery characteristics with single-breath inhaled inductions of anesthesia. Anesthesia and Analgesia 1996; 82: Chittleborough MC, Osborne GA, Rudkin GE, Vickers D, Leppard PI, Barlow J. Double-blind comparison of patient recovery after induction with propofol of thiopentone for day-case general anaesthesia. Anaesthesia and Intensive Care 1992; 20: DeGrood PMRM, Harbers JBM, Van Egmond J, Crul JF. Anaesthesia for laparoscopy. A comparison of five techniques including propofol, etomidate, thiopentone and isoflurane. Anaesthesia 1987; 42: