The choice of anaesthetic drugs and/or techniques may affect postoperative cognitive function [1,2]. Of concern, residual levels of volatile anaesthetics can produce changes in central nervous system activity [3-5]. Therefore, the use of a volatile anaesthetic that is rapidly eliminated may help reduce postoperative confusion and cognitive impairment in elderly surgical patients by facilitating a faster recovery from general anaesthesia [6–8]. It has been clearly demonstrated in procedures of greater than 1 h duration that the lower blood-gas coefficient of sevoflurane, in comparison to isoflurane, provides for more rapid elimination, facilitating a more rapid emergence and recovery of cognitive function . However, the potential for sevoflurane to speed up the return of cognitive function following procedures of short duration is not known.
Materials and methods
After obtaining approval from the Hospital Ethics Committee and written informed patient consent, we studied 71 ASA physical status I–III patients over the age of 60 yr scheduled for elective ambulatory urological procedures of 20–60 min duration under general anaesthesia in a prospective, randomized, double-blind and controlled clinical trial. The procedures included cystoscopy, urethral dilatation, ureteroscopy or ureteric stent insertion. Exclusion criteria included concurrent neurological or psychiatric disease, inability to perform baseline mini mental state examination (MMSE) or a baseline score less than 23, a history of alcohol or drug abuse, morbid obesity, hypersensitivity to anaesthetic agents or recent exposure (within 7 days) to such agents.
The allocation sequence was generated by random number tables. The allocation was concealed in sealed envelopes, which were not opened until patient consent had been obtained. Patients were allocated to receive maintenance of anaesthesia with sevoflurane or isoflurane in nitrous oxide and oxygen.
Preoperative management and anaesthesia
No sedative premedication was administered to any patient. Routine monitoring included non-invasive blood pressure (NIBP), electrocardiogram, pulse oximetry (SPO2) and end-tidal carbon dioxide monitoring (etCO2). Patients were preoxygenated with 100% O2. Induction of anaesthesia was standardized, with all patients receiving fentanyl 1 μg kg−1 and propofol 1.5–2.0 mg kg−1. A laryngeal mask airway (LMA) was used for airway maintenance and patients were manually ventilated post-induction until spontaneous respirations returned. The etCO2 was kept at 4–6.5 kPa throughout all procedures. End-tidal volatile agent concentrations were adjusted as necessary to maintain haemodynamic variables within 15% of pre-induction values , with target values of 1–1.5% for sevoflurane and 0.5–1.0% for isoflurane in 65% N2O and O2. A circle anaesthetic breathing system with a fresh gas flow of 3 L min−1 was used in all patients. All patients received urethral instillation of 2% lignocaine gel (Instillagel®; Farco-Pharma GmbH, Cologne, Germany) before insertion of the rigid cystoscope. Supplemental fentanyl was used for analgesia. Hypotension was treated with a crystalloid fluid bolus and/or ephedrine as appropriate. Any intraoperative adverse effects were recorded. Upon removal of the surgical instruments, the volatile agents were discontinued, 100% oxygen was administered at a fresh gas flow of 10 L min−1, and the patients were transferred to the post anaesthesia care unit (PACU) on regaining consciousness. Fentanyl was used to treat pain in the PACU.
All data, including routine physiological parameters, comprising heart rate (HR), SPO2 and NIBP, were recorded by a blinded investigator. The primary outcome measure was time to fitness for PACU discharge, as measured by the time taken to achieve a modified Aldrete score of 9–10 , as assessed by a blinded PACU nurse. The following parameters were also recorded: duration of anaesthesia (volatile gas administration from induction to discontinuation of the volatile agent), and time to eye opening, LMA removal, appropriate verbal response, orientation to name and date of birth. Adverse effects, total doses of analgesics and other administered medication during the 24 h postoperatively were also recorded.
Assessment of neurocognitive function
Cognitive function was assessed with the MMSE, a brief 30-point questionnaire test that is used to assess the cognitive state of patients . The digit repetition forward (DRF) and digit repetition backward (DRB) tests were used to assess attention, alertness, concentration and short-term memory [12-14]. These clinical tests assess immediate serial recall by the patient of a list of digits spoken by the investigator. In DRF patients repeat digits in the same order as they are presented, and in DRB they repeat them in reverse order [12–14]. These tests were carried out preoperatively on the morning of or evening before surgery to determine the baseline cognitive function, and postoperative tests were carried out at 1, 3 and 6 h. Both sets of tests were carried out by the same blinded investigator.
Sample size calculations were carried out for time to readiness for discharge from the PACU, which was taken as the primary outcome measure. Our calculations were based on prior data from our clinical practice. A maximum of 70 patients (35 per group) were required to detect a 5 min decrease in the time to PACU discharge with a power of 80% and alpha (α) was set at 0.05.
All analyses were performed on an intention-to-treat basis. Patient characteristics and data regarding emergence from anaesthesia were analysed using the t-test. The neurocognitive data were analysed with a two-way repeated measures ANOVA, with group and time as factors, following assessment of the data for normality. Subsequent one-way repeated measures ANOVA was followed by Student–Newman–Keuls or t-tests with Bonferroni's test as appropriate. Continuous data are presented as means ± standard error of the mean, ordinal data are presented as medians ± quartiles (interquartile range), and categorical data are presented as raw data or as frequencies. The α level for all analyses was set as P < 0.05.
Seventy-one patients fulfilled the inclusion criteria and were entered into the study. There were no between-group demographic differences (Table 1). Following enrolment into the study, one patient from the sevoflurane group was excluded due to the need to return the patient to theatre to control postoperative bleeding. No adverse effects attributable to the anaesthetic agents were seen in either group.
There were no differences in intraoperative anaesthetic management between both groups, except for the volatile anaesthetic used. There were no between-group differences (sevoflurane vs. isoflurane) in the amount of fentanyl (62.5 ± 4.0 vs. 65.7 ± 3.4 μg), propofol (1.94 ± 0.1 vs. 1.81 ± 0.1 mg kg−1), expired N2O concentrations (Table 2), minimum anaesthetic concentration of sevoflurane/isoflurane (Table 2) or postoperative narcotic use. There was no significant change in oxygen saturations over time in either group. There was a modest decrease in intraoperative blood pressure and in HR, and a small increase in etCO2 concentrations, over time in both groups (Table 2). The duration of anaesthesia was comparable in both groups (Table 3).
There were no between-group differences detected in the early postoperative recovery profile (Table 3). There were no between-group differences in baseline MMSE scores at any time point studied (Table 4). Postoperatively, MMSE scores were significantly reduced from baseline at 1 and 3 h with sevoflurane and 3 h with isoflurane (Table 4). There were no between-group differences in digit repetition scores at baseline or at any postoperative time point (Table 4). DRF scores were significantly reduced from baseline at 1 h with sevoflurane and 3 h with isoflurane (Table 4). DRB scores were significantly reduced from baseline at 1 h and 3 h with sevoflurane (Table 4).
Our study clearly demonstrates that, in older patients undergoing short procedures under general anaesthesia, there was no difference between sevoflurane and isoflurane with regard to postoperative recovery profile. Furthermore, we did not find any clinically important difference between sevoflurane and isoflurane with regard to recovery of cognitive function in this potentially high-risk group of patients.
Alterations in cognitive function following general anaesthesia place patients at higher risks from postoperative adverse events. In one study, patients undergoing ambulatory anaesthesia reported significantly more cognitive failures, including failures of perception, memory or misdirected action, 3 days postoperatively, compared to patients undergoing procedures under local anaesthesia .
The potential for volatile anaesthetic agents to contribute to adverse postoperative cognitive effects is clear. Even trace concentrations of volatile anaesthetic agents may affect task performance such as word recall and memory tests in healthy volunteers [16,17]. Hence, volatile anaesthetic agents that are more rapidly eliminated could have beneficial patient effects by limiting the overall duration of exposure and thereby reducing the residual effects of these agents. Specifically, the use of sevoflurane, with its lower blood : gas partition coefficient compared to isoflurane (0.69 vs. 1.4), might speed up the return of cognitive function in elderly surgical patients undergoing general anaesthesia [6-8]. Studies to date that have examined postoperative cognitive function have focused on procedures of greater than 1 h in duration [18–21]. Several of these studies have demonstrated improved recovery of cognitive function with sevoflurane compared to isoflurane [6–8,18–20], although there is some disagreement [21,22].
The potential for sevoflurane to speed the return of cognitive function in older patients undergoing procedures of shorter duration has received relatively little attention. Ebert and colleagues reported a progressive advantage in recovery profile with sevoflurane, compared to isoflurane, when case duration was longer than 1 h . However, they failed to show any benefit with the use of sevoflurane over isoflurane for procedures lasting less than 1 h. Philip and colleagues compared sevoflurane to isoflurane in a young low-risk adult ambulatory patient population . They reported an improved recovery profile with sevoflurane, in terms of reduced time to eye opening, command response, orientation and ability to sit without nausea and/or dizziness. Significantly more sevoflurane patients demonstrated an Aldrete recovery criterion of eight or more on arrival in PACU, and they were able to complete psychomotor tests during the first 60 min following anaesthesia. However, there was no difference in PACU discharge times, and there was considerable variability in the duration of anaesthesia in this study, with a range of 7–207 min reported . In contrast, Elcock and Sweeney found a higher incidence of respiratory and cardiovascular complications with sevoflurane compared to isoflurane, in an ambulatory surgical population undergoing knee arthroscopy procedures of approximately 30 min duration .
Our study demonstrates that there is no difference in the early or intermediate postoperative recovery profile of older patients undergoing short procedures, when sevoflurane or isoflurane is used to maintain anaesthesia. In fact, the small but statistically significant differences in postoperative neurocognitive function found in our study appeared to favour isoflurane over sevoflurane. However, the clinical importance of these relatively minor differences is likely to be minimal.
A number of potential explanations for our findings deserve consideration. Firstly, it is possible that in procedures of less than 1 h duration, which this study was specifically designed to examine, the drugs used to induce anaesthesia and provide analgesia may have residual hangover effects that negate any potential benefits of sevoflurane in this context. However, the duration of action of both fentanyl and propofol, the drugs used in this study, is relatively short. Secondly, while the lower blood-gas solubility of sevoflurane suggests that this agent should enter and leave the body more rapidly [24-26], the closeness of both agents' tissue/blood partition coefficients (48 vs. 45) suggests that the rates of equilibration with and elimination from tissues – including the brain – might be similar, although clearly this is not the only determinant of tissue/blood transfer rates. Thirdly, the absence of a significant difference in the two groups does not exclude the possibility that a more sensitive test of cognitive function might demonstrate a difference between the two volatile agents. In addition, the possibility of a learning effect, whereby the repeated administration of the cognitive tests may have had some impact on the results, might have obscured small between-group differences in cognitive function. However, any such minor differences in cognitive profile, should they exist, are likely to be of limited clinical relevance.
One clear limitation of the study is the fact that bispectral index (BIS) monitoring was not utilized to confirm that a comparable depth of anaesthesia was achieved in both groups. We did not use BIS as we did not consider this to constitute usual clinical practice for brief surgical procedures in which the anaesthetic technique did not involve the use of a muscle relaxant.
Our results are of direct clinical relevance, given that the number of older patients presenting for ambulatory procedures of short to medium duration continues to increase. Although our study did not directly address this issue, given the greater cost of sevoflurane  coupled with the lack of a demonstrable benefit in terms of recovery profile, it may make more economic sense to reserve the use of sevoflurane for cases of longer than 1 h duration in this population.
In conclusion, we report that isoflurane and sevoflurane anaesthesia resulted in similar clinical and neurocognitive recovery profiles in older patients undergoing ambulatory urological surgical procedures of short duration.
This study was financially supported by departmental resources.
1. Papaioannou A, Fraidakis O, Michaloudis D et al
. The impact of the type of anaesthesia on cognitive status and delirium during the first postoperative days in elderly patients. Eur J Anaesth
2. Riis J, Lomholt B, Haxholdt O et al
. Immediate and long-term mental recovery from general versus epidural anesthesia in elderly patients. Acta Anaesth Scand
3. Muravchick S. Preoperative assessment of the elderly patient. Anesthesiol Clin NA
4. Muravchick S. The aging process: anesthetic implications. Acta Anaesth Belg
5. Muravchick S. The effects of aging on anesthetic pharmacology. Acta Anaesth Belg
6. Philip BK, Kallar SK, Bogetz MS et al
. A multicenter comparison of maintenance and recovery with sevoflurane or isoflurane for adult ambulatory anesthesia. The Sevoflurane Multicenter Ambulatory Group. Anesth Analg
7. Ebert TJ, Robinson BJ, Uhrich TD et al
. Recovery from sevoflurane anesthesia: a comparison to isoflurane and propofol anesthesia. Anesthesiology
8. Gupta A, Stierer T, Zuckerman R et al
. Comparison of recovery profile after ambulatory anesthesia with propofol, isoflurane, sevoflurane and desflurane: a systematic review. Anesth Analg
9. Heavner JE, Kaye AD, Lin BK, King T. Recovery of elderly patients from two or more hours of desflurane or sevoflurane anaesthesia. Br J Anaesth
10. Day Surgery – Revised Edition 2005: Association of Anaesthetists of Great Britain and Ireland, 21 Portland Place, London, 2005.
11. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res
12. Powell DH, Hiatt MD. Auditory and visual recall of forward and backward digit spans. Percept Mot Skills
13. Black FW, Strub RL. Digit repetition performance in patients with focal brain damage. Cortex
14. Kanbak M, Saricaoglu F, Avci A et al
. Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100beta protein levels. Can J Anaesth
15. Tzabar Y, Asbury AJ, Millar K. Cognitive failures after general anaesthesia for day-case surgery. Br J Anaesth
16. Bruce DL, Bach MJ. Effects of trace anaesthetic gases on behavioural performance of volunteers. Br J Anaesth
17. Bruce DL, Bach MJ, Arbit J. Trace anesthetic effects on perceptual, cognitive, and motor skills. Anesthesiology
18. Gauthier A, Girard F, Boudreault D et al
. Sevoflurane provides faster recovery and postoperative neurological assessment than isoflurane in long-duration neurosurgical cases. Anesth Analg
19. Torri G, Casati A. Cardiovascular homeostasis during inhalational general anesthesia: a clinical comparison between sevoflurane and isoflurane. On behalf of the Italian Research Group on sevoflurane. J Clin Anesth
20. Campbell C, Nahrwold ML, Miller DD. Clinical comparison of sevoflurane and isoflurane when administered with nitrous oxide for surgical procedures of intermediate duration. Can J Anaesth
21. Dupont J, Tavernier B, Ghosez Y et al
. Recovery after anaesthesia for pulmonary surgery: desflurane, sevoflurane and isoflurane. Br J Anaesth
22. Behne M, Wilke HJ, Lischke V. Recovery and pharmacokinetic parameters of desflurane, sevoflurane, and isoflurane in patients undergoing urologic procedures. J Clin Anesth
23. Elcock DH, Sweeney BP. Sevoflurane vs. isoflurane: a clinical comparison in day surgery. Anaesthesia
24. Frink Jr EJ, Malan TP, Atlas M et al
. Clinical comparison of sevoflurane and isoflurane in healthy patients. Anesth Analg
25. Eger 2nd EI, Bowland T, Ionescu P et al
. Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products. Anesthesiology
26. Yasuda N, Lockhart SH, Eger 2nd EI et al
. Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg
27. Ries CR, Azmudeh A, Franciosi LG et al
. Cost comparison of sevoflurane with isoflurane anesthesia in arthro\scopic menisectomy surgery. Can J Anaesth