Comparison of propofol/remifentanil and sevoflurane/remifentanil for maintenance of anaesthesia for elective intracranial surgery

J. R. Sneyd1,*, C. J. H. Andrews2 and T. Tsubokawa2

1 Peninsula Medical School, C310 Portland Square, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK. 2 Department of Anaesthesia, Pain Management and Critical Care Medicine, Derriford Hospital, Plymouth PL6 8DH, UK

* Corresponding author. E-mail: robert.sneyd{at}pms.ac.uk

Accepted for publication February 10, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Propofol and sevoflurane are suitable agents for maintenance of anaesthesia during neurosurgical procedures. We have prospectively compared these agents in combination with the short-acting opioid, remifentanil.

Methods. Fifty unpremedicated patients undergoing elective craniotomy received remifentanil 1 µg kg–1 followed by an infusion commencing at 0.5 µg kg–1 min–1 reducing to 0.25 µg kg–1 min–1 after craniotomy. Anaesthesia was induced with propofol, and maintained with either a target-controlled infusion of propofol, minimum target 2 µg ml–1 or sevoflurane, initial concentration 2%ET. Episodes of mean arterial pressure (MAP) more than 100 mm Hg or less than 60 mm Hg for more than 1 min were defined as hypertensive or hypotensive events, respectively. A surgical assessment of operating conditions and times to spontaneous respiration, extubation, obey commands and eye opening were recorded. Drug acquisition costs were calculated.

Results. Twenty-four and twenty-six patients were assigned to propofol (Group P) and sevoflurane anaesthesia (Group S), respectively. The number of hypertensive events was comparable, whilst more hypotensive events were observed in Group S than in Group P (P=0.053, chi-squared test). As rescue therapy, more labetolol [45 (33) vs 76 (58) mg, P=0.073] and ephedrine [4.80 (2.21) vs 9.78 (5.59) mg, P=0.020] were used in Group S. Between group differences in recovery times were small and clinically unimportant. The combined hourly acquisition costs of hypnotic, analgesic, and vasoactive drugs appeared to be lower in patients maintained with sevoflurane than with propofol.

Conclusion. Propofol/remifentanil and sevoflurane/remifentanil both provided satisfactory anaesthesia for intracranial surgery.

Keywords: anaesthetics i.v., propofol ; anaesthetics volatile, sevoflurane ; surgery, neurosurgery, craniotomy


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Both i.v. and inhalation agents are in general use for maintenance of anaesthesia during neurosurgical procedures. Comparisons between i.v. and inhalation techniques have been inconclusive and the use of either technique would currently be considered ‘best practice’.14 Remifentanil has a rapid onset of action and is promptly eliminated when its infusion is discontinued.5 6 These characteristics, combined with the low instance of pain after surgery, make it a logical choice for neurosurgical anaesthetic procedures. However, there are no published reports, which compare sevoflurane/remifentanil anaesthesia and propofol/remifentanil anaesthesia in neurosurgery.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The protocol was approved by the South West Devon Research Ethical Committee and informed consent was obtained from each patient at the preoperative visit. Fifty patients undergoing elective craniotomy were enrolled in the study. Treatment allocations were generated using the random number function of Microsoft Excel Version 7.0 and concealed in individual opaque envelopes until shortly before the start of anaesthesia. We carefully considered the use of a double-blind design for this study but rejected it as placebo syringes of Intralipid with the necessary ‘tag’ to operate the target controlled infusion system are not available. The easy detection of sevoflurane by smell would also have made blinding difficult. In practice, the choice of anaesthetic agents was easily concealed from the operating surgeons and the nurses in the recovery area. The arterial pressures were recorded by direct measurement from the radial artery and stored at 1-min intervals on the DatexTM AS/3 clinical monitoring system (Datex-Ohmeda, Helsinki, Finland). Episodes of ‘hypertension’ and ‘hypotension’ were determined by inspection of the stored electronic record on the monitor. We therefore considered that an adequate degree of blinding and a satisfactory means of objectively identifying haemodynamic instability were established.

Anaesthesia
After establishment of standard monitoring and arterial and venous cannulation, all patients received a bolus of remifentanil 1 µg kg–1 followed by an infusion of 0.5 µg kg–1 min–1 reducing to 0.25 µg kg–1 min–1 after craniotomy. Patients were questioned about the onset of drug effect and when they began to feel light-headed or sleepy anaesthesia was induced with propofol. In patients randomized to receive propofol anaesthesia (Group P) anaesthesia was induced with a target-controlled infusion of propofol (Graseby 3500 infusion pump, Diprifusor® software, initial plasma concentration target, 1 µg ml–1), which was increased progressively until satisfactory anaesthesia was achieved. Anaesthesia was maintained by the target-controlled infusion of propofol with a minimum target concentration of 2 µg ml–1.

In the patients randomized to receive sevoflurane (Group S) anaesthesia was induced with a bolus injection of propofol, 0.5 mg kg–1 with supplementary doses of 10 mg every 10 s until loss of consciousness. Anaesthesia was then maintained with sevoflurane, initial end tidal concentration 2%, minimum concentration 1%. Tracheal intubation was facilitated with atracurium given as a bolus and followed by an infusion until dural closure. All patients were artificially ventilated to normocapnia using a circle breathing system and a fresh gas flow of 0.5 litre min–1 oxygen and 1.0 litre min–1 air during anaesthesia. At the end of surgery, residual neuromuscular blockage was then antagonized with 2.5 mg neostigmine and 0.5 mg glycopyrrolate. Remifentanil infusion was stopped after skin closure whilst sevoflurane and propofol were continued until head bandaging was completed. Mannitol 1 g kg–1 was given between induction of anaesthesia and craniotomy unless clinically contraindicated. Additional mannitol was given if clinically indicated. The surgeons, blind to anaesthetic technique, evaluated the state of brain as ‘tight’, ‘adequate’, or ‘soft’. The dose of mannitol was recorded.

Hypertensive episodes, defined as mean arterial pressure (MAP) more than 100 mm Hg for more than 1 min, were treated with remifentanil 1 µg kg–1 and the infusion rate increased by 0.125 µg kg–1 min–1. If the response was present 2 min later this was repeated. If the haemodynamic response persisted for a further 2 min the propofol target concentration or sevoflurane concentration were increased. Labetolol or hydralazine was given, if clinically appropriate. Hypotensive episodes, defined as MAP less than 60 mm Hg for more than 1 min, which did not respond to a fluid bolus, were treated by reducing the propofol target or sevoflurane concentration. A vasopressor was administered if necessary. Hypertensive and hypotensive episodes were recorded.

Arterial pressure was recorded on the ward using an automated sphygmomanometer and before induction of anaesthesia and continuously thereafter using an arterial cannula.

Times to adequate respiration, extubation, eye opening and obeying commands were recorded. Analgesia in the recovery area was provided by bolus injections of morphine 2 mg, given at 5-min intervals according to standard hospital protocol. Nausea and vomiting and the time of discharge from recovery were recorded by the nursing staff.

Statistical analysis
Data were recorded on specially produced paper record forms and then transferred to a database (Microsoft Access, Version 7.0). Statistical analysis was performed using Statview (version 5.0), and Excel Version 7 running on a personal computer. The size of the study was determined by a priori power calculation using data from a previous study,7 which suggested that enrolment of 20 patients per group would determine a difference in time to tracheal extubation of 4 min with a power of 80% and P<0.05. The comparison of continuous variables was performed by Mann–Whitney U-test. Categorical valuables were analysed using the chi-squared test. P<0.05 was considered statistically significant. Drug acquisition costs were calculated post-hoc.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Fifty patients were recruited into the study. Twenty-four were assigned to propofol anaesthesia (Group P) and 26 to sevoflurane anaesthesia (Group S). One patient in Group S required overnight ventilation for surgical reasons. We included intra-operative but not recovery data from this patient. The patient characteristics of the two groups were well matched (Table 1).


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Table 1 Patient characteristics. Data are presented as median and range

 
Propofol infusion rate was 5.45 (SD 1.0) mg kg–1 h–1 in Group P. Group S received 1.06 (0.6) mg kg–1 of propofol for induction and an end-tidal concentration of sevoflurane of 1.13 (0.19)%. Remifentanil infusion rate was similar in the two groups (Table 2). Anaesthesia time was longer in Group P, but the difference was not statistically significant. The brain condition evaluated by the surgeon and mannitol dosage was comparable in the two groups (Table 2).


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Table 2 Surgical and anaesthetic data. Data are presented as median and range. Brain condition was evaluated by the neurosurgeon subjectively

 
Arterial pressure before, during, and after surgery was similar in the two groups (Fig. 1). Hypertensive episodes were seen in seven and eight patients in Groups P and S, respectively. These patients experienced a median of 1 (range 1–7) and 1 (range 1–4) hypertensive episodes, respectively. There was no significant difference (P=0.374, chi-squared test) (Fig. 2A). To control hypertension, labetolol was given to 14 patients [mean total doses 45 (SD 33) mg] in Group P and 19 [76 (58) mg, P=0.073] in Group S. Hydralazine was given to two and five patients in Groups P and S, respectively. These agents were mainly used to control arterial pressure during emergence from anaesthesia. Hypotensive episodes were seen in 15 and 23 patients in Groups P and S, respectively. These patients experienced a median of 2 (range 1–4) and 3 (range 1–7) hypotensive episodes, respectively (Fig. 2B). There was no significant difference between groups (P=0.053, chi-squared test). Ephedrine was given to 63 and 88% of patients in Groups P and S, respectively. The total dose of ephedrine was 4.8 (2.2) mg in Group P and 9.8 (5.6) mg in Group S (P=0.02).



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Fig 1 Systolic arterial pressure measured at each perioperative point for propofol (Group P) or sevoflurane (Group S). Thin lines, range; boxes, 25–75th centiles; thick horizontal lines, median values. There were no significant differences between the two groups (Mann–Whitney U-test).

 


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Fig 2 Frequencies of (A) hypertensive and (B) hypotensive episodes with propofol (Group P) or sevoflurane (Group S). There was no significant difference between the groups for hypertension (P=0.374, {chi}-squared test) or hypotension (P=0.053).

 
Time to spontaneous respiration, was significantly shorter in Group P than in Group S (P=0.02) (Table 3). Time to spontaneous respiration was 7.0 (2.0–31.0) and 10.0 (1.0–24.0) min in Groups P and S, respectively [median (range), Mann–Whitney U-test]. Time to eye-opening was 7.5 (3.0–30.0) and 12.0 (3.0–33.0) min in Groups P and S, respectively. Time to extubation was 8.5 (3.0–40.0) and 11.0 (3.0–33.0) min in Groups P and S, respectively. Time to obeying commands was 10.5 (3.0–40.0) and 13.0 (4.0–48.0) min in Groups P and S, respectively. These differences were not statistically significant (Fig. 3). We performed a regression analysis to explore the relationship between recovery time and hypotensive episodes, these were not significantly correlated (P=0.5280 by Spearmann Rank correlation).


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Table 3 Duration, analgesia, and PONV data in recovery. Data are presented as median and range. PONV=postoperative nausea and vomiting

 


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Fig 3 Times to spontaneous respiration, eye-opening, extubation, and obeying commands in patients whose anaesthesia was maintained with propofol (Group P) or sevoflurane (Group S).

 
The requirement for morphine, dosages of morphine, incidences of nausea and vomiting and recovery room stay of the two groups were similar.

Propofol, sevoflurane, and remifentanil are expensive agents with associated equipment costs. Although this was not a health economic study, we conducted a post-hoc calculation of drug acquisition costs (Table 4). Propofol acquisition cost was £3.83 per 20 ml ampoule for Group S and £9.58 per 50 ml syringe for Group P. Remifentanil cost £5.98 per mg. The cost of sevoflurane was calculated by the method of Rosenberg16 with an acquisition cost of £137.30 per 250 ml and total flow 1.5 litre min–1. The total hypnotic and analgesic drug acquisition costs of Group P were significantly higher than in Group S, median cost £58.63 vs £39.03. Group S required more vasoactive medications (labetolol, £2.94 per 100 mg; hydralazine, £1.62 per 20 mg; and ephedrine £1 per 30 mg). Even after allowing for this, the combined hourly costs of hypnotic, analgesic, and vasoactive medications were higher in Group P than in Group S, median values £19.31 and £15.52 h–1, respectively, P=0.016.


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Table 4 Costs of anaesthetic drugs. Data are presented as median and range. Total hypnotic and analgesic costs means the sum of propofol, sevoflurane, and remifentanil costs. Sevoflurane costs were calculated based on the background flow of 1.5 litre min–1. Vasoactive drugs means the cost of labetolol, hydralazine, and ephedrine. Antibiotics and muscle relaxants are excluded from these calculations

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We found that both sevoflurane and propofol, in combination with remifentanil, are satisfactory agents for maintenance of anaesthesia in neurosurgical patients. Surgical conditions in the two groups were similar, possibly because of the frequent use of mannitol and differences in recovery times were not clinically significant.

We observed an increased number of hypotensive episodes in Group S, which also received a larger total dose of ephedrine as rescue therapy. One possible explanation is that the sevoflurane group was simply more deeply anaesthetized. Although doses of individual inhalation agents can readily be compared by describing them as fractions of the MAC, it is not possible to make a direct comparison with an i.v. agent. The CP50 of propofol for depression of bispectral index is 5.45 µg ml–1,8 whereas the IP50 of sevoflurane for depression of bispectral index was 1.14%.9 In our study, the average target propofol concentration was 3.67 (0.46) µg ml–1, and average end-tidal sevoflurane concentration was 1.13 (0.19)%. Viewed against the above data for bispectral index, Group S may have been slightly more deeply anaesthetized than Group P. The sevoflurane group contained more posterior fossa cases than the propofol group (5 vs 2). Posterior fossa surgery poses different problems to supratentorial surgery and haemodynamic disturbance may be more common in these patients. We explored our data and found no excess of haemodynamic instability in the patients undergoing posterior fossa surgery who were anaesthetized with sevoflurane.

We found small and clinically unimportant differences in recovery between Group P and Group S. There are many reports to compare recovery characteristics between propofol and sevoflurane anaesthesia. These reports concluded sevoflurane anaesthesia gave faster,10 11 similar,12 or slower7 13 recovery than propofol anaesthesia. Yli-Hankala and colleagues reported no difference of recovery time between propofol/fentanyl/nitrogen oxide and sevoflurane/fentanyl/nitrogen oxide anaesthesia under bispectral index control.14 We explored our data to evaluate whether hypotensive episodes, which might be a result of a deeper anaesthesia were associated with delayed recovery and found no correlation. The experiences of the two groups of patients whilst in the recovery area were similar, perhaps because this phase is dominated by clinical and nursing factors rather than the small differences between short-acting hypnotic agents.

Many studies have reported that sevoflurane caused postoperative nausea and vomiting (PONV) more frequently than propofol anaesthesia.7 10 12 PONV occurs in about 30% of patients receiving sevoflurane.7 10 12 15 In the present study, PONV occurred in only 15% of patients with no difference between propofol and sevoflurane.

Although there was a small difference in drug acquisition costs between the two groups, these differences in costs are very small in relation to the total cost of a neurosurgical procedure and should be interpreted cautiously as they ignore associated costs of equipment and disposables.

We selected realistic doses of propofol and sevoflurane, which recognize the strong synergism between these agents and remifentanil. We have evaluated previously remifentanil alone and as a sequential infusion following alfentanil in neuroanaesthesia practice.15 Common clinical doses of remifentanil give substantial sparing of sevoflurane and propofol when these agents are used for induction and maintenance of anaesthesia.17 18 In our previous study,15 the propofol infusion rate (100 µg kg–1 min–1) was probably too high.

We have carefully evaluated sevoflurane and propofol as maintenance agents with remifentanil for elective intracranial surgery. Both agents were satisfactory.


    Acknowledgments
 
Abbott Laboratories Limited, the manufacturers of sevoflurane, provided the drug free for patients participating in this study. Professor Sneyd has received lecture fees and research support from Astra-Zeneca, the manufacturers of propofol, and other research support from Abbott Laboratories Limited. Financial support: supported by a grant from Abbott Laboratories Limited, the manufacturers of sevoflurane.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Todd MM, Warner DS, Sokoll MD, et al. A prospective, comparative trial of three anesthetics for elective supratentorial craniotomy. Propofol/fentanyl, isoflurane/nitrous oxide, and fentanyl/nitrous oxide. Anesthesiology 1993; 78: 1005–20[ISI][Medline]

2 Van Hemelrijck J, Van Aken H, Merckx L, Mulier J. Anesthesia for craniotomy: total intravenous anesthesia with propofol and alfentanil compared to anesthesia with thiopental sodium, isoflurane, fentanyl, and nitrous oxide. J Clin Anesth 1991; 3: 131–6[CrossRef][Medline]

3 Artru AA, Lam AM, Johnson JO, Sperry RJ. Intracranial pressure, middle cerebral artery flow velocity, and plasma inorganic fluoride concentrations in neurosurgical patients receiving sevoflurane or isoflurane. Anesth Analg 1997; 85: 587–92[Abstract]

4 Ebert TJ, Robinson BJ, Uhrich TD, Mackenthun A, Pichotta PJ. Recovery from sevoflurane anesthesia: a comparison to isoflurane and propofol anesthesia. Anesthesiology 1998; 89: 1524–31[CrossRef][ISI][Medline]

5 Michelsen LG, Salmenpera M, Hug CC jr, Szlam F, VanderMeer D. Anesthetic potency of remifentanil in dogs. Anesthesiology 1996; 84: 865–72[CrossRef][ISI][Medline]

6 Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993; 79: 881–92[ISI][Medline]

7 Matsumoto H, Shingu K, Numata K, et al. [Total intravenous anesthesia with propofol is advantageous than thiopental-sevoflurane anesthesia in the recovery phase]. Masui 1998; 47: 1046–58[Medline]

8 Leslie K, Sessler DI, Schroeder M, Walters K. Propofol blood concentration and the Bispectral Index predict suppression of learning during propofol/epidural anesthesia in volunteers. Anesth Analg 1995; 81: 1269–74[Abstract]

9 Olofsen E, Dahan A. The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999; 90: 1345–53[CrossRef][ISI][Medline]

10 Raeder J, Gupta A, Pedersen FM. Recovery characteristics of sevoflurane- or propofol-based anaesthesia for day-care surgery. Acta Anaesthesiol Scand 1997; 41: 988–94[ISI][Medline]

11 Ku AS, Hu Y, Irwin MG, et al. Effect of sevoflurane/nitrous oxide versus propofol anaesthesia on somatosensory evoked potential monitoring of the spinal cord during surgery to correct scoliosis. Br J Anaesth 2002; 88: 502–7[Abstract/Free Full Text]

12 Lien CA, Hemmings HC, Belmont MR, Abalos A, Hollmann C, Kelly RE. A comparison: the efficacy of sevoflurane-nitrous oxide or propofol-nitrous oxide for the induction and maintenance of general anesthesia. J Clin Anesth 1996; 8: 639–43[CrossRef][ISI][Medline]

13 Schmidt J, Fechner J, Fritsch B, et al. [Propofol-remifentanil versus sevoflurane-remifentanil for anesthesia for pediatric procedures in infants, children and adolescents]. Der Anaesthesist 2001; 50: 757–66[CrossRef][ISI][Medline]

14 Yli-Hankala A, Vakkuri A, Annila P, Korttila K. EEG bispectral index monitoring in sevoflurane or propofol anaesthesia: analysis of direct costs and immediate recovery. Acta Anaesthesiol Scand 1999; 43: 545–9[CrossRef][ISI][Medline]

15 Sneyd JR, Whaley A, Dimpel HL, Andrews CJ. An open, randomized comparison of alfentanil, remifentanil and alfentanil followed by remifentanil in anaesthesia for craniotomy. Br J Anaesth 1998; 81: 361–4[CrossRef][ISI][Medline]

16 Rosenberg MK, Bridge P, Brown M. Cost comparison: a desflurane- versus a propofol-based general anesthetic technique. Anesth Analg 1994; 79: 852–5[Abstract]

17 Albertin A, Casati A, Bergonzi P, Fano G, Torri G. Effects of two target-controlled concentrations (1 and 3 ng/ml) of remifentanil on MAC(BAR) of sevoflurane. Anesthesiology 2004; 100: 255–9[CrossRef][ISI][Medline]

18 Cros AM, Lopez C, Kandel T, Sztark F. Determination of sevoflurane alveolar concentration for tracheal intubation with remifentanil, and no muscle relaxant. Anaesthesia 2000; 55:965–9[CrossRef][ISI][Medline]





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