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Anesth Analg 2002;95:1384-1388
© 2002 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Sevoflurane Provides Faster Recovery and Postoperative Neurological Assessment Than Isoflurane in Long-Duration Neurosurgical Cases

Alain Gauthier, MD*, Francois Girard, MD FRCPC*, Daniel Boudreault, MD FRCPC*, Monique Ruel, RN*, and Alexandre Todorov, PhD{dagger}

*Department of Anesthesiology, Centre Hospitalier de l’Université de Montréal, Hopital Notre-Dame, Montréal, Canada; and {dagger}Department of Psychiatry, Washington University Medical Center, St. Louis, Missouri

Address correspondence and reprint requests to Francois Girard, MD, FRCPC, Department of Anesthesiology, CHUM, Hopital Notre-Dame, 1560 Sherbrooke East, Montreal, Canada, H2L 4M1. Address e-mail to francois.girard.chum{at}ssss.gouv.qc


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane (SEVO) provides faster emergence than isoflurane (ISO). This advantage is thought to magnify with increased duration of exposure. In addition, SEVO has several of the characteristics of an ideal neuroanesthetic. We designed a prospective, randomized, double-blinded study to compare the recovery profile of SEVO versus ISO in neurosurgery. Sixty patients undergoing intracranial surgery were enrolled. They were randomized to receive SEVO or ISO in 40% oxygen as part of a balanced anesthetic regimen. The anesthetic concentration (0.5 to 1.0 minimum alveolar anesthetic concentration [MAC]) was adjusted to maintain mean arterial blood pressure within 20% of the preinduction baseline. At the end of the surgery, neuromuscular blockade was reversed, anesthetics were discontinued without prior tapering, and fresh gas flow was increased to 10 L/min. Recovery end-points were measured as the time from closure of the anesthetic vaporizer. Mean MAC-hours were identical in both groups (4.7). Patients in the SEVO group demonstrated a shorter time to emergence (P = 0.02) and for response to command (squeeze hand, P = 0.03; move feet, P = 0.01). Patients in the SEVO group obtained a Glasgow coma scale score of >=10 5 min before patients in the ISO group (P = 0.04). Obtaining an early neurological examination can be critical in neurosurgical patients. The observed difference in emergence between SEVO and ISO could therefore be of clinical importance.

IMPLICATIONS: The low-solubility anesthetic, sevoflurane, provides faster recovery and postoperative neurological assessment than isoflurane after long-duration (4.7 MAC-h) intracranial surgery.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The volatile anesthetic, sevoflurane (SEVO), has a favorable recovery profile because of its low blood/gas partition coefficient (1–4). A recent metaanalysis suggests that this advantage of rapid awakening over more soluble anesthetics, such as isoflurane (ISO), would be magnified in surgical cases of from 3 to 5 h duration, although we are not aware of a study that has specifically verified this assumption (5). Patients undergoing neurosurgery for intracranial procedures are a good population in which to undertake such a study. These cases usually last for several hours, and the short period of recovery attributed to the poorly soluble anesthetics could be critical to obtain an early neurological assessment of the patient in the postoperative period.

We designed this prospective, randomized, and controlled clinical trial to assess the recovery profile of SEVO as compared with ISO in long-duration neurosurgical cases. We hypothesized that the use of SEVO would result in a shorter emergence time than ISO and, therefore, in a shorter time interval between the end of the surgery and the first postoperative neurological assessment of the patient.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and written, informed consent, 60 ASA status I–III patients, aged 18 to 70 yr, undergoing intracranial surgery, were enrolled in this study. They were randomly divided into two groups to receive SEVO or ISO as a maintenance anesthetic. Exclusion criteria were severe intracranial hypertension (more than 5 mm of midline shift on the computed tomography scan with altered sensorium), alcohol or drug abuse, severe heart disease, increased creatinine blood level, familial or personal history of malignant hyperthermia, and body mass index >35. Patients could not have received general anesthesia within the previous 7 days. Female patients could not be pregnant or breast-feeding. Patient with a Glasgow coma scale (GCS) score <15 were excluded from the study (6).

The patients received their usual medications on the day of the surgery. On arrival in the operating room and application of standard monitoring, the patients received midazolam 0.03 mg/kg IV. Three minutes later, the baseline mean arterial blood pressure (MAP) and heart rate (HR) were noted. Induction consisted of IV sufentanil 0.5 µg/kg and IV thiopental 2 to 6 mg/kg, titrated for loss of the eyelid reflex. Endotracheal intubation was facilitated with rocuronium 0.9 mg/kg IV. Thiopental 1.0 to 2.0 mg/kg was administered for the Mayfield head-holder application. Throughout the study period, we used the calculated pharmacological body weight (7). Maintenance of anesthesia was provided, depending on the study group, with SEVO or ISO, 0.5 to 1.0 minimum alveolar anesthetic concentration (MAC), titrated according to surgical stimulation to maintain the MAP within 20% of the baseline value. The value of MAC was 1.15 for ISO and 2.05 for SEVO, according to the product monograph. Fresh gas flow (FGF) of 2 L/min consisted of 40% oxygen in air. An arterial blood gas value was obtained 30 min after induction, and ventilation was adjusted to maintain a PaCO2 of 30 to 35 mm Hg. An IV sufentanil infusion was started immediately after induction at a fixed rate of 0.25 µg · kg-1 · h-1. Rocuronium was given as needed to maintain a single twitch on the neurostimulator.

Dexamethasone and antibiotics were given as required by the surgical procedure. Mannitol (0.5 g/kg IV) was administered at skin incision. Periods of hypertension or tachycardia (increase of MAP or HR of more than 20% of baseline value) that failed to respond to an increase of the anesthetic concentration to 1.0 MAC were treated with 10-mg boluses of labetalol (maximum of 2 mg/kg IV). Episodes of hypotension (MAP decrease of more than 20% of baseline value) were first treated by decreasing the anesthetic concentration to 0.5 MAC, and then with ephedrine (5 mg IV) or phenylephrine (0.1 mg IV). Bradycardia (HR <45 bpm) was treated with atropine 0.01 mg/kg IV. At dural opening, brain relaxation was assessed by the attending neurosurgeon, who was blinded to the study group, by using a four-point scale: 1, relaxed brain; 2, mild brain swelling, acceptable; 3, moderate brain swelling, no treatment required; and 4, severe swelling, treatment required.

The sufentanil infusion was terminated at the beginning of dural closure. At the end of the surgical procedure, on removal of the Mayfield head holder, residual neuromuscular blockade was reversed with IV neostigmine and glycopyrrolate. The vaporizer was turned off, without prior tapering, and the FGF was increased to 10 L/min of oxygen.

Throughout the study period, the concentration of volatile anesthetic was recorded in real time by using the Datex-Ohmeda AS/3 PC data collection software (Datex-Ohmeda, Helsinki, Finland) for off-line analysis and MAC-hour calculation (average MAC x length of exposure).

Recovery data were assessed for at least 2 h after discontinuation of anesthesia by one of two investigators (AG or MR), blinded to the study group, using a normal tone voice. Recovery end points were defined as follows:

  1. Emergence: time from the discontinuation of anesthesia delivery to opening of the eyes, either spontaneously or on verbal prompting repeated every 2 min.
  2. Extubation: performed when the patient obeyed verbal commands.
  3. Basic neurological examination: time from the discontinuation of anesthesia delivery to obeying a specific command (squeeze hands and move feet), on verbal prompting every 2 min.
  4. Orientation: time from the discontinuation of anesthesia delivery to orientation (stating name, date of birth, and current location), on verbal prompting every 2 min after extubation.
  5. Recovery discharge: time from the discontinuation of anesthesia delivery to discharge from the recovery room by using the modified Aldrete score (8).

A neurological evaluation using the GCS was performed every 5 min after the termination of anesthesia. A creatinine blood level was obtained in both groups before surgery and 24 h after surgery.

Statistical analyses were performed by using the SAS statistical package, Release 6.12 (SAS Institute Inc., Cary, NC). Differences in demographic and intraoperative data between the two groups were sought with the {chi}2 test and the unpaired Student’s t-test for nonparametric and parametric variables, respectively. Because the recovery variables were not normally distributed, data are expressed as median with 95% confidence interval (95% CI) and were analyzed with Wilcoxon’s log-rank statistic. Means ± SD are also provided to facilitate comparison with other studies. We used linear regression analysis to check for outlying or influential observations. Pearson correlation coefficients were used between some of the recovery end points to ascertain the quality of the data obtained. A P value <0.05 was considered significant.

Assuming a ß of 0.2 and an {alpha} of 0.05, it was estimated that 30 patients in each group were needed to detect an 8-min difference in emergence time and a 15-min difference in time to orientation (2,3,5) between the two groups.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Sixty patients (ASA status II–III) participated in this study; 30 received SEVO and 30 received ISO as a maintenance anesthetic. There were no group differences in terms of demographic and intraoperative variables (Table 1).


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  		Table 1. Demographics and Intraoperative Data
 
The data indicate that emergence times were shorter for patients receiving SEVO than for those receiving ISO. The median emergence time was 18 min (95% CI, 15–21 min) for ISO and 14 min (95% CI, 10–16 min) for SEVO (Table 2; P = 0.02). Seventy-five percent of ISO patients opened their eyes within 28 min (95% CI, 20–35 min) and within 18 min (95% CI, 15–30 min) for SEVO patients. Seventy-five percent of ISO patients would squeeze a hand on command within 35 min (95% CI, 29–46 min) and move their feet on command within 43 min (95% CI, 31–55 min). For SEVO, 75% of patients would squeeze a hand on command within 22 min (95% CI, 19–37 min) and move their feet on command within 24 min (95% CI, 21–35 min).


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  		Table 2. Recovery Variables (min)
 
There was a strong correlation between "physical" recovery variables (e.g., squeezing a hand and moving feet on command; r = 0.90) and "intellectual" variables (e.g., giving name, date of birth, and current location; r = 0.98). In addition, physical and intellectual recovery variables were highly correlated (r = 0.90). The differences between the two groups did not reach statistical significance for intellectual recovery variables (Table 2).

Figure 1 shows the distribution of GCS scores for the first 60 min after surgery. For SEVO patients, the median time to reach a GCS score >=10 and that to reach a GCS score >=13 was 20 min (95% CI, 15–25 min) and 25 min (95% CI, 20–35 min), respectively. The corresponding times in the ISO group were 25 min (95% CI, 20–35 min; P = 0.04) and 30 min (95% CI, 25–45 min; P = 0.19).



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  		Figure 1. Glasgow Coma Scale (GCS) scores for both groups. White = isoflurane; black = sevoflurane.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The data confirm that patients who received SEVO as their maintenance anesthetic had a faster emergence than patients who received ISO. The results also indicate that SEVO allowed for faster postoperative basic neurological examination than ISO with equally good intraoperative brain conditions—two important goals of neuroanesthesia. The magnitude of the differences between the two groups for most recovery end points is greater than what is reported for anesthesia of shorter duration (2,4). In a metaanalysis, Robinson et al. (1) reported, with cases averaging 1.19 MAC-hours of anesthetic exposure, a mean difference of 2.9 minutes for emergence and 3.0 and 4.5 minutes, respectively, for response to commands and orientation, between SEVO and ISO patients. In our sample of longer cases (average of 4.7 MAC-hours), we observed differences that were two to three times longer.

This is in accordance with the metaanalysis of Ebert et al. (5), suggesting that the kinetic advantage of SEVO over ISO would be particularly manifest in surgery of longer duration (three to five hours). In the study of Ebert et al. (5), the data regarding long-duration surgery have been extracted from several different studies, some of them not providing the magnitude of the exposure. The differences in emergence time and time to orientation that they reported for cases of 3 to 5 hours’ duration, respectively 5 and 8.6 minutes, are close to what we are reporting for anesthetics of even longer duration. However, we observed longer times to recovery than those estimated by Ebert et al. (5) for long-duration cases. Our results do not support their finding that times to early recovery end points are not lengthened by case duration with low-solubility anesthetics. With available data, this assertion may be appropriate only with cases that do not exceed 2.5 MAC-hours (9).

Studies involving anesthetic exposure of approximately 1.0 MAC-hours show a time to emergence of 8 minutes with SEVO (5), whereas we obtained 15 minutes, a twofold difference. Frink et al. (9), in a study involving 2.5 MAC-hours of exposure, obtained a time to emergence of 7.5 minutes with SEVO. We are not aware of studies that examined the effects of intermediate exposure on emergence (2.5–4.7 MAC-hours). However, the longer emergence time we obtained could be a result of the study population we selected. Patients undergoing craniotomy, especially for large tumors, have delayed awakening as compared with those undergoing extracranial surgery (10). In addition, conditions such as the use of brain retractors in aneurysm surgery and brain swelling could further delay awakening.

The nature of the surgical procedure in this study mandates early postoperative assessment. Are the differences we found in emergence time and the time required to obtain a basic neurological examination of clinical importance? We report differences between the two groups ranging from 10 minutes (emergence) up to 19 minutes (move feet on command) to have 75% of patients executing a specific order. A 10- or 20-minute difference might not be an important gain in the general population of surgical patients, but in neurosurgical patients it could be. It might help distinguish which patient has a new neurological deficit and would therefore require a specialized diagnostic test or even an emergent reintervention.

The high correlation coefficients we obtained between the recovery variables indicate that these variables are in fact describing the same phenomenon, which is patient awakening. It also reflects the quality of the recovery data obtained in this study.

The choice of anesthetic we used might come under scrutiny, because in most studies involving comparisons in emergence time, desflurane shows a definitive advantage over SEVO (11–13). The choice was, in fact, straightforward, because in addition to its kinetic advantage, SEVO possesses many properties consistent with use in neuroanesthesia. SEVO preserves dynamic autoregulation better than ISO (14), a reflex that is completely abolished by 0.5 MAC of desflurane (15). In contrast to desflurane (16), SEVO does not increase intracranial pressure up to a concentration of 1.5 MAC (17). In addition, SEVO is not as potent a cerebral vasodilator as ISO or desflurane (18), and it preserves carbon dioxide reactivity and metabolic coupling (19).

However, there are concerns about the proconvulsant properties of SEVO. This problem appears to be prominent with large-concentration inhaled induction in children (20,21). In epileptic adults, Watts et al. (22) have shown an increase in interictal spike activity with SEVO and that to a greater extent than ISO. The clinical meaning of this phenomenon is unknown. It tends to appear at doses close to burst suppression and is virtually absent at the smaller dosages more often used for neuroanesthesia.

The issue related to the production of the nephrotoxic Compound A during low-flow anesthesia has also been addressed in several clinical studies (23–26). Eger et al. (23) showed an increase of sensitive markers of renal failure with no modification of serum creatinine, creatinine clearance, or glucosuria in 16 volunteers undergoing eight hours of anesthesia with SEVO as compared with desflurane at 2 L/min of FGF. Using a similar design, Ebert et al. (26) were not able to duplicate the increase of sensitive markers. In addition, the studies of Bito and Ikeda (25) and Kharasch et al. (24), involving respectively 100 and 73 patients, using low-flow (1 L/min) SEVO anesthesia, with an average of 13.1 MAC-hours of SEVO exposure in Bito and Ikeda’s study (25), showed no increase of renal failure biochemical markers as compared with ISO anesthesia. In this study, in conformation with the Canadian version of the product monograph, we used an FGF of 2 L/min and reported no increase of serum creatinine level in either group.

This study shows that the low-solubility anesthetic SEVO provides faster recovery than ISO for patients undergoing long-duration neurological surgery. SEVO also allowed for a faster basic neurological examination than ISO. This study has the additional advantage of a rather homogeneous population undergoing surgery of long duration (6.6 hours) with a higher level of anesthetic exposure (4.7 MAC-hours) than that reported in most studies published (1,5). In interpreting recovery results, it is important to note that neurosurgical patients may have a specific recovery evolution.


   Acknowledgments
 
Supported by a grant from Abbott Laboratories, Ltd., Canada.


   Footnotes
 
Presented in part at the Canadian Anesthesiologists Society meeting, Victoria, Canada, June, 2002.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 22, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press