A comparison of the recovery profiles of desflurane and isoflurane anesthesia in patients undergoing elective supratentorial craniotomy: A randomized controlled trial
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_1136_15
Source of Support: None, Conflict of Interest: None
Context: Few studies have compared recovery profiles of desflurane and isoflurane for patients undergoing elective supratentorial craniotomy. It is not known if the choice of inhalational agent can affect the duration of transient postoperative neurological deficits in these patients. Aims: To compare the effect of desflurane and isoflurane on time-to-emergence and time-to-recovery of transient postoperative neurological deficits in patients undergoing supratentorial craniotomy. Settings and Design: Prospective, double-blinded, randomized controlled trial at a tertiary care hospital. Methods and Materials: We randomly assigned 60 patients to receive either desflurane or isoflurane during elective supratentorial craniotomy for intra-axial mass lesions. Time-to-emergence and time-to-recovery of transient postoperative neurological deficits were recorded and compared. Statistical Analysis Used: Parametric variables were compared by the Student's t test. Baseline data was compared using Pearson's chi square test, Fisher's exact test and two proportion Z test. Results: There was a 35.7%, 31.4% and 34.5% reduction in median times to eye opening, obeying commands and orientation in the desflurane group (n=27) as compared to the isoflurane group (n=28). Five patients were enrolled but not included for analysis-Twelve patients sustained transient neurological deficits after surgery (desflurane, n=3; isoflurane, n=9). No significant difference in the time-to-recovery of transient postoperative neurological deficits was observed. Conclusions: Desflurane significantly reduced emergence times, and was able to facilitate an early neurological examination for patients. Additional studies are required to establish the impact of inhalational agents on transient postoperative neurological deficits.
Keywords: Desflurane, isoflurane, postoperative recovery, transient neurologic deficit
Supratentorial tumor resection often involves dissection close to the eloquent areas of the brain. The ideal anesthetic agent for these surgeries should preserve cerebral hemodynamics and provide rapid emergence to facilitate the early detection of postoperative deficits. Although isoflurane is used for neurosurgical procedures in many centers, it can cause delayed emergence, especially after long surgeries. Desflurane provides a more rapid recovery from anesthesia owing to its lower blood gas solubility. It may be superior to isoflurane in this respect if it can be established that, in addition to the rapid emergence from anesthesia due to faster cerebral elimination, which allows an early neurological examination, it also reduces the incidence or decreases the duration of the reversible postoperative deficits in patients undergoing cranial neurosurgery. However, it is not clear if desflurane anesthesia produces a superior recovery profile compared to isoflurane for patients undergoing elective supratentorial craniotomies.
During the early postoperative period after intracranial surgery, the presence of new or worsening neurological deficits is concerning. These deficits can indicate an active intracranial process such as a hematoma requiring surgical intervention. However, some of these neurological deficits improve within a few hours after surgery and do not require any intervention. It is reported that certain centrally acting drugs may be responsible for reversible neurological deficits in neurosurgical patients. It has also been suggested that central nervous system (CNS) depressants, including inhalational agents, may unmask or exacerbate pre-existing weakness in these patients. The administration of centrally acting agents, such as benzodiazepines or opioids, has been shown to induce worsening or reappearance of pre-existing motor deficits. The potential role of inhalational anesthetic agents in producing such deficits has not been explored to date, although it is likely that the central action of these agents could potentially affect the severity of neurological deficits. At present, it is not known if the use of desflurane, which has a faster cerebral elimination as compared to isoflurane, can reduce the duration of these reversible postoperative deficits in patients undergoing cranial neurosurgery.
We designed a prospective clinical trial to compare the effects of desflurane and isoflurane on the emergence from anesthesia as well as the on the incidence and recovery of transient neurological deficits in patients undergoing elective supratentorial craniotomy for intra-axial mass lesions.
We conducted a prospective, double-blinded, randomized controlled trial to determine the differences in the emergence and improvement of transient neurological deficits in patients undergoing elective surgery for supratentorial brain lesions. All patients were operated at a single institution, and the study protocol was approved by the institutional review board.
Patients with supratentorial intra-axial brain lesions (gliomas) were eligible for this study if they satisfied the following inclusion criteria: an age between 18–75 years, the American Society of Anaesthesiologists (ASA) grade I–III, and the Glasgow Coma Scale score of 15. There was no preoperative cognitive defect in any enrolled patient. Patients who had undergone a previous craniotomy; patients with a midline shift >5 mm and those in an altered sensorium; patients with hepatic/renal disease, alcohol/drug abuse, and body mass index (BMI) of >35; and pregnant/breastfeeding patients were excluded from the trial. Block randomization was performed to create 10 blocks with 6 patients in each block. Consecutive study numbers were assigned to the patients to receive either desflurane or isoflurane based on the randomization. An instruction regarding which inhalational agent should be used for a particular study number was placed in a sealed, numbered envelope by individuals who were not associated with the study.
The primary outcome measures were: (1) the time interval from stopping the inhalational agent to emergence at the end of the surgery; and, (2) the time taken for recovery of transient postoperative neurological deficits. Secondary outcomes were the brain relaxation score, intraoperative hemodynamic events, and opioid consumption. Emergence was assessed as the time from stopping inhalational anesthetic to eye opening.
Written informed consent was obtained, and all patients were assigned a unique study number before surgery. Patients were administered 200 μg of clonidine as premedication an hour before surgery. On entering the operating room, a sealed envelope, which corresponded to the study number of the patient, was opened and either isoflurane or desflurane was used based on the contents of the envelope. Using standard monitoring, anesthesia was induced with propofol (2 mg/kg), fentanyl 1 μg/kg, and vecuronium 0.15 mg/kg. Before the endotracheal intubation, 1.5 mg/kg of 2% lignocaine and 1 μg/kg of fentanyl were administered. A vecuronium infusion was started after intubation and titrated to two twitches using the neuromuscular monitor. Two percent lignocaine was infiltrated into the scalp at the pin site before application of the Mayfield clamp pins. All patients received 1 g of intravenous paracetamol, antibiotics, dexamethasone (0.1 mg/kg), mannitol (0.5–1 g/kg), and antiepileptics before the skin incision. Mannitol and antiepileptics were given as a normal practice to reduce cerebral edema and as seizure prophylaxis. An additional 1 μg/kg of fentanyl was given at the start of trephination. On opening the dura, the surgeon, who was blinded to the anesthetic agent being used, was asked to grade the appearance of the brain according to a brain relaxation score defined by Todd et al. Anesthesia was maintained using desflurane or isoflurane at a minimum alveolar concentration (MAC) of 0.8 throughout the surgery using fresh gas flows of 1 litre/min (50% O2 and 50% air), and the end-tidal CO2 was maintained between 30–35 mmHg. Episodes of hypertension (mean arterial pressure (MAP) >20% of baseline), hypotension (MAP <20% of baseline), and bradycardia (heart rate <45/min), if any, were noted. Hypertension was treated with boluses of 2.5–5 mg labetalol titrated to normalize the blood pressure. Hypotension was treated with fluids, bolus doses of phenylephrine (50 μg), or ephedrine (5 mg intravenous administration).
A single dose of diclofenac sodium (75 mg) was added to the intravenous fluid before the dural closure. The vecuronium infusion was stopped without tapering at the start of the skin closure. The inhalational agent was stopped once the head was removed from pins, and the time point was noted. Immediately after this, neuromuscular blockade was reversed with intravenous neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg). In this study, the inhalational anesthetic was discontinued when the pins were removed. In our institute, because the MAC of anesthetic was maintained at 0.8, patients were extubated on purposeful movements or on first cough without any external stimulation, after ascertaining spontaneous breathing with adequate tidal volumes and satisfactory double burst stimulation response. An arterial blood gas sample was analyzed after reversal of neuromuscular block while awaiting extubation. One of the investigators, who was blinded to the inhalational agent, was present in the room at the end of the case to assess patients for emergence, as shown in [Table 1]. All items for emergence were checked every 2 min till a positive response was obtained, and the time was noted. Patients were then transferred to the neurosurgical intensive care unit. In the intensive care unit, motor scores (manual muscle testing of the major muscle groups) for the upper and lower limbs, as well as the Glasgow Coma Scale scores were noted by blinded assessors every 30 min for 2 h and hourly thereafter for up to 12 hours.
We determined a sample size of 22 per group (based on data from the study by Kaye et al.,) to show a difference of 18 min in the time to obey commands, with an alpha error of 0.01, power of 90%, and dropout rate of 5% per group. To study the difference in time to neurological recovery of transient postoperative deficits, we estimated that at least 23 patients in each group were required using a power of 80%, an alpha error of 0.05, assuming a standard deviation of 20 min in each group, and accounting for 30% incidence of sedation-induced neurological deficits. Assuming a 20% withdrawal rate in each group, we calculated the final sample size to be 60 patients, with 30 patients in each group.
Data were entered into Epi Info 3.5.1 (CDC, Atlanta, GA) and analyzed using the Statistical Package for the Social Sciences version 20.0 (SPSS, IBM, Chicago, IL). As the primary outcome variables were not normally distributed, time durations were presented as medians, and the Mann–Whitney U test was used to compare the two groups. Parametric variables were compared by the Student's t-test. Baseline data for both the groups was compared using Pearson's chi-square test, Fisher's exact test and two-proportion Z test. Spearman's correlation coefficient was computed for all correlational analysis. Statistical significance was set at P < 0.05.
From July 2010 to June 2012, 60 patients were recruited for the study. Five patients were enrolled but not included for analysis [Figure 1]. Baseline data for both the groups are shown in [Table 2]. No significant differences in the surgical duration, intraoperative hemodynamic events, opioid consumption, and arterial blood gas tensions were observed between the two groups [Table 3].
Significant reduction in time-to-eye opening, obeying commands, and orientation was observed in the desflurane group [Table 3]. Patients who received desflurane had a 35.7%, 31.4%, and 34.5% reduction in the median time to eye opening, obeying commands, and orientation, respectively. In our institution, we considered awakening of more than 15 min as delayed awakening. The incidence of delayed awakening (time-to-eye opening >15 min) was significantly higher in patients who received isoflurane as compared to desflurane [Figure 2]. The incidence of prolonged extubation (>15 min after stopping the inhalational agent) was not significantly higher among patients who received isoflurane (chi-square test, P = 0.61). Tumor size correlated with time-to-extubation in the isoflurane group (Spearman's r = 0.38, P = 0.04) but not the desflurane group (Spearman's r = −0.34, P = 0.07). No significant correlation was found between the duration of surgery and the time-to-extubation for the desflurane group (P = 0.06) or the isoflurane group (P = 0.30). There was no significant correlation between the duration of surgery and the time-to-eye opening for both the groups (desflurane, P = 0.23; isoflurane, P = 0.43).
The incidences of neurological deficits before and after surgery in the desflurane and isoflurane groups are presented in [Table 4]. Of the 14 patients with postoperative neurological deficits, 12 patients showed recovery of the deficits within 12 hours. Postoperative deficits resolved in 75% of the patients in the desflurane group and in 90% of the patients in the isoflurane groups. Two patients in the desflurane group and 3 patients in the isoflurane group had preoperative neurological deficits that worsened after surgery. Of these patients, the deficit improved in one patient in the desflurane group and in two patients in the isoflurane group. The tumor size (largest diameter >4 cm) and intraoperative hypotensive episodes were not found to be associated with increased incidence of postoperative neurological deficits in either group (chi-square test: desflurane, P = 1.0, P = 0.26; isoflurane, P = 0.69, P = 0.63, respectively).
Twelve patients had transient neurological deficits that recovered within 12 hours after surgery (3 in the desflurane group and 9 in the isoflurane group, P = 0.059 by chi square test). Longer duration of surgery trended towards a longer time to reversal of the neurological deficit (Spearman's r = 0.55, P = 0.05). Higher fentanyl doses did not correlate with shorter time-to-reversal of neurological deficits (Spearman's r = 0.49, P = 0.1).
The median time-to-extubation was not significantly greater in patients with transient postoperative neurological deficits (n = 12) compared to patients without transient deficits (n = 43) (7.5 vs 6.0 min, P = 0.50). No significant difference in the fentanyl dose (Student's t-test, P = 0.22), surgical duration (P = 0.72) or time-to-eye opening (P = 0.20) was observed between these two groups. Arterial blood gas tensions were not significantly different for these two patient groups (P > 0.05).
Desflurane is 1, 2, 2, 2, tetrafluoroethyldifluoromethylether. It has a lower blood gas solubility (partition coefficient of 0.42) compared to isoflurane (partition coefficient of 1.4). Isoflurane is 1 chloro, 2, 2, 2, trifluoroethyldifluoromethylether. The difference in the partition coefficient is responsible for the early emergence from anesthesia associated with desflurane. This study demonstrates that desflurane, compared to isoflurane, significantly reduces the emergence times but not the extubation times in patients undergoing an elective craniotomy for supratentorial tumors with our anesthetic protocol. Although there was no significant difference in the time-to-recovery of transient postoperative neurological deficits between the two groups, the number of patients with transient postoperative neurological deficits in the desflurane group was limited.
The majority of previous studies have compared desflurane and isoflurane with regard to emergence and extubation times in a variety of non-neurosurgical procedures.,,,, Kaye et al., studying the impact of desflurane and isoflurane on the lumbar cerebrospinal fluid (CSF) pressures in patients with intracranial tumors, also documented emergence times after supratentorial craniotomies. Although the authors found that patients who received desflurane (n = 18) were able to open their eyes and obey commands in 50% less time than those who received isoflurane (n = 18), the differences were not significant. In a more recent study by Yildiz et al., patients received 1 MAC of either desflurane or isoflurane during a supratentorial craniotomy for tumors/aneurysms. Patients who received desflurane had a shorter eye opening, extubation, and orientation times. The results from the above two studies were remarkably divergent in terms of the actual recovery times (time-to-eye opening 30 min and 4.3 min, respectively). While differences in the anesthetic protocol may have contributed to this result, the rapid extubation time (mean extubation time of 1.98 min) in the study by Yildiz et al., has not been shown in other neurosurgical series using desflurane. Boisson-Bertrand et al., showed that, after acoustic neuroma surgery, patients who received desflurane awoke approximately 15 min earlier than those who received isoflurane. In this study, the mean duration of anaesthesia was high and the MAC was maintained at a higher range (1–1.5). This resulted in a higher consumption of the anesthetic inhalation agent. As desflurane has a lower blood gas partition co-efficient compared to isoflurane, there was a rapid washout of the former anesthetic, and these differences were pronounced with an increased duration of anesthesia.
In our study, patients receiving desflurane recovered from surgery at a median of 8 min earlier, facilitating an early postoperative neurological examination. Moreover, isoflurane anesthesia was associated with a higher incidence of delayed awakening. Our results are similar to those of non-neurosurgical studies in showing a faster anesthetic recovery with desflurane.,, While the downward titration of isoflurane towards the end of the case may reduce the time-to-extubation and emergence, the quality of recovery is different for the two agents, particularly with regard to the psychomotor function. Although we did not determine the quality of recovery in our series, we noticed that patients receiving desflurane were more alert. Furthermore, a shorter orientation time implied that, in addition to motor deficits, speech and language functions could also be assessed earlier. This could be important, especially for tumors around the language area in the dominant hemisphere.
In a meta-analysis of extubation times using different inhalational agents, Agoliati et al., showed that desflurane reduced the mean extubation time by 34% over isoflurane in a variety of surgeries. The time-to-extubation was not significantly different between desflurane and isoflurane in our study, and was similar to the results from a few other studies., We believe that our anesthetic protocol resulted in similar extubation times while comparing the two groups. Although fentanyl has synergistic effects with both isoflurane and desflurane, lower doses of opioids are known to limit the degree of respiratory depression enabling spontaneous breathing at the end of surgery. In our study, a total of 3 μg/kg of fentanyl was used and no patient received fentanyl after the initial trephination. As the majority of surgeries were of more than 4 hours in duration, the effect of fentanyl at the end of the surgery was minimal. The positive consequence of this finding was that our anesthetic protocol had the potential to reduce extubation times in patients undergoing cranial neurosurgery with isoflurane. Due to the fact that only a single patient required additional analgesia at the end of surgery, we believe that timely doses of opioids at the beginning of the case, as well as diclofenac sodium at the end of the surgery can provide adequate analgesia without significant respiratory depression. Interestingly, we found that larger tumors increased extubation times in the isoflurane group but not the desflurane group. These results suggest that desflurane may have its largest effect on extubation times for patients undergoing surgeries for large supratentorial tumours (>4 cm). This could also be because of faster desflurane elimination and intracranial pressure decrease after tumor resection.
The administration of centrally acting agents, such as benzodiazepines or opioids, has been shown to induce worsening or reappearance of pre-existing motor deficits., The potential role of inhalational anesthetic agents in producing such deficits has not been explored to date, though it is likely that the central action of these agents could potentially affect the severity of neurological deficits. In our study, 12 patients developed transient postoperative motor deficits that completely recovered within 12 hours. Although we found no significant difference in the time-to-neurological recovery in both the groups, our data demonstrates that reversible neurological deficits manifest after intracranial surgery and need to be acknowledged when evaluating the postoperative patient. While we cannot conclude that the anesthetic agent contributed to the neurological deficits, there was a smaller number of patients who had a temporary neurological dysfunction in the desflurane group. In addition, the near significant correlation between the length of surgery and time-to-reversal of the deficit suggests a pharmacological effect from the anesthetic drugs. Other factors that could contribute to this include prolonged brain retraction, edema, and local blood flow changes during surgery.
With an increasing focus on reducing anesthesia-related costs, the pharmacoeconomics of desflurane need to be considered before using it widely for neuroanesthesia. While the cost of using isoflurane is lower, desflurane facilitates shorter post-anesthetic care unit durations, which has been shown to potentially offset its higher cost, particularly, in busy operating rooms where space for post-anaesthetic care is limited. In addition, the use of low-flow anesthesia can reduce the consumption and costs of using desflurane. In the present study, extubation times were similar with both the agents, suggesting that the efficient use of isoflurane and opioids can produce comparable recovery times. We believe that, by following strict anaesthetic protocols, isoflurane can still be used for majority of neurosurgical patients, reserving desflurane for patients in whom early neurological assessment is vital.
This study has a few limitations. The recovery phase was not assessed using standard validatory scales such as the Modified Aldrete score or the Ramsay's sedation score. However, the two groups were compared using specific endpoints such as eye opening, obeying commands, and orientation. Patients were extubated when they exhibited purposeful movements or at the first cough because we did not want an increase in the blood pressure and the intracranial pressure. We did not record the MAC at extubation, and hence could not compare the MAC at which patients were extubated. Our sample size was probably inadequate to establish a clear supremacy of desflurane in reducing the incidence of transient neurological deficits. However, the near significance (P = 0.059) suggests that, with a larger number of patients, we could have had a definite answer to our study.
The present study shows that desflurane significantly reduces the time-to-eye opening, obeying commands, and orientation in patients undergoing elective supratentorial craniotomies for tumor resection. Desflurane scores over isoflurane for supratentorial craniotomies where an early neurological assessment of patient is required postoperatively.
Financial support and sponsorship
Internal fluid research grant, Christian Medical College, Vellore.
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]