Remifentanil appears promising as an anaesthetic for craniotomy for several reasons. First, it does not alter cerebral blood flow carbon dioxide reactivity and has minimal effects on intracranial pressure and cerebral blood flow itself [1-5]. Second, it controls the acute autonomic response during neurosurgical procedures providing good haemodynamic stability . Third, it has unique pharmacokinetic properties. The terminal plasma half-life of remifentanil is 8-10 min and its context-sensitive time is 3-5 min . The presence of an ester side-chain allows rapid metabolism by nonspecific esterases to remifentanil acid, which is approximately 4600 times less potent than remifentanil . Propofol also has potential advantages. The context-sensitive half-life of propofol infusions up to 8 h is less than 40 min . Propofol decreases the cerebral metabolic rate, cerebral blood flow and intracranial pressure [9,10]. In certain types of surgery, propofol reduces the frequency of postoperative nausea and vomiting (PONV) , and it is possible that it has the same effect after intracranial surgery .
From and colleagues found only small differences when comparing alfentanil, fentanyl and sufentanil during anaesthesia for craniotomy with respect to haemodynamic variables and emergence from anaesthesia . Many other anaesthetics have been used for intracranial surgery including volatile inhalation agents and N2O [4,12,14].
Quick recovery with 'fast-track' tracheal extubation may be beneficial after intracranial surgery. Neurosurgical patients are at risk of postoperative cerebral bleeding and procedural complications might be detected earlier in awake patients. In addition, prolonged endotracheal intubation is related to a higher incidence of postoperative pulmonary complications. In a recent study, patients sedated with propofol for 2 h after surgery had higher oxygen consumption and higher norepinephrine plasma concentrations than did patients extubated soon after surgery (fast-track group) .
One possible advantage of remifentanil could be the predictability of rapid offset of analgesic action allowing a rapid emergence from anaesthesia. The purpose of this randomized trial was to compare anaesthetists' individual practice with two TIVA regimens, sufentanil/propofol and remifentanil/propofol. This methodological approach follows criteria recommended recently by Coriat and Beaussier for clinical study designs . The primary end-point of the study was extubation time. Secondary end-points were further aspects on recovery (e.g. eye opening), haemodynamics, PONV, analgesic requirements and patient pain score.
The study was approved by the local Institutional Review Board, and written informed consent was obtained before randomization. We enrolled 36 adults (ASA I-III) who were scheduled to undergo craniotomy for supratentorial tumour resection under general anaesthesia. Group size (n) was calculated by assuming an effect size of 1.0 for differences between the two treatment groups in the primary end-point extubation time. With α = 0.05 and β = 0.20, this would result in n = 2 × 17 subjects to discover any effects (two-tailed). All patients were alert and oriented with respect of time and place and person before operation. The size of the tumour was not an entry criterion. Cranial computed tomography or magnetic resonance imaging was obtained within 4 weeks before operation. Exclusion criteria were age < 18 or >70 yr, ischaemic heart disease, congestive heart failure, liver disorder or renal disease, or severe chronic respiratory disease. Patients with previously known allergic reactions to study drugs or communication problems were also excluded. Chronic medications (e.g. dexamethasone, anticonvulsants, β-adrenoceptor blocking drugs and angiotensin-converting enzyme inhibitors) were discontinued on the evening before surgery.
Patients received nitrazepam 5 mg in the evening and clorazepate 10 mg on the morning of surgery. In the operating room, monitoring included continuous heart rate measurement with a three-lead electrocardiogram, continuous systemic arterial pressure (radial arterial catheter), capnography, pulse oximetry and relaxometry (Cicero EM®, PM 8060; Dräger, Lübeck, Germany); Innervator NS 252® (Fisher & Paykel, Welzheim, Germany). A central venous catheter was inserted in the antecubital vein. Four skin electrodes (Zipprep®; Aspect Medical Systems, Inc., Natick, MA, USA) were placed in a two-channel referential montage on the foreheads of the patients. The skin was prepared with isopropyl alcohol. All leads were connected to an electroencephalographic monitor (A-1000®; Aspect Medical Systems International B.V., Leiden, The Netherlands). Data were sampled 128 times s−1, and high- (70 Hz) and low-frequency (2 Hz) filters were used with Version 3.22 of the bispectral index (BIS). The BIS was used to monitor depth of anaesthesia (target 40-50). A patient warming system (Warm Touch®; Mallinckrodt Medical, Black & Decker, Idstein, Germany) kept the body temperature in normal range (36.9 ± 0.5°C).
Measurements were taken at the following times: the afternoon before surgery, preinduction, during intubation (I), pin head holder (P), incision (Op), dura incision (D), galeal closure (G), skin closure (E), endotracheal extubation, discharge, and arrival in the intensive care unit (ICU). Additional data were collected 10 min before D and G, 2 and 4 min after I, P, Op, D, G, and 15 min after I and D.
A random number table was used to generate assignment numbers, which were sealed in sequential envelopes. The admitting nurse opened each envelope to obtain the assignment.
Sufentanil/propofol (suf/prop) group. After preoxygenation, anaesthesia was induced with sufentanil (0.5 μg kg−1) and propofol (1-2 mg kg−1). At loss of consciousness, manual mask ventilation was begun (oxygen 100%), and propofol infusion (150 μg kg−1 min−1) was started. Cisatracurium (0.1 mg kg−1) was administered to facilitate endotracheal intubation, which was performed 3-5 min later. Mechanical ventilation of the lungs was started (oxygen/air; oxygen 30%). The propofol infusion was varied, and supplementary boluses of sufentanil were administered at the discretion of the anaesthesiologist to keep the BIS between 40 and 50. Atropine (0.5-1.0 mg), Akrinor®, which is a combination of cafedrine 20 mg and theodrenaline 1 mg, or urapidil (5-10 mg) could be given if the patient experienced unacceptable bradycardia (<40 beats min−1), hypotension (mean arterial pressure (MAP) < 30% of baseline pressure) or hypertension (MAP > 30% of baseline pressure). Muscle relaxation was maintained using cisatracurium in boluses (0.02 mg kg−1). The last dose of sufentanil was administered at closure of the dura. Propofol infusion was reduced to 30-60 μg kg−1 min−1 when the bone flap was replaced, and it was stopped at the start of skin closure.
Remifentanil/propofol (remi/prop) group. Anaesthesia was started with an infusion of remifentanil (0.2-0.35 μg kg−1 min−1). One minute later, propofol (1.5-2 mg kg−1) was administered. After loss of consciousness, manual mask ventilation (oxygen 100%) was begun and a propofol infusion (150 μg kg−1 min−1) started. Cisatracurium (0.1 mg kg−1) was administered. Three to 5 min later the trachea was intubated, and mechanical ventilation was started (oxygen/air; oxygen 30%). The remifentanil and propofol infusion rates were varied at the discretion of the anaesthesiologist to keep the BIS between 40 and 50. Medication for treatment of bradycardia, hypotension or hypertension was the same as in the suf/prop group. Again, muscle relaxation was maintained using cisatracurium in boluses of 0.02 mg kg−1. Propofol infusion was stopped at the start of skin closure. Remifentanil infusion was discontinued after removal of the pin head holder.
Procedures used in both groups
After the head dressing was completed, patients were assessed every 5 min on three aspects of recovery (spontaneous breathing, arm lifting, eye opening). Endotracheal extubation was performed when respiratory function (frequency <25 and >10 breaths min−1; FiO2 < 0.6; SaO2 > 95%) was adequate, haemodynamics were stable and upper airway reflexes were functioning well. Hypertension was treated using urapidil. Analgesics (pirinitramide (piritramide) 0.05 mg kg−1 or ibuprofen 500 mg) were given on the patient's request. No scalp infiltration was performed. The total amounts of remifentanil and sufentanil were calculated. The propofol amounts were calculated from the moment of endotracheal intubation to the end of the dural preparation (period 1) and from the end of dural preparation to the head dressing (period 2) separately. Patients were discharged from the operating room to the ICU after they were extubated and opened their eyes and lifted their arm on command.
The day before surgery, at 6 h after surgery and on the first, third and fifth days after surgery, patients completed a questionnaire about their physical condition (e.g. nausea, vomiting, pain especially headache) on a numerical scale from 0 (not at all) to 6 (very strong). They were also instructed in the use of a numerical rating scale for the assessment of pain (0 = no pain to 15 = worst imaginable pain). The numerical scale was combined with a verbal quantification of pain intensity: very strong, strong, severe, moderate and mild. At first, patients assessed pain on the adjective scale. Then the pain was assessed on the numerical scale . This scale was used on the day before surgery and hourly from the first to the fifth hour after surgery. During the first hour after surgery, no scale was used but the patients were frequently asked whether or not they suffered from pain. In addition, on the first day after surgery, patients underwent a structured interview to assess their intraoperative awareness . Unaware of the study medication, in addition the interviewer collected data about nausea/vomiting, and treatment of pain and PONV hourly until the fifth hour after surgery. Postoperative pain was treated on the patient's request with incremental intravenous doses of pirinitramide (0.05 mg kg−1) or with ibuprofen 500 mg rectally until pain relief was adequate. PONV was treated with dolasetron 12.5 mg or metoclopramide 10 mg. Postoperative shivering was treated using incremental doses of meperidine (0.15-0.5 mg kg−1).
Data are the means ± standard deviation. Statistical analysis for arterial pressure, heart rate and BIS was performed by analysis of variance (ANOVA) with repeated measurements for the factor time and group as a between factor. A t-test was used for patient characteristics data and recovery times. An analysis of covariance (ANCOVA) was carried out using the propofol dose as a covariate. The analgesic requirements and side-effects were calculated using cross tabs and χ2-tests (two-tailed). All tests were performed with the SPSS® v.9.0 (SPSS, Inc., Chicago, IL, USA) computer program, and P < 0.05 was considered as statistically significant.
There were no significant differences between the study groups with respect to patient characteristics data or ASA status. Similarly, there was no difference with respect to duration and type of surgery (Table 1). One patient in the suf/prop group was excluded from the analysis because of intraoperative bleeding. Abnormal signs were present on preoperative neurological examination in 65% of the suf/prop group and in 72% of the remi/prop group patients. The mean tumour diameter was 32 ± 11 mm in the suf/prop group and 30 ± 15 mm in the remi/prop group. A midline shift of 5 mm or more occurred in one suf/prop patient and in two remi/prop group patients. Complication rates were similar: postoperative hemiparesis occurred in one patient in each group; aphasia developed in two suf/prop and in one remi/prop group patients. Body temperature following surgery was in the normal range and similar. The end-tidal CO2 concentration and the arterial PCO2 values were comparable between groups. No intraoperative awareness occurred.
The remi/prop group had a shorter mean time to extubation (P = 0.007) and to discharge to ICU (0.003). Recovery times were taken from cessation of the propofol infusion (Fig. 1). The length of stay in the ICU and the hospital length of stay were comparable among groups. Using propofol as a covariate in ANCOVA, the adjusted means for all recovery variables were longer in the suf/prop group. Group differences remained significant for extubation time (P = 0.018), but there are no differences regarding time to spontaneous breathing (0.118), eye opening (0.092) and arm lifting (0.178).
Patients in the suf/prop group received a total amount of sufentanil 133.2 ± 50.7 μg and patients in the remi/prop group received remifentanil 6642 ± 2688 μg. Suf/prop patients received significantly more propofol during period 1 (endotracheal intubation to the end of dural preparation) resulting in a higher overall propofol dose (Table 2).
Heart rate in the two groups did not differ, except at arrival in the ICU (remi/prop group mean 90 ± 12 beats min−1, suf/prop group mean 75 ± 13 beats min−1; P = 0.01). Arterial pressure measurements were higher in the period between endotracheal intubation until endotracheal extubation in the suf/prop group (Fig. 2). There were no significant differences in the frequencies of various adjuvants administered for treatment of bradycardia, arterial hypotension or hypertension.
Patients in the remi/prop group received significantly more Ringer's solution between skin incision and head dressing than patients in the suf/prop group (1376 ± 307 versus 1639 ± 325 mL; P = 0.01). No differences were found in the amount of Ringer's infusion for the preincisional time (888 ± 379 versus 888 ± 278 mL; P = 0.99). Eight patients in each group received colloidal infusions before the incision (375 ± 177 versus 200 mL ± 122; P = 0.22) and between the incision and the head dressing (531 ± 208 versus 588 ± 367 mL; P = 0.71). Three suf/prop group patients were given mannitol 20% 100-125 mL, as were three remi/prop group patients (125-200 mL).
Self-reported pain was comparable in the two groups (suf/prop group 5.1 ± 3.1, remi/prop group 5.2 ± 3.6; P = 0.88, scale 0-15) from the first to the fifth hour after surgery. However, more patients in the remi/prop group requested analgesia during the first hour after surgery (Table 2). In addition, no differences in reported pain were detected on the day before surgery (P = 0.21), at 6 h (0.22), at 24 h (1.0), or on days 3 (0.59) and 5 (0.63) after surgery.
Overall, seven patients in the suf/prop group and 14 patients in the remi/prop group required some type of analgesic during the 24 h after surgery (Table 2). Four patients from each group suffered from PONV. Five of these patients were treated with dolasetron 12.5 mg, and the remaining three with metoclopramide 10 mg. When asked about nausea and vomiting by the interviewer, an additional three patients (one in the suf/prop, two in the remi/prop group) reported nausea during the first 6 h after surgery. On the first day after surgery, one suf/prop patient and two patients in the remi/prop group reported nausea (defined as a score >3 on a scale of 0-6; P = 0.30). On the third day, three suf/prop and no remi/prop group patients reported nausea (P = 0.03). On the fifth day, one patient of each group reported nausea (P = 0.07).
Our study has four important findings:
• Patients who received the remi/prop regimen were extubated earlier.
• Mean arterial pressures (MAP) were 10-20% lower in the remi/prop group, and there were no differences in heart rate.
• Two groups were similar in terms of frequency of haemodynamic instability and treatment.
• During the first hour after surgery analgesics were required by 50% of the remi/prop group but by only 12% of the suf/prop group.
Beside the significant difference between groups in the means of extubation time, one interesting aspect of the present study was the wide range of length of recovery in the suf/prop group. The predictability of the offset of anaesthetic action in the suf/prop group seemed to be low. Sufentanil was administered in boluses in the present study, which is the commonly used practice in our institution. A bolus of sufentanil 0.5 μg kg−1 was administered during induction. At least another bolus of sufentanil 0.5 μg kg−1 was given to the patient before adjustment of the pin head holder. About 85% of the total amount of sufentanil had been administered before the end of the dural preparation in the present study. Nevertheless, suf/prop patients received more propofol during period 1 (intubation to the end of dural preparation) than patients of the remi/prop group. This leads to the larger overall dosage of propofol in the suf/prop group and possibly to the delayed recovery in the suf/prop group. However, when using propofol as a covariate in ANCOVA, extubation time was still significantly longer in the suf/prop group. The pharmacokinetic characteristics of sufentanil are such that it could be used as an infusion. This might have led to a smaller overall dosage of sufentanil and a faster recovery in the suf/prop group. Furthermore, the context-sensitive half-life of sufentanil increases with a prolonged infusion time. As stated by Shafer and Varvel, this is of clinical relevance when the infusion time exceeds 3-4 h . Another possible explanation for the delayed recovery in the suf/prop group is the interaction between propofol and sufentanil . Despite the fact that propofol infusion was not reduced with bone replacement in the remi/prop group, recovery was quicker and more reliable in all patients of the group. We suppose that in the remi/prop group the propofol infusion determines the emergence from anaesthesia once the remifentanil infusion is discontinued. For this reason, propofol infusion was not reduced with bone replacement in the remi/prop group. Reduction of the propofol infusion would allow a faster emergence and further decrease of the recovery times. However, Warner has pointed out that it might be an advantage for the patients to provide a transition from the anaesthetized to awake state that is not too abrupt .
Anaesthesia in the remi/prop group was begun using a remifentanil infusion (0.25-0.35 μg kg−1 min−1). Endotracheal intubation was carried out 5-7 min later and only a slightly increase in MAP was detected. Five to 7 min of remifentanil infusion may be enough to reach a sufficient effect site concentration. This is in contrast to the results of other investigators who recommend the administration of a bolus of remifentanil (0.5 μg kg−1) followed by an infusion (0.25 μg kg−1 min−1) to attenuate the pressor response. However, endotracheal intubation was carried out 3 min after induction of anaesthesia by Hall and colleagues . The lack of the remifentanil bolus in the present study might have led to the slightly increased propofol induction dosage.
The depth of anaesthesia was monitored using standard autonomic variables. In addition, the BIS was used to ensure an adequate depth of anaesthesia. In the present study, a level of 50 ± 10 led to a state of anaesthesia accompanied by a constant heart rate and decrease in systolic, diastolic and MAPs of about 20% from baseline in the remifentanil group. The anaesthetists tended to treat the decreased arterial pressure with crystalloid infusions; however, crystalloid infusions may not increase arterial pressure sufficiently. It might have been possible to increase arterial pressure in patients of the remi/prop group by reducing the dosage of remifentanil and/or propofol.
Pain scoring systems may be unreliable postoperatively. For this reason, analgesics were simply administered as required. Owing to the short half-life of remifentanil, it is likely that remi/prop patients require analgesics immediately after surgery. However, only 50% of the remi/prop patients required some type of analgesic during the first hour postoperation. A possible cause for the low incidence of pain might be disorientation and inability to report pain. The arterial pressures in patients of the remi/prop group were higher during emergence from anaesthesia, but did not exceed the values in patients of the suf/prop group. Only two patients of the suf/prop group reported pain and received analgesics. De Benedittis and colleagues found an overall incidence rate of postoperative pain in neurosurgery of 60% . This is comparable with the suf/prop group of the present study. However, in the remi/prop group, 80% of the patients needed some type of analgesic during the 24 h after surgery. Guy and colleagues reported comparable analgesic requirements in their study groups within 8 h (remifentanil group 64%, fentanyl group 50%) . Balakrishnan and colleagues found comparable data as well; however, 39% of the remifentanil group in this study received fentanyl for transitional analgesia . Some patients did not require transitional analgesia after craniotomy. This may be due to independent patient factors.
Guy and colleagues conducted a double-blind comparison of fentanyl and remifentanil during long neurosurgical procedures (mean duration of 6 h). Patients of both groups recovered rapidly; the median time to extubation was 4 min in the fentanyl group and 5 min in the remifentanil group . These data are similar to those of the experimental group of the present study. However, in Guy and colleagues' study, seven patients in the fentanyl group needed naloxone. Also, the two groups in their study had similar mean times to emergence from anaesthesia, but patients who received the longer-acting opioid had much longer times to emergence (>1 h). We made the same observation concerning patients who received sufentanil, some of whom required >1 h to open their eyes or to lift their arms on command.
A similar effect was found by Balakrishnan and colleagues comparing remifentanil and fentanyl in patients undergoing surgery for intracranial mass lesions . The fentanyl group had much more variability in time to extubation than the remifentanil group (remifentanil median 5 min and IQ range 4-8 min; fentanyl median 6 min and IQ range 3-22 min). This finding corresponds to our data indicating greater a variability in recovery variables after sufentanil compared with remifentanil.
Todd and colleagues conducted a study with a higher total dose of propofol (3617 ± 2059 mg) and a fentanyl dose of 1216 ± 494 μg . The time from incision to completion of the dressing was 267 ± 114 min, leading to a corresponding longer induction to drug 'off' time of 333 ± 114 min. In Todd and colleagues' study, the median time to extubation was 3.5 min (1.3-6.4 min; 25th and 75th percentile), and the median time to an Aldrete score of 9 was 10 min (10-25 min; 25th and 75th percentile) (eight of 40 patients did not reach an Aldrete of 9 within 10 min). Our patients received an equipotent sufentanil dose (140 ± 40 μg) and a lower propofol dose (2092 ± 614 mg, control group), but had recovery times that were twice as long. It is possible that an interaction of sufentanil and propofol led to the longer recovery times in the sufentanil group of the present study .
The remifentanil infusion rates used by Balakrishnan and colleagues (0.33 ± 0.12 μg kg−1 min−1 without N2O or 0.27 with N2O) or those used by Sneyd and colleagues (0.37 ± 0.06 μg kg−1 min−1) were comparable with the infusion rate used in the present study [14,24].
A brain tumour >30 mm in diameter has been shown to prolong the emergence from anaesthesia . In the present study, the distribution of tumour size and locations was similar in both groups, and thus tumour size should not affect the group differences.
The incidence rate of PONV was 25% in both groups of the present study. The follow-up from the first to the fifth day postoperatively (up to three patients with nausea) indicates that PONV might be in part independent from the anaesthetic regimen, and possibly the kind of surgery may be important. Balakrishnan and colleagues and Guy and colleagues reported higher incidence rates in nausea of up to 50%. One reason of the slightly lower incidence in the present study might be that we did not use N2O, which has been linked with nausea [12,14]. Another reason could be the use of propofol, which may have intrinsic antiemetic properties [11,12,26].
A limitation of the present study is that we did not set a protocol for anaesthetic depth for either study group. In addition, we did not make attempts to dictate rigidly precise drug doses. In daily clinical routine, usually no rigid algorithms exist for the management of anaesthesia. We left dosing decisions to the discretion of the anaesthetist caring for the patient, within well-defined guidelines. These criteria should mimic daily clinical routine. Our aim was to compare a conventional clinical regimen with one that might improve the postanaesthesia state. Instead of following a pharmacokinetic or pharmacodynamic approach, we did not limit the treatments offered - this approach follows criteria recently recommended by Coriat and Beaussier for design of clinical studies. Double-blinded investigations should be followed by observational evaluations performed in clinical accordance with usual clinical practice . For this reason, no exact information about the pharmacological properties of the administered drugs can be derived.
In conclusion, rapid recovery after remifentanil/propofol anaesthesia occurs more reliably than after a sufentanil/propofol regimen. The two regimens were similar in terms of haemodynamic stability and heart rate, but the remifentanil regimen was associated with lower arterial pressures.
This work was supported by departmental funds from the Klinik für Anästhesiologie der Medizinischen Universität Lübeck.
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