The bispectral index (BIS) is a calculated multifactorial parameter derived from the electroencephalogram (EEG) . BIS is a dimensionless number between 0 and 100 that correlates with the level of sedation and hypnosis. In awake patients, BIS is above 90; total suppression of cortical electrical activity results in a BIS of 0. With BIS below 60, the probability of recall and conscious perception is very low [2-6]. BIS values between 45 and 60 are recommended for surgery under general anaesthesia [4,6-8]. BIS has been proposed as a measure of the hypnotic component of anaesthesia, and it has been suggested that the administration of hypnotic drugs can be guided by it. Since pain perception results in haemodynamic reactions, the administration of analgesic drugs can be guided by haemodynamic variables. Numerous studies have been published showing advantages of BIS-monitored and -guided anaesthesia over standard clinical practice [9-13]. Recently, a study evaluated the influence of opioid selection on BIS-guided anaesthesia. It was shown that BIS-guided remifentanil/propofol anaesthesia allows faster recovery than BIS-guided alfentanil/propofol anaesthesia . In elderly patients receiving BIS-guided anaesthesia, the selection of the hypnotic drug has been shown to have an influence on recovery [15,16]. This study compares BIS-guided total intravenous anaesthesia (TIVA) using remifentanil/propofol with BIS-guided balanced anaesthesia using remifentanil/isoflurane in adult, non-elderly patients. It was tested whether there were differences between TIVA and balanced anaesthesia in recovery, intraoperative haemodynamic stability, frequency of patients' reactions and undesirable events when BIS was used as a guide for anaesthetic administration.
Following Human Investigation Committee approval and informed written consent, 80 unpremedicated patients (18-70 yr) scheduled for elective surgery under general anaesthesia were enrolled into the study. Patients with neurological or psychiatric disorders, a history of drug abuse, or chronic use of opioids or sedative drugs, obesity (actual body weight more than 150% of ideal body weight), or poorly controlled hypertension were excluded. Patients were randomly assigned to two groups, receiving either remifentanil/propofol (PRO) or remifentanil/isoflurane (ISO) anaesthesia.
An intravenous (i.v.) catheter was placed and Ringer's solution, at least 500 mL, was infused. Standard monitors were placed. BIS was monitored, using the Aspect A1000® EEG monitor (Aspect Medical Systems, Newton, MA, USA). Following alcohol cleaning, ZipPrep® (Aspect Medical Systems) EEG electrodes were applied to obtain two-channel EEG (AT1 AT2 ref.: FpZ ground: F1). Impedances were below 5 kΩ.
Haemodynamic baseline was calculated as the mean of three measurements, in the 4 weeks before surgery, in the 24 h before surgery and within 2 h of induction.
The patient was preoxygenated. A continuous remifentanil infusion was then started at 0.5 μg kg−1 min−1. Thirty seconds later, a propofol bolus of 0.5 mg kg−1 was injected. Every 30 s, an additional propofol bolus (20 mg) was given until loss of consciousness, as defined by loss of reaction to a verbal command. Mask ventilation of the lungs was performed with 100% oxygen. Upon loss of consciousness, in the PRO group a continuous propofol infusion was started at 75 μg kg−1 min−1 for 3 min, then continued with 50 μg kg−1 min−1. In the ISO group, isoflurane was administered at 0.5% end-expiratory concentration.
Once BIS was stable between 45 and 60, succinylcholine 1.5 mg kg−1 was given to facilitate endotracheal intubation. Mechanical ventilation of the lungs was continued with 40% oxygen in air. Following intubation, the remifentanil infusion was decreased by 50%. If remifentanil had been decreased before intubation for haemodynamic reasons, it was not decreased further unless needed for haemodynamic instability.
BIS was used to guide administration of propofol (PRO group) and isoflurane (ISO group). The BIS target range during maintenance was 45-60. Clinical signs of inadequate anaesthesia (movement, grimacing) were treated with bolus administration and increase of infusion rate (PRO group) or isoflurane increase (ISO group).
Mean arterial pressure (MAP) and heart rate were used to guide the administration of remifentanil. Both variables were maintained within 20% of baseline. Hypotension or bradycardia lasting for more than 1 min were treated with a decrease of remifentanil by 50%. Hypertension or tachycardia for more than 1 min were treated with remifentanil (1 μg kg−1). If, 60 s following a remifentanil bolus, arterial pressure and heart rate were still increased above 20% of baseline, an additional bolus was given. Following a third bolus, the remifentanil infusion rate was increased by 50%. The remifentanil rate was not decreased below 0.1 μg kg−1 min−1 (minimum infusion rate). This regimen was maintained from loss of consciousness until the end of surgery.
Thirty minutes before the end of surgery, morphine (0.15 mg kg−1) was administered i.v. Fifteen minutes before the end of surgery, propofol or isoflurane were reduced to maintain BIS between 60 and 75. With completion of wound dressing, remifentanil and propofol or isoflurane were discontinued.
The following parameters were assessed in both groups: patients were observed for loss of consciousness (i.e. loss of verbal contact), loss of reaction to forehead tap and lash reflex. Patients were observed for muscle rigidity, classified as none (0), mild (1: mask ventilation still possible), moderate (2: thorax rigidity, difficulties with mask ventilation) or severe (3: thorax and extremities rigid, no mask ventilation possible). Patients were observed for haemodynamic and BIS reactions to endotracheal intubation and skin incision. During anaesthesia, events indicating inadequate anaesthesia and interventions for these events were recorded (Table 1). At the end of anaesthesia, patients were observed for return of spontaneous and adequate respiration, return of consciousness, following command and extubation. Recovery was assessed with a modified Aldrete score (0-10) . With a score of 9 or higher, patients were classified fully recovered. The following day, patients were asked for recall and signs of awareness, using a standardized interview .
Data are mean ± standard deviation (SD). Parametric data were analysed using an ANOVA and a t-test. Non-parametric data were analysed using χ2- and U-tests. Haemodynamic variables were calculated as the percentage of baseline. Preintubation and preincision baseline parameters are means of a 3 min period before intubation and skin incision. Postintubation and postincision parameters are maxima of a 3 min period following intubation and skin incision.
Patients' reactions during surgery were grouped to event types (Table 1). For every type of event, frequency per hour was calculated and compared between groups. Treatments were grouped to event type requiring treatment, and for every subgroup frequency of interventions per hour was calculated and compared between groups.
During the last 15 min, BIS was compared between groups: for every 1 min, BIS values were assigned to one of three groups: BIS < 60, > 75 or in the desired range for end of surgery (60-75). Time intervals with BIS in these three ranges were compared between groups. P < 0.05 was considered as statistically significant.
There were no significant differences in patients' characteristics or baseline data between groups (Table 2). Duration of the surgical procedure was significantly longer in the PRO group (118 ± 54 min) than in the ISO group (92 ± 40 min).
In the group that received a propofol infusion, the total remifentanil dose was significantly higher (0.30 ± 0.19 μg kg−1 min−1) than in the group that received isoflurane (0.18 ± 0.06 μg kg−1 min−1). In the PRO group, the propofol dose was 132 ± 51 μg kg−1 min−1; isoflurane concentration in the ISO group was 0.66 ± 0.13%.
Induction of anaesthesia
There was no significant difference in propofol bolus requirements for induction (PRO 1.5 ± 0.6 mg kg−1, ISO 1.4 ± 0.6 mg kg−1), nor in induction times or BIS at these times between groups (Fig. 1). There was no significant difference in the number of patients with haemodynamic or BIS reaction to endotracheal intubation between groups (PRO n = 14, ISO n = 19). BIS and normalized haemodynamic variables before and following intubation are shown in Figure 2.
There was no difference in the degree of rigidity following remifentanil between groups. There was no patient with severe rigidity. Thirteen patients showed mild (PRO n = 9, ISO n = 4), 10 moderate (PRO n = 5, ISO n = 5) rigidity.
Maintenance of anaesthesia
Figure 2 shows variables before and following skin incision in both groups. Before skin incision, MAP (as a percentage of baseline) was lower in the ISO group (P < 0.05). Following skin incision, there was still a trend towards a lower MAP in the ISO group. There was no significant difference in the number of patients with reaction to skin incision between groups (PRO n = 8, ISO n = 7).
Table 1 shows patients' reactions during anaesthesia and the number of treatment interventions necessary per hour, grouped to event types.
End of surgery
There was no significant difference in time interval from morphine administration to the end of surgery between groups (PRO 26 ± 12 min, ISO 22 ± 3 min). During the last 15 min, there was no significant difference in BIS ranges between groups. Table 3 shows emergence and recovery times and BIS at defined clinical end-points in both groups. There were no significant differences in recovery times between groups. During emergence from anaesthesia, at clinical end-points BIS tended to be higher in the ISO group.
Time from discontinuation of anaesthetic agents to complete recovery (Aldrete score ≥ 9) was 11.2 ± 4.6 min in the PRO group and 12.2 ± 9.0 min in the ISO group. There was no significant difference between groups. In the next-day postoperative interview, there was no patient with signs of intraoperative awareness or recall.
This study demonstrates that BIS-guided anaesthesia with both remifentanil/propofol and remifentanil/isoflurane produces satisfactory and reliable anaesthesia with intraoperative stability and fast recovery regardless of the primary anaesthetic agent used.
In our patients, remifentanil/propofol anaesthesia required a significantly higher dose of remifentanil to provide haemodynamic stability as compared with remifentanil/isoflurane anaesthesia. This may be due to differences between propofol and isoflurane. Propofol has mainly hypnotic properties , whereas isoflurane has additional analgesic effects [20,21]. As haemodynamic variables were used to guide remifentanil administration, one could assume that cardiovascular depression caused by isoflurane [22-24] may be the reason for lower remifentanil doses in the ISO group. However, with the isoflurane concentrations used, this effect is not expected to have a significant influence. The following consideration supports the view that cardiovascular depression by isoflurane is not the reason for differences in remifentanil requirements: if the haemodynamic status in the ISO group would not be caused by analgesic effects but by cardiovascular depression, as a consequence the analgesic level would be lower in the ISO group than in the PRO group (with comparable haemodynamic status). If we assume less analgesia in the ISO group, we would expect that intraoperative stimuli cause more reactions in the ISO group than in the PRO group. Comparing both groups for reactions during anaesthesia, in the ISO group there were - to the contrary - less reactions indicating insufficient analgesia. Hence, it is very unlikely that cardiovascular depression by isoflurane is a conforming factor for lower remifentanil requirements in the ISO group.
Differences in the duration of surgery may be an interacting factor. As surgery lasted significantly longer in the PRO group, the intensity of surgical stimuli may also be increased in the PRO group. This may contribute to higher remifentanil requirements in this group.
There were no significant differences in baseline data between groups. Although patients were randomized to one of the two groups, the duration of the surgical procedure was significantly longer in the PRO group. As events and interventions during anaesthesia were calculated as frequencies per hour, differences between groups were not due to differences in surgery time (duration of anaesthesia) but to differences between remifentanil/propofol and remifentanil/isoflurane anaesthesia.
Haemodynamic and autonomic reactions occurred in both groups. This is a consequence of the study design: to provide anaesthesia with the minimum drug dose and to use haemodynamic variables for remifentanil dose finding. In the ISO group there was more hypotension. The higher incidence of hypotension with isoflurane might be due to high isoflurane concentrations, i.e. too deep hypnosis. As BIS was maintained within the appropriate range for surgery under general anaesthesia (45-60), inappropriately high isoflurane concentrations were avoided. The higher frequency of hypotension in the ISO group is consistent with the lower dose of remifentanil in this group. With higher frequency of hypotension in this group, remifentanil is titrated down more often than in the PRO group. It is not clear if the higher incidence of hypotension in the ISO group is caused by analgesic [20,21] or cardiovascular depressing properties of isoflurane [22-24], or by differences in stimulus intensity between groups. With propofol, there were more somatic reactions per hour (i.e. grimacing and movement). Without BIS monitoring, this might be misinterpreted as 'light' anaesthesia. With BIS monitoring, the hypnotic effect is controlled at the site of the target organ, i.e. brain cortex, as conscious perception is related to cortical activity. However, movement is not necessarily related to consciousness and is mainly a function of subcortical activity, e.g. at the level of the spinal cord [25-28]. Thus, a higher incidence of movement in the PRO group does not mean patients receiving remifentanil/propofol had less hypnosis than patients receiving remifentanil/isoflurane anaesthesia.
BIS-guided administration of propofol or isoflurane guarantees a sufficient hypnotic component during anaesthesia. However, comparable BIS values in both groups cannot guarantee that identical hypnotic levels were maintained in both groups. It remains difficult to evaluate the level of hypnosis, especially with the use of different drug combinations. Possible monitors of the hypnotic state have to be validated using clinical signs of sedation and hypnosis. Unfortunately, we have very few clinical measures of sedation and hypnosis, especially in the range necessary for general anaesthesia. Loss of responsiveness is one clinical end-point, perhaps the occurrence of burst suppression in the EEG is another. Thus, an index of the hypnotic state can only be validated using very few clinical signs. Even in the ideal case that the index value at this limited number of clinical signs is independent from the anaesthetic agent, there is no guarantee that this independence is maintained at different levels of hypnosis. In the present study, we cannot guarantee identical degree of hypnosis in both groups from the fact that identical BIS values were maintained. However, in all patients included in this study the targeted BIS range of 45-60 produced sufficient anaesthesia without signs of awareness or postoperative recall in both groups.
To test for differences between BIS-guided remifentanil/propofol and remifentanil/isoflurane anaesthesia, groups were compared for differences at endotracheal intubation and skin incision. As an increase of BIS detects a decrease of the hypnotic component, an arousal reaction would manifest in BIS increase, resulting in a high BIS maximum. The 3 min maximum of haemodynamic parameters detects haemodynamic reactions. Before intubation, there was no difference in BIS or haemodynamic variables between groups. The lack of significant differences following intubation demonstrates again that, if guided by BIS and haemodynamic variables, anaesthesia with both remifentanil/propofol and remifentanil/isoflurane is stable.
At skin incision, again both groups were tested for differences in MAP, heart rate and BIS before and following the stimulus. The lower preincision MAP in the ISO group is consistent with the lower total dose of remifentanil administered, as MAP is used to guide remifentanil infusion rate. At the time of comparison, remifentanil is still further reduced due to haemodynamic variations. There were no other significant differences between groups at skin incision.
During the last 15 min of surgery, anaesthetic agents were reduced to keep BIS in the range 60-75 - indicating a low probability of awareness. During the last 15 min of surgery, there was skin closure and - if requested by surgeons - wound dressing under anaesthesia. For these procedures, a reduced level of hypnosis is still sufficient, with the advantage of faster wakeup and recovery. At this time, differences in the hypnotic level could cause differences in recovery times between groups. Comparable BIS values during the last 15 min are consistent with comparable and prompt recovery profiles. As our study demonstrates, with BIS-guided administration of anaesthetics, anaesthesia is comparably stable and recovery comparably short with both remifentanil/propofol and remifentanil/isoflurane.
This study was supported by a grant from Glaxo Wellcome, Inc. It was performed during G. S.'s research fellowship at the Emory University School of Medicine.
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