Various hypnotic endpoints have been used to assess anaesthetic depth during induction and maintenance. Traditionally, the hypnotic endpoints of unresponsiveness to verbal commands (UVC) and loss of eyelash reflex (LER) have been used to indicate loss of consciousness during induction with intravenous (i.v.) anaesthetic drugs [1,2]. Mechanical (noxious) stimulation of the nasal mucosa (via the trigeminal nerve) leads to sneezing and movement of different parts of the body including the extremities . In this study, we used nasal body movement response (NBMR), body movement and/or sneezing in response to mechanical stimulation of the nasal mucosa as an additional hypnotic endpoint during propofol ±fentanyl i.v. anaesthesia.
EEG variables, e.g. bispectral index (BIS), 95% spectral edge frequency (SEF) and median frequency (MF), have been studied in relation to the movement response to skin incision during propofol + alfentanil i.v. anaesthesia , emergence from propofol i.v. anaesthesia  and to predict the suppression of learning during propofol + epidural anaesthesia . EEG variables have also been studied in relation to the blood propofol concentrations during i.v. anaesthesia [5,6].
In this study, we determined the relation between the EEG variables, i.e. BIS, 95% SEF and MF, and the hypnotic endpoints of UVC, LER and inhibition of NBMR (INBMR) during anaesthetic induction with zero order propofol ± fentanyl i.v. infusion. In addition, we measured propofol doses and concentrations (measured at INBMR only) to determine their relation with the hypnotic endpoints and the EEG variables.
After approval from the Institutional Human Studies Committee, 42 ASA physical status I or II patients, 20-55 years old, scheduled for elective non-cranial surgery were recruited to participate in the study. Patients with a history of neurological or psychiatric disease, smoking (>10 cigarettes day−1), excessive alcohol intake (>30 g day−1) or intranasal pathology were excluded. Patients did not receive any sedative, hypnotic or analgesic premedication.
After preoxygenation with 100% O2, anaesthesia was induced in the two treatment groups as follows: propofol infusion, 30 mg kg−1 h−1 (group P, n = 22); and propofol infusion, 30 mg kg−1 h−1 + fentanyl bolus, 2 μg kg−1 i.v., 2 min before commencing propofol infusion (group PF, n = 20).
ECG for rate, rhythm and ischaemia, SpO2 (arterial oxygen saturation) and IABP (intra-arterial blood pressure) were monitored continuously during the study period. Hypotension (MAP<70% of baseline) during the study period was treated with fluid or an i.v. bolus of ephedrine. After commencing propofol infusion, the ability to open the eyes to verbal commands and the eyelash reflex were assessed every 30 s. After UVC and LER, NBMR was evaluated every minute by stimulating the nasal mucous membrane with a battery-operated rotating soft brush (diameter 3 mm, length 12 mm). The tip of the brush was inserted 3-4 cm past the nasal orifice after the application of 0.1% tramazoline hydrochloride to the brush to prevent nasal bleeding. The rotating stimulus was applied at 100 ± 10 Hz for three 2-s durations over a period of 10 s (Fig. 1). A positive response was defined as any visible movement and/or sneezing during or immediately after nasal stimulation. If the positive NBMR persisted for three consecutive attempts (3 min), supplemental propofol boluses, 30 mg i.v., were administered every minute until inhibition of the response.
After preparation of the skin, four disposable silver-silver chloride electrodes (two negatives: one each above the outer malar bones, one 4 cm above nasion and one ground) were applied as per two-channel reference montage. Impedance of the electrodes was less than 2000 Ω. BIS, 95% SEF and MF were monitored continuously using a microprocessor-based, two-channel A1050 EEG monitor (Aspect Medical Systems, Natick, MA, USA) containing software revision 1.1 (BIS 3.2 algorithm). BIS, 95% SEF and MF were calculated at 5-s epochs and recorded at 15-s intervals. BIS, 95% SEF and MF and doses of propofol administered (infusion times) to achieve the hypnotic endpoints (UVC, LER and INBMR) were monitored and recorded. Radial arterial blood (3 mL) was withdrawn at INBMR for the measurement of plasma propofol concentration. After centrifuging the blood at 3000 rpm for 20 min, separated plasma was stored at −70°C for the measurement of propofol concentrations by high-performance liquid chromatography.
Data are presented as mean ± SD. Data between the treatment groups were analysed using the analysis of variance (ANOVA) followed by Scheffe's test. Within each treatment group, baseline data and data at the time of UVC, LER and INBMR were analysed using repeated measures ANOVA followed by Scheffe's test. Regression analysis was performed to determine the relation between plasma propofol concentrations and EEG variables at INBMR in the P and PF groups. P<0.05 was considered statistically significant.
Demographic data (gender, age, weight, height and ASA status) were comparable in the two treatment groups (P>0.05). No study patient required treatment for hypotension (MAP<70% of baseline), and nasal stimulation was not associated with undesirable cardiovascular, bleeding or any other side-effect in any of the patients.
Doses of propofol (infusion times) to achieve the hypnotic endpoints were significantly lower in patients pretreated with fentanyl, 2 μg kg−1 i.v. Significantly higher doses (longer infusion times) of propofol were required for INBMR compared with UVC and LER. Plasma propofol concentrations at INBMR were significantly lower in patients pretreated with fentanyl (9.3 ± 2.0 μg mL−1 vs. 14.1 ± 4.2 μg mL−1) (Table 1). The regression analysis values (r-values) between BIS and plasma propofol concentrations at INBMR were 0.33 and 0.18 in the P and PF groups respectively (Fig. 2). The regression values (r-values) between 95% SEF and MF vs. plasma propofol concentrations were much lower when compared with those between BIS values and plasma propofol concentrations in both the treatment groups.
Baseline EEG data were similar in the two treatment groups. The BIS, 95% SEF and MF values decreased progressively from baseline to INBMR in the P group. BIS values at UVC, LER and INBMR were significantly higher in patients pretreated with fentanyl, 2 μg kg−1 i.v. The BIS values required to achieve INBMR were significantly lower than for UVC and LER in both the P and the PF groups. Of the three EEG variables, only BIS showed a significant difference between UVC and LER in the P group. BIS was the only parameter that decreased significantly from baseline to the hypnotic endpoints of UVC and LER in the PF group. However, BIS, 95% SEF and MF values decreased significantly from baseline to INBMR in the PF group (Tables 2-4).
The purpose of the study was to determine the relation between the EEG variables, e.g. BIS, 95% SEF and MF, and hypnotic endpoints of UVC, LER and INBMR during anaesthetic induction with zero order propofol ± fentanyl i.v. infusion. For nasal stimulation, we applied a rotating stimulus at 100 ± 10 Hz lasting intermittently for 10 s because, in the preliminary experiments, we found that a stimulus of longer duration increased the likelihood of nasal bleeding. The trigeminal nerve is a sensory nerve innervating the nasal mucosa and is the afferent pathway for the response. The sneezing centre comprises neurons in the trigeminal nucleus and the adjacent pontine-medullary reticular formation. The efferent pathways of the response are through the vagal, facial and bulbospinal nerves to the laryngeal, pharyngeal, facial and intercostal muscles and diaphragm. The central and efferent pathways causing movement of the upper extremities may be different from those of sneezing, as movements of the upper extremity were usually suppressed after sneezing was blocked.
Sebel et al. reported movement in response to skin incision in 20% patients at a BIS value of 10 with i.v. propofol anaesthesia. We observed a lowest BIS value of 20 for INBMR among 22 patients, with 80% of the patients demonstrating inhibition at a BIS value below 28 during i.v. propofol infusion (group P). Smith et al. reported a mean blood propofol concentration (Cpi50) of 15.2 μg mL−1 for inhibiting the response to skin incision in 50% of patients. Mean propofol concentration at INBMR was 14.1 μg mL−1 in our patients (group P) receiving propofol. These studies suggest that a lighter plane of hypnosis and lower propofol concentrations may be required for INBMR compared with movement response to skin incision. This may be related to differences in the intensity of these two stimuli and to the fact that it may be possible to depress the movement response to noxious stimuli by anaesthetic depression of the spinal neurons , whereas supraspinal depression may be more significant for inhibiting the nasal body movement response and/or sneezing.
The regression analysis values (r-values) between BIS and plasma propofol concentrations at INBMR were 0.33 and 0.18 in the P and PF groups, respectively, suggesting a weaker correlation between BIS and plasma propofol concentrations in the fentanyl-pretreated patients. This may further suggest the importance of an analgesic component for INBMR and the efficacy of BIS as a monitor of the hypnotic component during propofol ± fentanyl i.v. anaesthesia. Comparable with our findings, Doi et al. and Leslie et al. demonstrated that BIS correlates better with blood propofol concentrations than do other EEG variables. However, the less significant correlation between BIS values and plasma propofol concentrations in our study compared with the results of these two studies may be related to a smaller sample size in the present study (n = 22 vs. n = 349 and 278) [5,6].
In order to monitor the adequacy of propofol ± fentanyl i.v. anaesthesia, we monitored the multivariate discriminant variable, e.g. BIS, as well as the frequency variables, e.g. 95% SEF and MF. The BIS, which integrates the frequency and amplitude of the EEG waveforms, has been proposed as a measure of the pharmacodynamic anaesthetic effect on the central nervous system. Bispectral analysis is a mathematical analysis, which examines coupling among the sine wave components tracking non-linear as well as linear changes in the signals . The BIS development database consisted of segments of recorded EEG and associated clinically derived hypnotic states or sedation levels . The features discriminating different hypnotic states/sedation levels were combined using multivariate statistical modelling techniques to form a composite index, the BIS, varying from 100 to 0 . 95% SEF is the frequency below which 95% of the EEG power is distributed, whereas MF is the frequency at which half the frequency power is at higher frequencies and half at lower frequencies. As BIS is a statistical construct designed to decrease with increasing hypnosis, it does not demonstrate a biphasic pattern during i.v. propofol anaesthesia, as observed with frequency variables.
Fentanyl bolus, 2 μg kg−1 i.v., administered 2 min before i.v. propofol infusion reduced the propofol dose requirement by 48%, with a corresponding 32% reduction in the plasma propofol concentration at INBMR. This propofol dosage reduction for INBMR was greater compared with that for UVC and LER. In addition, the mean BIS value for INBMR was 13.3 higher in patients pretreated with fentanyl, suggesting the significance of analgesic activity for INBMR. The BIS value, therefore, does not correspond with the adequacy of all the components of anaesthesia, e.g. hypnosis, analgesia and areflexia. Similarly, previous studies have shown that the efficacy of BIS when predicting responses to noxious stimuli (skin incision) depends on the anaesthetic technique (regimen) [4,7].
The mean BIS value for UVC with propofol (group P) was 65.8 in our patients, a little higher than the BIS value of 61.0 reported by Flaishon et al.. Fentanyl bolus, 2 μg kg−1 i.v., reduced the propofol dose requirement by 20% for UVC. Similarly, the BIS values for UVC were higher in patients pretreated with fentanyl (74.7 ± 10.9 vs. 65.8 ± 9.8). The reported interaction between opiates and propofol during induction of unconsciousness is controversial. Moffat et al. reported that fentanyl, 1 μg kg−1 i.v., or alfentanil, 5 μg kg−1 i.v., failed to produce a significant effect on the induction dose of propofol. On the other hand, in agreement with our findings, Short et al. demonstrated that bolus doses of alfentanil reduced the propofol dose required to induce unconsciousness. Smith et al. observed a dose-dependent effect of fentanyl on propofol during induction of unconsciousness, and a plasma fentanyl concentration of 3 ng mL−1 decreased the propofol concentration required to render 50% of patients unresponsive to a skin incision by approximately 89%.
In routine clinical practice, responsiveness to verbal commands and eyelash reflex are often used to assess the state of consciousness/unconsciousness [2,12,15]. In some studies, neither differed as an indicator of the anaesthetic level [1,16]. In other instances, they were abolished at different anaesthetic levels, reflected by different drug doses or concentrations [2,17]. In our study, UVC and LER required similar doses of propofol (infusion times) in both the treatment groups. Surprisingly, BIS values differed significantly for UVC and LER, i.e. 65.8 ± 9.8 vs. 59.6 ± 10.0, in spite of the similar propofol dose requirement in the P group. However, with fentanyl supplementation of propofol, response to verbal commands and eyelash reflex were abolished at similar BIS values. BIS, 95% SEF and MF were reduced significantly following the change from the conscious state to UVC, LER and INBMR. However, the degree of change was less for 95% SEF and MF, with large interindividual variability in the latter. In patients pretreated with fentanyl, only BIS reflected the progressive anaesthetic state indicated by the hypnotic endpoints, but changes in 95% SEF and MF were not consistent.
In conclusion, BIS and 95% SEF reflected the developing anaesthetic state monitored by the hypnotic endpoints of UVC, LER and INBMR more accurately when compared against MF. In patients pretreated with fentanyl, only BIS reflected the progressive changes more accurately compared with 95% SEF and MF. Fentanyl pretreatment potentiated the effects of propofol to achieve the hypnotic endpoints at higher BIS values and lower propofol doses. BIS value is, therefore, not independent of the anaesthetic regimen for monitoring the depth of anaesthesia.
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