Bispectral index as an indicator of anaesthetic depth during isoflurane anaesthesia in the pig

J. vet. Anaesth. Vol. 2{[) (/999) Bispectral index as an indicator of anaesthetic depth during isoflurane anaesthesia in the pig H. A. Haga, A. Tevik and H. Moerch DepartmentofLarge Animal Clinical Science, The Norwegian School ofveterinary Science, PO Box 814 Dep, N- Oslo, Norway SUMMARY The objective of the study was to examine the relationship between the 'depth' of anaesthesia - as determined by clinical signs - and the bispectral index (ElS). Electroencephalograms (EEG)s were recorded in 8 female and 8 castrated male, healthy Norwegian landrace pigs undergoing isoflurane anaesthesia, from which the bispectral index (BIS) was calculated. Isotlurane was delivered in pure oxygen at end-tidal concentrations of 1., 1.9,2.2 and %, in randomised order, for min after which the EEG was recorded over a 5 min period. Anaesthetic depth was evaluated on a visual analogue scale (VAS) by an experienced anaesthetist. The 95% confidence interval for the mean correlation coefficient between BIS and VAS was calculated to be -.52-.. Confidence intervals (95%) for the mean change in the BIS obtained during the conscious state and that obtained during anaesthesia at different isotlurane concentrations was also calculated. There was a significant decrease in the BIS recorded during consciousness and after 1,% isotlurane anaesthesia, and between readings after inhalation of 2.2% and % isotlurane. This indicates that BIS does not accurately retlect 'depth' at surgical levels of isotlurane anaesthesia in the pig, and is of no use for this purpose. INTRODUCTION A means of being able to measure anaesthetic depth in the pig objectively would be of considerable value because in this, and other species, the dose of inhalation drug delivered (expressed in terms of minimum alveolar concentration [MAC]) is an unreliable indicator of anaesthetic depth: the response of different individuals to delivered anaesthetic concentration varies (Haskins 199). Evaluating the depth of anaesthesia present depends on the subject's physiological responses to surgery, eg heart rate and blood pressure, considered against a subjective assessment of general retlex activity, a knowledge of the drugs used and their doses. The electroencephalogram (EEG) that is recorded from the body surface and indicates cortical electrical activity has been shown to change according to anaesthetic depth in a variety of species (Prynn and Redding 198; Rose et al. 1972; Otto and Short 1991). Interpretation of the EEG signal is greatly facilitated by performing a Fourier transformation on collected data: this generates a collection ofsinusoids, which can be used to characterise the EEG as a single number such as spectral edge frequency 95% (SEF) and median frequency (MED). The bispectral index (ElS) is calculated from an algorithm empirically derived from EEG studies of people under anaesthesia. The algorithm takes into account power spectral parameters, burst suppression and the degree of phase coupling assessed through bispectral analysis, and generates a BIS value from -1 (Sigl and Chamoun 1994). Pigs are used extensively in biomedical research and may undergo major surgery. Thus it would be advantageous to have better indicators of anaesthetic 'depth' in this species. Little research has been performed in the field of electroencephalography and anaesthesia in the pig. Spectraledge and median-edge frequencies have been evaluated as potential indicators of anaesthetic depth in animals and man. Different conclusions have been reached in these studies regarding the suitability of spectral parameters as indicators of anaesthetic depth (Levy 1984; Otto and Short 1991; Dwyer et al. 1994; Johnson et al. 1994; Schwender et al. 199). Bispectral index (ElS) a parameter derived from the EEG, has been reported by several authors to retlect the sedative component of anaesthetic depth in man (Kearse el al. 1994; Sebel et al. 1995; Liu et al. 199, 1997; Billard et al. 1997; Glass et al. 1997). Isoflurane is a volatile anaesthetic agent, which allows rapid changes in anaesthetic depth (Hall and Clarke 1991), Its MAC value in pigs has been determined to be 1.55% (Eisele et al. 1985). The former property was desirable in the present study, which attempted to examine the relationship between BIS and anaesthetic depth in the pig, MATERIALS AND METHODS The study, which was approved by the National Animal Research Authority, involved 1 Norwegian landrace pigs weighing 2-4 kg, purchased from a farm with a known (good) health status. One female and one castrated male animal were selected from 8 different litters. The pigs were allocated randomly to one of 4 experimental groups each consisting of 2 unrelated females and 2 unrelated castrated

J. vet. Anaesth, Vol. 2( 1) (1999) TABLE 1: Schedule of administration of the 4 different sequences of isoflurane concentrations administered Sequence of isoflurane concentrations 1.% - 1.9% - 2.2% - % % - 1.% - 1.9% - 2.2% 2.2% - % - 1.% - 1.9% 1.9% - 2.2% - % - 1.% Pigs receiving specified sequence 1,, 11, 14,8,9,12 4,5,1,1 2,7,1,15 males. Each group received a specific pre-determined sequence of four different end-tidal isoflurane concentrations (see Table I) to eliminate any effect of the order in which isoflurane concentrations were administered. The 1 pigs were anaesthetised in a randomised order. The skin was shaved and defatted with diethyl ether before EEG electrodes (Zipprep Aspect Medical Systems) were applied. A previously used electrode configuration (Rampil et al. 1988) was adjusted to replicate the Fp-Cz configuration that has been used to evaluate isotlurane sedation in man (Glass et al. 1997). An electrode was placed I cm caudal to the lateral angle of the eye and 1 cm medial to the temporal line on each side of the head. These were referred to an electrode placed in the median plane 2 cm caudal to the recording electrodes. A ground electrode was placed on the neck behind the left ear. Before each recording, the impedance was checked and maintained below 2, ohms at 1Hz. The electrodes were connected to an EEG monitor (A-lOOOTM, Aspect Medical Systems). The pigs were placed on a purpose-built stretcher consisting of a wooden frame and nylon straps and a 5 min period of conscious-state EEG was recorded. The monitor used automatically detected EEG epochs with low quality signals, calculated BIS, suppression ratio ([SRI the percentage of epochs in the previous s where the EEG signal is considered suppressed) and Fourier transformation parameter in real time. These parameters were transferred to a computer (Dell Latitude Cpi D2XT). Anaesthesia was induced with isotlurane in oxygen administered by mask. When anaesthesia was judged to be adequate, 2% lidocaine was sprayed onto the larynx and the trachea intubated. The pigs were placed in right lateral recumbency on an electric blanket, with a thermometer placed in the rectum, and connected to an anaesthesia monitor (Datex-Engstrom AS/) to enable physiological responses to anaesthesia to be monitored and controlled. Oxygen saturation, end-tidal CO 2 concentration, inspiratory and expiratory isotlurane concentration, rectal temperature and ECG were monitored. A cuff was placed between the tarsus and knee to measure non-invasive blood pressure (NlBP) at 1 min intervals. Invasive blood pressure (lbp) was measured continuously through a cannula placed in the saphenous artery attached to an electronic transducer zeroed at the level of the thoracic inlet. Measured physiological variables were maintained within specified intervals throughout the sampling period. Rectal temperature was kept between 7.5 C and 4. C. To maintain mean IBP above 5 mmhg, Ringer acetate or, if necessary, dextran 7 in a concentration of mg/ml (Macrodex Medisan Pharmaceuticals) was infused at a rate of 1-1 ml/kg/h. End-tidal CO 2 was kept between 4.5% and 5.5% while the Orsaturation was maintained above 95%. Before EEG recording began, the end-tidal isotlurane concentration was maintained at the specified level for min. End-tidal concentrations of 1.%, 1.9%,2.2% and % were examined, which corresponds to a range of light to surgical anaesthesia. After 5 min of EEG registration an anaesthetist, who was unable to monitor the EEG signal, assessed the animal for the type of retlexes present, and their strength. This information was taken with the physiological variables being monitored to create a subjective judgement of the depth of anaesthesia present, which was scored on a 15 mm long visual analogue scale (VAS). The VAS was divided into 5 categories on the basis of which retlexes might be expected to be present at each 'level' of anaesthesia.:this in turn was based upon Smith's ranking of retlexes with increasing anaesthetic depth (Smith 1992). The procedure was repeated for the other isotlurane concentrations. After the last evaluation the pigs were allowed to recover from anaesthesia. 15 D 1 14 2 x 1 " 12 x 11 +... 5 1. 9 on ~ " [j) 8 x ~ ~ 7 + 9 + D +"" -a' x 1... ai!' 5 o 11 x " -I 4 " 12 <> - x. x 1 + " 2 + x <ii< " o 15 1 + 1 1 2 4 5 7 8 9 1 SIS Fig 1: VAS values plotted against median SIS at each evaluation (each pig is indicated by its individual symbol explained in the frame on the right hand side). 4

./. vet. Anaesth. Vol. 2(1) (1999) 1 9 8 7 ~ 5 CD 4 2 1.5 1.5 2 c 1 o 2 " + 9 c 1 12.. " 1 " 15 1 Fig 2: The median BIS of each 1 9 8 7 a: 5 CfJ 4 2 1.5 1.5 2 o 1 o 2 " + 9 a 1 12 " 1 " 15.. 1 Fig : The median SR at each The parameters calculated from a combination of both recording electrodes were used in the analyses. The EEG monitor calculated different BIS values, all of which were transferred to the computer. However only one, the socalled B1 U, was displayed on the monitor and used in further analyses. Standard monitor filter settings were applied. After completing anaesthesia, the recorded EEG parameters were checked and recordings with an error message were discarded. Spectral edge frequency and MED were discarded when a recording period contained burst suppression, as this renders Fourier analysis unreliable (Levy 1984; Billard et al. 1997). The median BIS values at each recording were calculated and their differences between the following treatments determined for each pig: a) consciousness and 1.% isoflurane; b) 1.% and 1.9% isotlurane; c) 1.9% and 2.2% isotlurane; and d) 2.2% and % isotlurane. The mean and a 95% confidence interval for these differences were calculated using Student-t analyses. A correlation coefficient between the VAS and the median BIS at each recording during anaesthesia was calculated for each pig. The mean and a 95% confidence interval for these correlation coefficients were also calculated. RESULTS Each pig had 4 pairs of VAS and BIS data (Fig I). The mean correlation coefficient between VAS and BIS was -.11, and the 95% confidence interval for the correlation coefficient was -.52-.. The correlation coefficients for VAS and SIS were calculated from the data from anaesthetised pigs: the differences between consciousness and the anaesthetised state were not evaluated. The 95% confidence interval for the mean correlation coefficient between VAS and BIS contained which means that no linear trend could be found between VAS and BIS. Analysis of the change in BIS from consciousness to 1.% end-tidal isotlurane, showed the 95% contidence interval for the mean difference did not encompass, indicating that there was a significant change in BIS. All the conscious state median SIS values were above 97, and all median BIS recorded during anaesthesia were below 87. There was no significant change in HIS between 1.% isoflurane and 1.9% isotlurane, or between 1.9% and 2.2% isoflurane. Bispectral index decreased signiticantly from 2.2% isotlurane to % isotlurane (Table 2) even though pigs actually showed an increase in median BIS between these 2 levels of isotlurane (Fig 2). 5

.I. vel. Anaesth. Vol. 2( 1) (1999) TABLE 2: Mean change in BIS for the 1 pigs between the conscious state recordings and 1.% isoflurane, and between each step in isoflurane concentration %-1.% isoflurane 1.%-1.9% isoflurane 1.9%- 2.2% isoflurane 2.2%- % isoflurane Conscious state recordings were the only ones where undisturbed SEF and MED values were obtained for all pigs, because burst suppression occurred, and the suppression ratio increased, with increasing isoflurane concentrations (Fig ). Even at 1.% end-tidal isoflurane, one pig (number 11) showed some burst suppression. As the design of the study is sensitive to missing data, SEF and MED with BlS could not be compared statistically. However, SEF and MED data are shown graphically in Figures 4 and 5. DISCUSSION Mean change in SIS 22. -1.4 1. 95% confidence interval 18.8 - -2.2.2-7. - 4.5 2.2 -. This study found little correlation between VAS scores, which were the most reliable means of assessing depth of anaesthesia, and BIS; and it is concluded that the latter is of little value during isoflurane anaesthesia in pigs. This is in contrast to man, where BIS has been shown to correlate well with an observer's assessment of a subject's level of unconsciousness during isoflurane anaesthesia (Glass et al. 1997). The VAS is based upon objective measurements such as heart rate, IBP, end-tidal isoflurane concentration as well as subjective measurements such as the degree of response to stimuli. The use of VAS as a 'golden standard' is questionable and the scale itself is not used in a clinical setting, but the evaluation of anaesthetic depth is done in a similar way (Haskins 199). Bispectral index was able to differentiate between the conscious state and light isoflurane anaesthesia, and between deep levels of anaesthesia. However, this is of little use: an ideal indicator of anaesthetic 'depth' should detect changes at clinical levels of anaesthesia. The results of the present study seem to indicate that BIS reaches a plateau level in the transition from the conscious state to a surgical depth of isoflurane anaesthesia. Comparing SR and BIS at different isoflurane concentrations revealed that the 7 pigs with the lowest BIS value at % isoflurane also had the highest SR value. This could indicate that the algorithm used for calculating BIS is very sensitive to burst suppression. In all pigs without burst suppression at 1.% isoflurane, median SEF and median MED fell from the conscious state to 1.% isoflurane. The conscious state median SEF were 25 2 N ~ 15 LL W (f) 1 5.5 1.5 2. D 1...~ 2.... x.. 4 7.. +.. 9... 1.. 11. &. 12...lC... 1... 14... 15.. 1 Fig 4: The median SEF of each 18 1 14 12 N ~ 1 ui :2: 8 4 2.5 1.5 2...<>... 1.. <>.. 2 - -7.. +.. 9 -e. 1.. 12.. 1..... 14.15.1 Fig 5: The median MED of each

J. vet. Anaesth. Vol. 2( /) (/999) always higher than the 1.% isoflurane median SEF, while some of the conscious state median MED was lower than the 1.% isoflurane median MED. This may indicate that, in pigs, SEF is a more sensitive parameter than MED for differentiating consciousness and light levels of isoflurane anaesthesia. In horses SEF was found to be a better indicator of anaesthetic depth than MED during halothane anaesthesia (Johnson et at. 1994). In a recent paper, it was reported that isoflurane does not cause any gradual depression of the EEG during surgical levels of anaesthesia in the horse (Johnson and Taylor 1998). Our results suggest this is the case in pigs. The 2 different approaches used to assess BIS as an indicator of anaesthetic depth gave somewhat different results. This is probably because the VAS-BIS evaluation only considers linear trends and does not take conscious state recordings into account. The evaluation of BIS against endtidal isoflurane concentration revealed that the most consistent change in BIS was found to occur from the conscious state to 1.% isoflurane recording. The threshold level for acceptable IBP in this study was lower than that in others recording EEG during anaesthesia. However, a minimum IBp of 5 mmhg was chosen because pre-trial studies had shown that it was difficult to maintain higher mean IBp without using vasopressor drugs, which may have affected the EEG. Although BIS values are able to differentiate a conscious state from a state of light anaesthesia, and also to detect deeper levels of anaesthesia in the pig, BIS does not seem to change according to anaesthetic depth at clinically useful isotlurane concentrations. It is not a useful indicator of anaesthetic depth during isoflurane anaesthesia in the pig. ACKNOWLEDGEMENTS This study was economically supported by the Norwegian Research Council. The authors thankfully acknowledge Dr L. 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