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The bispectral index during recovery from halothane and sevoflurane anaesthesia in horses
Veterinary Anaesthesia and Analgesia, 2010, 37, 25–34
doi:10.1111/j.1467-2995.2009.00507.x
RESEARCH PAPER
The bispectral index during recovery from halothane and sevoflurane anaesthesia in horses Eliseo Beldao*, Karen J Blissitt, Juliet C Duncan , Francisco G Laredo*, Mayte Escobar Gil de Montes* & R Eddie Clutton *Departamento de Medicina y Cirugı´a Animal, Hospital Clı´nico Veterinario, Universidad de Murcia, Murcia, Spain Royal (Dick) School of Veterinary Studies, Division of Veterinary Clinical Sciences, The University of Edinburgh, Equine Hospital, Easter Bush Veterinary Centre, Midlothian, UK
Correspondence: R Eddie Clutton, Veterinary Clinical Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian EH25 9RG, Scotland. E-mail: [email protected]
Abstract Objective To record the bispectral index (BIS) when horses moved during either halothane or sevoflurane anaesthesia and when they made volitional movements during recovery from these anaesthetics. Study design Randomized prospective clinical study. Animals Twenty-five client-owned horses undergoing surgery aged 8.8 (± 5.3; 1–19) years (mean ± SD; range). Methods Baseline BIS values were recorded before pre-anaesthetic medication (BISB) and during anaesthesia (BISA) maintained with halothane (group H; n = 12) or sevoflurane (group S; n = 13) at approximately 0.8–0.9 · minimum alveolar concentrations (MAC). Bispectral indices were recorded during the surgery when unexpected movement occurred (BISMA), during recovery when the first movement convincingly associated with consciousness was observed (BISM1) and once sternal recumbency was achieved (BISST). Results No significant difference in BISM1 was found between halothane- (85 ± 7; 75–93) and sevoflurane- (87 ± 10; 70–98) anaesthetized horses although BISA was significantly (p = 0.0002) lower in group S (62 ± 7; 53–72) than group H (74 ± 7;
60–84). Differences between BISM1 and BISA were significant in sevoflurane (p = 0.00001) and halothane recipients (p = 0.002) but were greater in group S (25 ± 9; 4–38) compared with group H (12 ± 10; )9–25). In six of eight horses, BISMA values ranged between those recorded during anaesthesia and at first movement. Conclusions and clinical relevance Bispectral indices appear to approximate levels of unconsciousness, suggesting that monitoring the BIS may assist equine anaesthesia. However, it does not predict intra-operative movement. Keywords anaesthesia, bispectral index, halothane, horses, sevoflurane.
Introduction The consequences of inaccurate depth of anaesthesia monitoring in horses are important. At best, over-anaesthetizing animals prolongs recovery. At worst, dose-dependent cardiopulmonary impairment may increase post-anaesthetic morbidity and mortality. In contrast, inadequate anaesthesia causes undesirable physiological and neuro-endocrinological changes and allows reflex or even volitional movement during surgery. Slight movement will complicate surgery and compromise surgical cleanliness whereas violent reactions may injure operating room staff and damage equipment. The 25
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use of neuromuscular blocking agents at effective doses prevents problems associated with movement. However, monitoring anaesthetic depth is complicated in animals paralysed with neuromuscular blocking agents because these eliminate cranial nerve reflexes, e.g. they immobilize the eye and ‘fix’ it centrally. They also prevent reflex and volitional somatic muscular responses to noxious stimulation. Under these conditions, autonomic nervous signs, e.g. blood pressure, heart rate, lacrimation, become more important as ‘depth of anaesthesia’ indicators even though they are unreliable (Struys et al. 2002; Weber et al. 2005) and may fail to indicate ‘awareness’ in paralysed human subjects. The distressing nature of awareness during surgery has prompted the development of various depth of anaesthesia monitors (Bruhn et al. 2006). One method – the bispectral index (BIS) – is derived from the electroencephalogram (EEG) to produce a single dimensionless numerical value that nominally reflects the hypnotic component of the anaesthetic state (Kearse et al. 1994; Vernon et al. 1995). In some studies, its use has reduced – but not eliminated – the incidence of awareness during operation when muscle relaxants are used in human subjects (Ekman et al. 2004; Myles et al. 2004). In others, no benefits were found (Avidan et al. 2008). Demonstrating benefits in animals is complicated: animals which are aware during operation cannot report so post-operatively, which precludes correlation of ‘awareness’ with intra-operative BIS values. To complicate matters further, the relationship between BIS and ‘depth of anaesthesia’ is drugdependent and does not always bear a linear association with dose. For example, ketamine increases BIS in humans during propofol (Vereecke et al. 2003) and sevoflurane (Hans et al. 2005) anaesthesia. The effects of nitrous oxide (N2O) are highly variable and depend on co-administered anaesthetic, the presence or absence of noxious stimulation and experimental methods (Sebel et al. 1997; Puri 2000; Hall et al. 2002; Goto et al. 2005). The BIS response to similar anaesthetics also varies. In adult humans, BIS values are higher during halothane, compared with equivalent levels of sevoflurane anaesthesia (Edwards et al. 2003; Schwab et al. 2004). Monitoring BIS in paralysed animals intentionally administered sub-anaesthetic doses during surgery, would facilitate the association of BIS values with ‘awareness’ but would be ethically indefensible. A marginally less objectionable option would be to 26
monitor BIS during surgery in non-paralysed animals whilst reducing anaesthetic depth until clear signs of nociception were detected. In this study, BIS was monitored during recovery from anaesthesia and recorded when the first volitional movements were made assuming that this would correspond to the lightest plane acceptable in a paralysed animal. The goal of this study was to determine the BIS values at which horses moved intra-operatively and at which they made their first volitional movement during recovery. A secondary goal was to determine whether the volatile anaesthetic used (halothane or sevoflurane) affected these values. Materials and methods Twenty-five (>18 months old) horses and ponies of either sex undergoing elective surgical procedures at the Royal (Dick) School of Veterinary Studies and judged to be healthy on the basis of medical history and physical examination were allocated by block randomization to be anaesthetized with either halothane or sevoflurane. Food and water were withheld pre-operatively for 12 and 1 hours, respectively. Subject characteristics are detailed in Table 1. The study received the prior approval of the Departmental Ethical Review Committee. A 13-gauge catheter was placed percutaneously in the external jugular vein and, following this procedure, an attempt was made to obtain baseline BIS values (BISB). A 7 cm wide strip of coat hair was clipped over the frontal bone at a level approximately 8–10 cm above the lateral canthi of the eyes and extending over the supraorbital fossae on both sides. The skin at the clipped site was cleaned with ethanol for 1 minute and then dried, before application of an adult-sized BIS sensor (BIS QUATRO; Medical Systems, the Netherlands). Electrode number 1 was positioned on the midline, approximately 8–10 cm caudal to the lateral canthi of the eyes, with electrodes 2 and 4 arrayed laterally away from the midline. The distance between electrodes was the maximum permitted by the physical dimensions of the nonelastic sensor strip. Sensor 3 was positioned over m. frontoscutularis in the supraorbital fossa, to record electromyographic (EMG) activity. The sensor strip was then covered and secured in place using sufficient elastic adhesive bandage to encircle the head 2–3 times although the connecting lead was left exposed. Values for BIS were then determined in the standing unsedated horse by connecting the sensor to the digital signal converter
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Table 1 Characteristics of horses in which anaesthesia was maintained with halothane or sevoflurane and in which bispectral index was monitored
Group
Gender
Breeds
Halothane (n = 12)
Males 2 Geldings: 6 Females: 4
Sevoflurane (n = 13)
Males 1 Geldings 8 Females 4
Thoroughbred 3 Warmblood 3 Appaloosa 1 Arab pony 2 Welsh cob 2 Highland pony 1 Thoroughbred 7 Thoroughbred·1 Holstein 1 Highland pony 1 Arab pony 1 Hunter 1 Welsh cob 1
Age (years)
Body mass (kg)
7.3 ± 4.5* (3.0–17.0)
497 ± 135 (380–620)
9.8 ± 5.5* (1.0–19.0)
507 ± 90 (415–593)
Surgery
Tieback 3 Tenoscopy 1 Colic – exploratory 3 Hoof wall resection 1 Sarcoid excision 1 Cryptorchiectomy 3 Tieback 2 Tenoscopy & sheath flush 3 Arthroscopy 2 Neurectomy 1 Desmotomy 1 Ocular tumour excision 1 Incisional hernia repair 1 Vaginal tunic debridement 1 Cryptorchiectomy 1
Body position
Duration of operation (minutes)
Dorsal 5 Left 2 Right 5
50 ± 26 (20–120)
Dorsal 5 Left 3 Right 5
51 ± 25 (30–110)
Data expressed as mean ± SD (range). *Significant difference (p < 0.05) between means (Student’s independent t-test).
(DSC, Bispectral index Monitor XP SRS compatible, Model A-2000; Aspect Medical Systems, the Netherlands) and observing the output. The smoothing time was set to 15 seconds and the means of the minimum and maximum values recorded over three separate 15-second recording periods were taken to indicate the values of the BIS. The signal quality index (SQI) – a measure of the signal quality for the EEG channel source based on impedance data, artefact and other variables – was simultaneously monitored throughout the study and data recorded only when the SQI was >50 arbitrary units. Sensors were replaced after site re-preparation when ‘sensor error’ or ‘low signal quality/intensity’ messages were displayed. Horses were then sedated with romifidine (Sedivet; Boehringer Ingelheim Ltd, UK) 0.1 mg kg)1 and morphine (Morphine Sulphate injection BP; Martindale Pharmaceuticals, UK) 0.1 mg kg)1 intravenously (IV) injected 3 minutes later. After a further 5 minutes, the BIS sensor and cable were disconnected and anaesthesia induced with ketamine 2.2 mg kg)1 (Vetalar V; Pharmacia & Upjohn Animal Health Ltd, UK) and diazepam 0.05 mg kg)1 (Diazepam injection BP; Hamelin Pharmaceuticals Ltd, UK) combined in the same syringe and administered IV. After orotracheal
intubation, animals were transferred to the operating room by mechanical hoist where the sensor was reconnected and BIS monitoring resumed. The endotracheal tube was connected to a large animal circle breathing system (Draeger Medical UK Ltd, UK) which incorporated a 30 L re-breathing bag filled with either 3.5% halothane (Halothane liquid; Concord Pharmaceuticals Ltd, UK) or 5% sevoflurane (Sevoflo; Abbott laboratories Ltd, UK) in a 50:50 oxygen (O2):nitrous oxide (N2O) mixture. Intermittent positive pressure ventilation was imposed using tidal volumes of 12–15 mL kg)1 and respiratory rates of 6–8 breaths minute)1. The vaporizer settings (Halothane Vapor 19.1; Draeger Medical UK Ltd., UK or Penlon Sigma Delta Sevoflurane vaporizer; Penlon Ltd., UK) were adjusted in an attempt to maintain fractional end-tidal halothane (FE¢HAL) and sevoflurane (FE¢SEVO) concentrations of 0.96% and 2.5% respectively, corresponding to 1.1 · the published minimum alveolar concentrations (MAC) for halothane (Steffey et al. 1977) and sevoflurane (Aida et al. 1994). Flows for O2 and N2O were set at 10 mL kg)1 minutes)1 although N2O was discontinued after 10 minutes. A 20 gauge cannula was placed in the facial artery for the continuous monitoring of arterial pressure
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and periodic (30 minutes) collection of samples for blood gas analysis (OPTI AVL Critical Care Analyser; Osmetach Inc., GA, USA). Arterial pressure, the electrocardiogram (ECG), end-tidal carbon dioxide (FE¢CO2), and FE¢HAL and FE¢SEVO were monitored using a pre-calibrated multi-channel physiological monitor (Datex-Engstrom Compact; Datex-Engstrom Inc., MA, USA). Flunixin 1.1 mg kg)1 IV (Flunixin injection; Norbrook Laboratories Ltd, Newry, Co. Down) was administered before surgery began. Additional morphine (0.1 mg kg)1 IV) was administered at the anaesthetist’s discretion. Lactated Ringer’s solution was infused IV throughout surgery at 10 mL kg)1 hour)1. The BIS was monitored during anaesthesia and values recorded (along with corresponding end-tidal anaesthetic concentrations) at least 30 minutes after connection to the breathing system and after end-tidal anaesthetic concentrations had been constant for at least 15 minutes (BISA). BIS values were recorded whenever horses moved and 15 seconds later. The value BISMA represented the mean value of these two readings. At the end of surgery, xylazine 0.2 mg kg)1 (Virbaxyl 10%; Virbac Limited, UK) was injected IV and the breathing system and BIS disconnected. Horses were then transferred back into the recovery box. Here, sound was kept to a minimum and the recovery monitored without interference using remote controlled CCTV with a zoom and variable focus facility. Digital video recording required a lighting level that allowed the recognition of recovery signs, and the horses’ eyes were covered with light-proof material. Oxygen was insufflated into the nares of recovering horses at flows of 10–15 L minute)1. BIS monitoring was resumed in recovery and the values at first movement, i.e. BISM1, recorded when movement was considered to indicate returning consciousness, e.g. head lift, thoracic limb movement preceding an attempt to move into sternal recumbency, or ear movement in response to sound, was observed. The BISST was recorded once the first successful attempt at sternal recumbency was made. Data were collected by a single observer (EB). Two additional variables were derived from BISB, BISA and BISM1: BIS(M1)A) was the difference between values recorded during anaesthesia and at first movement; BIS((M1/B)·100) was the value at first movement expressed as a percentage of the baseline value. 28
Statistical analyses Data are expressed as mean (±SD; range) unless otherwise stated, and were processed by Statistica (StatSoft Ltd, UK). Normally distributed BIS data (established by Shapiro-Wilk’s test) collected at the four main sampling points (baseline, stable anaesthesia, first recovery movement, sternal recumbency) were compared between groups using an independent t-test. The means of nonparametric data were compared using the Mann–Whitney U-test. Student’s t-test for dependent samples was used to compare mean BISA and BISM values in each group. Statistical significance was accepted when p < 0.05. Results Twenty-five animals were studied, 12 in group H and 13 in group S. Their characteristics are shown in Table 1. Noncompliance precluded baseline data collection from seven horses in each group. The mean ± SD FE¢HAL and FE¢SEVO measured when BISA was recorded were 0.79 ± 0.09% and 1.91 ± 0.14% respectively, which were lower than the target values of 0.96% for halothane and 2.53% for sevoflurane. Two horses in each group were administered additional morphine doses of 150 lg kg)1 IV. The median, interquartile and nonoutlier range of values for BISB, BISA, BISMA, BISM1 and BISST are shown in Fig. 1. BIS values broadly represented the apparent degree of CNS depression present at each sampling point: anaesthesia depressed BIS values compared with baseline whilst during recovery, BIS values increased at first movement and were a maxima once sternal recumbency was achieved. BIS values for movement during surgery were intermediate between those for anaesthesia and first movement in most animals. Descriptive statistics for five recorded, and two derived BIS data-sets are shown in Table 2. The mean (±SD) BIS values at first movement did not differ significantly between groups: mean BISM1 in group H was 85 ± 7 and 87 ± 9 in group S. Differences between BISA and BISM1 (Fig. 1) were statistically significant in both groups, but were larger (25 ± 9) in sevoflurane (p = 0.00001) compared with halothane (p = 0.002) recipients (12 ± 10) because BISA was significantly (p = 0.0002) lower in group S (62 ± 7) than group H (74 ± 7).
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100 b a
90
*
BIS units
80
a
70
b
60
50
0
BISB
BISA
BISMA
BISM1
BISST
Figure 1 Box and whisker plot showing median (line) 25th–75th percentiles (box) and nonoutlier maximum and minimum bispectral indices (BIS) (whisker) in five halothane- ( ) and six sevoflurane-anaesthetized ( ) horses before anaesthesia (BISB) and in 12 (halothane) and 13 (sevoflurane) animals after 15 minutes at constant end-tidal anaesthetic concentration (BISA), during the first recovery movements (BISM1) and when horses moved into sternal recumbency (BISST). Raw data plots for halothane- (•) and sevoflurane-anaesthetized (s) horses indicate BIS indices when intraoperative movement (BISMA) occurred. *Significant difference (p = 0.0002) between groups H and S. ( , à) Significant difference between BISA and BISM1. For anaesthesia details, see Table 2.
Table 2 Mean ± SD (range) of BIS values in horses in which anaesthesia was maintained with halothane (group H) or sevoflurane (group S)
BISB
Halothane 88 ± 8 (80–96) [5] Sevoflurane 92 ± 2 (89–94) [6]
BISA
BISMA
BISM1
BIS(M1)A)
BIS((M1/B)·100) %
BISST
74 ± 7 (60–84) [12]*à
81 ± 6 (74–87) [3]
85 ± 7 (75–93) [12]*
12 ± 10 (9–25) [12]
95 ± 12 (83–109) [5]
93 ± 4 (87–98) [12]
62 ± 7 (53–72) [13] à
79 ± 10 (66–94) [5]
87 ± 9 (70–98) [13]
25 ± 9 (4–38) [13]
93 ± 11 (76–108) [6]
90 ± 6 (77–98) [13]
Anaesthesia was induced in both groups using ketamine (2.2 mg kg)1) and diazepam (50 lg kg)1) IV after pre-anaesthetic medication with romifidine (0.1 mg kg)1) and morphine (0.1 mg kg)1). [n] Signifies number of animals from which data were gathered. * àStatistically significant difference (p < 0.05) between data sets with same letter. BIS subscripts: B, baseline (before sedation); A, during anaesthesia; MA, when intra-operative movement occurred; M1, at first movement during recovery; ST, when horse attained sternal recumbency.
Plots of BIS(M1)A) and BIS(M1/B)·100 for individual animals in groups H and S are shown in Figs 2a & b respectively. Bispectral indices at first movement exceeded those recorded during anaesthesia in most cases. However, BIS(M1)A) was negative in one horse in group H and unchanged in another (Fig. 2a).
Values of BIS(M1/B)·100 derived from horses in which baseline data were available are shown in Fig. 2b. Eight horses moved during surgery, five in the halothane group and three in the sevoflurane group (Figs 3a & b). Mean values for BISMA in group H were 79 ± 10; 66–94 and in group S: 81 ± 7;
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50
120
(b)
(a) 110
100
20
90
10
80
0
70
–10
60
BIS(M1-A) (BIS units)
30
(a)
BIS(M1/B)*100 (%)
40
Figure 2 (a) Box and whisker showing median (line) 25th–75th percentiles (box) and nonoutlier maximum and minimum bispectral indices (BIS) indices (whisker) in halothane- ( ) and sevoflurane-anaesthetized ( ) horses and a dot plot showing individual values for differences between BISM1 and BISA in halothane- (•) and sevoflurane-anaesthetized (s) horses. (b) Dot plots showing individual values for BIS at first movement expressed as a percentage of baseline. For anaesthesia details, see Table 2.
(b) Figure 3 Line plots showing individual values for bispectral indices (BIS) during anaesthesia (BISA), when intra-operative movement occurred (BISMA) and upon first movement during recovery (BISM1) in halothane- ( ) and sevoflurane-anaesthetized (s) horses. Superimposed box (interquartile range) and whisker (non-outlier minimum and maximum) plots (line: median) for animals in group H ( ) and S ( ) indicate that most horses moving intra-operatively were from the quartile with lowest BISA values. For anaesthesia details, see Table 2.
•
74–87. In group S and for three horses in group H, these values were intermediate between BISA and BISM1. BISMA values in two horses in group H exceeded BISM1. The small numbers in each group precluded statistical analysis. The probable cause of intra-operative movement was not recorded; although based on other clinical signs, no affected animal was judged to have recovered to full consciousness. No horses in this study 30
became hypercapnic anaesthesia.
nor
hypoxaemic
during
Discussion Bispectral indices recorded in this study broadly reflected the clinically judged degree of CNS depression present when data were recorded, although differences between groups were observed. The
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highest values obtained occurred at the first attempt to gain sternal recumbency, which slightly exceeded baseline values. Minimum values were associated with stable anaesthesia, but increased with intraoperative movement, and reached near-maximum levels when consciousness was thought to have returned. However, this was not always the case: BIS(M1)A) was negative in one horse in group H and unchanged in another (Fig. 2a), suggesting that the level of hypnosis increased during recovery in the former horse and remained constant in the second. Alternatively, the lack of positive BIS(M1)A) values in two horses may indicate that BIS does not reflect hypnosis in all horses. Despite these, the mainly positive relationship between BIS and levels of consciousness contrasts with a previous study in horses in which BIS values at end-tidal isoflurane concentrations of 1.8% were paradoxically higher than those recorded in another group receiving end-tidal concentrations of 1.4% (Haga & Dolvik 2002). This unexpected finding may have resulted from an effect isoflurane, but not halothane or methoxyflurane has on spectral edge frequency (SEF). Johnson & Taylor (1998) found that increasing the end-tidal isoflurane concentration from 1.25 MAC (1.5%) to 1.5 MAC (1.8%) increased SEF, whereas increasing halothane or methoxyflurane concentrations reduced it. The results suggest a 50% probability that halothane-anaesthetized horses with BIS values >85 and sevoflurane-anaesthetized horses >87 are at a depth of anaesthesia that allows movement. Similarly, a likelihood of movement in 95% of cases occurs at BIS values >99 (halothane) and at the maximum value of 100 (sevoflurane). In reality, movement is likely to occur at BIS values less than these because the calculations are based on BISM1: voluntary movement in undisturbed animals lying in recovery is not comparable with that arising during surgery. For similar reasons, mean increases in BIS values >12 over those recorded during stable halothane anaesthesia, and >25 during sevoflurane anaesthesia and BIS values greater than 95% (halothane) or 93% (sevoflurane) of baseline similarly indicate greater than a 50% probability of movement. Figures 2a and b reveal similar variation in both BIS(M1)A) and BIS(M1/B)·100, which suggests that recording pre-anaesthetic and intraoperative BIS values are of similar benefit. Values of BIS(M1/B)·100 derived from horses in which baseline data were available (Fig. 2b) indicate that anaesthetics had little influence on the percentage of baseline BIS at which first movement occurred.
That six of eight horses moved intra-operatively at BIS values less than their corresponding BISM1 confirm the invalidity of the central tenet of the study, i.e. that BISM1 represents a value at which movement is present or imminent in nonparalysed horses, or at which consciousness might return in horses that have received neuromuscular blocking agents. The results also confirm that movement before, during and after surgery (in recovery) arises from different neural processes (Antognini et al. 2005) and therefore may occur at different levels of anaesthesia, i.e. BIS values. Limb and neck movement before surgery indicate inadequate anaesthesia and returning consciousness so may be partly volitional. However, such movements may also represent righting reflexes, particularly in horses in dorsal recumbency. Similar factors may contribute to intra-operative movement but in most cases, a nociceptive reflex component is probably present. During recovery, movement will eventually be volitional but nociceptive and righting reflexes may also contribute. Consequently, intra- and post-operative movement may not indicate uncomplicated consciousness alone, and so bear little relationship to BIS, unless movement is associated with arousal patterns which simultaneously increase it. The latter seems probable because surgery changes the EEG – at least in halothaneanaesthetized horses (Murrell et al. 2003) in a way that should increase BIS indices. Evaluating the usefulness of BISM1’for predicting intra-operative movement or consciousness was complicated by the fact that signs of returning consciousness were seldom associated with the animal’s first movement. Unambiguous signs, e.g. deliberate attempts to roll into sternal recumbency or ear movement directed towards sound, were seen in some horses but in many others convincing signs of consciousness, e.g. blinking or even vocalization, occurred before movement began. Movements made during or after such observations were recorded as BISM1 which are equal to, or more likely in excess of the BIS value at which consciousness actually returned. A more precise method for determining the latter is required. Consequently, BISM1 values recorded in this study are likely to be greater than those values coinciding with intra-operative movement, although they may more accurately represent impending consciousness. As the range of operations performed in this study increased the external validity of its findings, it probably contributed to the variation in
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data – particularly BISMA – because different degrees of nocistimulation influence bispectral indices (Takamatsu et al. 2006). All horses received pre-surgical flunixin and morphine, whilst additional morphine was administered at the anaesthetist’s discretion. These measures probably reduced differences in nociception associated with different procedures, although the effects on BIS are difficult to predict: in dogs, morphine had negligible effect on BIS during isoflurane anaesthesia (Henao-Guerrero et al. 2009). Failing to record BISA at specified times probably increased data variation because plasma romifidine, ketamine, diazepam and N2O concentrations would have been different in all cases studied. This is important because all are likely to affect the EEG. Detomidine and butorphanol depress BIS in horses (Haga & Dolvik 2002), so it seems reasonable to expect other alpha-2-agonists to exert the same effect. Ketamine increases BIS in humans by shifting the EEG pattern towards higher frequencies and causing desynchronization; this increases BIS independently of anaesthetic depth (Hans et al. 2005). Therefore, its persistent effect into the sampling period may have diminished the difference between BIS values in the two groups. The mean duration of recumbency in horses sedated with romifidine then administered ketamine at a dose of 2.2 mg kg)1 is 20 minutes (Kerr et al. 1996) and BIS data were recorded in this study a minimum of 45 minutes after ketamine was injected. However, a ‘hang-over’ effect cannot be discounted and EEG effects may persist for longer than signs of an anaesthetic effect, e.g. recumbency. Nitrous oxide may have had a similar obfuscating effect, although the gas’s effect on human BIS values is extremely variable. In the absence of noxious stimulation, unchanged (Hall et al. 2002), increased (Glass et al. 1997; Sebel et al. 1997; Puri 2000) or decreased (Hans et al. 2001; Goto et al. 2005) BIS values have been reported when N2O was used. An absence of information in horses makes it impossible to predict the effects of N2O delivered in the first 10 minutes of this study on the BIS values recorded more than 35 minutes later. The gas’s low solubility in equine blood makes any effect likely to be small. The mean BIS values during halothane (74 ± 7) and sevoflurane (62 ± 7) anaesthesia in this study were higher than those considered compatible with hypnosis in humans (40–65 for general anaesthe32
sia, 65–85 for sedation; Johansen & Sebel 2000). However, it is possible that the device’s algorithm, which assesses the power and frequency, burst suppression, slow synchronized activity and b-activation of the EEG (Rosow & Manberg 2001; Hans et al. 2005) is less capable of deriving accurate information when applied to the horse, whose skull and nervous tissue differ in their size, density and shape. Nevertheless, BIS values during halothane anaesthesia were significantly higher than those recorded in group S horses – as it is in humans (Edwards et al. 2003, 2005; Davidson 2004; Schwab et al. 2004) which supports the possibility that the human and equine bispectral indices are similar physiological entities. Unlike sevoflurane, halothane does not induce burst suppression at clinical doses (Kuroda et al. 1997; Black et al. 2000) which may partially explain BIS value differences between these anaesthetics. Halothane also suppresses noxious stimuli to a greater degree than isoflurane (Dwyer et al. 1992) producing anaesthesia by decreasing arousing subcortical inputs (Davidson 2004) in addition to suppressing cortical activity. Sevoflurane and isoflurane do not possess the former property. Evidence for an alternative explanation, i.e. that horses in the halothane group were at a lighter plane of anaesthesia than those in the sevoflurane group, is conflicting. The mean ± SD end-tidal anaesthetic concentrations in halothane and sevoflurane recipients during BISA registration (0.79 ± 0.09% and 1.91 ± 0.14% respectively) corresponded to 0.89· and 0.83 · the MAC values reported in horses – 0.88% for halothane (Steffey et al. 1977) and 2.3% for sevoflurane (Aida et al. 1994) – and indicate if anything, that group H horses were more ‘deeply’ anaesthetized. However, more horses (5) moved during halothane compared with sevoflurane (3) anaesthesia. That more horses did not move during the administration of end-tidal concentrations less than MAC can be explained by the pre-administration of romifidine, ketamine, diazepam, morphine, flunixin and nitrous oxide. Five horses from group H and three from group S moved during surgery and although details were not recorded, it is likely that the movements were reflex, and indicated inadequate rather than an absence of anaesthesia. BISMA values in two horses in group H exceed BISM1 (Fig. 3a), suggesting that movement during halothane anaesthesia is associated with more arousal than that seen with sevoflurane. Although this points to possible drug-
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dependent differences in analgesic properties, the small number of horses involved in either group undermines meaningful speculation. BISMA values were, with the exception of two halothane recipients, intermediate between BISA and BISM1 but were appreciably less than those recorded at first movement. This supports the view that BISM1 is probably in excess of values at which intra-operative movement is likely to occur. The BIS monitor failed to indicate impending movement in one out of eight animals that moved in this study, which indicates a marginally greater predictive value than that previously reported: Haga & Dolvik (2002) anaesthetized eight horses with isoflurane (FE¢ = 1.4%) and encountered movement in four. Of these, two showed no obvious increase in BIS before movement. The ability of BIS to predict intra-operative movement depends on: 1) the movement being associated with arousal; 2) the algorithm’s smoothing time, and 3) the anaesthetist’s ability to detect rising BIS values. In this study, the smoothing time was set at the minimum possible (15 seconds) allowing the earliest possible indication of the latter. Unfortunately, BISMA was taken only once the horse had moved, values beforehand were not detailed but described simply as ‘rising’ or ‘unchanging.’ The data memory and the ‘Print Event’ facilities of the Model A-2000 used in this study were over-looked, otherwise pre-movement BIS changes could have been reviewed. However, it seems likely that even if nociceptive reflex movement were consistently associated with arousal, signal processing may not be rapid enough to alert even attentive personnel of imminent movement. Future studies would benefit from at least four refinements: 1) recording BIS values at fixed times after drug administration; 2) standardising operations; 3) devising more sensitive ways of judging the return of consciousness; and 4) identifying more accurately the cause of intra-operative movement. Thereafter, a larger scale study linking intra-operative movement with BIS may determine its ability to predict this complication. The challenge in devising a method that humanely tests the ability of BIS to identify consciousness in animals paralysed by neuromuscular blocking agents remain. This study shows that bispectral indices are of some value in evaluating the depth of anaesthesia in horses. During recovery, BIS values >85 for halothane, and >87 for sevoflurane anaesthesia indicate that movement is imminent although these values over-estimate those at which intra-operative move-
ment occurs. The study did not allow conclusions to be drawn about the usefulness of BIS for identifying consciousness in horses during neuromuscular blockade. Acknowledgement We are grateful to Carolyn Bertram of the Equine Hospital, Royal (Dick) School of Veterinary Studies for her assistance with this project. References Aida H, Muzino Y, Hobo S et al. (1994) Determination of the minimum alveolar concentration (MAC) and physical response to sevoflurane inhalation in horses. J Vet Med Sci 56, 1161–1165. Antognini JF, Barter L, Carstens E (2005) Overview movement as an index of anesthetic depth in humans and experimental animals. Comp Med 55, 413–418. Avidan MS, Zhang L, Burnside BA (2008) Anesthesia awareness and the bispectral index. N Engl J Med 358, 1097–108. Black S, Mahla ME, Cucchiara RF(2000) Neurologic monitoring. In: Anesthesia (5th edn). Miller RD (ed). Churchill Livingston, London. pp. 1324–1350. Bruhn J, Myles PS, Sneyd R et al. (2006) Depth of anaesthesia monitoring: what’s available, what’s validated and what’s next? Br J Anaesth 97, 85–94. Davidson A (2004) The correlation between bispectral index and airway reflexes with sevoflurane and halothane anaesthesia. Paediatr Anaesth 14, 241–246. Dwyer R, Bennett HL, Eger EI et al. (1992) Effects of isoflurane and nitrous oxide in subanesthetic concentrations on memory and responsiveness in volunteers. Anesthesiology 77, 888–898. Edwards JJ, Soto RG, Thrush D et al. (2003) Bispectral index scale is higher for halothane than sevoflurane during intraoperative anesthesia. Anesthesiology 99, 1453–1455. Edwards JJ, Soto RG, Bedford RF (2005) Bispectral indexTM values are higher during halothane vs. sevoflurane anesthesia in children, but not in infants. Acta Anaesthesiol Scand 49, 1084–1087. Ekman A, Lindholm ML, Lennmarken C et al. (2004) Reduction in the incidence of awareness using BIS monitoring. Acta Anaesthesiol Scand 48, 20–26. Glass PS, Bloom M, Kearse L et al. (1997) Bispectral analysis measures sedation and memory effect of propofol, midazolam, isoflurane, and alfentanil. Anesthesiology 86, 836–847. Goto T, Ishiguro Y, Nakata Y et al. (2005) The bispectral index predicts responsiveness to verbal commands in patients emerging from nitrous oxide anesthesia supplemented with a subhypnotic concentration of isoflurane. J Anesth 19, 102–105.
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Haga HA, Dolvik NI (2002) Evaluation of the bispectral index as an indicator of degree of central nervous system depression in isoflurane-anesthetized horses. Am J Vet Res 63, 438–442. Hall DL, Weaver J, Ganzberg S et al. (2002) Bispectral EEG index monitoring of high-dose nitrous oxide and lowdose sevoflurane sedation. Anesth Prog 49, 56–62. Hans P, Bonhomme V, Benmansour H et al. (2001) Effect of nitrous oxide on the bispectral index and the 95% spectral edge frequency of the electroencephalogram during surgery. Anaesthesia 10, 999–1002. Hans P, Dewandre PY, Brichant JF et al. (2005) Comparative effects of ketamine on Bispectral Index and spectral entropy of the electroencephalogram under sevoflurane anaesthesia. Br J Anaesth 94, 336–340. Henao-Guerrero PN, McMurphy R, Kukanich B et al. (2009) Effect of morphine on the bispectral index during isoflurane anesthesia in dogs. Vet Anaesth Analg 36, 133–143. Johansen JW, Sebel PS (2000) Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 93, 1336–1344. Johnson CB, Taylor PM (1998) Comparison of the effects of halothane, isoflurane and methoxyflurane on the electroencephalogram of the horse. Br J Anaesth 81, 748–753. Kearse LA, Manberg P, Chamoun N et al. (1994) Bispectral analysis of the electroencephalogram correlates with patient movement to skin incision during propofol/ nitrous oxide anesthesia. Anesthesiology 81, 1365– 1370. Kerr CL, McDonell WN, Young SS (1996) A comparison of romifidine and xylazine when used with diazepam/ ketamine for short duration anesthesia in the horse. Can Vet J 37, 601–609. Kuroda Y, Murakami M, Tsuruta J et al. (1997) Blood flow velocity of middle cerebral artery during prolonged anesthesia with halothane, isoflurane, and sevoflurane in humans. Anesthesiology 87, 527–532. Murrell JC, Johnson CB, White KL et al. (2003) Changes in the EEG during castration in horses and ponies anaesthetized with halothane. Vet Anaesth Analg 30, 38–46. Myles PS, Leslie K, McNeil J et al. (2004) Bispectral index monitoring to prevent awareness during anaesthesia:
34
the B-Aware randomised controlled trial. Lancet 363, 1757–1763. Puri GD (2000) Paradoxical changes in bispectral index during nitrous oxide administration. Br J Anaesth 86, 141–142. Rosow C, Manberg PJ (2001) Bispectral index monitoring. Anesthesol Clin N Am 19, 947–966. Schwab HS, Seeberger MD, Eger EI II et al. (2004) Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples. Anesth Analg 99, 1723–1727. Sebel P, Lang E, Rampil L et al. (1997) A multicenter study of bispectral encephalogram analysis for monitoring anesthetic effects. Anesth Analg 84, 891–899. Steffey EP, Howland D, Giri S et al. (1977) Enflurane, halothane and isoflurane potency in horses. Am J Vet Res 38, 1037–1039. Struys MM, Jensen EW, Smith W et al. (2002) Performance of the ARX-derived auditory evoked potential index as an indicator of anesthetic depth: a comparison with bispectral index and hemodynamic measures during propofol administration. Anesthesiology 96, 803– 816. Takamatsu I, Ozaki M, Kazama T (2006) Entropy indices vs the bispectral index for estimating nociception during sevoflurane anaesthesia. Br J Anaesth 96, 620–622. Vereecke HE, Struys MM, Mortier EP (2003) A comparison of bispectral index and ARX-derived auditory evoked potential index in measuring the clinical interaction between ketamine and propofol anaesthesia. Anaesthesia 58, 957–961. Vernon J, Lang E, Sebel P et al. (1995) Prediction of movement using BIS electroencephalographic analysis during propofol/alfentanil or isoflurane/alfentanil anesthesia. Anesth Analg 80, 780–785. Weber F, Seidl M, Bein T (2005) Impact of the AEPMonitor/2-derived composite auditory-evoked potential index on propofol consumption and emergence times during total intravenous anaesthesia with propofol and remifentanil in children. Acta Anaesthesiol Scand 49, 277–283. Received 24 April 2009; accepted 12 August 2009.
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doi:10.1111/j.1467-2995.2009.00507.x
RESEARCH PAPER
The bispectral index during recovery from halothane and sevoflurane anaesthesia in horses Eliseo Beldao*, Karen J Blissitt, Juliet C Duncan , Francisco G Laredo*, Mayte Escobar Gil de Montes* & R Eddie Clutton *Departamento de Medicina y Cirugı´a Animal, Hospital Clı´nico Veterinario, Universidad de Murcia, Murcia, Spain Royal (Dick) School of Veterinary Studies, Division of Veterinary Clinical Sciences, The University of Edinburgh, Equine Hospital, Easter Bush Veterinary Centre, Midlothian, UK
Correspondence: R Eddie Clutton, Veterinary Clinical Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian EH25 9RG, Scotland. E-mail: [email protected]
Abstract Objective To record the bispectral index (BIS) when horses moved during either halothane or sevoflurane anaesthesia and when they made volitional movements during recovery from these anaesthetics. Study design Randomized prospective clinical study. Animals Twenty-five client-owned horses undergoing surgery aged 8.8 (± 5.3; 1–19) years (mean ± SD; range). Methods Baseline BIS values were recorded before pre-anaesthetic medication (BISB) and during anaesthesia (BISA) maintained with halothane (group H; n = 12) or sevoflurane (group S; n = 13) at approximately 0.8–0.9 · minimum alveolar concentrations (MAC). Bispectral indices were recorded during the surgery when unexpected movement occurred (BISMA), during recovery when the first movement convincingly associated with consciousness was observed (BISM1) and once sternal recumbency was achieved (BISST). Results No significant difference in BISM1 was found between halothane- (85 ± 7; 75–93) and sevoflurane- (87 ± 10; 70–98) anaesthetized horses although BISA was significantly (p = 0.0002) lower in group S (62 ± 7; 53–72) than group H (74 ± 7;
60–84). Differences between BISM1 and BISA were significant in sevoflurane (p = 0.00001) and halothane recipients (p = 0.002) but were greater in group S (25 ± 9; 4–38) compared with group H (12 ± 10; )9–25). In six of eight horses, BISMA values ranged between those recorded during anaesthesia and at first movement. Conclusions and clinical relevance Bispectral indices appear to approximate levels of unconsciousness, suggesting that monitoring the BIS may assist equine anaesthesia. However, it does not predict intra-operative movement. Keywords anaesthesia, bispectral index, halothane, horses, sevoflurane.
Introduction The consequences of inaccurate depth of anaesthesia monitoring in horses are important. At best, over-anaesthetizing animals prolongs recovery. At worst, dose-dependent cardiopulmonary impairment may increase post-anaesthetic morbidity and mortality. In contrast, inadequate anaesthesia causes undesirable physiological and neuro-endocrinological changes and allows reflex or even volitional movement during surgery. Slight movement will complicate surgery and compromise surgical cleanliness whereas violent reactions may injure operating room staff and damage equipment. The 25
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use of neuromuscular blocking agents at effective doses prevents problems associated with movement. However, monitoring anaesthetic depth is complicated in animals paralysed with neuromuscular blocking agents because these eliminate cranial nerve reflexes, e.g. they immobilize the eye and ‘fix’ it centrally. They also prevent reflex and volitional somatic muscular responses to noxious stimulation. Under these conditions, autonomic nervous signs, e.g. blood pressure, heart rate, lacrimation, become more important as ‘depth of anaesthesia’ indicators even though they are unreliable (Struys et al. 2002; Weber et al. 2005) and may fail to indicate ‘awareness’ in paralysed human subjects. The distressing nature of awareness during surgery has prompted the development of various depth of anaesthesia monitors (Bruhn et al. 2006). One method – the bispectral index (BIS) – is derived from the electroencephalogram (EEG) to produce a single dimensionless numerical value that nominally reflects the hypnotic component of the anaesthetic state (Kearse et al. 1994; Vernon et al. 1995). In some studies, its use has reduced – but not eliminated – the incidence of awareness during operation when muscle relaxants are used in human subjects (Ekman et al. 2004; Myles et al. 2004). In others, no benefits were found (Avidan et al. 2008). Demonstrating benefits in animals is complicated: animals which are aware during operation cannot report so post-operatively, which precludes correlation of ‘awareness’ with intra-operative BIS values. To complicate matters further, the relationship between BIS and ‘depth of anaesthesia’ is drugdependent and does not always bear a linear association with dose. For example, ketamine increases BIS in humans during propofol (Vereecke et al. 2003) and sevoflurane (Hans et al. 2005) anaesthesia. The effects of nitrous oxide (N2O) are highly variable and depend on co-administered anaesthetic, the presence or absence of noxious stimulation and experimental methods (Sebel et al. 1997; Puri 2000; Hall et al. 2002; Goto et al. 2005). The BIS response to similar anaesthetics also varies. In adult humans, BIS values are higher during halothane, compared with equivalent levels of sevoflurane anaesthesia (Edwards et al. 2003; Schwab et al. 2004). Monitoring BIS in paralysed animals intentionally administered sub-anaesthetic doses during surgery, would facilitate the association of BIS values with ‘awareness’ but would be ethically indefensible. A marginally less objectionable option would be to 26
monitor BIS during surgery in non-paralysed animals whilst reducing anaesthetic depth until clear signs of nociception were detected. In this study, BIS was monitored during recovery from anaesthesia and recorded when the first volitional movements were made assuming that this would correspond to the lightest plane acceptable in a paralysed animal. The goal of this study was to determine the BIS values at which horses moved intra-operatively and at which they made their first volitional movement during recovery. A secondary goal was to determine whether the volatile anaesthetic used (halothane or sevoflurane) affected these values. Materials and methods Twenty-five (>18 months old) horses and ponies of either sex undergoing elective surgical procedures at the Royal (Dick) School of Veterinary Studies and judged to be healthy on the basis of medical history and physical examination were allocated by block randomization to be anaesthetized with either halothane or sevoflurane. Food and water were withheld pre-operatively for 12 and 1 hours, respectively. Subject characteristics are detailed in Table 1. The study received the prior approval of the Departmental Ethical Review Committee. A 13-gauge catheter was placed percutaneously in the external jugular vein and, following this procedure, an attempt was made to obtain baseline BIS values (BISB). A 7 cm wide strip of coat hair was clipped over the frontal bone at a level approximately 8–10 cm above the lateral canthi of the eyes and extending over the supraorbital fossae on both sides. The skin at the clipped site was cleaned with ethanol for 1 minute and then dried, before application of an adult-sized BIS sensor (BIS QUATRO; Medical Systems, the Netherlands). Electrode number 1 was positioned on the midline, approximately 8–10 cm caudal to the lateral canthi of the eyes, with electrodes 2 and 4 arrayed laterally away from the midline. The distance between electrodes was the maximum permitted by the physical dimensions of the nonelastic sensor strip. Sensor 3 was positioned over m. frontoscutularis in the supraorbital fossa, to record electromyographic (EMG) activity. The sensor strip was then covered and secured in place using sufficient elastic adhesive bandage to encircle the head 2–3 times although the connecting lead was left exposed. Values for BIS were then determined in the standing unsedated horse by connecting the sensor to the digital signal converter
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Table 1 Characteristics of horses in which anaesthesia was maintained with halothane or sevoflurane and in which bispectral index was monitored
Group
Gender
Breeds
Halothane (n = 12)
Males 2 Geldings: 6 Females: 4
Sevoflurane (n = 13)
Males 1 Geldings 8 Females 4
Thoroughbred 3 Warmblood 3 Appaloosa 1 Arab pony 2 Welsh cob 2 Highland pony 1 Thoroughbred 7 Thoroughbred·1 Holstein 1 Highland pony 1 Arab pony 1 Hunter 1 Welsh cob 1
Age (years)
Body mass (kg)
7.3 ± 4.5* (3.0–17.0)
497 ± 135 (380–620)
9.8 ± 5.5* (1.0–19.0)
507 ± 90 (415–593)
Surgery
Tieback 3 Tenoscopy 1 Colic – exploratory 3 Hoof wall resection 1 Sarcoid excision 1 Cryptorchiectomy 3 Tieback 2 Tenoscopy & sheath flush 3 Arthroscopy 2 Neurectomy 1 Desmotomy 1 Ocular tumour excision 1 Incisional hernia repair 1 Vaginal tunic debridement 1 Cryptorchiectomy 1
Body position
Duration of operation (minutes)
Dorsal 5 Left 2 Right 5
50 ± 26 (20–120)
Dorsal 5 Left 3 Right 5
51 ± 25 (30–110)
Data expressed as mean ± SD (range). *Significant difference (p < 0.05) between means (Student’s independent t-test).
(DSC, Bispectral index Monitor XP SRS compatible, Model A-2000; Aspect Medical Systems, the Netherlands) and observing the output. The smoothing time was set to 15 seconds and the means of the minimum and maximum values recorded over three separate 15-second recording periods were taken to indicate the values of the BIS. The signal quality index (SQI) – a measure of the signal quality for the EEG channel source based on impedance data, artefact and other variables – was simultaneously monitored throughout the study and data recorded only when the SQI was >50 arbitrary units. Sensors were replaced after site re-preparation when ‘sensor error’ or ‘low signal quality/intensity’ messages were displayed. Horses were then sedated with romifidine (Sedivet; Boehringer Ingelheim Ltd, UK) 0.1 mg kg)1 and morphine (Morphine Sulphate injection BP; Martindale Pharmaceuticals, UK) 0.1 mg kg)1 intravenously (IV) injected 3 minutes later. After a further 5 minutes, the BIS sensor and cable were disconnected and anaesthesia induced with ketamine 2.2 mg kg)1 (Vetalar V; Pharmacia & Upjohn Animal Health Ltd, UK) and diazepam 0.05 mg kg)1 (Diazepam injection BP; Hamelin Pharmaceuticals Ltd, UK) combined in the same syringe and administered IV. After orotracheal
intubation, animals were transferred to the operating room by mechanical hoist where the sensor was reconnected and BIS monitoring resumed. The endotracheal tube was connected to a large animal circle breathing system (Draeger Medical UK Ltd, UK) which incorporated a 30 L re-breathing bag filled with either 3.5% halothane (Halothane liquid; Concord Pharmaceuticals Ltd, UK) or 5% sevoflurane (Sevoflo; Abbott laboratories Ltd, UK) in a 50:50 oxygen (O2):nitrous oxide (N2O) mixture. Intermittent positive pressure ventilation was imposed using tidal volumes of 12–15 mL kg)1 and respiratory rates of 6–8 breaths minute)1. The vaporizer settings (Halothane Vapor 19.1; Draeger Medical UK Ltd., UK or Penlon Sigma Delta Sevoflurane vaporizer; Penlon Ltd., UK) were adjusted in an attempt to maintain fractional end-tidal halothane (FE¢HAL) and sevoflurane (FE¢SEVO) concentrations of 0.96% and 2.5% respectively, corresponding to 1.1 · the published minimum alveolar concentrations (MAC) for halothane (Steffey et al. 1977) and sevoflurane (Aida et al. 1994). Flows for O2 and N2O were set at 10 mL kg)1 minutes)1 although N2O was discontinued after 10 minutes. A 20 gauge cannula was placed in the facial artery for the continuous monitoring of arterial pressure
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and periodic (30 minutes) collection of samples for blood gas analysis (OPTI AVL Critical Care Analyser; Osmetach Inc., GA, USA). Arterial pressure, the electrocardiogram (ECG), end-tidal carbon dioxide (FE¢CO2), and FE¢HAL and FE¢SEVO were monitored using a pre-calibrated multi-channel physiological monitor (Datex-Engstrom Compact; Datex-Engstrom Inc., MA, USA). Flunixin 1.1 mg kg)1 IV (Flunixin injection; Norbrook Laboratories Ltd, Newry, Co. Down) was administered before surgery began. Additional morphine (0.1 mg kg)1 IV) was administered at the anaesthetist’s discretion. Lactated Ringer’s solution was infused IV throughout surgery at 10 mL kg)1 hour)1. The BIS was monitored during anaesthesia and values recorded (along with corresponding end-tidal anaesthetic concentrations) at least 30 minutes after connection to the breathing system and after end-tidal anaesthetic concentrations had been constant for at least 15 minutes (BISA). BIS values were recorded whenever horses moved and 15 seconds later. The value BISMA represented the mean value of these two readings. At the end of surgery, xylazine 0.2 mg kg)1 (Virbaxyl 10%; Virbac Limited, UK) was injected IV and the breathing system and BIS disconnected. Horses were then transferred back into the recovery box. Here, sound was kept to a minimum and the recovery monitored without interference using remote controlled CCTV with a zoom and variable focus facility. Digital video recording required a lighting level that allowed the recognition of recovery signs, and the horses’ eyes were covered with light-proof material. Oxygen was insufflated into the nares of recovering horses at flows of 10–15 L minute)1. BIS monitoring was resumed in recovery and the values at first movement, i.e. BISM1, recorded when movement was considered to indicate returning consciousness, e.g. head lift, thoracic limb movement preceding an attempt to move into sternal recumbency, or ear movement in response to sound, was observed. The BISST was recorded once the first successful attempt at sternal recumbency was made. Data were collected by a single observer (EB). Two additional variables were derived from BISB, BISA and BISM1: BIS(M1)A) was the difference between values recorded during anaesthesia and at first movement; BIS((M1/B)·100) was the value at first movement expressed as a percentage of the baseline value. 28
Statistical analyses Data are expressed as mean (±SD; range) unless otherwise stated, and were processed by Statistica (StatSoft Ltd, UK). Normally distributed BIS data (established by Shapiro-Wilk’s test) collected at the four main sampling points (baseline, stable anaesthesia, first recovery movement, sternal recumbency) were compared between groups using an independent t-test. The means of nonparametric data were compared using the Mann–Whitney U-test. Student’s t-test for dependent samples was used to compare mean BISA and BISM values in each group. Statistical significance was accepted when p < 0.05. Results Twenty-five animals were studied, 12 in group H and 13 in group S. Their characteristics are shown in Table 1. Noncompliance precluded baseline data collection from seven horses in each group. The mean ± SD FE¢HAL and FE¢SEVO measured when BISA was recorded were 0.79 ± 0.09% and 1.91 ± 0.14% respectively, which were lower than the target values of 0.96% for halothane and 2.53% for sevoflurane. Two horses in each group were administered additional morphine doses of 150 lg kg)1 IV. The median, interquartile and nonoutlier range of values for BISB, BISA, BISMA, BISM1 and BISST are shown in Fig. 1. BIS values broadly represented the apparent degree of CNS depression present at each sampling point: anaesthesia depressed BIS values compared with baseline whilst during recovery, BIS values increased at first movement and were a maxima once sternal recumbency was achieved. BIS values for movement during surgery were intermediate between those for anaesthesia and first movement in most animals. Descriptive statistics for five recorded, and two derived BIS data-sets are shown in Table 2. The mean (±SD) BIS values at first movement did not differ significantly between groups: mean BISM1 in group H was 85 ± 7 and 87 ± 9 in group S. Differences between BISA and BISM1 (Fig. 1) were statistically significant in both groups, but were larger (25 ± 9) in sevoflurane (p = 0.00001) compared with halothane (p = 0.002) recipients (12 ± 10) because BISA was significantly (p = 0.0002) lower in group S (62 ± 7) than group H (74 ± 7).
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100 b a
90
*
BIS units
80
a
70
b
60
50
0
BISB
BISA
BISMA
BISM1
BISST
Figure 1 Box and whisker plot showing median (line) 25th–75th percentiles (box) and nonoutlier maximum and minimum bispectral indices (BIS) (whisker) in five halothane- ( ) and six sevoflurane-anaesthetized ( ) horses before anaesthesia (BISB) and in 12 (halothane) and 13 (sevoflurane) animals after 15 minutes at constant end-tidal anaesthetic concentration (BISA), during the first recovery movements (BISM1) and when horses moved into sternal recumbency (BISST). Raw data plots for halothane- (•) and sevoflurane-anaesthetized (s) horses indicate BIS indices when intraoperative movement (BISMA) occurred. *Significant difference (p = 0.0002) between groups H and S. ( , à) Significant difference between BISA and BISM1. For anaesthesia details, see Table 2.
Table 2 Mean ± SD (range) of BIS values in horses in which anaesthesia was maintained with halothane (group H) or sevoflurane (group S)
BISB
Halothane 88 ± 8 (80–96) [5] Sevoflurane 92 ± 2 (89–94) [6]
BISA
BISMA
BISM1
BIS(M1)A)
BIS((M1/B)·100) %
BISST
74 ± 7 (60–84) [12]*à
81 ± 6 (74–87) [3]
85 ± 7 (75–93) [12]*
12 ± 10 (9–25) [12]
95 ± 12 (83–109) [5]
93 ± 4 (87–98) [12]
62 ± 7 (53–72) [13] à
79 ± 10 (66–94) [5]
87 ± 9 (70–98) [13]
25 ± 9 (4–38) [13]
93 ± 11 (76–108) [6]
90 ± 6 (77–98) [13]
Anaesthesia was induced in both groups using ketamine (2.2 mg kg)1) and diazepam (50 lg kg)1) IV after pre-anaesthetic medication with romifidine (0.1 mg kg)1) and morphine (0.1 mg kg)1). [n] Signifies number of animals from which data were gathered. * àStatistically significant difference (p < 0.05) between data sets with same letter. BIS subscripts: B, baseline (before sedation); A, during anaesthesia; MA, when intra-operative movement occurred; M1, at first movement during recovery; ST, when horse attained sternal recumbency.
Plots of BIS(M1)A) and BIS(M1/B)·100 for individual animals in groups H and S are shown in Figs 2a & b respectively. Bispectral indices at first movement exceeded those recorded during anaesthesia in most cases. However, BIS(M1)A) was negative in one horse in group H and unchanged in another (Fig. 2a).
Values of BIS(M1/B)·100 derived from horses in which baseline data were available are shown in Fig. 2b. Eight horses moved during surgery, five in the halothane group and three in the sevoflurane group (Figs 3a & b). Mean values for BISMA in group H were 79 ± 10; 66–94 and in group S: 81 ± 7;
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BIS monitoring in recovering horses E Beldao et al.
50
120
(b)
(a) 110
100
20
90
10
80
0
70
–10
60
BIS(M1-A) (BIS units)
30
(a)
BIS(M1/B)*100 (%)
40
Figure 2 (a) Box and whisker showing median (line) 25th–75th percentiles (box) and nonoutlier maximum and minimum bispectral indices (BIS) indices (whisker) in halothane- ( ) and sevoflurane-anaesthetized ( ) horses and a dot plot showing individual values for differences between BISM1 and BISA in halothane- (•) and sevoflurane-anaesthetized (s) horses. (b) Dot plots showing individual values for BIS at first movement expressed as a percentage of baseline. For anaesthesia details, see Table 2.
(b) Figure 3 Line plots showing individual values for bispectral indices (BIS) during anaesthesia (BISA), when intra-operative movement occurred (BISMA) and upon first movement during recovery (BISM1) in halothane- ( ) and sevoflurane-anaesthetized (s) horses. Superimposed box (interquartile range) and whisker (non-outlier minimum and maximum) plots (line: median) for animals in group H ( ) and S ( ) indicate that most horses moving intra-operatively were from the quartile with lowest BISA values. For anaesthesia details, see Table 2.
•
74–87. In group S and for three horses in group H, these values were intermediate between BISA and BISM1. BISMA values in two horses in group H exceeded BISM1. The small numbers in each group precluded statistical analysis. The probable cause of intra-operative movement was not recorded; although based on other clinical signs, no affected animal was judged to have recovered to full consciousness. No horses in this study 30
became hypercapnic anaesthesia.
nor
hypoxaemic
during
Discussion Bispectral indices recorded in this study broadly reflected the clinically judged degree of CNS depression present when data were recorded, although differences between groups were observed. The
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highest values obtained occurred at the first attempt to gain sternal recumbency, which slightly exceeded baseline values. Minimum values were associated with stable anaesthesia, but increased with intraoperative movement, and reached near-maximum levels when consciousness was thought to have returned. However, this was not always the case: BIS(M1)A) was negative in one horse in group H and unchanged in another (Fig. 2a), suggesting that the level of hypnosis increased during recovery in the former horse and remained constant in the second. Alternatively, the lack of positive BIS(M1)A) values in two horses may indicate that BIS does not reflect hypnosis in all horses. Despite these, the mainly positive relationship between BIS and levels of consciousness contrasts with a previous study in horses in which BIS values at end-tidal isoflurane concentrations of 1.8% were paradoxically higher than those recorded in another group receiving end-tidal concentrations of 1.4% (Haga & Dolvik 2002). This unexpected finding may have resulted from an effect isoflurane, but not halothane or methoxyflurane has on spectral edge frequency (SEF). Johnson & Taylor (1998) found that increasing the end-tidal isoflurane concentration from 1.25 MAC (1.5%) to 1.5 MAC (1.8%) increased SEF, whereas increasing halothane or methoxyflurane concentrations reduced it. The results suggest a 50% probability that halothane-anaesthetized horses with BIS values >85 and sevoflurane-anaesthetized horses >87 are at a depth of anaesthesia that allows movement. Similarly, a likelihood of movement in 95% of cases occurs at BIS values >99 (halothane) and at the maximum value of 100 (sevoflurane). In reality, movement is likely to occur at BIS values less than these because the calculations are based on BISM1: voluntary movement in undisturbed animals lying in recovery is not comparable with that arising during surgery. For similar reasons, mean increases in BIS values >12 over those recorded during stable halothane anaesthesia, and >25 during sevoflurane anaesthesia and BIS values greater than 95% (halothane) or 93% (sevoflurane) of baseline similarly indicate greater than a 50% probability of movement. Figures 2a and b reveal similar variation in both BIS(M1)A) and BIS(M1/B)·100, which suggests that recording pre-anaesthetic and intraoperative BIS values are of similar benefit. Values of BIS(M1/B)·100 derived from horses in which baseline data were available (Fig. 2b) indicate that anaesthetics had little influence on the percentage of baseline BIS at which first movement occurred.
That six of eight horses moved intra-operatively at BIS values less than their corresponding BISM1 confirm the invalidity of the central tenet of the study, i.e. that BISM1 represents a value at which movement is present or imminent in nonparalysed horses, or at which consciousness might return in horses that have received neuromuscular blocking agents. The results also confirm that movement before, during and after surgery (in recovery) arises from different neural processes (Antognini et al. 2005) and therefore may occur at different levels of anaesthesia, i.e. BIS values. Limb and neck movement before surgery indicate inadequate anaesthesia and returning consciousness so may be partly volitional. However, such movements may also represent righting reflexes, particularly in horses in dorsal recumbency. Similar factors may contribute to intra-operative movement but in most cases, a nociceptive reflex component is probably present. During recovery, movement will eventually be volitional but nociceptive and righting reflexes may also contribute. Consequently, intra- and post-operative movement may not indicate uncomplicated consciousness alone, and so bear little relationship to BIS, unless movement is associated with arousal patterns which simultaneously increase it. The latter seems probable because surgery changes the EEG – at least in halothaneanaesthetized horses (Murrell et al. 2003) in a way that should increase BIS indices. Evaluating the usefulness of BISM1’for predicting intra-operative movement or consciousness was complicated by the fact that signs of returning consciousness were seldom associated with the animal’s first movement. Unambiguous signs, e.g. deliberate attempts to roll into sternal recumbency or ear movement directed towards sound, were seen in some horses but in many others convincing signs of consciousness, e.g. blinking or even vocalization, occurred before movement began. Movements made during or after such observations were recorded as BISM1 which are equal to, or more likely in excess of the BIS value at which consciousness actually returned. A more precise method for determining the latter is required. Consequently, BISM1 values recorded in this study are likely to be greater than those values coinciding with intra-operative movement, although they may more accurately represent impending consciousness. As the range of operations performed in this study increased the external validity of its findings, it probably contributed to the variation in
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data – particularly BISMA – because different degrees of nocistimulation influence bispectral indices (Takamatsu et al. 2006). All horses received pre-surgical flunixin and morphine, whilst additional morphine was administered at the anaesthetist’s discretion. These measures probably reduced differences in nociception associated with different procedures, although the effects on BIS are difficult to predict: in dogs, morphine had negligible effect on BIS during isoflurane anaesthesia (Henao-Guerrero et al. 2009). Failing to record BISA at specified times probably increased data variation because plasma romifidine, ketamine, diazepam and N2O concentrations would have been different in all cases studied. This is important because all are likely to affect the EEG. Detomidine and butorphanol depress BIS in horses (Haga & Dolvik 2002), so it seems reasonable to expect other alpha-2-agonists to exert the same effect. Ketamine increases BIS in humans by shifting the EEG pattern towards higher frequencies and causing desynchronization; this increases BIS independently of anaesthetic depth (Hans et al. 2005). Therefore, its persistent effect into the sampling period may have diminished the difference between BIS values in the two groups. The mean duration of recumbency in horses sedated with romifidine then administered ketamine at a dose of 2.2 mg kg)1 is 20 minutes (Kerr et al. 1996) and BIS data were recorded in this study a minimum of 45 minutes after ketamine was injected. However, a ‘hang-over’ effect cannot be discounted and EEG effects may persist for longer than signs of an anaesthetic effect, e.g. recumbency. Nitrous oxide may have had a similar obfuscating effect, although the gas’s effect on human BIS values is extremely variable. In the absence of noxious stimulation, unchanged (Hall et al. 2002), increased (Glass et al. 1997; Sebel et al. 1997; Puri 2000) or decreased (Hans et al. 2001; Goto et al. 2005) BIS values have been reported when N2O was used. An absence of information in horses makes it impossible to predict the effects of N2O delivered in the first 10 minutes of this study on the BIS values recorded more than 35 minutes later. The gas’s low solubility in equine blood makes any effect likely to be small. The mean BIS values during halothane (74 ± 7) and sevoflurane (62 ± 7) anaesthesia in this study were higher than those considered compatible with hypnosis in humans (40–65 for general anaesthe32
sia, 65–85 for sedation; Johansen & Sebel 2000). However, it is possible that the device’s algorithm, which assesses the power and frequency, burst suppression, slow synchronized activity and b-activation of the EEG (Rosow & Manberg 2001; Hans et al. 2005) is less capable of deriving accurate information when applied to the horse, whose skull and nervous tissue differ in their size, density and shape. Nevertheless, BIS values during halothane anaesthesia were significantly higher than those recorded in group S horses – as it is in humans (Edwards et al. 2003, 2005; Davidson 2004; Schwab et al. 2004) which supports the possibility that the human and equine bispectral indices are similar physiological entities. Unlike sevoflurane, halothane does not induce burst suppression at clinical doses (Kuroda et al. 1997; Black et al. 2000) which may partially explain BIS value differences between these anaesthetics. Halothane also suppresses noxious stimuli to a greater degree than isoflurane (Dwyer et al. 1992) producing anaesthesia by decreasing arousing subcortical inputs (Davidson 2004) in addition to suppressing cortical activity. Sevoflurane and isoflurane do not possess the former property. Evidence for an alternative explanation, i.e. that horses in the halothane group were at a lighter plane of anaesthesia than those in the sevoflurane group, is conflicting. The mean ± SD end-tidal anaesthetic concentrations in halothane and sevoflurane recipients during BISA registration (0.79 ± 0.09% and 1.91 ± 0.14% respectively) corresponded to 0.89· and 0.83 · the MAC values reported in horses – 0.88% for halothane (Steffey et al. 1977) and 2.3% for sevoflurane (Aida et al. 1994) – and indicate if anything, that group H horses were more ‘deeply’ anaesthetized. However, more horses (5) moved during halothane compared with sevoflurane (3) anaesthesia. That more horses did not move during the administration of end-tidal concentrations less than MAC can be explained by the pre-administration of romifidine, ketamine, diazepam, morphine, flunixin and nitrous oxide. Five horses from group H and three from group S moved during surgery and although details were not recorded, it is likely that the movements were reflex, and indicated inadequate rather than an absence of anaesthesia. BISMA values in two horses in group H exceed BISM1 (Fig. 3a), suggesting that movement during halothane anaesthesia is associated with more arousal than that seen with sevoflurane. Although this points to possible drug-
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dependent differences in analgesic properties, the small number of horses involved in either group undermines meaningful speculation. BISMA values were, with the exception of two halothane recipients, intermediate between BISA and BISM1 but were appreciably less than those recorded at first movement. This supports the view that BISM1 is probably in excess of values at which intra-operative movement is likely to occur. The BIS monitor failed to indicate impending movement in one out of eight animals that moved in this study, which indicates a marginally greater predictive value than that previously reported: Haga & Dolvik (2002) anaesthetized eight horses with isoflurane (FE¢ = 1.4%) and encountered movement in four. Of these, two showed no obvious increase in BIS before movement. The ability of BIS to predict intra-operative movement depends on: 1) the movement being associated with arousal; 2) the algorithm’s smoothing time, and 3) the anaesthetist’s ability to detect rising BIS values. In this study, the smoothing time was set at the minimum possible (15 seconds) allowing the earliest possible indication of the latter. Unfortunately, BISMA was taken only once the horse had moved, values beforehand were not detailed but described simply as ‘rising’ or ‘unchanging.’ The data memory and the ‘Print Event’ facilities of the Model A-2000 used in this study were over-looked, otherwise pre-movement BIS changes could have been reviewed. However, it seems likely that even if nociceptive reflex movement were consistently associated with arousal, signal processing may not be rapid enough to alert even attentive personnel of imminent movement. Future studies would benefit from at least four refinements: 1) recording BIS values at fixed times after drug administration; 2) standardising operations; 3) devising more sensitive ways of judging the return of consciousness; and 4) identifying more accurately the cause of intra-operative movement. Thereafter, a larger scale study linking intra-operative movement with BIS may determine its ability to predict this complication. The challenge in devising a method that humanely tests the ability of BIS to identify consciousness in animals paralysed by neuromuscular blocking agents remain. This study shows that bispectral indices are of some value in evaluating the depth of anaesthesia in horses. During recovery, BIS values >85 for halothane, and >87 for sevoflurane anaesthesia indicate that movement is imminent although these values over-estimate those at which intra-operative move-
ment occurs. The study did not allow conclusions to be drawn about the usefulness of BIS for identifying consciousness in horses during neuromuscular blockade. Acknowledgement We are grateful to Carolyn Bertram of the Equine Hospital, Royal (Dick) School of Veterinary Studies for her assistance with this project. References Aida H, Muzino Y, Hobo S et al. (1994) Determination of the minimum alveolar concentration (MAC) and physical response to sevoflurane inhalation in horses. J Vet Med Sci 56, 1161–1165. Antognini JF, Barter L, Carstens E (2005) Overview movement as an index of anesthetic depth in humans and experimental animals. Comp Med 55, 413–418. Avidan MS, Zhang L, Burnside BA (2008) Anesthesia awareness and the bispectral index. N Engl J Med 358, 1097–108. Black S, Mahla ME, Cucchiara RF(2000) Neurologic monitoring. In: Anesthesia (5th edn). Miller RD (ed). Churchill Livingston, London. pp. 1324–1350. Bruhn J, Myles PS, Sneyd R et al. (2006) Depth of anaesthesia monitoring: what’s available, what’s validated and what’s next? Br J Anaesth 97, 85–94. Davidson A (2004) The correlation between bispectral index and airway reflexes with sevoflurane and halothane anaesthesia. Paediatr Anaesth 14, 241–246. Dwyer R, Bennett HL, Eger EI et al. (1992) Effects of isoflurane and nitrous oxide in subanesthetic concentrations on memory and responsiveness in volunteers. Anesthesiology 77, 888–898. Edwards JJ, Soto RG, Thrush D et al. (2003) Bispectral index scale is higher for halothane than sevoflurane during intraoperative anesthesia. Anesthesiology 99, 1453–1455. Edwards JJ, Soto RG, Bedford RF (2005) Bispectral indexTM values are higher during halothane vs. sevoflurane anesthesia in children, but not in infants. Acta Anaesthesiol Scand 49, 1084–1087. Ekman A, Lindholm ML, Lennmarken C et al. (2004) Reduction in the incidence of awareness using BIS monitoring. Acta Anaesthesiol Scand 48, 20–26. Glass PS, Bloom M, Kearse L et al. (1997) Bispectral analysis measures sedation and memory effect of propofol, midazolam, isoflurane, and alfentanil. Anesthesiology 86, 836–847. Goto T, Ishiguro Y, Nakata Y et al. (2005) The bispectral index predicts responsiveness to verbal commands in patients emerging from nitrous oxide anesthesia supplemented with a subhypnotic concentration of isoflurane. J Anesth 19, 102–105.
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the B-Aware randomised controlled trial. Lancet 363, 1757–1763. Puri GD (2000) Paradoxical changes in bispectral index during nitrous oxide administration. Br J Anaesth 86, 141–142. Rosow C, Manberg PJ (2001) Bispectral index monitoring. Anesthesol Clin N Am 19, 947–966. Schwab HS, Seeberger MD, Eger EI II et al. (2004) Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples. Anesth Analg 99, 1723–1727. Sebel P, Lang E, Rampil L et al. (1997) A multicenter study of bispectral encephalogram analysis for monitoring anesthetic effects. Anesth Analg 84, 891–899. Steffey EP, Howland D, Giri S et al. (1977) Enflurane, halothane and isoflurane potency in horses. Am J Vet Res 38, 1037–1039. Struys MM, Jensen EW, Smith W et al. (2002) Performance of the ARX-derived auditory evoked potential index as an indicator of anesthetic depth: a comparison with bispectral index and hemodynamic measures during propofol administration. Anesthesiology 96, 803– 816. Takamatsu I, Ozaki M, Kazama T (2006) Entropy indices vs the bispectral index for estimating nociception during sevoflurane anaesthesia. Br J Anaesth 96, 620–622. Vereecke HE, Struys MM, Mortier EP (2003) A comparison of bispectral index and ARX-derived auditory evoked potential index in measuring the clinical interaction between ketamine and propofol anaesthesia. Anaesthesia 58, 957–961. Vernon J, Lang E, Sebel P et al. (1995) Prediction of movement using BIS electroencephalographic analysis during propofol/alfentanil or isoflurane/alfentanil anesthesia. Anesth Analg 80, 780–785. Weber F, Seidl M, Bein T (2005) Impact of the AEPMonitor/2-derived composite auditory-evoked potential index on propofol consumption and emergence times during total intravenous anaesthesia with propofol and remifentanil in children. Acta Anaesthesiol Scand 49, 277–283. Received 24 April 2009; accepted 12 August 2009.
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