ORIGINAL ARTICLE
Acute alcohol intoxication and bispectral index monitoring M. D. Gerstman1, A. F. Merry2, D. R. McIlroy1,3, J. A. Hannam2, S. J. Mitchell2 and P. S. Myles1,3 1
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Vic, Australia Department of Anaesthesiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 3 Monash University, Melbourne, Australia 2
Correspondence M. D. Gerstman, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Commercial Road, Melbourne, Australia E-mail: [email protected] Conflicts of interests PM was lead author on the B-AWARE Trial, published in The Lancet in 2004. B-AWARE was an investigator-initiated trial that was (minority) part-funded by Aspect Medical, the previous manufacturers of the BIS monitor. Funding This work was supported by departmental research funds. Submitted 12 March 2015; accepted 7 April 2015; submission 10 December 2014. Citation Gerstman MD, Merry AF, McIlroy DR, Hannam JA, Mitchell SJ, Myles PS. Acute alcohol intoxication and bispectral index monitoring. Acta Anaesthesiologica Scandinavica 2015
Background: Bispectral index (BIS) monitoring is commonly used to decrease the risk of awareness during anaesthesia. We aimed to determine the relationship between blood alcohol concentration and brain function (as measured by BIS) in healthy adults. Methods: In this prospective observational study, 21 anaesthetic registrars self-regulated alcohol consumption over a 3-h period. Expired alcohol concentration (breathalyser) and BIS measurements were performed hourly for 4 h. A venous blood alcohol sample was taken at the conclusion of the study period. Results: The main outcome measures were the correlation between blood alcohol and brain function as measured by BIS and the change in BIS from baseline (ΔBIS) at 4 h. The median number of standard drinks consumed was 9.1 (IQR 7.7–12.3), range 5.4–17. At 4 h, there was a moderate inverse correlation between BIS and blood alcohol (r = 0.49, P = 0.029) and between ΔBIS and blood alcohol (r = 0.46, P =0.043). Conclusion: In healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when providing anaesthesia to intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind.
doi: 10.1111/aas.12546
Editorial comment: what this article tells us
This article tells us that alcohol intoxication may influence BIS recordings. The effect is variable and moderate, but may still be important to have in mind when performing emergency anaesthesia on intoxicated patients.
The bispectral index (BIS) (Covidien, CO, USA) brain function monitor has been shown to reduce the risk of awareness in at-risk patients.1–4 It may also facilitate titration of anaesthetic depth to minimise excessive exposure to anaesthetic agents5 and expedite emergence at the completion of surgery.3 It captures and processes EEG activity such that as the depth of anaesthesia
increases, brain wave activity changes to a lower frequency and higher amplitude pattern leading to a reduction in BIS. Acute alcohol intoxication slows the EEG and therefore is likely to affect BIS.6–8 The effect of numerous anaesthetic drugs,3 and pathological factors such as head injuries9,10 and cognitive impairment,11,12 on BIS have been extensively
Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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studied. However, there are few data on the effect on BIS of alcohol intoxication, a common presentation in trauma patients who may require urgent surgery. Such patients are at high-risk for anaesthetic over- or under-dosing, with the latter leading to awareness13 and the former to haemodynamic instability during surgery. We therefore sought to determine the relationship between alcohol consumption and BIS. Methods Ethics approval to conduct this study was given by The Alfred Hospital Ethics Committee (ref 183/13), Melbourne, Australia (approval 17 June 2013) and the Northern A Health and Disability Ethics Committee, New Zealand (reference 13/NTA/90AM01, approval 16 July 2013). The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000801718). Anaesthetic registrars from teaching hospitals in Melbourne, Australia and Auckland, New Zealand were invited to participate in a prospective observational study. Written informed consent was obtained from the 21 registrars who chose to enrol in the study. Exclusion criteria included: being rostered to clinical duties within 12 h of participation; a history of epilepsy; current use of sedating medication including analgesics such as codeine and opioids, benzodiazepines, antiepileptics and sleeping medications; history of liver disease; or pregnancy. The study was conducted on a Friday afternoon in one centre and a Friday evening in the other, over 4 h (Fig. 1), with alcohol consumption self-regulated by each participant through the first 3 h followed by a fourth and final hour with no further alcohol consumption. Participants were instructed to abstain from alcohol consumption for at least 12 h, and caffeine consumption for at least 5 h, prior to study commencement. Baseline BIS values were established in all participants. The BIS Quatro XP sensor was placed in a frontoparietal position over the dominant hemisphere as determined by self-reported handedness and in accordance with the manufacturer’s instruction; the sensor was secured using a transparent adhesive dressing for the duration of the study. At both study sites, the devices were configured
Fig. 1. Study design.
with BIS VISTA application Revision 3.2, VISTA platform Revision 2.03, BISx Protocol Revision 1.05, Hardware 4.0. The monitor had a BIS smoothing time of 15/30 s, and displayed the BIS, signal quality index and electromyography artefact. Senior clinician-researchers experienced in BIS monitoring conducted the testing at each site. BIS measurements were done with the participants supine, in a quiet room with eyes closed and ear plugs in situ for a period of 2–5 min; signal quality index was recorded at each time-point. The lowest BIS reading persisting for at least 30 s was recorded. After baseline readings, study participants were given a choice of red wine, white wine, beer or vodka. All drink mixers were caffeine free and light snacks were provided throughout the study. Research staff provided participants with their chosen drinks in measured quantities to allow hourly calculation of the number of standard drinks consumed (one standard drink contains 10 g of pure alcohol14). At the end of each hour, BIS was re-measured under the above resting conditions. Expired breath alcohol concentration (breathalyser) analysis was performed using a calibrated AlcoSense precision plus fuel cell breathalyser (Andatech, Melbourne, Vic, Australia) which is accurate to Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021
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0.005% BAC at 0.100% BAC.15 Each participant was given a disposable mouthpiece and instructed to forcibly expire for at least 4 seconds as per breathalyser operating instructions. The breathalyser device was allowed to return to zero prior to testing the next participant. Prior to each breathalyser test, food consumption was suspended for 20 min, alcohol consumption for 5 min, and participants rinsed their mouth with water. After 3 h, alcohol consumption ceased and a meal was provided. At 4 h, in addition to measurement of the BIS and predicted and actual breath alcohol, a single venous blood alcohol concentration sample was taken from each participant. Senior investigators, who were present throughout the study, monitored the safety of the participants. All participants were provided with a taxi voucher and provided with an escort if their breathalyser reading remained over 0.1 g/dl at study completion. The co-primary outcomes for this study were the correlation between blood alcohol and BIS, and ΔBIS at 4 h; the latter was calculated as the BIS difference between 0 h and 4 h. Secondary outcomes included correlation between breathalyser and BIS at each measured time-point throughout the study. We hypothesised that there would be an inverse relationship between blood alcohol concentration and BIS. Statistical analysis Our sample size was based on opportunity, but we aimed to recruit at least 15 participants to have at least 80% power with an alpha error of 0.05 to detect a correlation of 0.3 or more, which we deemed clinically important. Continuous data are presented as mean (SD) or median (IQR). After checking for normality, the Pearson correlation coefficient was used to describe the relationship between blood alcohol and both BIS and ΔBIS. A linear mixed model determined the relationship between breathalyser and BIS at repeated time-points throughout the study, adjusting for participant gender and study site. Agreement was measured using the intra-class correlation coefficient (ICC) and Bland–Altman method. All analyses were done using SPSS for Windows v.20 (IBM, Chicago,
IL, USA); a P value of < 0.05 was considered statistically significant. Results Twenty-one anaesthetic registrars participated in the study. Data collection occurred between 12 July and 2 August 2013. There were 14 male and seven females, with a mean age 31 (3) [range 27–35] years, and mean body mass index 21.7 (2.5) kg/m2. Self-reported mean average weekly alcohol intake was 9.6 (4.5) [range 3–18] standard drinks and a mean maximum daily alcohol intake over the last 2 months of 8.8 (4.8) [range 3–20] standard drinks. There were no differences in demographics, drinking habits and baseline BIS between the two sites. We had complete data capture for all, except one participant who withdrew at the end of the second hour because of feeling nauseated while lying down for study measurements (blood alcohol 0.068% at last reading). Most (90%) BIS readings had a very good (≥ 70) signal quality index. The median number of standard drinks consumed during the study period was 9.1 (IQR 7.7–12.3), range 5.4–17. The individual raw data are shown in Table 1. At the conclusion of the study period, there was a moderate inverse correlation between BIS and blood alcohol (r = 0.49, P = 0.029) and between ΔBIS and blood alcohol (r = 0.46, P = 0.043). Figure 2 shows a box and whisker plot of venous blood alcohol levels at 4 h and Fig. 3 the scatterplot of the relationship between BIS and venous blood at 4 h. There were inadequate data to perform subgroup analysis investigating the relationship between BIS and individual alcohol consumption and tolerance. The breathalyser blood alcohol measurements were lower than the venous blood alcohol measurements at 4 h (mean difference 0.029%; limits of agreement 0.015–0.043%). There was no significant correlation between BIS and breathalyser measurements across the 4-h study period (P = 0.11) (Fig. 4). The amount of standard drinks consumed during the study period was comparable to the mean maximum daily alcohol intake for the cohort, and the resultant mean breathalyser and
Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 1 Hourly bispectral index (BIS), breathalyser and venous blood alcohol measurements (g/dl).
Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Baseline BIS 91 89 89 96 86 85 97 95 93 94 91 92 94 97 97 88 94 92 90 90 97
At 1 h
At 2 h
At 3 h
At 4 h
BIS
Breathalyser
BIS
Breathalyser
BIS
Breathalyser
BIS
Breathalyser
Venous blood alcohol
86 83 90 94 83 98 89 92 96 96 83 92 89 94 92 93 89 88 91 86 91
0.107 0.060 0.076 0.043 0.039 0.078 0.028 0.097 0.057 0.030 0.028 0.058 0.036 0.034 0.068 0.011 0.036 0.048 0.089 0.059 0.101
88 96 81 96 83 97 92 77 93 93 85 93 86 88 80 62 87 78 88 87 97
0.171 0.083 0.066 0.097 0.070 0.065 0.051 0.130 0.159 0.057 0.062 0.120 0.080 0.069 – 0.050 0.064 0.067 0.120 0.091 0.130
86 91 89 95 84 97 92 74 73 97 83 89 62 89 – 89 82 78 83 84 73
0.207 0.094 0.100 0.162 0.091 0.165 0.055 0.115 0.192 0.093 0.110 0.152 0.142 0.102 – 0.086 0.123 0.096 0.148 0.108 0.193
71 92 87 97 83 92 88 73 74 96 85 95 88 90 – 87 78 91 86 78 73
0.190 0.083 0.072 0.161 0.120 0.160 0.053 0.110 0.185 0.099 0.091 0.109 0.117 0.103 – 0.073 0.129 0.102 0.121 0.080 0.170
0.244 0.115 0.097 0.184 0.138 0.189 0.064 0.147 0.221 0.092 0.115 0.172 0.166 0.120 – 0.097 0.179 0.087 0.156 0.120 0.216
Fig. 2. Box and whisker plot of venous blood alcohol concentrations (%) of the participants (n = 20) at the end of the study period (4 h). The box indicates the median and interquartile range; the whiskers indicate the range. The interrupted line indicates the legal limit for blood alcohol concentration for drivers in Victoria, Australia.
blood alcohol levels exceeded the legal driving limits in Australia (0.05%) and New Zealand (0.08%). There were four adverse events: four participants vomited.
Fig. 3. A scatterplot and regression line with 95% CI showing the relationship between bispectral index (BIS) and venous blood alcohol concentration at 4 h.
Discussion We found that in healthy young adults, there is a moderate correlation between brain function as measured by BIS and venous blood alcohol concentration. There is very limited previous Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021
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Fig. 4. Changes in bispectral index (BIS) and expired alcohol (EtOH) over 4 h, corrected for between-subjects variability. Mean (95% CI).
data describing the impact of alcohol intoxication, a common problem in many trauma patients requiring urgent surgery,16,17 on BIS. To our knowledge, no clinical studies investigating the relationship between alcohol and BIS in anaesthetised patients have been published to date. There has been a single report of intracranial arterial alcohol embolisation leading to systemic alcohol intoxication where the BIS decreased to zero.18 In a cohort study of 98 intoxicated patients presenting to the emergency department, BIS was compared with a standardised Altered Mental Status scale, but the relationship between blood alcohol and BIS was not reported.19 The intoxicated patients had a mean blood alcohol of 0.24 (SD 0.07) and mean presenting BIS of 78 (SD 18), comparable to our volunteer study and suggestive of a likely correlation between BIS and alcohol intoxication. However, this was a non-anaesthetised, heterogeneous, often injured population that may have consumed other drugs which can also affect BIS. Our findings are relevant to anaesthetists and other hospital doctors caring for intoxicated trauma patients who require urgent surgery. In interpreting depressed BIS in patients with elevated blood alcohol levels, the potential contribution of alcohol should be taken into account. Furthermore, it seems that a MAC-sparing effect of acute alcohol intoxication is at least possible. However, participants in the current study were not anaesthetised so caution should be exercised in extrapolating our study results to clinical con-
texts involving such patients. In fact, this is a challenging patient population to study as there are many potential confounding factors that would be difficult to control for in a clinical study. Intoxicated patients requiring emergency surgery have frequently consumed other drugs in addition to alcohol, which may also have an effect on BIS. This was one reason for choosing to study a healthy population who were not anaesthetised. If our hypothesis that anaesthetised intoxicated patients have a lower BIS is correct, they may require less anaesthetic agent. The extent of the decrease in BIS seen with intoxication in our study is comparable to heavy sedation used for colonoscopy.20 Similarly, sedative premedication decreases BIS,21 and also decreases the dose requirement for subsequent anaesthesia.22 It should be noted, however, that no study participant had a BIS in the range recommended for surgical anaesthesia (40–60) despite clearly being intoxicated. Alcohol is also known to have an analgesic effect that has been reported to be similar to morphine; this may also impact on anaesthesia for intoxicated patients.23,24 BIS reflects the hypnotic state of general anaesthesia,25 but has also been shown to be lower in patients with head injuries9,10 and cognitive impairment.11 It may be of use as a predictor of neurological recovery after ischaemichypoxic brain injury26 and to guide prognostication of patients with brain injuries both in the emergency department and in intensive care.27,28 Although this is another off-label use
Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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of BIS monitoring, acute alcohol intoxication potentially limits the predictive utility of BIS in the acute setting. The finding of no correlation between breathalyser alcohol measurements and BIS may be due to several factors. Firstly, the study may have been too small to detect a real and important effect (type II error). Secondly, it may be due to a slightly lower mean difference between the breathalyser and blood alcohol readings as seen at 4 h. Limitations The BIS monitor was designed to measure the hypnotic depth of anaesthesia and thus decrease the risk of awareness; it is not a validated tool to measure the effects of alcohol intoxication. BIS is derived from the EEG, and alcohol causes alpha activation and then slowing – a biphasic response – in the EEG.8 We did not monitor a control group of nondrinking subjects. However, the identical pattern of change in BIS at both sites despite one conducting the study in the afternoon and one in the early evening mitigates concerns regarding an effect of subject fatigue. The size of the study population was not large enough to perform sub group analysis on the relationship between alcohol and BIS in different ranges of intoxication. There is insufficient data to allow the clinician to predict an individual patient’s BIS based on their level of intoxication. In conclusion, in healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when anaesthetising intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind. Authors’ contributions M. G. and P. M.: Responsible for conception and design. M. G.: Drafted the manuscript. M. G., A. M., D. M., J. H., S. M. and P. M.: Contributed to data collection, analysis and
interpretation, and critically revised the manuscript for important intellectual content. References 1. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–63. 2. Zhang C, Xu L, Ma YQ, Sun YX, Li YH, Zhang L, Feng CS, Luo B, Zhao ZL, Guo JR, Jin YJ, Wu G, Yuan W, Yuan ZG, Yue Y. Bispectral index monitoring prevent awareness during total intravenous anesthesia: a prospective, randomized, double-blinded, multi-center controlled trial. Chin Med J (Engl) 2011; 124: 3664–9. 3. Shepherd J, Jones J, Frampton G, Bryant J, Baxter L, Cooper K. Clinical effectiveness and costeffectiveness of depth of anaesthesia monitoring (EEntropy, Bispectral Index and Narcotrend): a systematic review and economic evaluation. Health Technol Assess 2013; 17: 1–264. 4. Mashour GA, Shanks A, Tremper KK, Kheterpal S, Turner CR, Ramachandran SK, Picton P, Schueller C, Morris M, Vandervest JC, Lin N, Avidan MS. Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial. Anesthesiology 2012; 117: 717–25. 5. Chan MT, Cheng BC, Lee TM, Gin T. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013; 25: 33–42. 6. Engel GL, Webb JP, Ferris EB. Quantitative electroencephalographic studies of anoxia in humans; comparison with acute alcoholic intoxication and hypoglycemia. J Clin Invest 1945; 24: 691–7. 7. Freemon FR, Goodwin DW, Halikas JA, Othmer E. An electroencephalographic study of memory loss during alcoholic intoxication. Dis Nerv Syst 1971; 32: 848–52. 8. Schwarz E, Kielholz P, Hobi V, Goldberg L, Gilsdorf U, Hofstetter M, Ladewig D, Miest PC, Reggiani G, Richter R. Alcohol-induced biphasic background and stimulus-elicited EEG changes in relation to blood alcohol levels. Int J Clin Pharmacol Ther Toxicol 1981; 19: 102–11. 9. Haug E, Miner J, Dannehy M, Seigel T, Biros M. Bispectral electroencephalographic analysis of headinjured patients in the emergency department. Acad Emerg Med 2004; 11: 349–52.
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10. Ebtehaj M, Yaqubi S, Seddighi AS, Seddighi A, Yazdi Z. Correlation between BIS and GCS in patients suffering from head injury. Ir J Med Sci 2012; 181: 77–80. 11. Erdogan MA, Demirbilek S, Erdil F, Aydogan MS, Ozturk E, Togal T, Ersoy MO. The effects of cognitive impairment on anaesthetic requirement in the elderly. Eur J Anaesthesiol 2012; 29: 326–31. 12. Liu J, Singh H, White PF. Electroencephalographic bispectral index correlates with intraoperative recall and depth of propofol-induced sedation. Anesth Analg 1997; 84: 185–9. 13. Lubke GH, Sebel PS. Awareness and different forms of memory in trauma anaesthesia. Curr Opin Anaesthesiol 2000; 13: 161–5. 14. Australian Government Department of Health. Available at: http://www.alcohol.gov.au/internet/ alcohol/publishing.nsf/Content/standard (accessed 20 February 2015). 15. Andatech. Available at: http://www.alcosense.com. au/breathalyzers/alcosense-precision-plus (accessed 20 February 2015). 16. Dinh MM, Bein KJ, Roncal S, Martiniuk AL, Boufous S. The impact of alcohol intoxication in patients admitted due to assault at an Australian major trauma centre: a trauma registry study from 1999 to 2009. Emerg Med J 2014;31:390–3. 17. Kowalenko T, Burgess B, Szpunar SM, IrvinBabcock CB. Alcohol and trauma–in every age group. Am J Emerg Med 2013; 31: 705–9. 18. Unnikrishnan KP, Sinha PK, Sriganesh K, Suneel PR. Case report: alterations in bispectral index following absolute alcohol embolization in a patient with intracranial arteriovenous malformation. Can J Anaesth 2007; 54: 908–11. 19. Miner JR, Gaetz A, Biros MH. The association of a decreased level of awareness and blood alcohol
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concentration with both agitation and sedation in intoxicated patients in the ED. Am J Emerg Med 2007; 25: 743–8. Leslie K, Absalom A, Kenny G. Closed-loop control of propofol sedation for colonoscopy. Anaesthesia 2002; 57: 690–709. Brosius KK, Bannister CF. Oral midazolam premedication in preadolescents and adolescents. Anesth Analg 2002; 94: 31–6. Wilder-Smith OH, Ravussin PA, Decosterd LA, Despland PA, Bissonnette B. Midazolam premedication reduces propofol dose requirements for multiple anesthetic endpoints. Can J Anaesth 2001; 48: 439–45. James MF, Duthie AM, Duffy BL, McKeag AM, Rice CP. Analgesic effect of ethyl alcohol. Br J Anaesth 1978; 50: 139–41. Perrino AC Jr, Ralevski E, Acampora G, Edgecombe J, Limoncelli D, Petrakis IL. Ethanol and pain sensitivity: effects in healthy subjects using an acute pain paradigm. Alcohol Clin Exp Res 2008; 32: 952–8. Sigl JC, Chamoun NG. An introduction to bispectral analysis for the EEG. J Clin Mon 1994; 10: 392–404. Myles P, Daly D, Silvers A, Cairo S. Prediction of neurological outcome using bispectral index monitoring in patients with severe ischemichypoxic brain injury undergoing emergency surgery. Anesthesiology 2009; 110: 1106–15. Fabregas N, Gambus PL, Valero R, Carrero EJ, Salvador L, Zavala E, Ferrer E. Can bispectral index monitoring predict recovery of consciousness in patients with severe brain injury? Anesthesiology 2004; 101: 43–51. Gilbert TT, Wagner MR, Halukurike V, Paz HL, Garland A. Use of bispectral electroencephalogram monitoring to assess neurologic status in unsedated, critically ill patients. Crit Care Med 2001; 29: 1996–2000.
Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1021
Acute alcohol intoxication and bispectral index monitoring M. D. Gerstman1, A. F. Merry2, D. R. McIlroy1,3, J. A. Hannam2, S. J. Mitchell2 and P. S. Myles1,3 1
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Vic, Australia Department of Anaesthesiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 3 Monash University, Melbourne, Australia 2
Correspondence M. D. Gerstman, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Commercial Road, Melbourne, Australia E-mail: [email protected] Conflicts of interests PM was lead author on the B-AWARE Trial, published in The Lancet in 2004. B-AWARE was an investigator-initiated trial that was (minority) part-funded by Aspect Medical, the previous manufacturers of the BIS monitor. Funding This work was supported by departmental research funds. Submitted 12 March 2015; accepted 7 April 2015; submission 10 December 2014. Citation Gerstman MD, Merry AF, McIlroy DR, Hannam JA, Mitchell SJ, Myles PS. Acute alcohol intoxication and bispectral index monitoring. Acta Anaesthesiologica Scandinavica 2015
Background: Bispectral index (BIS) monitoring is commonly used to decrease the risk of awareness during anaesthesia. We aimed to determine the relationship between blood alcohol concentration and brain function (as measured by BIS) in healthy adults. Methods: In this prospective observational study, 21 anaesthetic registrars self-regulated alcohol consumption over a 3-h period. Expired alcohol concentration (breathalyser) and BIS measurements were performed hourly for 4 h. A venous blood alcohol sample was taken at the conclusion of the study period. Results: The main outcome measures were the correlation between blood alcohol and brain function as measured by BIS and the change in BIS from baseline (ΔBIS) at 4 h. The median number of standard drinks consumed was 9.1 (IQR 7.7–12.3), range 5.4–17. At 4 h, there was a moderate inverse correlation between BIS and blood alcohol (r = 0.49, P = 0.029) and between ΔBIS and blood alcohol (r = 0.46, P =0.043). Conclusion: In healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when providing anaesthesia to intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind.
doi: 10.1111/aas.12546
Editorial comment: what this article tells us
This article tells us that alcohol intoxication may influence BIS recordings. The effect is variable and moderate, but may still be important to have in mind when performing emergency anaesthesia on intoxicated patients.
The bispectral index (BIS) (Covidien, CO, USA) brain function monitor has been shown to reduce the risk of awareness in at-risk patients.1–4 It may also facilitate titration of anaesthetic depth to minimise excessive exposure to anaesthetic agents5 and expedite emergence at the completion of surgery.3 It captures and processes EEG activity such that as the depth of anaesthesia
increases, brain wave activity changes to a lower frequency and higher amplitude pattern leading to a reduction in BIS. Acute alcohol intoxication slows the EEG and therefore is likely to affect BIS.6–8 The effect of numerous anaesthetic drugs,3 and pathological factors such as head injuries9,10 and cognitive impairment,11,12 on BIS have been extensively
Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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studied. However, there are few data on the effect on BIS of alcohol intoxication, a common presentation in trauma patients who may require urgent surgery. Such patients are at high-risk for anaesthetic over- or under-dosing, with the latter leading to awareness13 and the former to haemodynamic instability during surgery. We therefore sought to determine the relationship between alcohol consumption and BIS. Methods Ethics approval to conduct this study was given by The Alfred Hospital Ethics Committee (ref 183/13), Melbourne, Australia (approval 17 June 2013) and the Northern A Health and Disability Ethics Committee, New Zealand (reference 13/NTA/90AM01, approval 16 July 2013). The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12613000801718). Anaesthetic registrars from teaching hospitals in Melbourne, Australia and Auckland, New Zealand were invited to participate in a prospective observational study. Written informed consent was obtained from the 21 registrars who chose to enrol in the study. Exclusion criteria included: being rostered to clinical duties within 12 h of participation; a history of epilepsy; current use of sedating medication including analgesics such as codeine and opioids, benzodiazepines, antiepileptics and sleeping medications; history of liver disease; or pregnancy. The study was conducted on a Friday afternoon in one centre and a Friday evening in the other, over 4 h (Fig. 1), with alcohol consumption self-regulated by each participant through the first 3 h followed by a fourth and final hour with no further alcohol consumption. Participants were instructed to abstain from alcohol consumption for at least 12 h, and caffeine consumption for at least 5 h, prior to study commencement. Baseline BIS values were established in all participants. The BIS Quatro XP sensor was placed in a frontoparietal position over the dominant hemisphere as determined by self-reported handedness and in accordance with the manufacturer’s instruction; the sensor was secured using a transparent adhesive dressing for the duration of the study. At both study sites, the devices were configured
Fig. 1. Study design.
with BIS VISTA application Revision 3.2, VISTA platform Revision 2.03, BISx Protocol Revision 1.05, Hardware 4.0. The monitor had a BIS smoothing time of 15/30 s, and displayed the BIS, signal quality index and electromyography artefact. Senior clinician-researchers experienced in BIS monitoring conducted the testing at each site. BIS measurements were done with the participants supine, in a quiet room with eyes closed and ear plugs in situ for a period of 2–5 min; signal quality index was recorded at each time-point. The lowest BIS reading persisting for at least 30 s was recorded. After baseline readings, study participants were given a choice of red wine, white wine, beer or vodka. All drink mixers were caffeine free and light snacks were provided throughout the study. Research staff provided participants with their chosen drinks in measured quantities to allow hourly calculation of the number of standard drinks consumed (one standard drink contains 10 g of pure alcohol14). At the end of each hour, BIS was re-measured under the above resting conditions. Expired breath alcohol concentration (breathalyser) analysis was performed using a calibrated AlcoSense precision plus fuel cell breathalyser (Andatech, Melbourne, Vic, Australia) which is accurate to Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021
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ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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0.005% BAC at 0.100% BAC.15 Each participant was given a disposable mouthpiece and instructed to forcibly expire for at least 4 seconds as per breathalyser operating instructions. The breathalyser device was allowed to return to zero prior to testing the next participant. Prior to each breathalyser test, food consumption was suspended for 20 min, alcohol consumption for 5 min, and participants rinsed their mouth with water. After 3 h, alcohol consumption ceased and a meal was provided. At 4 h, in addition to measurement of the BIS and predicted and actual breath alcohol, a single venous blood alcohol concentration sample was taken from each participant. Senior investigators, who were present throughout the study, monitored the safety of the participants. All participants were provided with a taxi voucher and provided with an escort if their breathalyser reading remained over 0.1 g/dl at study completion. The co-primary outcomes for this study were the correlation between blood alcohol and BIS, and ΔBIS at 4 h; the latter was calculated as the BIS difference between 0 h and 4 h. Secondary outcomes included correlation between breathalyser and BIS at each measured time-point throughout the study. We hypothesised that there would be an inverse relationship between blood alcohol concentration and BIS. Statistical analysis Our sample size was based on opportunity, but we aimed to recruit at least 15 participants to have at least 80% power with an alpha error of 0.05 to detect a correlation of 0.3 or more, which we deemed clinically important. Continuous data are presented as mean (SD) or median (IQR). After checking for normality, the Pearson correlation coefficient was used to describe the relationship between blood alcohol and both BIS and ΔBIS. A linear mixed model determined the relationship between breathalyser and BIS at repeated time-points throughout the study, adjusting for participant gender and study site. Agreement was measured using the intra-class correlation coefficient (ICC) and Bland–Altman method. All analyses were done using SPSS for Windows v.20 (IBM, Chicago,
IL, USA); a P value of < 0.05 was considered statistically significant. Results Twenty-one anaesthetic registrars participated in the study. Data collection occurred between 12 July and 2 August 2013. There were 14 male and seven females, with a mean age 31 (3) [range 27–35] years, and mean body mass index 21.7 (2.5) kg/m2. Self-reported mean average weekly alcohol intake was 9.6 (4.5) [range 3–18] standard drinks and a mean maximum daily alcohol intake over the last 2 months of 8.8 (4.8) [range 3–20] standard drinks. There were no differences in demographics, drinking habits and baseline BIS between the two sites. We had complete data capture for all, except one participant who withdrew at the end of the second hour because of feeling nauseated while lying down for study measurements (blood alcohol 0.068% at last reading). Most (90%) BIS readings had a very good (≥ 70) signal quality index. The median number of standard drinks consumed during the study period was 9.1 (IQR 7.7–12.3), range 5.4–17. The individual raw data are shown in Table 1. At the conclusion of the study period, there was a moderate inverse correlation between BIS and blood alcohol (r = 0.49, P = 0.029) and between ΔBIS and blood alcohol (r = 0.46, P = 0.043). Figure 2 shows a box and whisker plot of venous blood alcohol levels at 4 h and Fig. 3 the scatterplot of the relationship between BIS and venous blood at 4 h. There were inadequate data to perform subgroup analysis investigating the relationship between BIS and individual alcohol consumption and tolerance. The breathalyser blood alcohol measurements were lower than the venous blood alcohol measurements at 4 h (mean difference 0.029%; limits of agreement 0.015–0.043%). There was no significant correlation between BIS and breathalyser measurements across the 4-h study period (P = 0.11) (Fig. 4). The amount of standard drinks consumed during the study period was comparable to the mean maximum daily alcohol intake for the cohort, and the resultant mean breathalyser and
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Table 1 Hourly bispectral index (BIS), breathalyser and venous blood alcohol measurements (g/dl).
Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Baseline BIS 91 89 89 96 86 85 97 95 93 94 91 92 94 97 97 88 94 92 90 90 97
At 1 h
At 2 h
At 3 h
At 4 h
BIS
Breathalyser
BIS
Breathalyser
BIS
Breathalyser
BIS
Breathalyser
Venous blood alcohol
86 83 90 94 83 98 89 92 96 96 83 92 89 94 92 93 89 88 91 86 91
0.107 0.060 0.076 0.043 0.039 0.078 0.028 0.097 0.057 0.030 0.028 0.058 0.036 0.034 0.068 0.011 0.036 0.048 0.089 0.059 0.101
88 96 81 96 83 97 92 77 93 93 85 93 86 88 80 62 87 78 88 87 97
0.171 0.083 0.066 0.097 0.070 0.065 0.051 0.130 0.159 0.057 0.062 0.120 0.080 0.069 – 0.050 0.064 0.067 0.120 0.091 0.130
86 91 89 95 84 97 92 74 73 97 83 89 62 89 – 89 82 78 83 84 73
0.207 0.094 0.100 0.162 0.091 0.165 0.055 0.115 0.192 0.093 0.110 0.152 0.142 0.102 – 0.086 0.123 0.096 0.148 0.108 0.193
71 92 87 97 83 92 88 73 74 96 85 95 88 90 – 87 78 91 86 78 73
0.190 0.083 0.072 0.161 0.120 0.160 0.053 0.110 0.185 0.099 0.091 0.109 0.117 0.103 – 0.073 0.129 0.102 0.121 0.080 0.170
0.244 0.115 0.097 0.184 0.138 0.189 0.064 0.147 0.221 0.092 0.115 0.172 0.166 0.120 – 0.097 0.179 0.087 0.156 0.120 0.216
Fig. 2. Box and whisker plot of venous blood alcohol concentrations (%) of the participants (n = 20) at the end of the study period (4 h). The box indicates the median and interquartile range; the whiskers indicate the range. The interrupted line indicates the legal limit for blood alcohol concentration for drivers in Victoria, Australia.
blood alcohol levels exceeded the legal driving limits in Australia (0.05%) and New Zealand (0.08%). There were four adverse events: four participants vomited.
Fig. 3. A scatterplot and regression line with 95% CI showing the relationship between bispectral index (BIS) and venous blood alcohol concentration at 4 h.
Discussion We found that in healthy young adults, there is a moderate correlation between brain function as measured by BIS and venous blood alcohol concentration. There is very limited previous Acta Anaesthesiologica Scandinavica 59 (2015) 1015–1021
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Fig. 4. Changes in bispectral index (BIS) and expired alcohol (EtOH) over 4 h, corrected for between-subjects variability. Mean (95% CI).
data describing the impact of alcohol intoxication, a common problem in many trauma patients requiring urgent surgery,16,17 on BIS. To our knowledge, no clinical studies investigating the relationship between alcohol and BIS in anaesthetised patients have been published to date. There has been a single report of intracranial arterial alcohol embolisation leading to systemic alcohol intoxication where the BIS decreased to zero.18 In a cohort study of 98 intoxicated patients presenting to the emergency department, BIS was compared with a standardised Altered Mental Status scale, but the relationship between blood alcohol and BIS was not reported.19 The intoxicated patients had a mean blood alcohol of 0.24 (SD 0.07) and mean presenting BIS of 78 (SD 18), comparable to our volunteer study and suggestive of a likely correlation between BIS and alcohol intoxication. However, this was a non-anaesthetised, heterogeneous, often injured population that may have consumed other drugs which can also affect BIS. Our findings are relevant to anaesthetists and other hospital doctors caring for intoxicated trauma patients who require urgent surgery. In interpreting depressed BIS in patients with elevated blood alcohol levels, the potential contribution of alcohol should be taken into account. Furthermore, it seems that a MAC-sparing effect of acute alcohol intoxication is at least possible. However, participants in the current study were not anaesthetised so caution should be exercised in extrapolating our study results to clinical con-
texts involving such patients. In fact, this is a challenging patient population to study as there are many potential confounding factors that would be difficult to control for in a clinical study. Intoxicated patients requiring emergency surgery have frequently consumed other drugs in addition to alcohol, which may also have an effect on BIS. This was one reason for choosing to study a healthy population who were not anaesthetised. If our hypothesis that anaesthetised intoxicated patients have a lower BIS is correct, they may require less anaesthetic agent. The extent of the decrease in BIS seen with intoxication in our study is comparable to heavy sedation used for colonoscopy.20 Similarly, sedative premedication decreases BIS,21 and also decreases the dose requirement for subsequent anaesthesia.22 It should be noted, however, that no study participant had a BIS in the range recommended for surgical anaesthesia (40–60) despite clearly being intoxicated. Alcohol is also known to have an analgesic effect that has been reported to be similar to morphine; this may also impact on anaesthesia for intoxicated patients.23,24 BIS reflects the hypnotic state of general anaesthesia,25 but has also been shown to be lower in patients with head injuries9,10 and cognitive impairment.11 It may be of use as a predictor of neurological recovery after ischaemichypoxic brain injury26 and to guide prognostication of patients with brain injuries both in the emergency department and in intensive care.27,28 Although this is another off-label use
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of BIS monitoring, acute alcohol intoxication potentially limits the predictive utility of BIS in the acute setting. The finding of no correlation between breathalyser alcohol measurements and BIS may be due to several factors. Firstly, the study may have been too small to detect a real and important effect (type II error). Secondly, it may be due to a slightly lower mean difference between the breathalyser and blood alcohol readings as seen at 4 h. Limitations The BIS monitor was designed to measure the hypnotic depth of anaesthesia and thus decrease the risk of awareness; it is not a validated tool to measure the effects of alcohol intoxication. BIS is derived from the EEG, and alcohol causes alpha activation and then slowing – a biphasic response – in the EEG.8 We did not monitor a control group of nondrinking subjects. However, the identical pattern of change in BIS at both sites despite one conducting the study in the afternoon and one in the early evening mitigates concerns regarding an effect of subject fatigue. The size of the study population was not large enough to perform sub group analysis on the relationship between alcohol and BIS in different ranges of intoxication. There is insufficient data to allow the clinician to predict an individual patient’s BIS based on their level of intoxication. In conclusion, in healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when anaesthetising intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind. Authors’ contributions M. G. and P. M.: Responsible for conception and design. M. G.: Drafted the manuscript. M. G., A. M., D. M., J. H., S. M. and P. M.: Contributed to data collection, analysis and
interpretation, and critically revised the manuscript for important intellectual content. References 1. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–63. 2. Zhang C, Xu L, Ma YQ, Sun YX, Li YH, Zhang L, Feng CS, Luo B, Zhao ZL, Guo JR, Jin YJ, Wu G, Yuan W, Yuan ZG, Yue Y. Bispectral index monitoring prevent awareness during total intravenous anesthesia: a prospective, randomized, double-blinded, multi-center controlled trial. Chin Med J (Engl) 2011; 124: 3664–9. 3. Shepherd J, Jones J, Frampton G, Bryant J, Baxter L, Cooper K. Clinical effectiveness and costeffectiveness of depth of anaesthesia monitoring (EEntropy, Bispectral Index and Narcotrend): a systematic review and economic evaluation. Health Technol Assess 2013; 17: 1–264. 4. Mashour GA, Shanks A, Tremper KK, Kheterpal S, Turner CR, Ramachandran SK, Picton P, Schueller C, Morris M, Vandervest JC, Lin N, Avidan MS. Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial. Anesthesiology 2012; 117: 717–25. 5. Chan MT, Cheng BC, Lee TM, Gin T. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013; 25: 33–42. 6. Engel GL, Webb JP, Ferris EB. Quantitative electroencephalographic studies of anoxia in humans; comparison with acute alcoholic intoxication and hypoglycemia. J Clin Invest 1945; 24: 691–7. 7. Freemon FR, Goodwin DW, Halikas JA, Othmer E. An electroencephalographic study of memory loss during alcoholic intoxication. Dis Nerv Syst 1971; 32: 848–52. 8. Schwarz E, Kielholz P, Hobi V, Goldberg L, Gilsdorf U, Hofstetter M, Ladewig D, Miest PC, Reggiani G, Richter R. Alcohol-induced biphasic background and stimulus-elicited EEG changes in relation to blood alcohol levels. Int J Clin Pharmacol Ther Toxicol 1981; 19: 102–11. 9. Haug E, Miner J, Dannehy M, Seigel T, Biros M. Bispectral electroencephalographic analysis of headinjured patients in the emergency department. Acad Emerg Med 2004; 11: 349–52.
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