ANESTH ANALG 1991;72:661-6
661
Alcohol After Midazolam Sedation: Does It Really Matter? J. Lance Lichtor, MD,James Zacny, PhD, Kari Korttila, MD, PhD, Jeffrey L. Apfelbaum, MD, Bradford S. Lane, BA, Gita Rupani, MD,Ronald A. Thisted, PhD, and Cathleen Dohrn, MA LICHTOR JL, ZACNY J, KORTTILA K, APFELBAUM JL, LANE BS, RUPANI G, THISTED RA, DOHRN C. Alcohol after midazolam sedation: Does it really matter? Anesth Analg 1991;72:661-6.
Patients who arrive home several hours after ambulatory surgery may drink alcohol. The extent to which the residual effects of drugs used in ambulatory surgery interact with alcohol, perhaps potentiating alcohol effects, is not known. Accordingly, the purpose of this study was to determine whether intravenous midazolam had residual effects that would interact with alcohol consumed 4 h after the midazolam injection. Healthy male volunteers (n = 16) participated in a double-blind, randomized, placebo-controlled crossover trial. Subjects were studied four times successively with 1 w k between trials. On each test day the subjects randomly received by slow intravenous injection (30 s) either saline or 0.1 mglkg of rnidazolam. Four hours after injection, the subjects consumed a beverage that either
Little is known about the postprocedure habits of ambulatory patients after discharge from surgical centers. A survey conducted more than 18 yr ago revealed that within 24 h of ambulatory surgery, despite being told not to, 73% of respondents who owned a car drove (1).The survey also revealed that 6% of the respondents ingested alcohol within 24 h after their surgery. Given that a majority of people may drive within 24 h after ambulatory surgery and that some of these people may also drink alcohol, it is important to understand the residual effects of drugs commonly used in ambulatory surgery or endoscopy and the extent to which these residual effects interact with alcohol. If patients after ambulatory surgical procePresented in part at the 64th Congress of the International Anesthesia Research Society, Honolulu, Hawaii, March 1990. Received from the Departments of Anesthesia and Critical Care, Psychiatry, Statistics, and Psychology, University of Chicago, Chicago, Illinois. Accepted for publication January 8, 1991. Address correspondence to Dr. Lichtor, Department of Anesthesia and Critical Care, Box 428, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. 01991 by the International Anesthesia Research Society 0003-29991911$3.50
did or did not contain 0.7 glkg of alcohol. Before and 1, 3 , 5 , and 7 h after injection (and before and 1 and 3 h after beverage consumption), psychomotor performance and mood were assessed. Whereas both midazolam and alcohol alone had effects on the dependent measures in this study, there were no significant interactions between the two drugs (i.e., potentiation of alcohol effects by midazolam or potentiation of midazolam by alcohol). W e conclude that the effects of a short-acting benzodiatepine used in ambulatory surgery have probably dissipated by the time a patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent administration of a short-acting benzodiazepine such as midazolam.
Key Words: HYPNOTICS, BENZODIAZEPINES midazolam. ALCOHOL, INTERACTION WITH BENZODIAZEPINES. ANESTHESIA, OUTPATIENTmidazolam-alcohol interaction.
dures drink alcohol after they have been discharged, it is possible that the risk of harm to themselves or others would be even greater than the risk from alcohol alone because the residual effects of the central nervous system-depressant drugs used in ambulatory surgery may potentiate the psychomotor effects of alcohol. Indeed, there are numerous studies demonstrating that the psychomotor-impairing effects of alcohol are potentiated by benzodiazepines (2-7). However, there are no studies that have examined the interaction between alcohol and benzodiazepines using a time frame in which alcohol use follows benzodiazepine administration by several hours. Such a study would be important from a clinical standpoint because this would mimic a scenario in which a patient after arriving home several hours following ambulatory surgery consumes alcohol. In the present study, healthy volunteers were given intravenous injections of either midazolam or placebo, and then 4 h later consumed a beverage that either did or did not contain alcohol. Psychomotor and cognitive functioning was assessed before and after midazolam and alcohol administration. This
662
ANESTH ANALG 1991;72:66I-6
protocol assays independent effects of each drug and determines if alcohol effects are potentiated by administration of midazolam using a time-course similar to that of a patient drinking alcohol upon arriving home after outpatient surgery.
Methods In this study, 16 healthy men (mean age, 23.6 t 3.1 yr; mean weight, 68.1 & 10.1 kg) with a history of recreational alcohol use served as subjects. The study was approved by our institutional review board. An anesthesiologist took a history and performed a physical examination to determine the suitability of subjects for the study. Excluded from this study were persons who had an adverse experience with alcohol, general or intravenous anesthesia, or sedation/ analgesia previously, or in whom contraindications became apparent after physical examination. Persons accepted into the study also could not take prescription or recreational drugs (excluding alcohol) or overthe-counter medication during the 3 wk of the study. Informed written consent was obtained from subjects before the first session. On testing days, subjects were not allowed to eat or drink before the tests (i.e., neither overnight drinking nor eating). Subjects were instructed to refrain from drinking alcohol for 24 h before sessions. Alcohol abstinence was verified by measuring the blood alcohol level when subjects arrived for the session. Subjects were told not to drive a car, operate heavy machinery, or cook until the day after the study and were required to have an escort accompany them home after sessions. Subjects were paid for their participation upon completion of the study. The study was performed as a double-blind, randomized, crossover trial. Each subject was tested in four different test sessions at 1-wk intervals. Subjects received intravenous injections of either 0.1 mg/kg of midazolam or saline (rate of injection, 30 s); 4 h later the subjects consumed a beverage that either did or did not contain 0.7 g/kg of alcohol. The dose of midazolam used was a high normal dose usually given during ambulatory procedures (surgical or medical) in this age group. The dose of alcohol used was approximately equivalent to 1.4 L of beer, 950 mL of wine, or 180 mL of hard liquor and would be expected to result in a blood alcohol level of approximately 0.6 mg/l00 mL (13.0 mmol/L) in a fasting 70-kg male. The lemonade-and-Iime flavored beverages that contained alcohol had 10% ethyl alcohol by volume in the 450 mL (per 70 kg) that subjects
LICHTOR ET AL.
consumed in 20 min. Beverages were served cold in cups. Before the first session of the experiment, subjects were trained (three practice sessions) to use the apparatus in order to prevent further learning of the task during the actual testing. Psychomotor tasks and subjective effects evaluations (see below) were performed before intravenous sedation and 1, 3, 5, and 7 h after intravenous sedation. Blood alcohol levels were measured before intravenous sedation and 5 and 7 h after intravenous sedation (I and 3 h after beverage consumption). A snack was served approximately 2 h after drug injection, and lunch was served to subjects approximately 6 h after drug injection (1.5 h after alcohol ingestion). Psychomotor effects, mood, and blood alcohol levels served as the dependent measures in this study. The Maddox wing test was used to measure esophoria and exophoria and motor function of the eyes (8). An action judgment tester, similar to a driving test, was used to measure eye-hand coordination; using a steering wheel, subjects attempted to keep two pointers on a moving track without striking objects; number of mistakes (i.e., when pointers struck objects) was recorded. Body sway was measured by using a computerized strain gauge technique to reveal defects in vestibular, motor, and proprioceptive functions; subjects stood on a force plate for 60 s with their eyes closed, and variations in movement of the anterior-posterior and lateral direction were recorded. Subjects performed three psychomotor tests on a computer (Apple Macintosh). Simple auditory and visual reaction times were determined by measuring the time it took the subject to press a button after hearing a sound or seeing a letter on the computer screen. Eye-hand coordination was measured by having the subject track a moving circle on a computer screen with a cross controlled by a ”mouse.” Coordination mistakes were measured by counting the number of times that the cross exceeded a certain distance from the target circle. Coordination accuracy was obtained by measuring the mean distance (in pixels) between the cross and the circle during the test. Subjective effects were measured at baseline and 1, 3, 5, and 7 h after drug injection with the Profile of Mood States (POMS). The POMS, chosen because it is sensitive to transient mood states, consists of 72 adjectives commonly used to describe transient mood states (9). Subjects indicate how they feel at the moment in relation to each of these adjectives, from “not at all” (0) to ”extremely” (4). Eight clusters of items have been previously derived using factor analysis and have been given names that best de-
ALCOHOL AFTER MIDAZOLAM SEDATION
ANESTH ANALG I991;72:h61-h
scribe the clustered adjectives (anxiety, depression, anger, vigor, fatigue, confusion, friendliness, and elation). Blood alcohol level was measured from breath air using an Alco-sensor 3 breath analyzer (Intoximetrics Instruments, St. Louis, Mo.). For each test, repeated-measures multivariate analysis of variance (10) was used to study the effect of drug (present or absent) and of alcohol (present or absent), and the interaction of these effects if any. P < 0.05 was considered significant. Post hoc tests were used, when significant drug or alcohol effects were obtained, to determine the duration of psychomotor performance impairment. In addition, we determined whether significant learning effects were present by using week of testing as a covariate.
663
placebo injection-alcohol beverage and midazolam injection-alcohol beverage). Alcohol caused significant impairment in eye-hand coordination (accuracy, P < 0.005; mistakes, P < 0.01),action judgment ( P < 0.001), and esophoriaiexophoria ( P < 0.005); these impairing effects had dissipated by 3 h after ingestion. Confusion scores (POMS) increased ( P < 0.005) after alcohol administration and remained significantly elevated 3 h after beverage ingestion. Subjects were also more fatigued and friendly ( P < 0.05). In no instance was any significant interaction noted between residual midazolam and alcohol. The analyses of covariance using weeks as a covarjate revealed that no significant learning effects took place during the study.
Discussion
Results Table 1 presents psychomotor performance and subjective effects measures before and 1 and 3 h after intravenous injection of either saline (averaged across the two saline conditions, i.e., saline injectionplacebo beverage and saline injection-alcohol beverage) or midazolam (averaged across the two midazolam conditions, i.e., midazolam injection-placebo beverage and midazolam injection-alcohol beverage). Midazolam caused significant impairment in auditory and visual reaction times, eye-hand coordination, action judgment, and esophoriaiexophoria (all P < 0.001 except eye-hand coordination accuracy for which P < 0.01). Elation ( P < O.OS), friendliness ( P < 0.01)’ and vigor (P < 0.001) scores from the POMS significantly decreased after midazolam, whereas confusion ( P < 0.001), depression ( P < O.OS), and fatigue ( P < 0.001) scores significantly increased. In general, effects of midazolam peaked at 1 h after injection and had dissipated by 3 h after injection. The two exceptions were esophoria/exophoria and fatigue scores; these dependent measures were still significantly elevated 3 h after injection. Mean 2 SD blood alcohol concentration 1 h after alcohol ingestion was 0.56 k 0.13 mg/100 mL (12.2 2.8 mmol/L). In most states, a motorist with a blood alcohol concentration of 1 mg/100 mL (21.7mmol/L) is considered to be driving under the influence of alcohol. Table 2 presents psychomotor performance and subjective effects measures at baseline (0 h) and 1 and 3 h after ingestion of either the placebo beverage (averaged across the two placebo conditions, i.e., saline injection-placebo beverage and midazolam injection-placebo beverage) or the alcohol beverage (averaged across the two alcohol conditions, i.e.,
*
The number of freestanding ambulatory surgery centers grew from 39 in 1982 to nearly 1000 in 1988 and it is estimated that by 1990 about 40% of all surgical procedures performed in the United States will be done in surgicenters (11,12). It is difficult to know exactly, but at least 60%-75% of these procedures probably involve either general anesthesia or intravenous sedation. Patients are routinely released after ambulatory surgery or endoscopy when they have demonstrated rudimentary psychomotor functioning (e.g., ability to get dressed and to walk without assistance). However, this does not mean that the whole spectrum of psychomotor functioning (including those skills necessary to safely operate a motor vehicle, cook, or care for small children) has returned to normal. Many of the drugs used in ambulatory surgery for analgesia or sedation are known to impair various psychomotor functions well after the patient is released from the surgicenter or endoscopy suite (13). If patients drink alcohol and then drive, cook, or even care for children, they may be increasing the risk of harm to themselves or others because of alcohol/drug interactions. In the present study, midazolam and alcohol independently impaired psychomotor performance and affected mood. The impairment of performance by midazolam is consistent with a number of other studies that have documented the deleterious effects of benzodiazepines on psychomotor/cognitive performance (2,3,14). The impairment for the most part was not long-lasting; most measures of psychomotor performance had returned to baseline levels by 3 h after the injection. The alterations in mood by midazolam in the present study, including increases in sedation and confusion, have been noted in other studies
664
LICHTOR ET AL.
ANESTH ANALG 1991;72:661-6
Table 1. Measurements of Psychomotor Performance and Mood at Baseline (0 h) and 1 and 3 h After Either Saline or Midazolam Injections" Saline injection Oh Auditory RT (ms) Visual RT (ms) Eye-hand coordination (mistakes) Eye-hand coordination (MDFC) Action judgment (mistakes) Esophorialexophoria (diopters) Body swayanterior-posterior (pixels) Body sway-lateral (pixels) POMS anxiety (score) POMS depression (score) POMS anger (score) POMS vigor (score) POMS fatigue (score) POMS confusion (score)
POMS friendliness (score) POMS elation (score)
l h
Midazolam injection 3h
0.270
0.263
0.257
t 0.011
t 0.009
t 0.008
0.355
0.322
0.318
t 0.015
t 0.011
t 0.009
17.0 2 2 11.4 t 0.4 27.6 2 4.5 3.1 t 0.6 627.9 t 37.6 648.8 t 39.5 0.1 t 0.1 0.2 t 0.1 0.3 t 0.1 1.4 t 0.1 0.8 t 0.1 0.1 t 0.1 1.8 t 0.1 1.1 t 0.1
15.8
16.8
t 1.6
t 1.8
11.2
11.6
t 0.4
t 0.5
23.9
24.2
t 4.2
t 4.5
3.6 t 0.6
774.8 t 39.8
805.9 t 61.3
0.0 t 0.1
0.1 t 0.0
0.2 t 0.0
1.4 t 0.1
0.6 t 0.1
0.0 t 0.1 1.9 t 0.1
1.1 t 0.1
3.4 0.6 744.2 t 48.8 733.7 t 48.1 -0.0 t 0.0 0.1 t 0.0 0.2 t 0.1 1.3 ? 0.1 0.6 t 0.1 0.0 t 0.1 1.8 t 0.1 1.1 2 0.1 ?
Oh
0.253 t 0.01 0.344 t 0.013 16.8 t 2.3 11.8 ? 0.5 30.0 t 5.1 3.2 t 0.6 708.1 2 50.8 811.1 t 99.5 0.2 t 0.1 0.3 ? 0.1 0.3 t 0.0 1.3 t 0.1 0.8 t 0.1 0.1 t 0.1 1.8 t 0.1 1.2 t 0.1
l h 0.373 t 0.035b
0.433 t 0.033b
3h 0.260 0.333 20.6 t 2.1
13.4
57.9
31.0 t 4.7
7.0
4.7
1963.7
908.5 t 84.7
1819.2
884.6 t 81.3 -0.1 t 0.0 0.1 t 0.0 0.2 t 0.0 1.1 t 0.1 0.9 t 0.1' 0.1 t 0.1 1.6 t 0.1 1.1 t 0.1
0.0 t 0.0
0.2 t 0.0
0.2 t 0.0
1.0 ? O.ld
1.2 t 1.2b
0.4 t O.lb
1.5 t O.ld
1.3 t 0.1
0.01
0.001
0.001
t 0.6'
t 519.4
t 476.6
0.001
t 0.9
2 6.3b
t 0.7b
0.001
t 0.011
31.5 19.4
0.001
t 0.01
t 3.5h t 2.lb
P
NS NS NS 0.05
NS 0.001 0.001
0.001 0.01
0.05
MDFC, mean distance from center of circle, measured in pixels; NS, main effect not significant; RT, reaction time. Values are mean ? SE. "Significance ( P value) is based on repeated measures multivariate analysis of variance comparing midazolam with saline, using hours 0, 1, 3, 5, and 7 as time points. "Difference score (1 h - 0 h) in midazolam injection condition significantly different ( P < 0.001) from difference score (1 h - 0 h) in saline injection condition. 'Difference score (3 h - 0 h) in midazolam injection condition significantly different (P < 0.0025) from difference score (3 h - 0 h) in saline injection condition. dDifference score (1h - 0 h) in midazolam injection condition significantly different ( P < 0.01) from difference score (1h - 0 h) in saline injection condition. 'Difference score (3 h - 0 h) in midazolam injection condition significantly different ( P < 0.05) from difference score (3 h - 0 h) in saline injection condition.
examining the effects of benzodiazepines on mood (15,16). Alcohol had an impairing effect on psychomotor performance, but to a lesser extent than that of midazolam. The dose of alcohol that was used in the present study was roughly equivalent to 1.4 L of beer, 950 mL of wine, or 180 mL of hard liquor. Other studies assessing the impairing effects of alcohol using amounts similar to the one we used have reported mixed results. Some studies find substantial psychomotor impairment (2,17), whereas other studies find only mild (18,19) or no impairment (4,20,21). It is probable that had a higher dose of alcohol been used in the present study, psychomotor impairment
would have been more severe, but we wanted to use a dose of alcohol that was relevant to our clinicaI situation. No major interaction was noted between residual midazolam and alcohol. These results stand in contrast to a number of other studies that have documented that benzodiazepines potentiate the effects of alcohol (2,4-7,14). However, differences in results between the present study and these other studies can probably be accounted for by differences in interval between drug administration: in the other studies benzodiazepines and alcohoI were jointly administered, whereas in the present study, the interval between the two was set at 4 h. The half-lives
ALCOHOL AFTER MIDAZOLAM SEDATION
ANESTH ANALG 1991;72:661-6
665
Table 2. Psychomotor Performance and Mood Measures at Baseline (0 h) and 1 and 3 h After Either Placebo or Alcohol Beverage (and 5 and 7 h After Either Saline or Midazolam 1njections)a Placebo beverage Oh Auditory RT (s) Visual RT (s) Eye-hand coordination (mistakes) Eye-hand coordination (MDFC) Action judgment (mistakes) Esophoriaiexophoria (diopters) Body swayanterior-posterior (pixels) Body sway-lateral (pixels) POMS anxiety (score) POMS depression (score) POMS anger (score) POMS vigor (score) POMS fatigue (score)
0.263 t 0.011 0.353 2 0.014 17.1 t 2.2 11.8 2 0.6 28.8 2 4.8 2.9 t 0.6 651.9 t 36.8 671.1 2 45.5 0.2 t 0.1 0.3 t 0.1 0.3 t 0.1 1.3 t 0.1 0.9
0.1 0.1 t 0.1 1.8 t 0.1 1.2 -t 0.1 f
POMS confusion (score) POMS friendliness (score) POMS elation (score)
Alcohol beverage
5h 0.272 t 0.008
0.323 t 0.009
17.8 t 1.8
11.7 t 0.5
26.1 t 3.9
3.3 t 0.6
716.5 t 55.8
719.3 51.5 0.0 t 0.1 0.2 t 0.1 0.3 t 0.1 1.4 t 0.1 0.6 2 0.1 0.1 t 0.1 1.7 t 0.1 1.2 2 0.1
-t
7h
Oh
5h
0.250 0.008 0.314 2 0.01 15.5 t 1.7 11.7 t 0.5 26.0 -t 4.3 3.2 t 0.6 740.7 t- 68.7 721.4 2 49.2 0.0 ? 0.0 0.1 ? 0.0 0.3 t 0.1 1.5 t 0.1 0.6 t 0.1 0.0 t 0.1 1.6 t 0.1 1.1 ? 0.1
0.260 0.01 0.347 t 0.015 16.7 t 2.2 11.4 t 0.4 28.7 t 4.8 3.3 t 0.7 684.1 t 52.2 788.8 t 97.9 0.1 t 0.1 0.2 t 0.06 0.3 t 0.0 1.4 t 0.1 0.7 t 0.1 0.1 t 0.1 1.8 t 0.1 1.1 t 0.1
0.292 0.011 0.346 2 0.011 24.4 5 2.5b 12.7 2 0.6‘ 32.5 2 4.9d 5.2 2 0.7‘ 950.2 t 117.1 868.7 t 89.7 -0.1 t 0.1 0.1 F 0.0 0.2 F 0.1 1.4 F 0.1 0.7 F 0.1 0.4 t 0.1” 1.9 F 0.1 0.9 F 0.1
%
2
f
7h 0.256
P NS
t 0.01
0.311
NS
2 0.01
18.2
0.01
2 2.2
11.8 0.5 27.3 f 4.2 4.0 2 0.6 778.1 2 85.6 743.8 t 67.6 -0.0 f 0.0 0.1 2 0.0 0.2 t 0.0 1.2 fO.1 0.9
0.005
2
0.001 0.005
NS NS
NS NS NS NS 0.05
t O.lf
0.2 0.lf 1.6 2 0.1 1.0 F 0.1
0.005
f
0.05 NS
MDFC, mean distance from center of circle, measured in pixels; NS, main effect not significant; RT, reaction time. “Significance ( P value) is based on repeated measures multivariate analysis of variance comparing alcohol with placebo, using hours 0, 5, and 7 as time points. “Differencescore (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.005) from difference score (5 h - 0 h) in placebo beverage condition. ‘Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.01) from difference score (5 h - 0 h) in placebo beverage condition. “Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.025) from difference score (5 h - 0 h) in placebo beverage condition. ‘‘Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.001) from difference score (5 h - 0 h) in placebo beverage condition. ’Difference score (7 h - 0 h) in alcohol beverage condition significantly different ( P < 0.01) from difference score (7 h - 0 h) in placebo beverage condition.
of midazolam and triazolam are similar (22,23). Recently, an interaction between triazolam and alcohol was noted: three neurologists were described who used triazolam to reduce jet lag, drank alcohol (albeit not at a level to be intoxicated), and then developed anterograde amnesia (24). The time frame between triazolam and alcohol ingestion was probably similar to that of our study. However, no impairment of activity was described. Other factors may have contributed to the amnesia: two of the three were taking other long-term medications and their sleep was disrupted by the long air ride. It appears, then, that the residual effects of the short-acting benzodiazepine, midazolam, do not potentiate to any great degree the effects of alcohol given 4 h or more later.
It should be acknowledged that the generality of these results may be somewhat limited by the lack of parametric manipulations of midazolam and alcohol doses, and interdrug interval, as well as the use of only young, healthy men. It is possible, for example, that had an interdrug interval shorter than 4 h been used, more significant midazolam-alcohol interactions may have been obtained. However, such results would be less meaningful to anesthesiologists and other medical personnel because patients typically would arrive home no sooner than 3-4 h after ambulatory surgery. No midazolam or alcohol doseresponse analyses were performed because we wanted to use clinically relevant doses of both drugs. Similarly, we did not include either women or older
666
ANESTH ANALG 1991;72:661-6
patients. It is clear that alcohol pharmacokinetics may differ as a function of gender, although it is not so clear whether psychomotor, cognitive, or subjective responses to alcohol are affected by gender (25-28). Similarly, midazolam elimination half-life is prolonged significantly and total clearance is decreased significantly in elderly as opposed to younger subjects or patients (29,30). We are presently conducting additional studies to see if longer acting drugs commonly used in ambulatory surgical procedures will interact with alcohol when drug injection precedes alcohol ingestion by several hours. In these studies, we will also be including women and older subjects to examine the role of menstrual cycle and age. However, the results of the present study suggest that if patients are sedated only with midazolam during ambulatory surgery, then any deleterious effects of midazolam on psychomotor performance will have probably dissipated by the time the patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent administration of midazolam.
References 1. Ogg TW. An assessment of postoperative outpatient cases. Br Med J 1972;4:573-6. 2. Linnoila M, Hakkinen S. Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther 1974;15:368-73. 3. Aranko K, Seppala T, Pellinen J, Mattila MJ. Interaction of diazepam or lorazepam with alcohol. Psychomotor effects and bioassayed serum levels after single and repeated doses. Eur J Clin Pharmacol 1985;28:55945. 4. Hindmarch I, Subhan Z . The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability. Int J Clin Pharm Res 1983;3:323-9. 5. Willumeit HI', Ott H, Neubert W, Hemmerling KG, Schratzer M, Fichte K. Alcohol interaction of lormetazepam, mepindolol sulphate and diazepam measured by performance on the driving simulator. Pharmacopsychiatry 1984;17:3&43. 6. Morland J, Setekleiv J, Haffner JF, Stromsaether CE, Danielsen A, Wethe GH. Combined effects of diazepam and ethanol on mental and psychomotor functions. Acta Pharmacol Toxicol 1974;34:5-15. 7. Palva ES, Linnoila M, Saario I, Mattila MJ. Acute and subacute effects of diazepam on psychomotor skills: interaction with alcohol. Acta Pharmacol Toxicol 1979;45:257-64. 8. Hannington-Kiff JG. Measurement of recovery from outpatient general anaesthesia with a simple ocular test. Br Med J 1970; 3:132-5. 9. McNair DM, Frankenthaler LM, Czerlinsky T, White TW, Sasson S, Fisher S. Simulated public speaking as a model of clinical anxiety. Psychopharmacology 1982;77:7-10.
LICHTOR ET AL.
10. Wilkinson L. SYSTAT: the system for statistics. Evanston, 111.: SYSTAT, Inc., 1986. 11. Larkin H. Less money, more players in outpatient market. Hospitals 1989;63:26. 12. Shannon K. Outpatient surgery up 77 percent: data. Hospitals 1985;59:54. 13. Korttila K. Postanesthetic cognitive and psychomotor impairment. Int Anesthesiol Clin 1986;24:59-74. 14. Saario I, Linnoila M. Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving. Acta Pharmacol Toxicol 1976;3838292. 15. Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology 1980;71:269-73. 16. De Wit H, Uhlenhuth EH, Hedeker D, McCracken SG, Johanson CE. Lack of preference for diazepam in anxious volunteers. Arch Gen Psychiatry 1986;43:53341. 17. Erwin CW, Linnoila M, Hartwell J, Erwin A, Guthrie S. Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials. J Clin Psychopharmacol 1986;6:199-209. 18. Fagan D, Tiplady B, Scott DB. Effects of ethanol on psychomotor performance. Br J Anaesth 1987;59:961-5. 19. McManus IC, Ankier SI, Norfolk J, Phillips M, Priest RG. Effects on psychological performance of the benzodiazepine, loprazolam, alone and with alcohol. Br J Clin Pharmacol 1983;16:291-300. 20. Palva ES, Linnoila M, Routledge P, Seppala T. Actions and interactions of diazepam and alcohol on psychomotor skills in young and middle-aged subjects. Acta Pharmacol Toxicol 1982;50:363-9. 21. Nuotto E, Mattila MJ, Seppala T, Konno K. Coffee and caffeine and alcohol effects on psychomotor function. Clin Pharmacol Ther 1982;31:68-76. 22. Greenblatt DJ, Locniskar A, Ochs HR, Lauven PM. Automated gas chromatography for studies of midazolam pharmacokinetics. Anesthesiology 1981;55:176-9. 23. Eberts FS Jr, Philopoulos Y, Reineke LM, vliek RW. Triazolam disposition. Clin Pharmacol Ther 1981;29:81-93. 24. Morris HH 111, Estes ML. Traveler's amnesia. Transient global amnesia secondary to triazolam. JAMA 1987;258:945-6. 25. Dubowski KM. Human pharmacokinetics of ethanol. I. Peak blood concentrations and elimination in male and female subjects. Alcohol Tech Rep 1976;5:55-63. 26. Sutker PB, Tabakoff B, Goist KC, Randall CL. Acute alcohol intoxication, mood states and alcohol metabolism in women and men. Pharmacol Biochem Behav 1983;18:349-54. 27. Niaura RS, Nathan PE, Frankenstein W, Shapiro AP, Brick J . Gender differences in acute psychomotor, cognitive, and pharmacokinetic response to alcohol. Addict Behav 1987;12:345-56. 28. Tabener PV. Sex differences in the effects of low doses of ethanol on human reaction time. Psychopharmacology 1980; 70:283-6. 29. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984;61:27-35. 30. Harper KW, Collier PS, Dundee JW, Elliott P, Halliday NJ, Lowry KG. Age and nature of operation influence the pharmacokinetics of midazolam. Br J Anaesth 1985;57:866-71.
661
Alcohol After Midazolam Sedation: Does It Really Matter? J. Lance Lichtor, MD,James Zacny, PhD, Kari Korttila, MD, PhD, Jeffrey L. Apfelbaum, MD, Bradford S. Lane, BA, Gita Rupani, MD,Ronald A. Thisted, PhD, and Cathleen Dohrn, MA LICHTOR JL, ZACNY J, KORTTILA K, APFELBAUM JL, LANE BS, RUPANI G, THISTED RA, DOHRN C. Alcohol after midazolam sedation: Does it really matter? Anesth Analg 1991;72:661-6.
Patients who arrive home several hours after ambulatory surgery may drink alcohol. The extent to which the residual effects of drugs used in ambulatory surgery interact with alcohol, perhaps potentiating alcohol effects, is not known. Accordingly, the purpose of this study was to determine whether intravenous midazolam had residual effects that would interact with alcohol consumed 4 h after the midazolam injection. Healthy male volunteers (n = 16) participated in a double-blind, randomized, placebo-controlled crossover trial. Subjects were studied four times successively with 1 w k between trials. On each test day the subjects randomly received by slow intravenous injection (30 s) either saline or 0.1 mglkg of rnidazolam. Four hours after injection, the subjects consumed a beverage that either
Little is known about the postprocedure habits of ambulatory patients after discharge from surgical centers. A survey conducted more than 18 yr ago revealed that within 24 h of ambulatory surgery, despite being told not to, 73% of respondents who owned a car drove (1).The survey also revealed that 6% of the respondents ingested alcohol within 24 h after their surgery. Given that a majority of people may drive within 24 h after ambulatory surgery and that some of these people may also drink alcohol, it is important to understand the residual effects of drugs commonly used in ambulatory surgery or endoscopy and the extent to which these residual effects interact with alcohol. If patients after ambulatory surgical procePresented in part at the 64th Congress of the International Anesthesia Research Society, Honolulu, Hawaii, March 1990. Received from the Departments of Anesthesia and Critical Care, Psychiatry, Statistics, and Psychology, University of Chicago, Chicago, Illinois. Accepted for publication January 8, 1991. Address correspondence to Dr. Lichtor, Department of Anesthesia and Critical Care, Box 428, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. 01991 by the International Anesthesia Research Society 0003-29991911$3.50
did or did not contain 0.7 glkg of alcohol. Before and 1, 3 , 5 , and 7 h after injection (and before and 1 and 3 h after beverage consumption), psychomotor performance and mood were assessed. Whereas both midazolam and alcohol alone had effects on the dependent measures in this study, there were no significant interactions between the two drugs (i.e., potentiation of alcohol effects by midazolam or potentiation of midazolam by alcohol). W e conclude that the effects of a short-acting benzodiatepine used in ambulatory surgery have probably dissipated by the time a patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent administration of a short-acting benzodiazepine such as midazolam.
Key Words: HYPNOTICS, BENZODIAZEPINES midazolam. ALCOHOL, INTERACTION WITH BENZODIAZEPINES. ANESTHESIA, OUTPATIENTmidazolam-alcohol interaction.
dures drink alcohol after they have been discharged, it is possible that the risk of harm to themselves or others would be even greater than the risk from alcohol alone because the residual effects of the central nervous system-depressant drugs used in ambulatory surgery may potentiate the psychomotor effects of alcohol. Indeed, there are numerous studies demonstrating that the psychomotor-impairing effects of alcohol are potentiated by benzodiazepines (2-7). However, there are no studies that have examined the interaction between alcohol and benzodiazepines using a time frame in which alcohol use follows benzodiazepine administration by several hours. Such a study would be important from a clinical standpoint because this would mimic a scenario in which a patient after arriving home several hours following ambulatory surgery consumes alcohol. In the present study, healthy volunteers were given intravenous injections of either midazolam or placebo, and then 4 h later consumed a beverage that either did or did not contain alcohol. Psychomotor and cognitive functioning was assessed before and after midazolam and alcohol administration. This
662
ANESTH ANALG 1991;72:66I-6
protocol assays independent effects of each drug and determines if alcohol effects are potentiated by administration of midazolam using a time-course similar to that of a patient drinking alcohol upon arriving home after outpatient surgery.
Methods In this study, 16 healthy men (mean age, 23.6 t 3.1 yr; mean weight, 68.1 & 10.1 kg) with a history of recreational alcohol use served as subjects. The study was approved by our institutional review board. An anesthesiologist took a history and performed a physical examination to determine the suitability of subjects for the study. Excluded from this study were persons who had an adverse experience with alcohol, general or intravenous anesthesia, or sedation/ analgesia previously, or in whom contraindications became apparent after physical examination. Persons accepted into the study also could not take prescription or recreational drugs (excluding alcohol) or overthe-counter medication during the 3 wk of the study. Informed written consent was obtained from subjects before the first session. On testing days, subjects were not allowed to eat or drink before the tests (i.e., neither overnight drinking nor eating). Subjects were instructed to refrain from drinking alcohol for 24 h before sessions. Alcohol abstinence was verified by measuring the blood alcohol level when subjects arrived for the session. Subjects were told not to drive a car, operate heavy machinery, or cook until the day after the study and were required to have an escort accompany them home after sessions. Subjects were paid for their participation upon completion of the study. The study was performed as a double-blind, randomized, crossover trial. Each subject was tested in four different test sessions at 1-wk intervals. Subjects received intravenous injections of either 0.1 mg/kg of midazolam or saline (rate of injection, 30 s); 4 h later the subjects consumed a beverage that either did or did not contain 0.7 g/kg of alcohol. The dose of midazolam used was a high normal dose usually given during ambulatory procedures (surgical or medical) in this age group. The dose of alcohol used was approximately equivalent to 1.4 L of beer, 950 mL of wine, or 180 mL of hard liquor and would be expected to result in a blood alcohol level of approximately 0.6 mg/l00 mL (13.0 mmol/L) in a fasting 70-kg male. The lemonade-and-Iime flavored beverages that contained alcohol had 10% ethyl alcohol by volume in the 450 mL (per 70 kg) that subjects
LICHTOR ET AL.
consumed in 20 min. Beverages were served cold in cups. Before the first session of the experiment, subjects were trained (three practice sessions) to use the apparatus in order to prevent further learning of the task during the actual testing. Psychomotor tasks and subjective effects evaluations (see below) were performed before intravenous sedation and 1, 3, 5, and 7 h after intravenous sedation. Blood alcohol levels were measured before intravenous sedation and 5 and 7 h after intravenous sedation (I and 3 h after beverage consumption). A snack was served approximately 2 h after drug injection, and lunch was served to subjects approximately 6 h after drug injection (1.5 h after alcohol ingestion). Psychomotor effects, mood, and blood alcohol levels served as the dependent measures in this study. The Maddox wing test was used to measure esophoria and exophoria and motor function of the eyes (8). An action judgment tester, similar to a driving test, was used to measure eye-hand coordination; using a steering wheel, subjects attempted to keep two pointers on a moving track without striking objects; number of mistakes (i.e., when pointers struck objects) was recorded. Body sway was measured by using a computerized strain gauge technique to reveal defects in vestibular, motor, and proprioceptive functions; subjects stood on a force plate for 60 s with their eyes closed, and variations in movement of the anterior-posterior and lateral direction were recorded. Subjects performed three psychomotor tests on a computer (Apple Macintosh). Simple auditory and visual reaction times were determined by measuring the time it took the subject to press a button after hearing a sound or seeing a letter on the computer screen. Eye-hand coordination was measured by having the subject track a moving circle on a computer screen with a cross controlled by a ”mouse.” Coordination mistakes were measured by counting the number of times that the cross exceeded a certain distance from the target circle. Coordination accuracy was obtained by measuring the mean distance (in pixels) between the cross and the circle during the test. Subjective effects were measured at baseline and 1, 3, 5, and 7 h after drug injection with the Profile of Mood States (POMS). The POMS, chosen because it is sensitive to transient mood states, consists of 72 adjectives commonly used to describe transient mood states (9). Subjects indicate how they feel at the moment in relation to each of these adjectives, from “not at all” (0) to ”extremely” (4). Eight clusters of items have been previously derived using factor analysis and have been given names that best de-
ALCOHOL AFTER MIDAZOLAM SEDATION
ANESTH ANALG I991;72:h61-h
scribe the clustered adjectives (anxiety, depression, anger, vigor, fatigue, confusion, friendliness, and elation). Blood alcohol level was measured from breath air using an Alco-sensor 3 breath analyzer (Intoximetrics Instruments, St. Louis, Mo.). For each test, repeated-measures multivariate analysis of variance (10) was used to study the effect of drug (present or absent) and of alcohol (present or absent), and the interaction of these effects if any. P < 0.05 was considered significant. Post hoc tests were used, when significant drug or alcohol effects were obtained, to determine the duration of psychomotor performance impairment. In addition, we determined whether significant learning effects were present by using week of testing as a covariate.
663
placebo injection-alcohol beverage and midazolam injection-alcohol beverage). Alcohol caused significant impairment in eye-hand coordination (accuracy, P < 0.005; mistakes, P < 0.01),action judgment ( P < 0.001), and esophoriaiexophoria ( P < 0.005); these impairing effects had dissipated by 3 h after ingestion. Confusion scores (POMS) increased ( P < 0.005) after alcohol administration and remained significantly elevated 3 h after beverage ingestion. Subjects were also more fatigued and friendly ( P < 0.05). In no instance was any significant interaction noted between residual midazolam and alcohol. The analyses of covariance using weeks as a covarjate revealed that no significant learning effects took place during the study.
Discussion
Results Table 1 presents psychomotor performance and subjective effects measures before and 1 and 3 h after intravenous injection of either saline (averaged across the two saline conditions, i.e., saline injectionplacebo beverage and saline injection-alcohol beverage) or midazolam (averaged across the two midazolam conditions, i.e., midazolam injection-placebo beverage and midazolam injection-alcohol beverage). Midazolam caused significant impairment in auditory and visual reaction times, eye-hand coordination, action judgment, and esophoriaiexophoria (all P < 0.001 except eye-hand coordination accuracy for which P < 0.01). Elation ( P < O.OS), friendliness ( P < 0.01)’ and vigor (P < 0.001) scores from the POMS significantly decreased after midazolam, whereas confusion ( P < 0.001), depression ( P < O.OS), and fatigue ( P < 0.001) scores significantly increased. In general, effects of midazolam peaked at 1 h after injection and had dissipated by 3 h after injection. The two exceptions were esophoria/exophoria and fatigue scores; these dependent measures were still significantly elevated 3 h after injection. Mean 2 SD blood alcohol concentration 1 h after alcohol ingestion was 0.56 k 0.13 mg/100 mL (12.2 2.8 mmol/L). In most states, a motorist with a blood alcohol concentration of 1 mg/100 mL (21.7mmol/L) is considered to be driving under the influence of alcohol. Table 2 presents psychomotor performance and subjective effects measures at baseline (0 h) and 1 and 3 h after ingestion of either the placebo beverage (averaged across the two placebo conditions, i.e., saline injection-placebo beverage and midazolam injection-placebo beverage) or the alcohol beverage (averaged across the two alcohol conditions, i.e.,
*
The number of freestanding ambulatory surgery centers grew from 39 in 1982 to nearly 1000 in 1988 and it is estimated that by 1990 about 40% of all surgical procedures performed in the United States will be done in surgicenters (11,12). It is difficult to know exactly, but at least 60%-75% of these procedures probably involve either general anesthesia or intravenous sedation. Patients are routinely released after ambulatory surgery or endoscopy when they have demonstrated rudimentary psychomotor functioning (e.g., ability to get dressed and to walk without assistance). However, this does not mean that the whole spectrum of psychomotor functioning (including those skills necessary to safely operate a motor vehicle, cook, or care for small children) has returned to normal. Many of the drugs used in ambulatory surgery for analgesia or sedation are known to impair various psychomotor functions well after the patient is released from the surgicenter or endoscopy suite (13). If patients drink alcohol and then drive, cook, or even care for children, they may be increasing the risk of harm to themselves or others because of alcohol/drug interactions. In the present study, midazolam and alcohol independently impaired psychomotor performance and affected mood. The impairment of performance by midazolam is consistent with a number of other studies that have documented the deleterious effects of benzodiazepines on psychomotor/cognitive performance (2,3,14). The impairment for the most part was not long-lasting; most measures of psychomotor performance had returned to baseline levels by 3 h after the injection. The alterations in mood by midazolam in the present study, including increases in sedation and confusion, have been noted in other studies
664
LICHTOR ET AL.
ANESTH ANALG 1991;72:661-6
Table 1. Measurements of Psychomotor Performance and Mood at Baseline (0 h) and 1 and 3 h After Either Saline or Midazolam Injections" Saline injection Oh Auditory RT (ms) Visual RT (ms) Eye-hand coordination (mistakes) Eye-hand coordination (MDFC) Action judgment (mistakes) Esophorialexophoria (diopters) Body swayanterior-posterior (pixels) Body sway-lateral (pixels) POMS anxiety (score) POMS depression (score) POMS anger (score) POMS vigor (score) POMS fatigue (score) POMS confusion (score)
POMS friendliness (score) POMS elation (score)
l h
Midazolam injection 3h
0.270
0.263
0.257
t 0.011
t 0.009
t 0.008
0.355
0.322
0.318
t 0.015
t 0.011
t 0.009
17.0 2 2 11.4 t 0.4 27.6 2 4.5 3.1 t 0.6 627.9 t 37.6 648.8 t 39.5 0.1 t 0.1 0.2 t 0.1 0.3 t 0.1 1.4 t 0.1 0.8 t 0.1 0.1 t 0.1 1.8 t 0.1 1.1 t 0.1
15.8
16.8
t 1.6
t 1.8
11.2
11.6
t 0.4
t 0.5
23.9
24.2
t 4.2
t 4.5
3.6 t 0.6
774.8 t 39.8
805.9 t 61.3
0.0 t 0.1
0.1 t 0.0
0.2 t 0.0
1.4 t 0.1
0.6 t 0.1
0.0 t 0.1 1.9 t 0.1
1.1 t 0.1
3.4 0.6 744.2 t 48.8 733.7 t 48.1 -0.0 t 0.0 0.1 t 0.0 0.2 t 0.1 1.3 ? 0.1 0.6 t 0.1 0.0 t 0.1 1.8 t 0.1 1.1 2 0.1 ?
Oh
0.253 t 0.01 0.344 t 0.013 16.8 t 2.3 11.8 ? 0.5 30.0 t 5.1 3.2 t 0.6 708.1 2 50.8 811.1 t 99.5 0.2 t 0.1 0.3 ? 0.1 0.3 t 0.0 1.3 t 0.1 0.8 t 0.1 0.1 t 0.1 1.8 t 0.1 1.2 t 0.1
l h 0.373 t 0.035b
0.433 t 0.033b
3h 0.260 0.333 20.6 t 2.1
13.4
57.9
31.0 t 4.7
7.0
4.7
1963.7
908.5 t 84.7
1819.2
884.6 t 81.3 -0.1 t 0.0 0.1 t 0.0 0.2 t 0.0 1.1 t 0.1 0.9 t 0.1' 0.1 t 0.1 1.6 t 0.1 1.1 t 0.1
0.0 t 0.0
0.2 t 0.0
0.2 t 0.0
1.0 ? O.ld
1.2 t 1.2b
0.4 t O.lb
1.5 t O.ld
1.3 t 0.1
0.01
0.001
0.001
t 0.6'
t 519.4
t 476.6
0.001
t 0.9
2 6.3b
t 0.7b
0.001
t 0.011
31.5 19.4
0.001
t 0.01
t 3.5h t 2.lb
P
NS NS NS 0.05
NS 0.001 0.001
0.001 0.01
0.05
MDFC, mean distance from center of circle, measured in pixels; NS, main effect not significant; RT, reaction time. Values are mean ? SE. "Significance ( P value) is based on repeated measures multivariate analysis of variance comparing midazolam with saline, using hours 0, 1, 3, 5, and 7 as time points. "Difference score (1 h - 0 h) in midazolam injection condition significantly different ( P < 0.001) from difference score (1 h - 0 h) in saline injection condition. 'Difference score (3 h - 0 h) in midazolam injection condition significantly different (P < 0.0025) from difference score (3 h - 0 h) in saline injection condition. dDifference score (1h - 0 h) in midazolam injection condition significantly different ( P < 0.01) from difference score (1h - 0 h) in saline injection condition. 'Difference score (3 h - 0 h) in midazolam injection condition significantly different ( P < 0.05) from difference score (3 h - 0 h) in saline injection condition.
examining the effects of benzodiazepines on mood (15,16). Alcohol had an impairing effect on psychomotor performance, but to a lesser extent than that of midazolam. The dose of alcohol that was used in the present study was roughly equivalent to 1.4 L of beer, 950 mL of wine, or 180 mL of hard liquor. Other studies assessing the impairing effects of alcohol using amounts similar to the one we used have reported mixed results. Some studies find substantial psychomotor impairment (2,17), whereas other studies find only mild (18,19) or no impairment (4,20,21). It is probable that had a higher dose of alcohol been used in the present study, psychomotor impairment
would have been more severe, but we wanted to use a dose of alcohol that was relevant to our clinicaI situation. No major interaction was noted between residual midazolam and alcohol. These results stand in contrast to a number of other studies that have documented that benzodiazepines potentiate the effects of alcohol (2,4-7,14). However, differences in results between the present study and these other studies can probably be accounted for by differences in interval between drug administration: in the other studies benzodiazepines and alcohoI were jointly administered, whereas in the present study, the interval between the two was set at 4 h. The half-lives
ALCOHOL AFTER MIDAZOLAM SEDATION
ANESTH ANALG 1991;72:661-6
665
Table 2. Psychomotor Performance and Mood Measures at Baseline (0 h) and 1 and 3 h After Either Placebo or Alcohol Beverage (and 5 and 7 h After Either Saline or Midazolam 1njections)a Placebo beverage Oh Auditory RT (s) Visual RT (s) Eye-hand coordination (mistakes) Eye-hand coordination (MDFC) Action judgment (mistakes) Esophoriaiexophoria (diopters) Body swayanterior-posterior (pixels) Body sway-lateral (pixels) POMS anxiety (score) POMS depression (score) POMS anger (score) POMS vigor (score) POMS fatigue (score)
0.263 t 0.011 0.353 2 0.014 17.1 t 2.2 11.8 2 0.6 28.8 2 4.8 2.9 t 0.6 651.9 t 36.8 671.1 2 45.5 0.2 t 0.1 0.3 t 0.1 0.3 t 0.1 1.3 t 0.1 0.9
0.1 0.1 t 0.1 1.8 t 0.1 1.2 -t 0.1 f
POMS confusion (score) POMS friendliness (score) POMS elation (score)
Alcohol beverage
5h 0.272 t 0.008
0.323 t 0.009
17.8 t 1.8
11.7 t 0.5
26.1 t 3.9
3.3 t 0.6
716.5 t 55.8
719.3 51.5 0.0 t 0.1 0.2 t 0.1 0.3 t 0.1 1.4 t 0.1 0.6 2 0.1 0.1 t 0.1 1.7 t 0.1 1.2 2 0.1
-t
7h
Oh
5h
0.250 0.008 0.314 2 0.01 15.5 t 1.7 11.7 t 0.5 26.0 -t 4.3 3.2 t 0.6 740.7 t- 68.7 721.4 2 49.2 0.0 ? 0.0 0.1 ? 0.0 0.3 t 0.1 1.5 t 0.1 0.6 t 0.1 0.0 t 0.1 1.6 t 0.1 1.1 ? 0.1
0.260 0.01 0.347 t 0.015 16.7 t 2.2 11.4 t 0.4 28.7 t 4.8 3.3 t 0.7 684.1 t 52.2 788.8 t 97.9 0.1 t 0.1 0.2 t 0.06 0.3 t 0.0 1.4 t 0.1 0.7 t 0.1 0.1 t 0.1 1.8 t 0.1 1.1 t 0.1
0.292 0.011 0.346 2 0.011 24.4 5 2.5b 12.7 2 0.6‘ 32.5 2 4.9d 5.2 2 0.7‘ 950.2 t 117.1 868.7 t 89.7 -0.1 t 0.1 0.1 F 0.0 0.2 F 0.1 1.4 F 0.1 0.7 F 0.1 0.4 t 0.1” 1.9 F 0.1 0.9 F 0.1
%
2
f
7h 0.256
P NS
t 0.01
0.311
NS
2 0.01
18.2
0.01
2 2.2
11.8 0.5 27.3 f 4.2 4.0 2 0.6 778.1 2 85.6 743.8 t 67.6 -0.0 f 0.0 0.1 2 0.0 0.2 t 0.0 1.2 fO.1 0.9
0.005
2
0.001 0.005
NS NS
NS NS NS NS 0.05
t O.lf
0.2 0.lf 1.6 2 0.1 1.0 F 0.1
0.005
f
0.05 NS
MDFC, mean distance from center of circle, measured in pixels; NS, main effect not significant; RT, reaction time. “Significance ( P value) is based on repeated measures multivariate analysis of variance comparing alcohol with placebo, using hours 0, 5, and 7 as time points. “Differencescore (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.005) from difference score (5 h - 0 h) in placebo beverage condition. ‘Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.01) from difference score (5 h - 0 h) in placebo beverage condition. “Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.025) from difference score (5 h - 0 h) in placebo beverage condition. ‘‘Difference score (5 h - 0 h) in alcohol beverage condition significantly different ( P < 0.001) from difference score (5 h - 0 h) in placebo beverage condition. ’Difference score (7 h - 0 h) in alcohol beverage condition significantly different ( P < 0.01) from difference score (7 h - 0 h) in placebo beverage condition.
of midazolam and triazolam are similar (22,23). Recently, an interaction between triazolam and alcohol was noted: three neurologists were described who used triazolam to reduce jet lag, drank alcohol (albeit not at a level to be intoxicated), and then developed anterograde amnesia (24). The time frame between triazolam and alcohol ingestion was probably similar to that of our study. However, no impairment of activity was described. Other factors may have contributed to the amnesia: two of the three were taking other long-term medications and their sleep was disrupted by the long air ride. It appears, then, that the residual effects of the short-acting benzodiazepine, midazolam, do not potentiate to any great degree the effects of alcohol given 4 h or more later.
It should be acknowledged that the generality of these results may be somewhat limited by the lack of parametric manipulations of midazolam and alcohol doses, and interdrug interval, as well as the use of only young, healthy men. It is possible, for example, that had an interdrug interval shorter than 4 h been used, more significant midazolam-alcohol interactions may have been obtained. However, such results would be less meaningful to anesthesiologists and other medical personnel because patients typically would arrive home no sooner than 3-4 h after ambulatory surgery. No midazolam or alcohol doseresponse analyses were performed because we wanted to use clinically relevant doses of both drugs. Similarly, we did not include either women or older
666
ANESTH ANALG 1991;72:661-6
patients. It is clear that alcohol pharmacokinetics may differ as a function of gender, although it is not so clear whether psychomotor, cognitive, or subjective responses to alcohol are affected by gender (25-28). Similarly, midazolam elimination half-life is prolonged significantly and total clearance is decreased significantly in elderly as opposed to younger subjects or patients (29,30). We are presently conducting additional studies to see if longer acting drugs commonly used in ambulatory surgical procedures will interact with alcohol when drug injection precedes alcohol ingestion by several hours. In these studies, we will also be including women and older subjects to examine the role of menstrual cycle and age. However, the results of the present study suggest that if patients are sedated only with midazolam during ambulatory surgery, then any deleterious effects of midazolam on psychomotor performance will have probably dissipated by the time the patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent administration of midazolam.
References 1. Ogg TW. An assessment of postoperative outpatient cases. Br Med J 1972;4:573-6. 2. Linnoila M, Hakkinen S. Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther 1974;15:368-73. 3. Aranko K, Seppala T, Pellinen J, Mattila MJ. Interaction of diazepam or lorazepam with alcohol. Psychomotor effects and bioassayed serum levels after single and repeated doses. Eur J Clin Pharmacol 1985;28:55945. 4. Hindmarch I, Subhan Z . The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability. Int J Clin Pharm Res 1983;3:323-9. 5. Willumeit HI', Ott H, Neubert W, Hemmerling KG, Schratzer M, Fichte K. Alcohol interaction of lormetazepam, mepindolol sulphate and diazepam measured by performance on the driving simulator. Pharmacopsychiatry 1984;17:3&43. 6. Morland J, Setekleiv J, Haffner JF, Stromsaether CE, Danielsen A, Wethe GH. Combined effects of diazepam and ethanol on mental and psychomotor functions. Acta Pharmacol Toxicol 1974;34:5-15. 7. Palva ES, Linnoila M, Saario I, Mattila MJ. Acute and subacute effects of diazepam on psychomotor skills: interaction with alcohol. Acta Pharmacol Toxicol 1979;45:257-64. 8. Hannington-Kiff JG. Measurement of recovery from outpatient general anaesthesia with a simple ocular test. Br Med J 1970; 3:132-5. 9. McNair DM, Frankenthaler LM, Czerlinsky T, White TW, Sasson S, Fisher S. Simulated public speaking as a model of clinical anxiety. Psychopharmacology 1982;77:7-10.
LICHTOR ET AL.
10. Wilkinson L. SYSTAT: the system for statistics. Evanston, 111.: SYSTAT, Inc., 1986. 11. Larkin H. Less money, more players in outpatient market. Hospitals 1989;63:26. 12. Shannon K. Outpatient surgery up 77 percent: data. Hospitals 1985;59:54. 13. Korttila K. Postanesthetic cognitive and psychomotor impairment. Int Anesthesiol Clin 1986;24:59-74. 14. Saario I, Linnoila M. Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving. Acta Pharmacol Toxicol 1976;3838292. 15. Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology 1980;71:269-73. 16. De Wit H, Uhlenhuth EH, Hedeker D, McCracken SG, Johanson CE. Lack of preference for diazepam in anxious volunteers. Arch Gen Psychiatry 1986;43:53341. 17. Erwin CW, Linnoila M, Hartwell J, Erwin A, Guthrie S. Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials. J Clin Psychopharmacol 1986;6:199-209. 18. Fagan D, Tiplady B, Scott DB. Effects of ethanol on psychomotor performance. Br J Anaesth 1987;59:961-5. 19. McManus IC, Ankier SI, Norfolk J, Phillips M, Priest RG. Effects on psychological performance of the benzodiazepine, loprazolam, alone and with alcohol. Br J Clin Pharmacol 1983;16:291-300. 20. Palva ES, Linnoila M, Routledge P, Seppala T. Actions and interactions of diazepam and alcohol on psychomotor skills in young and middle-aged subjects. Acta Pharmacol Toxicol 1982;50:363-9. 21. Nuotto E, Mattila MJ, Seppala T, Konno K. Coffee and caffeine and alcohol effects on psychomotor function. Clin Pharmacol Ther 1982;31:68-76. 22. Greenblatt DJ, Locniskar A, Ochs HR, Lauven PM. Automated gas chromatography for studies of midazolam pharmacokinetics. Anesthesiology 1981;55:176-9. 23. Eberts FS Jr, Philopoulos Y, Reineke LM, vliek RW. Triazolam disposition. Clin Pharmacol Ther 1981;29:81-93. 24. Morris HH 111, Estes ML. Traveler's amnesia. Transient global amnesia secondary to triazolam. JAMA 1987;258:945-6. 25. Dubowski KM. Human pharmacokinetics of ethanol. I. Peak blood concentrations and elimination in male and female subjects. Alcohol Tech Rep 1976;5:55-63. 26. Sutker PB, Tabakoff B, Goist KC, Randall CL. Acute alcohol intoxication, mood states and alcohol metabolism in women and men. Pharmacol Biochem Behav 1983;18:349-54. 27. Niaura RS, Nathan PE, Frankenstein W, Shapiro AP, Brick J . Gender differences in acute psychomotor, cognitive, and pharmacokinetic response to alcohol. Addict Behav 1987;12:345-56. 28. Tabener PV. Sex differences in the effects of low doses of ethanol on human reaction time. Psychopharmacology 1980; 70:283-6. 29. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984;61:27-35. 30. Harper KW, Collier PS, Dundee JW, Elliott P, Halliday NJ, Lowry KG. Age and nature of operation influence the pharmacokinetics of midazolam. Br J Anaesth 1985;57:866-71.
