Drug Impairment Reviews: Anesthetics and Foreign Tranquilizers

2015

STUDY: Doenicke, A., J. Kugler, M. Laub. Evaluation of Recovery “Street Fitness” by E.E.G. and Psychodiagnostic Tests After Anaesthesia. Can. Anaes. Soc. J., 14:567-583. 1967. (This study has been conducted in West Germany, but the address of the authors is not indicated in the reference.)

Subjects: The total number of subjects is not evident but it must be above 200. Eighty-one subjects completed the psychomotor test battery. Demographic data on the subjects and descriptions of their health or drug use prior to the study are not given. They are, however, described as healthy volunteers.

Method: This is an experimental study conducted in a clinical laboratory. The drugs administered as a single dose were thiobutabarbital (500 mg), methohexital (150 mg), and propanidid and C1-581 in doses which are not reported. Some subjects received repeated anesthesia but their number is not reported, nor is the order of or the interval between the anesthesias. Some subjects also received halothane, diethylether, or nitrous oxide after propanidid. Halothane was administered for 15 minutes. None of the concentrations of the inhalation anesthetics are reported in the text.

EEG was continuously recorded for 12 or 24 hours from the time of anesthesia. Several psychomotor tests, such as Track tracer, Chapuis’ labyrinth, down counting, simple and choice reaction time and accuracy, and mental concentration ability tests were administered to the subjects up to 8 hours after anesthesia. No description of the exact test times can be found in the text. From figure 8, one can conclude that the tests were probably given at 1, 2, and 4 hours after anesthesia. No statements concerning preexperimental training of the subjects are available. Certain cardiac and circulatory functions were continuously recorded during the experiment. Their exact nature, however, is not specified in the text.

Drugs: Some subjects received alcohol in addition to the above treatments. The dose was calculated to induce a blood alcohol concentration of 0.08 percent. Additional subject groups of unknown size received propanidid (7 mg/kg) or methohexital (2 mg/kg) in combination with alcohol. The exact time of the alcohol administration remains unclear, even though in the legend for figure 14 a statement can be found that alcohol was administered “one-half hour before beginning test.”

Dependent variables: Scores of the psychomotor tests and manually scored EEG’s were the dependent variables. However, it remains obscure to the reader how the results of the psychomotor tests were really scored. Even though there are statistically significant differences among the results of the psychomotor tests after different treatments, no statement is made how these were obtained. In 20 subjects, the blood barbiturate levels were measured as well. However, no correlations between the blood levels and performance effects of the drugs have been computed.

Results: The authors sum up their results by stating that drowsiness lasting for 12 hours was observed after barbiturates or ether anesthesia, but not after propanidid and halothane. This was confirmed by both psychodiagnostic tests and FEG. The authors suggest that after propanidid, street fitness should be regained within 2 hours. They stress the importance of the simultaneous measurement of psychodiagnostic and psychophysiological variables in the evaluation of street fitness after anesthesia.

Comment: This report concerns one of the first large-scale human experimental studies investigating the “hangover” effects after anesthesia. The writing is regrettably fussy and in many respects obscure, as indicated above. It is therefore, impossible for the reader to evaluate the conclusions of the authors based on the text per se. However, a comparison of these conclusions with more recent experiments reveals that they are valid. The necessity of recording EEG in measuring late sedation and its concomitants after anesthesia has not been confirmed in later experiments.

STUDY: Schuel, H., C. Shienle, G. Reinhardt. Vergleichende Untersuchungen Uber die Strassen Verkehrstauglichkeit Nach Kurznarkosen und Unter Alkoholeinfluss. Anaesthesist, 17:131-134, 1968.

Site: Department of Dental Surgery and Department of Forensic Medicine, University of Erlanger, Nurnberg, West Germany.

Subjects: The 78 subjects were dental patients aged between 17 and 58 years, and healthy except for their dental problems. They were divided into the experimental groups without selection; this is an obvious drawback, taking into account their wide age distribution. No statements are available concerning the sex distribution of the subjects.

Method: The present study can be classified as a controlled clinical experiment as to the administration of the drugs. However, no statements are made concerning the quality of the operations and their distribution among the experimental groups. If their pain-fulness varied among groups, as one is led to believe, uncontrol-ling this variable among groups could reduce the reliability of the results. The psychomotor tests included Mierke’s Determinationsgerat, Tachistoscope, Fallstab, as well as an attention test, a combined tapping-coordination test, and a projective personality test. The recorded variables included cumulative reaction times, accuracy of reactions in a choice reaction test, speed of comprehension, concentration ability, eye-hand coordination, and certain personality characteristics. BAL was measured according to the Widmark method. The tests were repeated 30, 45, 60, 90, 120, and 240 minutes after the anesthesia, and 30, 90, and 150 minutes after the ingestion of alcohol.

Dosage: Atropin (0.5 mg, intramuscularly) was used as a premedication 30 minutes before the anesthesia. Propanidid (500 mg), which was repeated in 10 patients, and thiobarbital (0.8 to 1.0 g) were the anesthetics investigated.

Dependent variables: The variables mentioned above were measured, but no statistical treatments were computed to correlate the drug effects with BAL or to compare the effects of the drugs with each other.

Results: After propanidid (500 mg), driving skills were regained in 60 minutes. The effect of thiobarbital lasted for a longer period of time; however, this period has not been defined. The effect of alcohol has been used as control for the late sedation after anesthesia.

Conclusions: The authors conclude that driving for 4 hours after propanidid should be prohibited. They recommend this period because of the lack of knowledge of other potentially harmful postoperative effects of propanidid.

Comment: The subject material has not been well controlled, and therefore the results are somewhat questionable. The followup period after anesthesia is much too short. That is why the authors are unable to demonstrate the period required to abstain from driving after thiobarbital. The results from the group ingesting alcohol are of little benefit. No comparisons of the sensitivities of the different tests in detecting the late sedation after anesthesia have been made. On the other hand, the results concerning the length of the late sedation after propanidid agree well with literature.

STUDY: Healy, T.E.J., H. Lautch, N. Hall, P.J. Tomlin, M.D. Vickers. Interdisciplinary Study of Diazepam Sedation for Outpatient Dentistry. Brit. Med. J., 3:13-17, 1970.

STUDY: Hannington-Kiff, J.G. Measurement of Recovery From Gut-patient General Anesthesia With a Simple Ocular Test. Brit. Med. J., 3:132-135, 1970.

Site: Department of Anaesthetics, Farnham Group of Hospitals, Farnham, Great Britain.

Subjects: Sixty-five of 80 dental patients who were able to cooperate in using the test apparatus participated in the study. The age of the subjects varied considerably, from 5 to 64 years. Care was taken to keep the female/male ratio constant between the experimental groups receiving different treatments. No other demographic data of the subjects are available. No statements concerning the general health of the patients were made.

Method: The study can be classified as a controlled clinical experiment. Methohexital, propanidid, and thiopental were given intravenously. Anesthesia was maintained by NO2 or halothane inhalation. Halothane (0.5 to 1.0%) was administered to subjects who needed a deeper anesthesia than that obtained with NO2. The operation times varied very little–between 3 to 11 minutes. The only test used was Maddox wing, which measures mainly the muscle tone of the medial rectal extraocular muscles. It is pointed out in the introduction that Maddox wing, when used as in the present experiment, is not very sensitive to the changes in accomodative power induced by general anesthesia.

Dosage: The patients received methohexital (1.2 mg/kg), propanidid 4.0 mg/kg), or thiopental (3.6 mg/kg). No premeditation was given. One group of patients received an entirely inhalational anesthetic which consisted of a 2:1 mixture of NO2 and oxygen with the addition of halothane (1-2%).

Results: In the measurements that were repeated every 5 minutes for a minute period, it became evident that a full recovery appeared in 50 percent of the patients 4.5 minutes after the cessation of the operation in the halothane group, 12.5 minutes after the operation in the methohexital group, and 16.3 minutes after the operation in the propanidid group. However, 30 minutes postoperatively extraocular imbalance was still present in 30 percent of patients after methohexital, 30 percent after propanidid, and 70 percent after thiopental.

Comment: The experimental method measures only one aspect of the drug-induced late impairment after anesthesia–muscle relaxation. Even though this method is a very sensitive indicator of the ability of drugs to induce muscle relaxation, it is inadequate in assessing late sedation after anesthesia. The time of ocular imbalance is much shorter than the time necessary for recovery when skills such as eye-hand coordination and choice reaction performance are measured. The large age variation of the subjects should have enabled the author to compute correlation between drug effects and age. However, this opportunity was not taken.

STUDY: Baird, E.S. and D.M. Hailey. Delayed Recovery From a Sedative: Correlation of the Plasma Levels of Diazepam With Clinical Effects After Oral and Intravenous Administration. Brit. J. Anaesth., 44:803-808. 1972.

Site: Royal Dental Hospital of London, London WC2, Great Britain.

Subjecfs Healthy male volunteers, aged between 30 to 23 years, participated in the experiments. In part one, 29 subjects were used; in part two, 5 subjects received a high dose of diazepam.

Method: The experiment can be classified as a controlled clinical experiment. Single doses of diazepam were used. Seven subjects received diazepam orally, and venous blood samples were taken at intervals of 0.25, 0.50, 1.0, 1.5, 2.0, and 2.5 hours after drug administration. Twenty-two subjects received diazepam intravenously. Venous blood samples were collected 3, 5, 10, 15, 30, and 60 minutes after drug administration. The subjects were followed clinically and they were asked to report their drowsiness to the investigators. In this part, the benzodiazepines were analyzed after hydrolysis. In the second part the volunteers received diazepam intravenously and venous blood samples were drawn for 48 hours. This time the glc-procedure for the analysis was a direct one without hydrolysis of the agents. Again the subjects were asked to report feeling drowsy during the experiment.

Dosage: In part one, the oral dose of diazepam was 10 mg, and the intravenous ones were 10 and 20 mg. In the second part, the intravenous dose of diazepam was again 20 mg.

Dependent variables: The investigators were interested in the plasma diazepam, and N-desmethyldiazepam concentrations as a function of time after drug administration. They assessed the relationship between the feeling of drowsiness, the plasma levels of diazepam, and N-desmethyldiazepam as well.

Results: A late increase in the plasma diazepam concentration was observed. In four out of five subjects, the plasma diazepam concentration increased about 6 hours after the drug administration. Plasma N-desmethyldiazepam levels increased throughout the experiment. The subjects showing an increased plasma diazepam concentration at 6 hours reported an increased feeling of drowsiness as well.

Conclusions: The authors discuss the role of a possible enterohepatic cycle of diazepam in the late drowsiness and elevation of plasma diazepam concentrations after intravenously diazepam.

Comment: No objective measurements were used to quantitate possible impairments of performance concomitant to the subjective feeling of drowsiness. Therefore, no conclusions concerning the importance of this finding to driving and controlling machinery can be made. Since this study, it has become evident that no significant enterohepatic cycling of diazepam occurs in man.

STUDY: Dixon, R.A. and J.A. Thornton. Tests of Recovery From Anaesthesia and Sedation: Intravenous Diazepam in Dentistry. Brit. J. Anaesth., 45:207-215. 1973.

STUDY: Trieger, N., W.J. Loskota, A. W. Jacobs, M.G. Newman. Nitrous Oxide – A Study of Physiological and Psychomotor Effects. J. A. D. A., 82: 142-150. 1971.

Site: Division of Oral Surgery, School of Dentistry, University of California at Los Angeles.

Subjects: Twenty white male UCLA dental students volunteered for the study. No other data concerning the subjects are available.

Method: This experiment is a controlled clinical study. The subjects received three different combinations of NO2 and oxygen in a fixed order with the highest NO2 concentration in the middle. An interim period of 7 days was allowed between each administration. Psychomotor tests were performed according to the following schedule: a test after 1 minute of 100% 02, a test after 1 minute of NO2 and O2 at the prescribed concentration, two tests at 2-minute intervals immediately thereafter, a test 30 seconds after the anesthetic had been discontinued and while the subject breathed 100% 02, and two tests at 2-minute intervals immediately thereafter, with the subjects breathing only room air.

The psychomotor test was a modification of a drawing test from the Bender Motor Gestalt Test. It consists of a series of dots spaced approximately 1 mm apart in a geometric figure that, when drawn, measures psychomotor function and coordination.

Several physiological parameters and possible alterations in the pain threshold were also measured during the experimental sessions as well. However, their relevance to the present problem is minor.

Dosage: Doses of 25, 50, and 75% NO2 in combination with 02 were given. The anesthetic was administered for 6 minutes, with an administration of 100% 02 immediately preceding and following the anesthetic.

Dependent variables: The number of dots missed and the deviations of the pencil line from a straight one were counted and added to give a single score.

Results: At the highest dose of NO2, many students were unresponsive to verbal commands. In each instance, however, a complete psychomotor recovery was achieved within 5 minutes, as measured by the above-mentioned test. With the lower concentrations of NO2, a complete recovery became evident within 3 minutes.

Conclusions: The authors note that local anesthesia in addition to NO2 has to be used for dental procedures.

Comment: The conclusions of the authors concerning psychomotor recovery after NO2 intake are based on results obtained in healthy young volunteers. In addition, only one test of eye-hand coordination was used. One must therefore be more careful in generalizing the results than the authors are, particularly, since later studies have shown that NO2 may indeed have longer after effects on psychomotor skills than those mentioned above.

STUDY: Tetsch, P., E. Esser, A. Stumborg. Verkehrsmedizinische Probleme bei Operativen Eingriffen in Lokalanaesthesie Unter B-Receptorenblockade. Anaesthesist, 22:251-254. 1973.

Site: Abteilung fur fur Mund- und Keiferchirurgie, der Westf. Wilhelms-Dniversitgt, Miinster, West Germany.

Subjects: One hundred and fifty-nine dental patients were divided unevenly in five experimental groups. No other data concerning the patients are available.

Method: This study can be classified as a partially controlled clinical experiment. The test apparatus was a choice reaction machine delivering alternatively three different visual stimuli (lights with different colors), and a sound. The subjects had to respond to the stimuli by pressing a lever, one for each type of stimulus, as soon as possible after the stimulus appeared. The total number of stimuli in every experiment was 30. Only reaction times were recorded. The subjects were trained on the apparatuses in order to reach a stable pretest performance. Whether the allocation was random does not appear in the text. The first group received a local anesthetic, the second group received a local anesthetic and a beta-receptor blocking drug (Betadrenol R), the third group received the beta-receptor blocking agent 20 minutes before the local anesthetic, the fourth group received 10 mg of diazepam orally as premedication, and the fifth group received.5 mg atropin intramuscularly 30 minutes before the operation. The choice reaction test was completed twice, 10 and 30 minutes after the operation.

Dosage: The average dose of the local anesthetic was 3 ml of 0.05% solution and that of the beta-receptor blocking drug was 1.5 mg.

Dependent variables: The dependent variable was the average reaction time in the choice reaction test. The students’ t-test was used for the statistical treatment of the data.

Results: The average choice reaction times were shorter in all groups receiving premeditation. In all groups, the test completed immediately before the medications for the operation demonstrated prolonged reaction times. This was interpreted to be due to the stress caused by awareness’of the operation.

Conclusions: The authors discuss the euphoria-inducing effect of diazepam, and stress this as an extra risk factor in traffic. However, no such effect was demonstrated in the experiment.

Comment: There is a considerable variation in the average choice reaction times between the groups; this leads one to believe that there were considerable differences among the groups of subjects. Since a shortening of choice reaction times was demonstrated after diazepam as a clear central effect of the drug, and because it is known that such effects are often accompanied by impairments (e.g., in coordination), one should be more cautious drawing conclusions than were the authors. The conclusions should not be based on results of a single psychomotor test. The lack of data concerning the number of mistakes in the choice reaction test is suspicious.

STUDY: Korttila, K. Outpatient Anaesthesia in Finland: Drugs Used and Postoperative Care of Patients. Ann. Chir. Gyn. Fenn., 64. 1975.

Site: Department of Anaesthesia, University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki 29, Finland.

Method: In this study, the author mailed a questionnaire concerning the drugs used in outpatient anesthesia to the physicians responsible for their administration in 126 medical facilities in Finland. Eighty-one of them responded. The time of hospital stay and the time the patients were advised not to drive after anesthesia were reported as well.

Results: Drugs most commonly used were diazepam, propanidid, thiopental, N02, diazepam plus meperidine, halothane, divinyl ether, diethyl ether, methohexital, and droperidol, in that order. The intravenous dose ranges for propanidid, thiopental, diazepam, and methohexitone were 200-1,500, 125-1,000, 3-35, and 75-200 mg, respectively. The ranges of the time the subjects were not allowed to drive after the same drugs were 2-27, 10-24, 6-24, and 6-36 hours, respectively.

Conclusions: The author concludes that the highest doses of the intravenous agents propanidid and thiopental, in particular, are dangerous. According to him, droperidol should not be used at all due to the very later recovery it causes and the common extrapyramidal symptoms after it. The rapidity of recovery after propan-idid or halothane with NO2 has not been generally appreciated.

Comment: There are no attempts in the article to compare the length of the recommended recovery periods with the doses of anaesthetics used in different hospitals. It is not apparent whether high doses were associated with prolonged times of recommended avoidance of driving and vice versa.

STUDIES: 1. Korttila, K. Psychomotor Skills Related to Driving After IntraMuscular Lidocaine. Acta Anaesth. Stand., 18:290-206. 1974. Driving After IntraMuscular Lidocaine, Bupivacaine and Etidocaine

2. Korttila, K., S. Hakkinen, M. Linnoila. Side Effects and Skills Related to Driving After Intramuscular Administration of Bupivacaine and Etidocaine. Acta Anaesth. Stand., 19:384-391. 1975. Driving After IntraMuscular Lidocaine, Bupivacaine and Etidocaine

Comment: Anesthetics and Foreign Tranquilizers: Anesthetics

Comment:  Anesthetics and Foreign Tranquilizers: Tranquilizers

 

Selections from the book: “Drugs and Driving”. Robert Willette, Ph.D., editor. State-of-the art review of current research on the effects of different drugs on performance impairment, particularly on driving. National Institute on Drug Abuse Research Monograph 11. March 1977.