DIAZEPAM AND DROPERIDOL AS I.V. PREMEDICANTS

Br.J. Anaesth. (199), 51, 5 DIAZEPAM AND DROPERIDOL AS I.V. PREMEDICANTS G. P. HERR, J. T. CONNER, R. L. KATZ, F. DOREY, J. L'ARMAND AND D. SCHEHL SUMMARY The effects of i.v. diazepam and droperidol both alone and in combination administered as premedication were studied in 24 patients. Relief of anxiety, sedation, lack of recall, acceptance by both patient and physician and side-effects were evaluated. Overall, the combination of droperidol 2.5 mg with diazepam 5 mg produced better ratings of these variables than could be achieved with either droperidol mg or diazepam mg alone. Larger doses of droperidol with diazepam produce an increased frequency of anxiety; larger doses of diazepam with droperidol may cause over-sedation. In a previous study (Conner et al., 198) fentanyl and morphine were studied both alone and and in combination with droperidol. The results were largely unfavourable to droperidol because of poor acceptance by the patient. We have studied droperidol alone at a greater dose and in combination with diazepam, hoping to improve acceptance by the patient. Relief of anxiety, sedation, lack of recall, acceptance by both patient and physician and side-effects were evaluated. METHODS Two hundred and forty patients (ages 18-69 yr, mean 8. yr) in good health and undergoing a variety of operative procedures with the exception of cardiac surgery and neurosurgery were studied. None had received a sedative or narcotic on the day of study. One hour before surgery an i.v. infusion was started and the drugs were administered i.v. over a 1-min period. When in combination with droperidol, diazepam was given first. The drugs were administered in a double-blind manner using a randomized Latinsquare sequence: droperidol 5 mg and mg, diazepam 5 mg and mg, and the combinations diazepam 5 mg plus droperidol 2.5 mg, diazepam mg plus droperidol 2.5 mg, diazepam 5 mg plus droperidol 5 mg and diazepam mg plus droperidol 5 mg. Each group consisted of patients. All observations before operation were made by a trained nurse observer. Before premedication, the patient was asked to evaluate his level of anxiety as negligible, mild, moderate or severe. Four minutes GEORGE P. HERR, M.D.; JAMES T. CONNER, M.D.; RONALD L. KATZ, M.D.; FRED DOREY, PH.D.; JILL L'ARMAND, M.D.; DONNA SCHEHL, R.N.; Department of Anesthesiology, U.C.L.A. School of Medicine, Los Angeles, CA 924, U.S.A. -912/9/65-6 $1. after the injection of the drug his sedation as compared with the unpremedicated state was rated as (unchanged), 1, 2,, 4 (improved), or 1, 2,, 4 (worsened). The patient was asked to rate the level of anxiety in comparison with the unpremedicated state using a similar scale. The evaluation of sedation and the relief of anxiety was repeated at 8, 16 and 2 min. Any signs of drug sensitivity or side-effects were noted. The patients were shown a randomized series of "memory cards" (pictures of familiar objects or scenes) at 1, 2, 4, 8, 16 and 2 min to allow testing of recall. The anaesthetists rated the premedication without knowledge of the nature of medication. The overall effect was graded poor (), fair (1 ), good (2 ) or excellent ( ). They stated whether they would like their patients to receive the medication again. Comments on what they liked or disliked most about the effect of the drug were invited. Interviews at 24 h after operation were made by the nurse observer who was unaware of the identity of the premedicant. The patients were asked to rate the study drugs as poor (), fair (1), good (2 ) or excellent ( ) and if they would like to have the drug again. Each patient was asked to identify the "memory cards" from a composite picture of eight pictures. Evidence of recall for the administration of the drug, the operating room and the recovery room was sought. Statistical analysis of the evaluations by both patient and nurse were carried out by transforming the raw scores to ridits based on the corresponding diazepam scores at 4 min. Ridit scores for the degree of acceptance by the patient and physician were based also on the corresponding diazepam scores. Macmillan Journals Ltd 199

58 BRITISH JOURNAL OF ANAESTHESIA Overall differences between group means were tested with a Chi square statistic. Paired comparisons were tested by a Bonferroni procedure using an appropriate Z statistic. Significance was taken at the 5% level. This is a conservative statistical approach to the analysis of the data. RESULTS No statistically significant correlation could be demonstrated between the height, weight or age of the patient and the variables studied. Anxiety (table I and fig. 1 (Ridit score)) Diazepam mg produced significantly better relief of anxiety than diazepam 5 mg at all times. While droperidol mg provided slightly greater scores for relief of anxiety over droperidol 5 mg, the difference was not significant. At 4 min, diazepam was better than droperidol while at 2 min the response to droperidol was better than that to diazepam. In all patients, the addition of droperidol to diazepam produced a significant improvement over either droperidol or diazepam alone. No significant dose effect was demonstrated, thus the responses to diazepam 5 mg and diazepam mg in combination with droperidol at either the 2.5 mg or 5 mg dose were similar. Sedation (table I and fig. 2 (Ridit score)) The curves are statistically indistinguishable from those of the relief of anxiety as scored by the patient. TABLE I. Anxiety and sedation (mean scores). DZ = diazepam; DR = droperidol Diazepam 5 mg Diazepam mg Droperidol 5 mg Droperidol mg DZ 5mg DR 2.5 mg DZ mg DR 2.5 mg DZ 5mg DR 5. mg DZ mg DR 5. mg By patient (±4) 4 min 8 min 16 min 2 min 1.2.95.6.55 2.2 2.2 2.2 1.9.28.82 1.55 2.5 1.5 1.8 2.1 2.5 1.52 2.45.2.52 2.5.2.9 4. 1.58 2.95.6.81 2.4.5.8.95 By nurse observer ( 4) 4 min 8 min 16 min 2 min.5.2..19 1.68 1.2 1.48 1.4.1.22 1.1 1.4.O8 1.2 1.8 2.5 1.1 2.48.5.4 1.65.1.8 4. 1.6 2.6.45.9.2..89.95 1.-1 ANXIETY RELIEF ANXIETY RELIEF BZIDR5 a ^ IODR 5& _5DR5 DZ5DR2.5O RI H I/) H Q.8- -2- DZ5 4 8 16 2 4 8 16 2 FIG. 1. Mean change in anxiety scored by the patient compared with the patient's unpremedicated state v. time from injection. DZ = diazepam, DR = droperidol; dose in mg. The higher the score the greater the relief of anxiety.

DIAZEPAM AND DROPERIDOL 59 SEDATION SEDATION 1.- DRIO -.8-.2-4DZ5 8 16 2 8 16 FIG. 2. Mean change in sedation scored by the observer compared with the patient's unpremedicated state v. time from injection. DZ = diazepam, DR = droperidol; dose in mg. The higher the score the greater the sedation. TABLE II. Patient acceptance at 24 h. Percentage of patients scoring (poor), 1 (fair), 2 (good) or (excellent); mean and ridit scores; percentage of patients who would take drug again (repeat). DZ = diazepam; DR = droperidol DZ 5 mg DZ mg DZ 5 mg DZ mg Diazepam Diazepam Droperidol Droperidol 5 mg mg 5 mg mg DR 2.5 mg DR 2.5 mg DR 5. mg DR 5. mg 2 Poor Fair Good Excellent Mean score Ridit score Repeat (%) 2 4 1.1.62 5 2.1.6 1 28 1 1.21. 2 1.6.5 14 2 4 2.4.618 1 59 2.45.5 2 1.8.55 5 9 5 5 82 89 9 2 2.5.8 Acceptance by the patient 24 h after surgery {table II and fig. {Ridit score)) The acceptance of diazepam mg was significantly better than either diazepam 5 mg or droperidol 5 mg. Droperidol mg was significantly better than diazepam 5 mg. The combination of droperidol 2.5 mg and diazepam 5 mg was significantly better than diazepam 5 mg or droperidol 5 mg alone, but not significantly better than droperidol mg or diazepam mg. While greater doses of diazepam and droperidol in combination scored higher than droperidol 2.5 mg with diazepam 5 mg, the difference was not significant. Acceptance by the physician {table III and fig. (Ridit score)) No significant dose effect was demonstrated for either drug or combination. Droperidol in all doses both alone and in combination was scored significantly higher by physicians than diazepam at either 5 mg or mg. Failure to recall Recall data were expressed as per cent failing to recall the given memory card (maximum 1% at 1 min). Diazepam 5 mg had little effect on recall. There was a slight effect with droperidol 5 mg (maximum 24 26% at 16-2 min). Diazepam mg had a maximum effect of 5% at 1-2 min following injection and decreasing to 5% by 2 min. Droperidol mg alone had essentially no effect until 2 min, when it was similar to diazepam during the 1st min (52%). The combinations containing diazepam 5 mg had greater than 4% effect from 8 to 2 min. The combinations with diazepam mg had greater than 4% effect from 1 to 2 min from injection and

54 BRITISH JOURNAL OF ANAESTHESIA PATIENT ACCEPTANCE PHYSICIAN ACCEPTANCE l. n.8-.4-.2" 5mg DIAZEPAM lomg 1 \ 5 mg lomg DIAZEPAM FIG.. Mean patient acceptance as scored by the patient 24 h after surgery and the mean physician score v. the dose of diazepam (DZ) for diazepam alone and in combination with droperidol (DR). The acceptance by patient and physician for droperidol alone is marked. Dose in mg. The higher the score the greater the degree of acceptance. TABLE III. Physician's acceptance at surgery. Percentage of patients scoring (poor), 1 (/air), 2 (good) or (excellent); mean scores; percentage of physicians who would use the drug again (repeat). DZ = diazepam; DR droperidol DZ 5 mg DZ mg DZ 5 mg DZ mg Diazepam Diazepam Droperidol Droperidol 5 mg mg 5 mg mg DR 2.5 mg DR 2.5 mg DR 5. mg DR 5. mg Poor Fair Good Excellent 55 4 4 6 18 25 25 9 14 24 52 4 4 2 21 28 41 2 6 Mean scores.552 O.i 1.6 1.59 1.5 1. 1.41 1. Repeat (%) 44 48 54 5 8 59 66 TABLE IV. Side effects (%) before operation. DZ = diazepam; DR = droperidol DZ 5 mg DZ mg DZ 5 mg DZ mg Diazepam Diazepam Droperidol Droperidol 5 mg mg 5 mg mg DR 2.5 mg DR 2.5 mg DR 5 mg DR 5 mg None Dizziness Increased anxiety Crying Restlessness 2 4 61 4 21 14 6 2 1 6 2 5 6 2 appeared to plateau at 4 8 min. Maximums: diazepam 5 mg plus droperidol 5 mg %, diazepam mg and droperidol 2.5 mg 8%. None of the drugs produced much effect on lack of recall of the operating room. Lack of recall in the recovery period did not appear to be related to the premedication. Side-effects in more than % of patients {table IV) Diazepam caused dizziness initially in 2-4% of patients. This was a mild and self-limited problem. Droperidol alone produced an increase in anxiety in approximately 2% of patients and also an increased frequency of restlessness. The effects were noted to a lesser extent when diazepam was added to droperidol.

DIAZEPAM AND DROPERIDOL 541 The frequency of other side-effects for all drugs and combinations was small. DISCUSSION A decrease of anxiety during the period before operation is a desired function of premedication. It has been established in several studies that droperidol may actually cause an increase in anxiety in a certain number of patients when used alone (Morrison, 19; Morrison, Clarke and Dundee, 19; Ellis and Wilson, 192) or in combination with a narcotic (Conner et al., 198). Although it might seem that a drug which produces such an effect would not be used frequently by physicians, droperidol is a popular premedicant and has been found to rate highly with physicians (Stephen, 19). Our study helps to illuminate this paradox. The contrast between diazepam and droperidol when used alone is striking. A -mg dose of diazepam provides good relief of anxiety and sedation and would be taken again by 9% of patients. Droperidol, while providing better relief of anxiety and sedation scores at 2 min, would be taken again by only slightly more than half the patients. From the standpoint of the physician, the opposite result was obtained in that droperidol was chosen consistently over diazepam. A careful review of the data which included comments by both patients and physicians suggests an explanation. The majority of physicians who did not rate diazepam highly felt the patients were too alert. The mean time for the rating by the physician was 58 min following administration of the premedication. From the sedation curves it can be seen that the effect of diazepam is on the decline at 2 min, while that of droperidol is increasing or peaking. The most frequent reason given by patients for not wishing to receive droperidol again was that it increased their anxiety. This effect was noted in 2% of patients before operation. Some patients stated that they felt unable to express their anxiety while under the influence of the drug. A smaller number complained they had little or inadequate effect from the drug. Increased anxiety was noted most frequently shortly following injection of the droperidol. Often the sedation scores were high by 2 min. It appears likely that patients who were initially anxious may have been too sedated to complain at the time they were rated by the physician. The implication of this for clinical practice is clear: without follow-up on the day after surgery, the undesirable effects of medication may be missed. The frequency of increased anxiety before operation was the same for both doses of droperidol when used alone. The large -mg dose was chosen to exclude the possibility that this phenomenon was related to small concentrations of drugs. The overall frequency of increased anxiety was greater than these figures show because additional patients reported increased anxiety when interviewed after operation. The addition of diazepam to droperidol did decrease the frequency of the increase in anxiety. Increase in anxiety was reported by 1% who received the diazepam 5 mg-droperidol combinations. Five per cent reported this occurrence with the diazepam mg-droperidol combinations. Only one patient reported this in the group receiving diazepam mg plus droperidol 2.5 mg. While we did not study the effects of droperidol i.m., our results are similar to those of Ellis and Wilson (192) who studied the effect of droperidol 5 mg with atropine.4 mg i.m. and reported a 4% frequency of increased anxiety. Patients receiving the combinations did not appear aware of their surroundings in the preoperative area and the majority were sleeping. The degree to which they were able to be aroused to answer questions and look at the memory cards varied considerably. Four patients who received diazepam mg plus droperidol 5 mg were unrousable for varying periods. About half the group was thought to be difficult or impossible to arouse during the first min. While there were no changes in vital signs or untoward consequences, they were thought to be over-sedated. Only five patients receiving diazepam 5 mg and droperidol 2.5 mg were thought to be difficult to arouse and none was rated as over-sedated. We did not adjust doses to patient size and most instances of over-sedation occurred in small patients. This possibility could be avoided in clinical practice by adjusting the dose to patient size. There is little advantage in using more than the smallest (2.5-mg) dose of droperidol in adults of average size. Diazepam 5 mg in combination with droperidol 2.5 mg is adequate for many patients, with the greater, -mg, dose of diazepam being reserved for larger patients or those with inadequate response to the smaller dose. Droperidol is thought to work by blocking dopaminic pathways, an action not shared by diazepam which produces its sedative effects primarily by affecting the limbic system (Dundee and Wyant, 194). It is interesting that combining moderate doses of

542 BRITISH JOURNAL OF ANAESTHESIA either drug produces such potent effects. This suggests that other combinations of tranquillizers and sedatives with differing modes of action may lead to valuable interactions producing effects difficult to obtain with either drug alone. REFERENCES Conner, J. T., Herr, G. P., Katz, R. L., Dorey, F., Pagano, R. R., and Shehl, D. (198). Droperidol, fentanyl and morphine for i.v. surgical premedication. Br. J. Anaesth,, 5, 46. Dundee, J. W., and Wyant, G. (194). Intravenous Anaesthesia, Chapter. London: Churchill Livingstone. Ellis, F. R., and Wilson, J. (192). An assessment of droperidol as a premedicant. Br. J. Anaesth., 44, 1288. Morrison, J. D. (19). Studies of drugs given before anaesthesia. XXII: Phenoperidine and fentanyl, alone and in combination with droperidol. fir. J. Anaesth., 42, 19. Clarke, R. S. J., and Dundee, J. W. (19). Studies of drugs given before anaesthesia. XXI: Droperidol. Br. J. Anaesth., 42,. Stephen, C. R. (19). Premedication with droperidol. Can. Anaesth. Soc. J., 1, 4. LE DIAZEPAM ET LE DROPERIDOL EN TANT QUE PREMEDICATIONS INTRAVEINEUSES RESUME Les effets du diazepam et du droperidol administres par voie intraveineuse, seuls ou ensemble, en tant que pr medication ont ete Studies sur 24 malades. On a procede a une estimation du soulagement de Panxi6te, de la sedation, du manque de souvenir, de l'acceptation aussi bien par le malade que par le medecin, ainsi qu'a celle des effets secondaires. Dans l'ensemble, le melange de droperidol a raison de 2,5 mg et de diaz pam a raison de 5 mg a donne de meilleurs rapports de ces elements variables que ceux Ton a pu obtenir soit avec le droperidol seul a raison de mg, soit avec le diazepam seul aussi a raison de mg. De plus fortes doses de droperidol contenant du diazepam produisent une augmentation de la frequence de l'anxiete, alors que de plus fortes doses de diazepam contenant du droperidol peuvent provoquer un exces de sedation. DIAZEPAM UND DROPERIDOL ALS INTRAVENOSE VORBEHANDLUNGSMITTEL ZUSAMMENFASSUNG Die Wirkungen von intravenos verabreichtem Diazepam und Droperidol, sowohl allein als kombiniert, als Vorbehandlung, wurden bei 24 Patienten studiert. Beruhigung, Sedierung, Gedachtnisverlust, Akzeptierung durch Patienten und Arzte, sowie Nebenerscheinungen wurden untersucht. Allgemein ergab die Kombination von 2,5 mg Droperidol mit 5 mg Diazepam dabei bessere Ergebnisse als mit mg Droperidol allein oder mg Diazepam allein. Grossere Dosen von Droperidol mit Diazepam ergaben ein haufigeres Auftreten von Nervositat; grossere Dosen von Diazepam mit Droperidol konnten iibermassige Sedierung bewirken. DIAZEPAM Y DROPERIDOL COMO PREMEDICACION I.V. SUMARIO En 24 pacientes, se estudiaron los efectos del diazepam y del droperidol administrados i.v., ya sea cada uno por separado, ya sea en combinacion, como premedicacion. Se evaluaron el alivio de la ansiedad, la sedation, la falta de memoria, la aceptacion por ambos paciente y medico, asi como los efectos colaterales. En general, la combinacion de 2,5 mg de droperidol con 5 mg de diazepam arrojaba mejores calibraciones de dichas variables que las que pudieron obtenerse con cualquiera de los dos productos, ya sea con mg de droperidol solo, ya sea con mg de diazepam. Cuando se administraron mayores dosis de droperidol con diazepam, se registraron una mayor frecuencia de ansiedad; mayores dosis de diazepam con droperidol pueden ocasionar una sobre-sedaci6n.