Intravenous midazolam in oral surgery

Int. J. Oral Maxillofac. Surg. 1987: 16:325-332 (Key words:

midazolam, intravenous;preraedication; sedation; diazepam; surgery, oral and maxillofacial)

Intravenous midazolam in oral surgery P. VAN DER BIJL, J. A. ROELOFSE, J. J. DE V. JOUBERT AND H. S. BREYTENBACH Departments of Oral Medicine and Periodontics, Anaesthetics and Maxillo-Facial and Oral Surgery, University of Stellenbosch, South Africa.

ABSTRACT- - Intravenously administered midazolam (0.1 mg/kg) was compared with placebo in a randomized study in 50 patients undergoing oral surgical procedures under local anaesthesia. The results obtained from this study showed that midazolam when compared to placebo had slight cardiovascular and respiratory depressant effects, diminished anxiety and caused amnesia. It also provided better operating conditions and possibly stimulated appetite. (Accepted for publication 2 August 1986)

Although regional anaesthesia has many advantages, its use may be limited by the unwillingness of patients to remain awake during surgery. This may be overcome by the induction of light general anaesthesia or by the administration of sedative drugs. Few would fail to agree that the emotional stress situation resulting from profound fear or anxiety in a dental patient is one in which the practitioner and his staff inevitably become involved and invariably results in working under strain. Anxiety towards dental procedures varies from a suppressed fear of pain to a phobia which may make treatment impossible. Not only do many patients find these procedures unpleasant but they may also exhibit peripheral manifestations of excessive sympathetic activity such as xerostomia, tachycardia, sweating and tremors which in some instances may lead to anxiety-induced arrhythmias and vasovagal reactions. Since it

is unreasonable to treat all these patients under general anaesthesia, a variety of different classes and combinations of drugs have been clinically evaluated to diminish anxiety-induced stress during dental procedures. Of the drugs used for this purpose, much attention has been focused on the benzodiazepines, particularly on intravenously-administered diazepam 4,9,t°,13,17. The latter drug when injected into veins, however, may cause pain and thrombosis; furthermore its long plasma half-life (20-30 h) and that of its even longer-acting metabolites (30-100 h) result in unnecessarily prolonged recovery times. The recent availability of midazolam, a water-soluble imidazobenzodiazepine with a short plasma elimination half-life (1.5-2.5 h) and no clinically significant active metabolites, has opened new and exciting avenues for intravenous drug sedation in dentistry 11. In a previous study on apprehensive adult

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BIJL, ROELOFSE, J O U B E R T A N D BREYTENBACH

patients w h o r e q u i r e d dental t r e a t m e n t , the effect o f i n t r a v e n o u s m i d a z o l a m was c o m p a r e d to t h a t o f similarly a d m i n i s t e r e d dia z e p a m TM. P a r a m e t e r s such as heart rate, b l o o d pressure, respiration rate, degree o f sedation, o p e r a t i n g conditions, r e c o v e r y time and p a t i e n t s ' o p i n i o n s o f drugs used were all e v a l u a t e d d u r i n g this study. In the p r e s e n t study, all these p a r a m e t e r s were e x a m i n e d , but in a d d i t i o n , the ade q u a c y o f o x y g e n s a t u r a t i o n in p e r i p h e r a l tissues after i n t r a v e n o u s m i d a z o l a m was assessed.

Material and methods Patients 50 ASA - I adult patients of both sexes, between the ages 18-50 years requiring surgical removal of impacted wisdom teeth participated in this study. The study was approved by the local ethical committee and written informed consent was obtained from all patients prior to their inclusion in the study. None of the patients refused to participate in the study after the informed consent. Patients were asked not to have breakfast on the morning of the procedure. Treatment was carried out with patients sitting in a reclining dental chair. On arrival in the operating room, a previously calibrated Dinamap ~ adult/paediatric vital signs monitor (Critikon Inc., Tampa, Florida, USA), a Ohmeda Biox ~ III pulse oximeter (Bioximetry Technology Inc., Boulder, Colorado, USA) and a Simonsen & Weel ECG monitor with a memory twinscope facility (Denmark) were connected to each patient. A no. 23 butterfly needle was inserted in a vein on the dorsum of the hand and connected via an infusion set to a bag containing 200 ml of dextrose B.P. 5% (m/v) solution. The dextrose solution was administered at a slow constant rate throughout the dental procedure. Drugs The patients were allocated at random to 2 groups, each consisting of 25 patients. 1 group received midazolam (0.1 mg/kg) and the other group placebo, injected over a period of 2 rain via the infusion set. To keep the trial blind to the surgeon as well as the patients, a nurse prepared the syringes "A" and "B" containing 10 mg/10

ml of midazolam or 10 ml of saline, respectively. Verbal contact was maintained with patients throughout the procedure.

Assessments Systolic, diastolic and mean arterial pressure (MAP) readouts from the Dinamap ® as well as pulse and respiratory rates and oxygen saturation were all recorded pre-operatively, 10 min after midazolam or placebo administration, immediately after the local anaesthetic injection, 15, 30 and 45 min, after arrival in the recovery room and at discharge. Citanest ® 3% with octapressin was used in all cases for local anaesthesia. The pegboard test 6.z2was used as a measure of recovery following midazolam or placebo administration. This test is widely recognised as being suitable for a study of this nature. The patient is required to move pegs from one side of a board to the other after familiarisation with the method, and the time is taken in which he can do this. 2 control times (s) were obtained prior to drug or placebo injection and thereafter at 10 min after administration, at arrival in the recovery room as well as after 60 and 90 min in the recovery room, at discharge and ! week after the procedure. Anxiety levels of patients were noted by an independent observer according to the scale 0-3 which corresponded to zero, slight, moderate and severe anxiety prior to and 10 rain after drug or placebo administration, as well as immediately after the local anaesthetic injection and on arrival in the recovery room. Alertness of patients was recorded according to an arousability scale ranging from 1-5 which corresponded to the patient being alert and active, 1; resting quietly and being aware of surroundings, 2; sleeping but easily aroused, 3; sleeping but difficult to arouse, 4; sleeping and no reaction to shaking, 5. Post-operative pain was assessed in patients using a visual analoque pain scale according to which patients were asked to describe their level of pain. Assessments were made pre-operatively (control), on arrival in and at 60, 90 and 120 min after arrival in the recovery room. Operating conditions were assessed by the dental surgeon at the end of the procedure. These were designated as excellent, good fair and poor according to the degree of patient cooperation, access to the oral cavity and tongue movement. After injection of midazolam or placebo, sideeffects such as nausea, vomiting, slurred speech, headache, giddiness/dizziness, diplopia, restlessness, confusion, excessive salivation, coughing,

INTRAVENOUS MIDAZOLAM hiccups, hysteria, euphoria, crying, pain at site of injection/elsewhere, hypotension, sweating, bradycardia, hypoxia and ptosis were all noted by means of a checklist. Patients' amnesia was tested in the recovery room by means of a checklist asking if they remembered getting onto dental chair, receiving injections, whether these were painful, receiving local anaesthetic, any driUing, teeth removal, suturing, the monitor's sound, going to the operating room and whether they would have the same drug again or rather prefer a general anaesthetic. At discharge, i.e., 2 h after arriving in the recovery room and after 1 week post-operatively, patients were again asked the above questions. Patients were also given a questionnare on discharge which they were asked to complete at home. Questions included were, e.g., whether the patient remembered going home, felt like vomiting at any stage, was sleepy, lost appetite, had a headache, felt giddy/dizzy, had pains or other problems, would have the same operation again and whether they had followed their normal occupation the next day.

Statistical methods Considering the number of patients involved in this study, univariate rather than multivariate techniques were employed. Since many tests were performed on the same set of data, adaptions to the test level according to Bonferroni19 would have been desirable, but this was not possible due to the many variables involved. In all instances, p-values below 0.05 were considered as statistical significance. Continuous variables were compared by means of the/-test I while for categorised variables, the ;(:-test was usedz. If the expected number in any cell was below 1, the rows were combined for statistical test purposes. When the table became a 2 × 2 table, Fisher's exact test 7was calculated instead of the z2-test.

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Results Details of patients used in this study and the length of procedures performed are given in Table 1, which shows that both groups of patients receiving either midazolam or placebo were similar with respect to age and weight and that the procedures carried out were of comparable duration. Systolic and diastolic blood pressures fell by approximately 11 and 5 m m of Hg, respectively, in the midazolam group 10 rain after administering the drug, significantly lower than the placebo group. This remained so for the systolic pressure until arrival in the recovery room, after which the differences between the 2 groups were no longer significant. Fairly sharp rises in both systolic and diastolic pressures were observed in both the midazolam and placebo groups following injection of the local anaesthetic, after which pressures started levelling off to preinjection values. Fig. 1 shows the differences in average M A P obtained for patients receiving midazolam and placebo. The gen-

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Table 1. Details of adult patients and length of procedure for midazolam and placebo Midazolam Placebo n mean SD n mean age (years) 25 23.84 4.97 25 23.96 weight (kg) 25 69.76 11.32 25 67.04 length of procedure (min) 25 38.08 7.36 25 36.56

SD 9.55 13.87 6.12

328

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eral trend of these curves is representative of that of the systolic and diastolic pressures. Both curves rise sharply following the injection of local anaesthetic with the midazolam curve remaining significantly lower than that of placebo between 10 and 30 min after administering the drug. No significant differences were observed, however, in pulse and respiratory rates between the midazolam and placebo groups. Oxygen saturation values were determined pre-operatively, 10 rain post-drug, after the local anaesthetic injections and every 15 min during the procedure as shown in Fig. 2. At 10 min post-drug, the average % oxygen saturation was significantly lower in the midazolam group when compared with that of the placebo group. This difference, however, disappeared at the next stage. Patient recovery as measured by the pegboard test showed a highly significant difference (p<0.05) between the 2 groups at l0 rain post-injection, the mean times for completion of the test being 66 and 28 s for the midazolam and placebo groups, respectively. Relative %s of cases per category of anxiousness for midazolam and placebo groups at various times are shown in Fig. 3. At the pre-injection stage, approximately half the patients had moderate and half had severe anxiety levels in both the midazolam and placebo groups. This changed rapidly after injection of midazolam, when all pa-

iousness for midazolam and placebo groups at various times.

tients were only slightly anxious (score l) at 10 min post-drug and post-block and only 5% were moderately anxious (score 2) on arrival in the recovery room. For the placebo group of patients, anxiety levels remained more-or-less as at the pre-injection stage throughout the procedure until arrival in the recovery room. Here, only 4% had severe, and approximately half of the remaining moderate and the other half slight levels of anxiety. At all stages following drug-injection, the midazolam group had significantly lower anxiety levels than the placebo group. Fig. 4 shows the relative %s of cases per category of arousability for midazolam and placebo groups. After administration of mi-

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INTRAVENOUS MIDAZOLAM dazolam, more than half of the patients in this group slept, while less than 10% of patients were difficult to rouse in the preand post-block stages. In the recovery room, however, about 2/3 of this group were resting, while the remainder were alert. Most of those who had received placebo were either alert or resting during the procedure, while about 4% slept in the recovery room. At discharge, 80% of patients in the midazolam group were alert, the remainder resting, while all patients in the placebo group were alert. For all 3 pre-discharge stages, the patients in the midazolam group were significantly less anxious than those in the placebo group. Fig. 5 shows the %s of cases per category of operating conditions f o r the midazolam and placebo groups. These were significantly better for the midazolam than for the placebo group with operating conditions having being rated as excellent in more than 80% of cases and none as poor in the former groups. As far as the placebo group was concerned, only 45% of cases were rated as good while the remainder was equally divided in 2 groups and rated as excellent and poor, respectively. Of all the side-effects noted during and after the procedure, only those of slurred speech, sweating and ptosis were significantly different between the midazolam and placebo

329

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Fig. 6. %s of cases per side-effect for midazolam and placebo.

groups as shown in Fig. 6. Of all the patients in the midazolam group, 2/3 had slurring of speech and/or ptosis while only 1/5 sweated. In the placebo group, however, 84% of patients sweated while no ptosis or slurring of speech was noted. %s of cases recollecting peri-operative events immediately and 1 week after the procedure for midazolam and placebo are shown in Fig. 7. Significant differences in recollective ability between midazolam and placebo groups were found on both occasions for aspects such as the injection in the mouth, the removal of teeth, the sound of the monitor and the question on whether the same drug would be taken again. In addition, there was a significant difference

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events immediately and 1 week after procedure for midazolam and placebo.

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BIJL, ROELOFSE, JOUBERT AND BREYTENBACH

after 1 week between the midazolam and placebo groups when it came to recollecting the placement of sutures in the mouth. The midazolam group of patients in general had more difficulty in recollecting peri-operative events than the placebo group both immediately and 1 week after procedures. All patients in this group would have taken the same drug again when asked immediately and 1 week after the procedure, while at both occasions, 84% of the placebo group wanted the "drug" again. No significant differences between midazolam and placebo groups were observed at any stage with regard to post-operative pain.

Discussion While new sedatives should ideally be evaluated against other drugs used for the same purpose, this may sometimes create certain difficulties. In the present study, placebo rather than diazepam was chosen as a control, since the latter drug is dissolved in an organic vehicle which often causes pain on injection and venous thrombosis, has a distinct yellow colour and is poorly miscible with many aqueous infusion fluids. Diazepam furthermore has active metabolites with long plasma half lives which may cause prolonged sedation. This, however, had to be weighed up against the sometimes observable effects of midazolam, e.g., slurred speech, sweating and ptosis when compared to placebo. In both cases, unfortunately, whether diazepam or placebo is used as a control, problems may arise in keeping the study perfectly blind. From the results obtained in the above (Fig. 1) and other studies ",18, there seems little doubt as to the cardiovascular depressant action of intravenous midazolam in doses of 0.1 mg/kg when compared to placebo. At these low dosages, this effect is probably due to a reduction of emotionally-induced

changes of the cardiovascular system via hypothalamic and limbic sites, but it has been suggested that benzodiazepines may interfere directly with medullary cardiovascular control areas ~6. It is interesting to note that although systolic, diastolic and average MAP (Fig. l) rise sharply after injection of the local anaesthetic in both midazolam and placebo groups, that of the former group is somewhat more attenuated than that of the latter group. Midazolammediated blunting of the sympathetic response to pain could plausibly explain this observation. However, in contrast to the results obtained in a previous study TM, no increases in pulse rate worth mentioning were found in either the midazolam or placebo groups of patients during the surgical procedure. This may be associated with parasympathetic dominance, despite greatly enhanced sympathetic activity in the face of severe emotional stress, a phenomenon which has been shown to occur2°. It is clear from the results obtained in this study that intravenous midazolam, which has a similar depressant effect on respiration to that of diazepam 14, lowers the oxygen saturation levels, 10 min after administration, to a level significantly lower than that of the placebo group (Fig. 2). This oxygen saturation lowering effect is, however, of short duration, having disappeared after injection of the local anaesthetic about l0 min later. Both midazolam and diazepam probably exercise a direct depressant effect on the respiratory centre. The effects are, however, transient, but can be intensified by the simultaneous administration of opiatelike analgesics. No significant differences in recovery times, as determined by the pegboard test, were found between the midazolain and placebo groups except at l0 min post-injection when the difference was significant (p<0.05). This corresponds well with the so-called rapid transitory "buzz" or "high" phase 15which occurs when benzo-

INTRAVENOUS MIDAZOLAM diazepines, especially the lipid-soluble ones are injected intravenously and achieve high concentrations in the central nervous system causing maximum sedation. Anxiety levels of the midazolam group of patients were significantly less than for the corresponding placebo group (Fig. 3). This is commensurate with the pharmacological properties of the benzodiazepine group as a whole ~6. As was expected, patients receiving placebo were significantly more arousable during the surgical procedure than those receiving midazolam, except at discharge (Fig. 4). Interesting to note is, however, the observation that between 4% and 8% of patients who had received midazolam were difficult to rouse in the pre- and post-block phases of the procedure. Since these numbers would certainly increase if higher dosages of midazolam were used, administration of 0.1 mg/kg is probably very close to the ideal bolus dose if we are to remain within the limits of intravenous sedation. It is also interesting to note that it was possible to communicate verbally with the patient when using this dose of midazolam. Fig. 5 shows the operating conditions as assessed by the surgeon and these were significantly better for the midazolam as opposed to the placebo group. Slurred speech and ptosis were the most commonly observed side-effects with the midazolam group. In the placebo group, a high incidence of sweating was observed. This is a well-known peripheral manifestation of increased sympathetic activity due to anxiety. Mainly for this reason, sweating is probably not so pronounced in the patients who experienced the anxiolytic effects of midazolam, although certain side-effects of the benzodiazepines such as aggravation of narrowangle glaucoma and xerostomia are reminiscent of anticholinergic mechanisms of action, which may also have played a role 8,n. Amnesia as tested by questioning patients on peri-operative events immediately and 1

331

week after the procedure showed a decreased ability to recollect these events among the group of patients who had received midazolam when compared to the placebo group (Fig. 7). The former group of patients were also prepared to have the drug again should the occasion arise, while this was somewhat less so with the placebo group of patients. Clinically speaking, however, these differences may be considered to be irrelevant. Of further interest is the fact that according to the patient's post-operative questionnaire, half of the placebo-group of patients lost their appetite, while the same held true only for 12% of the midazolam group. This is an interesting observation since benzodiazepines have been shown to affect appetites of a wide variety of laboratory animals and humans3.5.2~. The ideal sedative drug, suitable for use during local anaesthesia, should produce reliable sedation with maintenance of the airway. There should be minimal effects on circulation and respiration and recovery should be rapid with no residual drowsiness. On the basis of this study, one can foresee midazolam coming into wider use as an injectable drug for sedation not only in dental surgical procedures but also as a sedative-hypnotic during regional anaesthesia.

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