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Table 4. Postoperative erect of premedication. Pain and sedation after I hour, and time to administration of analgesia

Group MST20mg Placebo

n
25 25

Pain intensity. median (ranee) .

86 (3&100) 94.5 (50-100)

I .

Sedation scoret mean (SEM) . . I .26 (0.19)

1.77

Time to analgesic.. hours median (ranee) . -.

1.25 (0.2-1 8) I

(0.22)

(0.3-1 2)

*p <0.05; Mann-Whitney U test. tp < 0.05; Medians test. Yates correction.

Medians test, Yates correction), and had a lower pain score than the group who had received placebo (Mann Whitney U test, p i0.05). Arterial blood pressure did not change significantly throughout the period of study in either of the groups. While the pulse rate was higher postoperatively than pre-operatively in both groups, there was no significant difference in the rise between the groups. No patient suffered from nausea or vomiting during the observation period. and there were no complaints of any other side-effects.
Discussion

The oral route of medication is convenient and pleasant and particularly suitable for the treatment of preoperative apprehension. Sustained-release morphine tablets have been shown to be slowly but well absorbed, and to maintain clinically effective blood levels for many hours.* Thus administration of this medication 2 hours before operation might be expected not only to have an effect on pre-operative anxiety, but also to supplement the analgesic and hypnotic components of anaesthesia, and therefore contribute to a reduction in postoperative pain. It is suggested by the results presented here that a clinical effect of sustained release morphine occurred before induction of anaesthesia, the patients in this group being significantly more sedated than the group who received placebo. However sedation in itself may not contribute to the reduction in anxiety required by

the anaesthetist. Although anxiety did appear to be reduced by the morphine treatment, in contrast to the increased anxiety of the patients who received the placebo, the effect was not statistically significant. A dose of MST 30 mg given 2 hours before operation must therefore be judged inadequate as premedication. Similarly, the sustained release morphine premedication provided an ineffective supplement to anaesthesia, although it produced a significant. if clinically small, decrease in postoperative pain. No other effects of the medication were observed. Nausea and vomiting did not occur and there were negligibleeffects on the cardiovascular system and on recovery from anaesthesia. It is suggested, therefore, that the 30-mg dose of sustained releasemorphine used in this study did not relieve pre-operative anxiety nor did it appear to influence the management of anaesthesia, in spite of contributing to a small reduction in postoperative pain. The clinical impressions gained during this study might have achieved a significance if a 60-mg dose of sustained release morphine had been used though the incidence of side effects may also increase.
References
I. FELL CHMIELEWSKI D. A, SMITH Postoperative analgesia G. with controlled-release morphine sulphate: comparison with intramuscular morphine. British Medical Journal 1982; 285: 924. 2. LESLIE RHODES BLACK ST, A. FM. Controlled release morphine sulphate tablets-a study in normal volunteers. Brirish f Journal o Clinicul Pharmacologv 1980; 9 5314.

Anaeshsia, 1984, Volume 39, pages 589-593

A comparison of midazolam and diazepam for intravenous sedation in dentistry

C. Aun, MB, BS, FFARCS, Lecturer, P.J. Flynn, MB, DCH, DObst, FFARCSI, Senior Lecturer, Anaesthetics Unit, London Hospital Medical College, J. Richards, BDS, DRD, LRDCS, Lecturer in Conservation Dentistry, Dental Institute, Whitechapel, London El 1BB, E. Major, MB, BS, FFARCS, Consultant Anaesthetist, Anaesthetics Department, Morriston Hospital, Swansea.

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Summary

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In a randomised cross-over trial. midazolam. a new water soluble benzodiazepine was compared with the conventional diazepam preparation ( Valium) in 34 patients aged 16-45 years who were undergoing outpatient conservation dentistry. Midazolam hydrochloride (0.17mglkg)was virtuallyfree of venous complications andshowedadvantages over diazepam (0.32 mglkg) in providing a faster onset of action, higher incidence o amnesia and more rapid recovery. Midazolam f produced a higher incidence of respiratory side effects: hiccough ( I 7.6% compared with 2.9%). brief apnoea following 8 8 /compared with PA). These induction (II.sO/, compared with 5.873, and airway obstruction during maintenance ( . 0 , may be related to the greater potency of midazolam as suggested by the smaller total dose required. Cardiovascular changes and operating conditions were similar.
Key words
Benzodiazepines; midazolam, diazepam. Dentistry; intravenous sedation.

Since its introduction in 1962, diazepam (Valium, Roche) has been widely used for intravenous sedation in anxious patients undergoing conservative dental procedures. Its advantages include a wider margin of safety compared with other intravenous agents, and marked anterograde amnesia. However, it is associated with slow recovery'** and a high incidence of venous seq~elae.~Midazolam hydrochloride is a new water soluble benzodiazepine with a short elimination halflife of I .3-2.2 hours6 which has been shown to produce anterograde amnesia' and a very low incidence of venous c o m p l i c a t i ~ n s .This double-blind, third~~~ party open, within-patient, crossover study was conducted to compare the use of midazolam and diazepam in outpatient conservation dentistry.

Method

Patients were included in the study if, following dental assessment, they seemed unable to accept conventional dental treatment under local analgesia because of fear or anxiety. Many of them were referrals from other clinics. Patients who were pregnant or with a history of cardiorespiratory, neurological, hepatic, renal or psychiatric disease were excluded. Patients requiring dental extraction or procedures likely to cause bleeding were not included. The study was approved by the local Ethics Committee. Written consent to participate in the investigation was obtained from all patients selected. Patients were prepared as for outpatient dental general anaesthesia. They were instructed to have nothing to eat or drink for at least 6 hours and to arrange to be accompanied home after treatment. No premedication was given. All patients received both midazolam and diazepam, but on separate visits at least 1week apart. The standard preparation of diazepam in organic solvent (Valium) was used since the emulsion (Diazemuls) was not commercially available at the beginning of the study. A different a m was used for each drug. The order of drug administration was randomised. The patient was placed in the supine position. The initial dose of either

midazolam (0.1 mg/kg) or diazepam (0.2 mg/kg) was administered into a large or medium sized peripheral vein through a 21-gauge butterfly a t a rate of 5 mg/min. Increments of SO% of the original dose were given every 2 minutes until the desired level of sedation (ptosis, drowsiness, slurred speech) was obtained. Supplementary doses of the relevant drug were given during the procedure as required. Local nerve block was achieved with 2 ml of 3% prilocaine with felypressin 0.03 iu/ml. Blood pressure and heart rate were monitored by a Dinamap automatic recorder. A stethograph monitored respiratory rate and the electrocardiogram (ECG) was continuously displayed. A wide variety of restorative procedures were carried out under local analgesia. These included fillings, crown preparations, root canal treatments and prosthetic tooth preparation. A rubber dam was used to separate the oral cavity from the pharynx. The operating conditions were evaluated by the dentist, based on the assessments of cooperation during nerve block and quality of sedation during the procedure. The scores were classified as, I, patient was very restless and showed active resistance; 2, patient was slightly restless and showed mild resistance; 3, patient was relaxed, calm, responsive to command and showed no resistance to treatment; 4, patient was too sedated and not responsive to command. All side effects during the procedure were also recorded. The patients' recovery was assessed by a trained nurse. On arrival in the recovery room, the level of drowsiness was graded from 0 to 5 as 0, not drowsy; 1, slightly drowsy; 2. moderately drowsy; 4, asleep but rousable and 5. asleep and not rousable. The patient was assessed again 2 hours after the end of the procedure for drowsiness, walking ability and fitness for discharge. Patients were allowed to go home provided they were wide awake and could walk along a straight line unaided without swaying from side to side. Prior to discharge, the patient was asked to complete a questionnaire about recall of the injection in the arm, the injection in the mouth and the dental

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procedure. These were graded as no recall, some recall, or remembered everything. The venous sequelae and continued recovery at home were assessed by questionnaire. Results Thirty-four patients, eight males and 26 females between 16 and 47 years of age were studied. Their mean weight was 60 kg (SD 9.5 kg) and all conformed to ASA classifications I and 11. The mean times from induction to desired level of sedation were 6.3 min (SD 4.9) for diazepam and 4.7 min (SD 3.1) for midazolam. There were more patients sedated in less than 5 minutes time following midazolam than diazepam and the difference was statistically significant (p < 0.0s) (Wilcoxon signed rank test). Cardiovascular meusurements. There was a statistically significant reduction of systolic arterial pressure following induction with both benzodiazepines (p <0.01 calculated by one way analysis of variance), with the maximum decrease being immediately after the establishment of sedation (Fig. I). The mean reduction was greater after midazolam than diazepam, 16.3 mmHg (SD 14.8) as compared with 7.6 mmHg (SD 12.0). The systolic blood pressure remained steady during the injection of local analgesic. However with the stimulation of dental treatment, the blood pressure rose to near pre-induction level in the case of diazepam. whereas the reduction was maintained in the case of midazolam. The difference was statistically significant (p < 0.002. Student's paired t-test). None of the changes in mean heart rate following sedation, local analgesic

59 1

injection and treatments reached statistical significance (Fig. I). Total dosage. During the procedures, additional doses of diazepam were required in 20 patients, and 16 needed extra doses of midazolam. The mean total dose required for diazepam was 0.32 mg/kg (SD 0.12) and 0.17 mg/kg (SD 0.08) for midazolam. The mean duration of procedures (from induction to end of procedure) were similar for diazepam (55.2 min; SD 20.1) and midazolam (59.6 min; SD 19.0). Operating conditions. The drugs produced broadly comparable operating conditions. As the trial was a cross over study, McNemar's test for correlated proportion was used to test whether the drugs had different effects. The proportions of scores were similar (p > 0.2) (Tables 1 and 2). However, one patient in whom 32 mg of diazepam had no sedative effect was successfully treated following IS mg of midazolam. Side effects. Eighteen patients complained of pain on injection with diazepam, whereas only one patient reported pain with midazolam. However a higher incidence of hiccough and brief apnoea ( 3 W S sec) was observed following induction with midazolam when compared with diazepam (Table 3). No intervention was required on any occasion. Three patients during midazolam sedation appeared to have airway obstruction as suggested by the presence
Table 1. Sedation scores during nerve block (number of patients)
Drue Midazolam Diazepam

9 6

14 13

10

0
0

14

33 33

N o significant difference between groups McNemar's test x* ( I ) = I . I , p > 0.2.

Table 2. Sedation scores during dentdl procedure (number of patients)

Drug Midazolam Diazepam

I
3 5

Scores 2 10 9

3
19

4 2 0

Total 34 34

20

N o significant difference between groups. McNemar's test xz ( I ) = 0.2, p >0.2.

Table 3. Complications
Diazepam (Valium) Midazolam

60

Fig. I. Cardiovascular measurements (mean. SEM) following administration of midazolam ( - - 0 - - )and diazepam (-9-), T , = baseline; T, = sedation established: T, = local analgesic injection; T, = treatment commenced; T , =end of procedure.

Early ( n = 34) Pain on injection Hiccough Apnoea 3&45 sec Airway obstruction Retching Headache Late Drowsiness (same evening) ( n = 24) Thrombophlebitis

19 (79"")

8 (33.3:")
0

7 (22.6"")

(0)

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midazolam given in this study is larger than that recommended by the manufacturer for intravenous sedation (0.07 mg/kg). However. none of the patients was premedicated. many of them were extremely nervous and were described as unmanageable on previous visits. These factors coupled with the relatively prolonged duration of the procedures may be responsible for the higher dose of benzodiazepine required in this study. Systolic blood pressure decreased from the preinduction level after both drugs. Although statistically significant. the reductions were not so substantial as to be of clinical significance, and may suggest that the patients were relaxed. All patients remained supine throughout the procedure, and the decrease in blood pressure may have been greater had they been upright. Tachycardia in response to local analgesic injection and dental treatment had been demonstrated in unsedated patients.'".14 In this study, the absence of tachycardia during the procedure supports the effectiveness of sedation with both drugs. The patients appeared to be better sedated with midazolam because the systolic blood pressure remained stable during dental treatment whereas it tended to return to pre-induction level with diazepam. The incidence of hiccough, brief apnoea and airway obstruction was higher following induction with midazolam. This may be related to its greater potency and slower administration may reduce this. There were no other serious side effects observed during the procedure. Midazolam provided a higher incidence of anterograde amnesia. A greater percentage of patients who received midazolam did not recall the local anaesthetic injection when compared with diazepam (78.8% and 48.5% respectively). The amnesic action appeared to wane gradually over the period of the dental procedure, but the quality of amnesia was consistently better with midazolam. The immediate recovery was similar for both drugs. However, significantly fewer patients felt drowsy during the evening following midazolam than diazepam. This suggests a more rapid recovery. Another very important difference was the significantly lower incidence of pain on injection and absence of venous sequelae following the administration midazolam. In conclusion, the results of this study suggest that midazolam hydrochloride has advantages over diazepam for intravenous sedation in conservation dentistry, since it is associated with a faster onset of action, more consistent anterograde amnesia, more rapid recovery and is virtually free of venous complications. The relatively greater incidence of apnoea and hiccough may be related to the greater potency of midazolam and a slower rate of administration may reduce this.

of snoring. This was relieved either by lifting the jaw or waking the patient up. Retching was more common following diazepam (seven patients) than midazolam (four patients). The incidence of the other noteworthy adverse effect. headache during recovery, was similar for both drugs (three diazepam and four midazolam). Amnesia. Thirty-three patients received a local analgesic injection at similar times after induction. The mean time was 11.18 min (SEM 1.31) for midazolam and I1.73min(SEM 0.91)in thecaseofdiazepam. Ofthese. 78.87, of patients did not recall the injection after receiving midazolam compared with 48.5:d after diazepam. Thirty-one (ten total and 21 partial) out of 34 patients (91.2%) had amnesia for the dental procedure following midazolam whereas only 20 patients (two total and 18 partial) (58.8"/,) were so affected by diazepam. Recovery. The recovery while in thc hospital was similar for both drugs. and the majority ofpatients were fit for discharge 2 hours after the end of their dental procedure (midazolam 76.5"& diazepam 61.8%). Most patients (70.5"~)returned the questionnaire. Results showed that significantly fewer patients felt drowsy in the evening after midazolam (33.3%) than after 0.01) (Table 3) diazepam (79y") (McNemar's test, p i and the trend continued the following morning, though the difference became less pronounced (midazolam = 20.8: diazepam = 41.67;). Venous sequelae. Thirty-one out of 34 patients (91.27") responded to the questionnaire on venous sequelae. Seven developed thrombophlebitis; these all followed the administration of diazepam. There were no venous sequelae following intravenous midazolam (Table 3). Discussion The purpose of this study was to compare the use of midazolam and diazepam for intravenous sedation in outpatient conservation dentistry. Each patient acted as his o r her own control. Midazolam had a significantly faster onset of action than diazepam (mean time, 4.7, SD 3.1 min as compared with 6.3. SD 4.9 min, p <0.05). However there was a considerable variation in onset for both drugs as demonstrated by their wide standard deviation. This finding is supported by other s t ~ d i e s .There was also ~,~ a wide inter-patient variation in dose-effect response. as shown by the standard deviation (0.08 mg/kg) of total dose required. These variations in response are typical of benzodiazepines'O and may be partly explained by high plasma protein binding.8 The mean total dose of midazolam required to produce COmpdrdbk operating conditions in the same set of patients was half that of tiiazepam (0.17 mg/kg vs 0.32 mg/kg). This suggests that midazolam is about twice as potent as diazepam, which is consistent with the results of other studies.11.12The mean dose of

A ckno wledgmenIS
Our thanks are due to the many nurses who assisted

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with the study. and to Miss Mandy Miller who typed the manuscript. We are grateful to Roche Products Limited for support of the investigation and supplies of midazolam and to Mr R.I. Harris for helping with the statistical analysis. ReJereerenres
1 . BAIRDES. HAILEY DM. Delayed recovery from a sedative:

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2. 3. 4.

5.

Correlation of the plasma levels of diazepam with clinical effects after oral and intravenous administration. British 4 Journal of Anaesthesiu 1972; 4 : 803-1 3. DIXON THORNTON Tests of recovery from anaesRA. JA. thesia and sedation: intravenous diazepam in dentistry. British Journal of Anaestheriu 1973; 45: 207-1 5. HEGARTY DUNDEE Sequelae after the intravenous JE. JW. injection of three benzodiazepines diazepam, lorazepam and Runitrazepam. Briti.sh Medical Journal 1977; 2 13865. KAWAR DUNDEE Frequency of pain on injection P. JW. and venous sequelae following the i.v. administration of certain andesthetics and sedatives. Brifish Journul o/ Anaesthesia 1982; 54: 935-9. OLE~EN AS. HUTTELMS. Local reactions to i.v. diazepam in three different formulations. British Journal of Anaesthesia 1980: 5 2 609- I I .

6. BROWNCR, SARNGUIST CANUP FH. CA. F'EDLEY TA. Clinical. electroencephalographic and pharmacokinetic studies of a water-SOhIbk benzodiazepine, midazolam maleat. Anesthesiology 1979; 50: 467-70. 7. DUNDEE WILSON JW. DB. Amnesic action of midazolam. Anaesthesia 1980; 35: 459-61. 8. GAMBLE JAS, KAWAR DUNDEE MOORE BRIWS P, JW. J. LP. Evaluation of midazolam as an intravenous induction 6 agent. Anaesthe.rio 1981; 3 : 868-73. 9. AL-KHUDHAIRI D. WHITWAMJG, MCCLOY RF. Midazolam and diazepam for gaslroscopy. Anaesthesia 1982; 37: 1002-6. 10. BOND HAILY AJ, DM. LmtR MH. Plasma concentrations of benzodiazepines. British Journal of Clinicul Pharmaco1og.v 1977; 4: 51 ~ 6 . I I . DUNDEE JW. SAMUEL 0, TONER W, HOWARDPJ. 1 Midazolam: a water soluble benzodiazepine, Studies in volunteers. Anaesthesia 1980; 35: 4548. N. 12. F R A G t N RJ. GAHLF. CALDWELL A water-soluble benzodiazepine R02 1-398 I for induction of anesthesia. Anesthesio1og.v 1978: 4 9 41-3. 13. MAJOR WINDER BnmK AH, BERMAN An evaluaE. M. DS. tion of nitrous oxide in the dental treatment of anxious children. British Dental Journal 1981; 151: 18691. 14. MESER JG. Stress in dental patients undergoing routine procedures. Journal of Dental Reseurch 1977; 56. 362-7.

Anaesthesia, 1984, Volume 39. pages 593-596

An assessment of the Humphrey ADE anaesthetic system in the Mapleson A mode during spontaneous ventilation

J. Dixon, MB, BS, FFARCS, Registrar, M.K. Chakrabarti, BSc, MPhil, ChiefTechnician, M. Morgan, MB, BS, FFARCS. Reader, Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Road, London W I2 OHS

Summary
The Humphrev ADE anaesthetic breathing system in the Mapleson A mode has been compared with the Magill system in spontaneously breathing conscious volunteers and anaesthetised patients. In the latter. rebreathing occurred at a sign$cantly lower.fresh ga.~.flon with the A DE system than when the Magill system was used (mean 45.6 mllkglminute und 56.5 mllkglminute respectively). There was no significant difference between the fresh gasflon at which rebreathing orcurred in conscious volunteers. Key words Equipment: breathing systems, Magill. ADE
A new anaesthetic breathing system has recently been described' which the designer claims 'offers a new concept in low flow anaesthetic breathing systems for universal use'. It can function as a Mapleson A. D or E system and can be used for adults. children and neonates with either spontaneous or controlled ventila-

tion. It can easily bechanged from one mode to another. The system exists in coaxial and non coaxial versions. Maplesonz predicted that during spontaneous ventilation with the Magill (Mapleson A) attachment, rebreathing would not occur if the fresh gas flow equalled or exceeded the alveolar ventilation, and this