THE BENZODIAZEPINES: A review of their actions and uses relative to anaesthetic practice

Brit. J. Anaesth. (1970), 42, 217

THE BENZODIAZEPINES A review of their actions and uses relative to anaesthetic practice BY J. W. DUNDEE AND W. H. K. HASLETT

NH— CHj

CHjO ^

N—C , = N

>

N=C

[ v

CjH, O Diazepam (Vallum)

C*H, 0 Chlordiazepoxide (Libnum)

O N—C "C—OH C»H, Oxozepam (Seraxl

CcHj Nitrazepam IMogadon)

FIG. 1 Chemistry of the benzodiazepines. (Serax is now known as Serenid-D.) CHEMICAL AND PHYSICAL PROPERTIES

Chlordiazepoxide is a colourless crystalline substance which is highly soluble in water, but unstable in solution. It is available in tablet and capsule form. It is made up freshly for intramuscular injection by adding 2 ml of a special solvent to 100 mg powder. Diazepam is a colourless crystalline compound which is insoluble in water. It is available as tablets, as syrup and in ampoules for injection.

The latter contain 5 mg/ml in an aqueous vehicle of organic solvents consisting mainly of propylene glycol, ethyl alcohol and sodium benzoate in benzoic acid. This combination produces a slightly viscid solution that requires a large-bore needle for rapid intravenous injection. Doses of die solvents well in excess of those likely to be injected intravenously are devoid of toxic effects (Morris, Nelson and Calvery, 1942). The pH is in the 6.4-6.9 range. Although transitory cloudiness sometimes occurs when diazepam is diluted with water or saline solution, no loss of potency occurs. However, dilution of the currently available preparation is not recommended by the manufacturers, since it produces an emulsion of small particles. Diazepam should not be mixed with other drugs. Oxazepam is a white, practically odourless, crystalline powder, which is very slightly soluble in water, and slighdy soluble in alcohol and chloroform. It can be dissolved in organic solvents, but is only available commercially in tablet form. Nitrazepam is a yellowish crystalline compound, insoluble in water but soluble in alcohol. It is presented in tablet form. Although some studies refer to the use of a preparation for intramuscular use, this caused pain and is not available commercially (Jaquenoud and Sauvan, 1966). PHARMACOLOGY

The benzodiazepines possess certain common properties which have been studied in more detail for chlordiazepoxide and diazepam than for oxazepam and nitrazepam. Nervous system. Both chlordiazepoxide and diazepam depress the limbic system in animals without causing cortical depression. Their tranquillizing effects JOHN W. DUNDEE, PH.D., MJ>., F.F.A.R.C.S., The Queen's

University of Belfast, Northern Ireland; W. H. K. HASLETT, M J . , F.F.A.R.C.S.I., Ulster Hospital, Dun-

donald, Northern Ireland.

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The benzodiazepines are a relatively new group of compounds of which four are in current clinical use (fig. 1). Chlordiazepoxide was the first of these to be introduced (Randall et al., I960), followed by diazepam (Randall et al., 1961). Oxazepam is a breakdown product of diazepam resulting from demethylation and hydroxylation. These are used as "minor tranquillizers" in contrast to the so-called major tranquillizers of the phenothiazine series. Nitrazepam, the other benzodiazepine, is employed as a hypnotic, but in view of the similarity in its clinical effects to those of the other members of the series, this action may be due to the employment of relatively higher doses. Chlordiazepoxide and diazepam are widely used in anaesthetic practice and will be discussed in greater detail than the other drugs.

218

Amnesia with diazepam. One important action of diazepam which has not been studied in detail is its ability to produce amnesia. This cannot be evaluated in animals, but was studied in anaesthetized patients by Stovner

and Endresen (1966), McOish (1966), and Brown and Dundee (1968). It is not always dear whether diazepam can cause "retrograde" amnesia, or whether this is purely anterograde, paralleling the soporific action of the drugs. It is also not clear whether amnesia is only associated with the intravenous route of administration. Dundee and Keilty (1969) reported preliminary findings of an unpublished study. From table I, which sets out the results, it would appear that retrograde amnesia—lack of recall of the pre-injection object—was not produced to any extent by the doses of drugs used in this study. Memory for subsequent events was markedly reduced when diazepam was given in combination with pethidine or hyoscine, but was little affected by 10 mg diazepam alone. A survey of the ability of patients premedicated with intramuscular diazepam (10-20 mg) or chlordiazepoxide (100 mg) to recall the visit to the operating theatre or the induction of anaesthesia, shows neither anterograde or retrograde amnesia for events in the pre-operative period (Dundee and Keilty, 1969). TABLE I

Data on amnesia described in text. Percentage incidence of amnesia for

Premedication Saline solution Diazepam 10 mg Hyoscine 0.4 mg Pethidine 100 mg Diazepam-hyoscine Diazepam-pethidine Hyoscine-pethidine

Pre-

Visit to

lnjecDon object

operating

0 0 0 0

5 10 0

room 0 15 15 10 95 90 35

Induction of anaesthesia

0 25 25 10 90 85 50

These findings with intramuscular diazepam premedication are at variance with those of Steen and Hahl (1969), who found an almost complete lack of recall of induction of anaesthesia following minor operations in patients premedicated with 10-20 mg diazepam, given by intramuscular injection, with or without atropine, and little or no memory loss in similar subjects receiving either a placebo or atropine as premedication. Clinical data from two scries of dental patients, in whom diazepam was given by slow intravenous

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are thought to be due to an action on the amygdala, that part of the limbic system which is the relay area for the expression of the emotions. They reduce aggression more than activity in monkeys, whereas meprobamate, chlorpromazine and pentobarbitone appear to affect both actions to a similar degree (Randall et al., 1960; Svenson and Gordon, 1965). The accompanying electroencephalographic effects consist of low to moderate voltage fast activity that may persist for a week after medication is discontinued (Towler, 1962). These effects are the basis for the employment of these drugs in psychiatric practice, particularly in anxiety states. Diazepam is an effective oral hypnotic in adult doses of 20-30 mg; it produces light sleep which is more marked when the drug is given intramuscularly. Because of its psychosedative action, it is more likely to be effective as a hypnotic in patients suffering from mild to moderate degrees of anxiety and tension. The hypnotic effect following intravenous injection has only been studied with diazepam and will be discussed under intravenous anaesthesia. Oxazepam appears to have an action similar to that of diazepam, but produces its sedative action with less accompanying hypnosis (Tobin, Lorenz and Brousseau, 1964). With nitrazepam the hypnotic effect appears to be dominant and it is as effective in producing sleep in normal subjects as in those suffering from anxiety. Opiates and barbiturates enhance the hypnotic action of the benzodiazepines. The interaction with alcohol is complicated, in that large doses of chlordiazepoxide tend to antagonize its soporific effect (Dundee, Isaac and Clarke, 1969). Studies with intravenous ethanol showed that after doses of 100-140 mg chlordiazepoxide higher blood alcohol levels were required to produce loss of consciousness (Dundee et al., 1969) and that this tranquillizer often altered the response to ethanol, increasing the incidence of delirium both before and after loss of consciousness. This effect was not observed with diazepam.

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THE BENZODIAZEPINES

I

TABLE n

Data on amnesia associated with the intravenous injection of sub-hypnotic doses of diazepam, taken from two publications on its use prior to dental surgery. Percentage remembering Dose Intravenous Intra-oral injection injection (nig) 10 94 16 15 93 6 20 95 15 (from Keilty and Blackwood, 1969) Memory of Getting on the table Intravenous injection Intra-oral injection Drilling tooth Removal of tooth Injection at end of operation (from O'Neil et aL, 1970)

100 98 20 25 8 79

These findings show die administration of subhypnotic doses of diazepam to be followed by a useful degree of amnesia, but they provide no evidence to suggest that it can cause retrograde memory loss. This aspect of the action of chlordiazepoxide or odier benzdiazepines does not appear to have been studied. Cardiovascular system. Most of the animal pharmacological data concentrate on tie cerebral effects of the benzodiaze-

pines, with little attention paid to their action on the cardiovascular system. Randall and his colleagues (1961) found very slight transient hypotension with doses up to 8 mg diazepam per kilogram in dogs. Cumulated doses of IS mg/kg given over 3 hours led to an average fall in mean pressure of only 24 mm Hg. No electrocardiographic changes were noted, and the blood pressure responses to adrenaline, acetylcholine, serotonin, carotid occlusion, or central vagal stimulation were unaltered. The cardiovascular effects of tilting 12 healthy adult male volunteers were studied before and after intravenous administration of 10 mg diazepam by Katz, Finestone and Pappas (1967). No changes in blood pressure or pulse rate were produced by die drug. Sedation of varying degrees occurred in 11 of the 12 subjects and lasted from 20 to 48 minutes. All workers comment on the lack of cardiovascular depression with the doses of chlordiazepoxide and diazepam used for premedication. Brown and Dundee (1968) found that intravenous doses of 0.6-0.8 mg/kg diazepam did not produce a fall in systolic pressure in excess of 20 mm Hg, whereas die incidence was 24 per cent with 4 mg/kg thiopentone and 8 per cent after 1.6 mg/kg methohexitone in strictly comparable series of cases. Dundee and Keilty (1969) found negligible effects in moderately shocked "abortion cases" receiving 50-70 mg diazepam intravenously. For die sake of completeness it must be mentioned diat Rollason (1968) has reported cardiovascular collapse following diazepam. A fit robust labourer who received 20 mg by intravenous injection developed hypotension, bradycardia, sweating, cyanosis and vomiting, which responded to oxygen, intravenous atropine, and posture changes. Respiratory system. Most workers agree diat clinical doses of diazepam cause a slight degree of respiratory depression, and Hunter (1967) has shown diat if the drug is given during anaesdiesia, and especially in those premedicated with an opiate, it may cause apnoea. This action may be due to hypotonia of muscles rather dian to depression of the respiratory centre, since intramuscular doses of 10 mg

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4

injection, is summarized in table II. In Keilty and Blackwood's (1969) study, virtually all patients remembered the administration of the diazepam while few recalled the intra-oral injection which was given 2-3 minutes later. O'Neil et al. (1970) used a slightly higher dose of diazepam, with very similar results. The interval between the end of administration and the local injection was similar in the two studies, each of which involved 40-50 patients. The quality of the local anaesthesia may have been a contributory factor in both of these studies, particularly in view of the small percentage reported by O'Neil et al. as recalling either the drilling or removal of the toodi. The time between the administration of die diazepam and the postoperative penicillin injection would have been variable, but the low incidence of amnesia suggests that the action of diazepam was wearing off after about 30 minutes.

220

Placental transfer. Diazepam rapidly passes the placental barrier and within a few minutes equilibrium is reached between maternal and cord blood levels (Bepko, Lowe and Waxman, 1965; Cavanagh and Condo, 1964; De Silva, D'Arconte and Kaplan, 1964). Muscle relaxant effects. Reports indicate that the benzodiazepines have muscle relaxant properties and are clinically effective in the treatment of various forms of muscle spasm. There is some species difference in the extent of this action which will be reviewed in detail. In early papers, Randall and colleagues (1960, 1961) demonstrated a depressant action on the neurones of the spinal cord in various animals with chlordiazepoxide and diazepam. This is a particularly prominent effect in cats, occurring at very low doses and resulting in hypotonia, although not interfering with normal motion. Mice and rats are similarly affected and this may be partly responsible for their taming action in monkeys. In animals, diazepam is about ten times

as effective as meprobamate in suppressing skeletal activity. It is twenty times as effective as chlordiazepoxide in blocking decerebrate rigidity but has only five times the action of the latter drug on the electroencephalogram. Although there are good indications as to the site of the muscle relaxant effect of diazepam in animals, rlinirai investigators have not identified this site with any degree of certainty. In man it is difficult to separate sedative (calming) and muscle relaxant properties of the benzdiazepines and Zbinden and Randall (1967) consider that their marked anti-anxiety effect certainly contributes to the muscle relaxant action observed in dystonic-athetoid children with cerebral palsy. However, the clinical experience of many workers indicates that at least part of its beneficial effect is due to a pharmacological action on polysynaptic pathways within the spinal cord or on supraspinal structures. This is supported by observations that non-hypnotic doses of diazepam suppress the "startle reflex" in patients with cerebral palsy (Marsh, 1965) and relieve severe muscle spasm in patients suffering from "stiff man" syndrome (Howard, 1963). As will be seen later, it is also moderately effective in tetanus. It is obvious that these latter actions cannot be explained by its sedative action alone. In view of the above properties Hunter (1967) gave intravenous diazepam to 13 adult patients during nitrous oxide-oxygen-halothane anaesthesia. Abdominal relaxation was not regularly produced by doses of 2.5-10 mg and the dose of tubocurarine required subsequently to produce relaxation was the same as that required in patients who had not had diazepam. Although the injection of diazepam necessitated ventilatory assistance in 3 patients, this was associated with straining on the endotracheal tube, and curarization was necessary before easy artificial ventilation of the lungs was possible. In other studies, Stovner and Endresen (1965, 1966) found that doses as high as 0.2-0.5 mg/kg produced no significant potentiation of the action of either tubocurarine or suxamethonium during abdominal surgery. Aniiccnvulsaii action. All the clinically used benzodiazepines appear to be effective against pentamethylenetetrazole-

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(Sadove, Balagot and McGrath, 1965) or intravenous doses of 0.66 mg/kg (Steen et al., 1966) do not affect the respiratory response to carbon dioxide. In common with 10 mg chlordiazepoxide the above doses of diazepam do not alter the response of pethidine to carbon dioxide. Zsigmond (1969) also found no fall in arterial oxygen tension after 10 mg diazepam, and changes induced by pcthidine-diazepam were similar to those caused by pethidine alone. The effects of the pethidine-diazepam mixtures (100 mg: 10 mg) were less than those of pethidine alone (100 mg) in patients with lung disease. Buskop, Price and Molnar (1967) have reported an unusual response to diazepam. An 81-year-old man who was given 10 mg intravenously during extradural anaesthesia lost consciousness and became apnoeic and cyanotic within a few seconds, but was resuscitated with artificial ventilation, which had to be continued for 3-4 hours before consciousness was regained. This condition occurred again later, but to a lesser degree, when the same dose was given intramuscularly. No explanation can be offered for their findings, except possibly a sensitivity to diazepam.

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THE BENZODIAZEPENES

CLINICAL U S E : PREMEDICATION

Because of the different popularity and clinical use of the individual benzodiazepines, it is not possible to discuss their clinical use in an orderly manner, but it is logical to start with premedication. The ability of the benzodiazepines to allay apprehension (anxiolytic action), particularly under conditions of stress, should make them ideal premedicants since they should be able to achieve tranquillity without a marked soporific action. For a single-dose parenteral injection the ampoules of diazepam offer obvious advantages over the unstable chlordiazepoxide injection which has to be freshly prepared. If anaesthesia is to include halothane, irritant vapours or intermittent doses of suxamethonium, the benzodiazepines

should be combined with an appropriate vagolytic drug. The use of diazepam as a conventional form of premedication, i.e. given by intramuscular injection 1-2 hours before operation, was first described in France by Thuries and Poncet and by Du Cailar and his colleagues in 1964, and in the United States by Tometta (1963, 1965) who used 50-100 mg. Haslett and Dundee (1968) studied 10 and 20 mg doses and found no advantages from the larger dosage, but concluded that the 10 mg dose had many advantages over the opiates. Workers from Montreal (Cormier et al., 1966) were unable to detect any significant differences between the actions of pethidine 100 mg and diazepam 10 mg (given intramuscularly), but any slight preference favoured diazepam. The most recent study is that of Steen and Hahl (1969) who found diazepam 10 mg to be a "near ideal" form of premedication. Some of the findings of Haslett and Dundee (1968) are summarized in table HI. This dearly shows that both benzodiazepines are as effective as morphine or promethazine, without causing the emetic and other side effects of these two popular premedicants. In an extensive survey of the relative efficacy of equipotent doses of 17 opiates and other drugs as premedicants, Dundee, Loan and Morrison (1970) placed diazepam 10 mg high in the rank order of merit of the drugs studied. It

TABLE III

Percentage incidence of effects of drugs given before anaesthesia and assessed 60-90 minutes after intramuscular injection. Observations are expressed in percentage frequency (to nearest 5 per cent), and each series is based on at least 100 observations (from Haslett and Dundee, 1968). Drowsiness (moderate and good)

Good

Fair

Poor

Severe

Slight

Nil

Sedation*

Side effects

Saline solution

25

20

35

45

0

10

90

Chlordiazepoxide 50 mg 100 mg

28 60

25 55

30 25

45 20

0 0

30 15

70 85

Diazepam 10 mg 20 mg

75 60

60 50

25 35

15 15

0 5

25 20

75 75

75

65

20

15

5

50

45

56

50

25

25

20

60

20

Morphine 10 mg Promethazine 50 mg

*This included lack of apprehension as well as drowsiness.

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induced seizures in animals (Zbinden and Randall, 1967). From these and other studies, it would appear that all of this group of drugs would have broad-spectrum anticonvulsant properties in man, with particular effectiveness in psychomotor and perit-mal seizures. Nitrazepam is die most promising in this respect because of its greater activity in depressing the after-discharges which follow stimulation of the thalamus and the limbic systems. The clinical reports of the use of diazepam in convulsive states will be reviewed later in this paper.

222

Normally one would give diazepam with atropine when a parasympatholytic action is required, but it can safely be given with hyoscine (0.4 mg for adults). This markedly enhances its soporific effect, but because of the greater incidence of excitatory phenomena makes it less acceptable as a premedication before a memohexitone induction, as well as causing a delay in recovery after minor operations. The addition of hyoscine to a pethidine-diazepam mixture results in a very soporific premedication, but with the risks of hypotension and delayed recovery time (Dundee et al., 1970). Oral use. The benefit of single-dose oral premedication with these benzodiazepines has not been adequately evaluated, but its use in children has not been very promising (Bush, 1968). Haq and Dundee (1968) found that syrup of diazepam (1 mg per 6.4 kg—14 lb.) and trimeprazine (20 mg per 6.4 kg) were equally effective as premedicants, but salivation was more troublesome with diazepam. Trimeprazine was preferred before adenotonsillectomy because of the lesser blood

loss associated with its use. This was attributed to the lower incidence of crying (and resulting raised venous pressure) with diis premedicant. The time-honoured use of a single dose of premedication has been challenged by Brandt, Lui and Briggs (1962) and more recendy by Inglis and Barrow (1965), who recommended the intermittent oral use of a tranquillizer on the day before operation. These workers employed chlordiazepoxide while Bruha (1964), Brandt and Oakes (1965) and Dowell (1966) have used diazepam. All workers claimed that both preparations were particularly helpful in allaying apprehension, but it is obviously very difficult to make a true evaluation of their therapeutic value. It is doubtful if this effect can be achieved without some hypnotic action. In a study limited to patients considered to require psychosedarion, Murray, Bechtoldt and Berman (1968) compared single oral doses of pentobarbitone 200 mg, ethchlorvynol 400 and 1000 mg, diazepam 10 and 20 mg, hydroxyzine 200 mg, and oxazepam 60 mg. Anti-apprehensive activity could be demonstrated only in patients who also became drowsy; pentobarbitone, ethchlorvynol and diazepam were superior to the other drugs for the relief of anxiety. These workers pointed out that, irrespective of the drugs used or the route of administration, many patients experience neither a placebo nor pharmacological effect, but this may not apply to repeated administration. Studies with oral chlordiazepoxide in the treatment of psychosomatic disease and anxiety associated with organic illnesses showed that the maximum benefit was not obtained until treatment had been continued for several days. Psychiatrists, however, use smaller doses than those employed before surgery. Brandt, Lui and Briggs (1962) gave 50 mg on the night before operation and 50 mg 2 hours before induction of anaesthesia—so that a dose response cannot be excluded. The time taken for the maximum effect of oral diazepam to occur has not been well documented, but personal experience of the authors suggests djat 20 mg at night and next morning are very effective in relieving anxiety. With both tranquillizers care should be taken in administering a subsequent dose of opiate. If time allows, obviously smaller and more frequent doses should be given. Oxazepam may well have a place here,

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was superior to 100 mg pethidine, 20 mg papaveretum or 10 mg morphine. In view of the lack of analgesic action of diazepam, there would appear to be a place for combining it with an opiate, particularly before "light" anaesthesia. Surprisingly, there appears to be only one detailed controlled study of this combination (Dundee et al., 1970), 100 mg pethidine being given with 10 mg diazepam. Both the intramuscular and intravenous routes of administration were employed. The most significant finding with this mixture was a lowered incidence of prcand postoperative emetic symptoms as compared with a similar series of patients receiving the opiate alone. Pethidine-diazepam had a significandy greater soporific action than diazepam alone, but did not cause more drowsiness than pethidine alone, although it did increase the ability of the opiate to allay pre-operative apprehension. However, when given intravenously, the diazepam-opiate mixture was followed by a much greater degree of pre-operative and operative hypotension than when either constituent was used alone. Since diese studies were carried out on fit subjects, it is recommended that for routine use in unselected patients the dose of opiate should be reduced when given wim diazepam.

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223

THE BENZODIAZEPINES while nitrazepam is an effective single-dose hypnotic and would seem to have a place the night before surgery. DIAZEPAM AS AN ADJUVANT TO INTRAVENOUS ANAESTHESIA

&>O*OO

o

o -

8

o

o

O O 000

«I

o

oo

UJ

I iO O

• o

O

o»o o

oo

o

8

° o

O«O ASLEEP

t • o

Ois DOSE

OF

I DIAZEPAM

1-5 mg/kg

FIG. 2 Dose response curves. (Solid circles indicate opiate premedication.)

oo

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Diazepam can never be considered to be primarily an intravenous anaesthetic and is not a suitable routine substitute for thiopentone, methohexitone or propanidid. Adequate dosage, however, causes drowsiness and nystagmus in about half a minute with sleep after a further 30 seconds or so. Loss of consciousness occurs quietly without excitement but occasionally there may be transient hiccup. There is a great individual variation in response to diazepam, with especially wide varia-

tions in the dose required to produce sleep. This was shown by the study of Brown and Dundee (1968) who gave varying doses to fit subjects, with or without opiate premedication and recorded the maximum depth of drowsiness on an arbitrary scale. Their data (with additional cases—figure 2) show that on occasion doses as small as 0.2 mg/kg may induce sleep following opiate premedication, the comparable dose being about 0.4 mg/kg with atropine premedication. However, to be certain to induce anaesthesia in every case doses of 0.8-1.0 mg/kg may be required, irrespective of the premedication used. The first report of the intravenous use of diazepam appears to be that of Farb in 1963 who gave 10-30 mg as "pre-interview" pre-

224

Stovner and Endresen (1966) used diazepam as an induction agent in 300 patients in doses of 5-10 mg at 1 and 2-minute intervals to a total of 0.2-0.6 mg/kg. The slow onset of action of the drug was obvious, and thickened speech and nystagmus preceded the onset of sleep. With diazepam alone, patients responded to painful stimuli, but when the stimulus was withdrawn they went back to sleep again quickly and had complete amnesia for the incident afterwards. For major surgery, nitrous oxide-oxygen-pethidine and muscle relaxants were used in addition as supplements to diazepam; anaesthesia appeared to be uneventful. About 30 per cent of patients receiving diazepam had retrograde amnesia for the period shortly before injection, compared with 8 per cent in a similar series of patients induced with thiopentone. These workers commented on the cardiovascular stability, although noting a 20-30 per cent reduction in pulmonary minute volume, which could be attributed to the combined effect of the diazepam and opiate premedi cation. McQish (1966) has investigated intravenous diazepam as an induction agent mainly before halothane in 88 patients. Most were scheduled for cardiovascular operations, and 60 per cent were very poor risks. This may explain the low average induction dose of 10.7 mg, which was non-toxic in these very ill patients. The additional use of 5-20 mg by mouth on the night before operation and again on the morning of operation (combined with barbiturates and opiates) may also have played a part in this low dosage. Brown and Dundee (1968) studied the use of the drug in fit, and often unpremedicated, subjects. They noted the variation in response to the drug, illustrated in figure 2, and once again the absence of cardiovascular toxicity from large doses of diazepam was noted. Detailed liver function tests revealed no abnormalities in 23 patients, and vomiting was no more frequent than after the use of thiopentone or methohexitone. Table IV (from Brown and Dundee, 1968) shows a useful comparison of intravenous diazepam with two barbiturates as the main anaesthetic (with nitrous oxide-oxygen) for minor gynaecological procedures. This shows the limitations of diazepam, particularly with regard to delay in onset of action and in recovery times.

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medication in psychiatric practice. Following this, Campan and Espagno (1964) used the drug in clinical anaesthesia, with doses up to 1 mg/kg in a continuous infusion (80 mg per 250 ml). Since the intensity of the hypnotic action depended largely on the rate of infusion, effective doses had to be given in 5-8 minutes (approximately 10 mg/min). Anaesthesia was continued with nitrous oxide and various inhalational supplements along with intravenous opiates. Contrary to later (and better documented) reports (Hunter, 1967; Stovner and Endresen, 1965, 1966) they found that abdominal relaxation was adequate in about one-third of their cases without curarizing agents. Their most favourable comment was that diazepam was almost completely devoid of circulatory side effects, although potentiating other drugs used in anaesthesia. Recovery was not prolonged in any of their 200 patients. Many European continental workers (Du Cailar, Gestin and Galibert, 1966; Huguenard and Margelidon, 1964) have employed diazepam as part of neuroleptanaesthesia, usually combined with dextromoramide (Aquado and Aquerreta, 1964) or pethidine (Lanot, 1964). Since most patients received a multiplicity of agents, it is not always easy to decide what part of the neuroleptanaesthesia could be attributable to the diazepam, but it has been claimed (Aquado and Aquerreta, 1964) that diazepam gives better protection than do other agents from the autonomic effects of reflex stimulation during abdominal surgery. It also potentiates the hypotensive action of trimetaphan (Arfonad) and other ganglion blocking drugs, as does chlordiazepoxide. Du Cailar, Gestin and Galibert (1966), reporting on the use of diazepam as part of an ataralgesic or neuroleptanalgesic technique, sounded a note of caution concerning the occurrence of slight hypotension and respiratory depression. They commented particularly on the decrease of pulmonary compliance, and these effects may contraindicate its use in patients with hypertension or asthma. Huguenard and Margelidon (1964) described the use of a single rapid injection of 20-30 mg diazepam followed by either local blocks or neuroleptanaesthesia. They commented specifically on the obvious potentiation by diazepam of subsequent doses of barbiturates.

BRITISH JOURNAL OF ANAESTHESIA

THE BENZODIAZEPINES

225 TABLE IV

Percentage incidence of side effects and sequelae after induction with thiopentone, methohexitone and diazepam. Diazepam Methohexitone

0.8

Thiopcntone 4.0

10 0 10 0 5 60 5 0

0 8 4 24 64 5 20 11

0 25 32 8 61 6 23 14

50 mg

Doses in mg/kg

0.6

Not asleep in 1 minute Excitatory phenomena Respiratory upset Hypotension Awake at end Unsafe at end Postoperative vomiting Postoperative nausea

40 0 0 0 0 50 5 5

Large induction doses of diazepam may also enhance the depressed effects of opiates given in the early postoperative period, particularly after short operations. These views are substantiated by a comparison of diazepam and thiopentone as induction agents for unpremedicated patients prior to nitrous oxide-oxygen-halothane (Fox, Synands and Bhambhami, 1968). These workers used doses of 0.33 mg/kg diazepam and 4.1 mg/kg thiopentone. Patients induced with diazepam were slower in going to sleep than those given thiopentone; in some instances, this dose of diazepam did not produce loss of consciousness, although patients were very co-operative and readily accepted the inhalational agents. When used in this manner the cardiovascular effects of the two drugs were comparable, although respiratory depression was less evident after diazepam. Patients induced with diazepam were more drowsy and tended to have longer periods of amnesia postoperatively than diose in the thiopentone series. Reports vary as to the degree of local intolerance following intravenous diazepam. Pain on injection was noted in some of the early French studies (Touchard and Bobin, 1966), as well as by Stovner and Endresen (1966). It was recorded in approximately 25 per cent of the patients studied by McClish (1966), but only in 15 per cent of those given 2 mg/ml or 5 mg/ml by Brown and Dundee (1968). The latter found a 15 per cent incidence of painless localized thrombosis after 35 mg and this increased to 30 per cent after 50 mg. These data were obtained using the original commercial preparation in which glycofurol was the solvent. In a recent paper Baker (1969), using a

1.6

newer solvent, reported superficial venous thrombosis in 15 per cent of patients studied. His adult doses were in the order of 0.4-0.6 mg/kg. He comments that neither the frequency of injection pain nor the incidence of thrombosis was altered. There have been no more serious venous sequelae than painless thrombosis. Diazepam may have a place for certain minor surgical procedures. One such example is uterine evacuation, or similar minor gynaecological procedures. In fit subjects, doses up to 0.5 mg/kg can be given fairly rapidly and will produce good basal sedation. This can be supplemented with nitrous oxide where necessary. Although there may be some slight movement on intense stimulation, this should not interfere with the operation. Doses must be reduced if heavy opiate premedication has been given, or if the patient is suffering from blood loss. Abdominal relaxation is usually good, and pelvic examination can be performed without difficulty. However, in view of the slight tendency to increased salivation with diazepam, atropine should be given preoperatively. It must be appreciated that diazepam will not produce "surgical anaesthesia" of the same order as a barbiturate-nitrous oxide-oxygen sequence, but nevertheless it may be useful on occasions and absence of memory of the procedure will be complete. Another similar, yet unexplored, field is that of examination under anaesthesia. There is, too, a distinct possibility that diazepam may be a valuable adjuvant for the reduction of fractures under local anaesthesia. In a short trial of 21 children, Healy (1969) found that intravenous diazepam produced ideal conditions for cardiac

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35 mg

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BASAL SEDATION WITH DIAZEPAM

Smaller doses of intravenous diazepam cause a useful degree of sedation, which has been used to good purpose in a variety of circumstances. In contrast to the action of the intravenous barbiturates, the effects of this benzdiazepine persist for 30-40 minutes and can be used to make procedures under local anaesthesia more acceptable to patients. Since moderate sedation (as evidenced by drooping of the eyelids or nystagmus) is usually accompanied by amnesia—even though the patient may still be conscious—small doses of diazepam can also be used for procedures such as cardioversion. These uses will all be grouped under the general heading of basal sedation. This is preferred to the most commonly used term, basal hypnosis, since drowsiness is not an essential constituent of sedation. Cardioversion. To avoid anaesthesia in poor-risk cases undergoing cardioversion, where other forms of anaesthesia can be dangerous (Grogono, 1963) and where conscious defibrillation (Stock, 1963) is not thought desirable, or where a competent anaesthetist is not available, it has been suggested that sedation alone be used. In 1965 Nutter and Massumi recommended the use of diazepam ( 5 20 mg intravenously) as an alternative to a barbiturate for these patients, and this dose has since been recommended by Kahler, Burrow and Felig (1967) and by Kernohan (1966). Increments of 2.5-5 mg can be given at 30-second intervals

until slurring of speech or light sleep occurs. At the time of the shock there may be a brief muscle contraction and slight arousal of patients from their quiet state. However, this latter need not cause concern since Kahler, Burrow and Felig (1967) found that 91 per cent of 34 patients had complete amnesia and only 2 experienced any pain or discomfort associated with the procedure. The discomfort was avoided on a later occasion in these patients when the dose of diazepam was increased by 5 mg. Respiratory depression was not obvious in any patient before or after cardioversion, but blood pressure did tend to fall slightly following administration of diazepam. Hypotension was not marked and vasopressors were not required. Although patients could be readily roused and responded to command, they remained drowsy for a variable time following the procedure. In one study in which the effects of thiopentone and diazepam were compared, Muenster and colleagues (1967) induced patients with a slow infusion of 1 per cent thiopentone (250-400 mg) or with 15-20 mg diazepam. All patients received their usual maintenance doses of digitalis during the preceding 48 hours. The cardiac status of the patients was similar in each group and included some with rheumatic, ischaemic or hypertensive heart disease. The electrocardiograph record showed no premature ventricular beats in either series prior to the onset of sleep. Both drugs produced unconsciousness within 3 minutes and, although a few patients momentarily groaned with the countershock, none recalled the event. After induction of anaesthesia, the frequency of premature ventricular beats in the two series was strikingly different. In the half-minute preceding countershock they were recorded in 11 of the 18 patients who were given thiopentone, but in none of the 17 who were given diazepam. The incidence was similar in both series in the 10 seconds immediately following countershock, but later arrhythmias were recorded in 12 of the patients receiving thiopentone and only in 4 who were given diazepam. The eventual conversion rate was unaffected by the anaesthesia. The results of Zsigmond (1969) support the claims for the superiority of diazepam over thiopentone in these cases. He found mat the cardiac output was less depressed with diazepam than

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catheterization in children. There occurred minimal cardiovascular upset or changes in blood carbon dioxide tension, despite the use of heavy opiate-phenothiazine premedication. Baker (1969) suggests additional indications for its use, including cardiac patients, the aged, seriously ill and shocked patients, and where there is a risk from vomiting, such as obstetric patients or those suffering from gut obstruction. He also includes porphyria and status epilepticus, to which the present authors would add surgery for tetanus patients and those undergoing tracheostomy for positive pressure ventilation. Superficial thrombosis could well contraindicate the administration of diazepam during a planned procedure (Baker, 1969).

THE BENZODIAZEPINES with thiopentone in patients with mitral stenosis undergoing cardioversion. The doses used in his study are equivalent to about 30 mg diazepam or 400 mg thiopentone in a 154-lb. (70 kg) subject. The use of diazepam in place of conventional anaesthesia for cardioversion does not remove the need for an expert anaesthetist, for he must still be at hand to carry out respiratory assistance.

Dentistry. The increasing demand for patients to be asleep during dental treatment has been partly met by the administration of intermittent methohexitone to produce "ultra-light" anaesthesia, but there have been disturbing reports about the safety of

this technique (Thornton, 1970). Alternatively the intravenous injection of pentobarbitone, pethidine and scopolamine, as described by Jorgensen and his colleagues (1961, 1963) to produce a state of basal narcosis has had extensive use, with local nerve block. The dentist requires a technique which can be safely used single-handedly in out-patients. It should reduce nervous tension and blunt consciousness and memory of events without suppressing the voluntary efforts and reflexes of the patient. In addition, the agents used should be relatively free from toxic effects, should not depress the circulation or respiration, and should be relatively short-acting, so that the patient may be able to leave soon after treatment. Neither methohexitone nor the Jorgensen technique is ideal in these respects. There have been many reports indicating that the tranquillizing, soporific, and amnesic effects of diazepam when given intravenously, in combination with local analgesia, provide just such conditions. Peabody (1965) employed oral diazepam to premedicate children undergoing dental treatment and reported favourably on its sedative effects. The intravenous use of diazepam for apprehensive dental patients was first described in France by Davidau in 1966. He gave 1020 mg intravenously and noted that the anxiolytic and soporific effects were rapid in onset (3090 seconds). Despite the appearance of sleep, the swallowing and laryngeal reflexes were intact, and the patient reacted to painful stimuli; local analgesia was essential. The duration of these effects was from 15 to 30 minutes and could be renewed by further doses of diazepam without any ill effects. Since these reports, others have commented on the efficacy and safety of diazepam for the nervous dental patient. Brown, Main and Murray Lawson (1968) have been pioneers in this field since 1966, and in a recent paper they report their findings in 108 patients treated with diazepam intravenously. All were prepared as for general anaesthesia and treated in the supine position. Atropine 0.4 mg was given intravenously, followed by diazepam injected at a rate of 5 mg/min. Early in the series, a dose of 10 mg for adults was rarely exceeded and small (50-60 mg) doses of methohexitone were given to "cover" injection of the local

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Endoscopy. The success of any procedure carried out under local analgesia will depend on the degree of cooperation of the patient, and this can be improved by diazepam. In addition, its amnesic effect is of great benefit. Rogers and his colleagues (1965) obtained good results in 94 per cent of 201 patients who were given 5—10 mg diazepam intravenously prior to bronchoscopy under local analgesia. They found that a certain amount of muscle relaxation occurred which facilitated the procedure. The amnesic effects of diazepam were marked, and though most patients could recall the administration of the topical analgesic, they had little memory of the remainder of the procedure. Intravenous diazepam (10 mg) and pethidine (100 mg) were used by Ticktin and Trujillo (1965) prior to oesophagoscopy and gastroscopy in 204 patients, without local analgesia. Conditions were graded as good or excellent in 90 per cent of cases, even though there was some coughing and gagging when the endoscope was first introduced. This combination of pethidine and diazepam caused a comatose state for approximately 20-45 minutes in 6 elderly patients, without apparent respiratory or cardiovascular depression, and another 2 patients required treatment for moderate respiratory depression. In 6 patients, in whom diazepam was administered alone, there was diminution of anxiety and muscle tone relaxation, but the gag reflex was not suppressed and a satisfactory endoscopic examination could not be performed. Ideally diazepam should be used with topical anaesthesia.

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Keilty and Blackwood (1969) had similar results using diazepam alone followed by local anaesthesia for prolonged dental conservation in 40 patients. Their patients, who were all very apprehensive, either had refused to have treatment under local analgesia alone or were quite unmanageable during previous attempts. Atropine was not given in this series, and salivation was not troublesome. No depression of respiration or circulation was encountered. The amnesic effects of diazepam were again marked in this series, and few patients had any memory of the injection of the local anaesthetic, even though they may have reacted at the time by grimacing or clenching their fists (table II). This amnesic effect has also been noted by Poswillo (1967). The doses of diazepam recommended by Brown, Main and Murray Lawson (1968) and by Keilty and Blackwood (1969) were mostly in the 10-20 mg range for adults (approximately 1 mg/ 5 kg) which is less than the 0.3 mg/kg recommended by O'Neil and Verrill (1969). Adequate dosage results in the upper eyelid covering half of the pupil, and O'Neill et al. (1970) used the occurrence of ptosis as a suitable end-point to judge their ideal dose of diazepam. Although the soporific effects of small doses of diazepam are relatively short-lived, and most patients appear to be quite awake after 30-40

minutes, the anxiolytic effects seem to last much longer. Patients must not therefore be allowed to go home unaccompanied and, as mentioned previously, care should be taken lest the occasional patient develop hypotonia following the drug. Diazepam is a useful sedative to "cover" local analgesia during out-patient dentistry for adults; but the response is very variable and it should therefore be given slowly (5 mg/min) and should never be employed to produce deep levels of sedation. Although hypotension following large doses of diazepam is rare, some workers have noted this complication (Rollason, 1968) and the supine position should be adopted when it is given, even though the sitting position may be preferred by the operator. The musde relaxant properties of diazepam may be useful in the treatment of trismus following dental extraction. Sorabjee (1967) reported a case which responded to oral treatment with the drug. USE IN THE POSTOPERATIVE PERIOD

The amnesic action of intravenous diazepam has been used with advantage to minimize psychiatric reactions following open-heart surgery. McQish, Andrew and Tetreault (1968) found that about one-third of patients developed psychiatric complications when they were subjected to postoperative mechanical ventilatory support following open-heart surgery. However, in another group of patients who received the usual postoperative analgesic medication, supplemented by intravenous doses of 2.5—5 mg diazepam six times a day, the incidence was reduced to under 5 per cent. This latter group had better patient behaviour and improved patient-nurse and patient-doctor relationships. Because of its amnesic properties, these authors recommend the use of diazepam as a sedative in intensive care units. In the management of postoperative excitement when standard methods of sedation had failed, Cushman (1966) found that an intravenous injection of 10 mg diazepam produced immediate sleep without disturbances of blood pressure or respiration. This was particularly valuable in patients who had undergone genito-urinary operations and in those with head injuries. Bruce (1968) also found diazepam to be useful as a postoperative "analgesic", but in view of Cushman's findings.

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anaesthetic. When the effect of this latter had worn off the operation was started. In later cases methohexitone was omitted and the dose of dia2epam increased. The end-point taken to denote a satisfactory depth of sedation was a drowsy patient who had slurred speech but who was still able to respond to requests. The average adult dose needed to produce this effect was 17 mg, and the maximum dose used was 20 mg. All patients were kept in the recovery room for about 1 hour after completion of the procedure, then accompanied home by a responsible adult and warned not to drive nor to operate machinery for the rest of the day. Of 108 patients, only 5 in the early series commented that the experience had been unpleasant or diat they felt pain. The authors comment on the marked amnesia, patients failing to recall the injection of local anaesthetic or details of the procedure. Recovery was fairly rapid, and all patients were able to leave about an hour after the end of treatment.

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THE BENZODIAZEPENES

THE MANAGEMENT OF CONVULSIONS

Tetanus. In view of the muscle-relaxant effects of diazepam, already described, it is not surprising that this drug has been used to control the muscle rigidity and spasms in patients with tetanus. Other agents, such as mephenesin and chlorpromazine, have a similar action on the spinal internuncial neurones. These latter two drugs produce some amelioration of symptoms in mild cases, but they do not control the rigidity and convulsions if the disease is severe. Furthermore, they have toxic effects when used in high dosage, and today curarization and intermittent pressure ventilation is the treatment of choice in severe cases. Nevertheless, diazepam, when used in properly selected cases, can play an important part in the management of tetanus. The first reported use of diazepam in tetanus was by Shershin and Katz (1964) and by Weinberg (1964). Both reports dealt with a single case where the patients responded dramatically to the use of diazepam, with reduced spasms and rigidity, and recovery occurred on both occasions. Complications due to the toxic effects of the diazepam did not occur. The two largest reports to date have come from Nigeria, and deal with neonatal tetanus or tetanus in young children. Hendrickse and Sherman (1966) compared die use of diazepam, combined widi phenobarbitone and chlorpromazine, with phenobarbitone and chlorpromazine alone. Their total series included 159 patients, of whom 104 were neonates. The drugs were given by a nasogastric tube, and although die mortality rate was unaffected by its use, diazepam was effective in relieving rigidity, particularly that of jaw muscles.

The dosage required was as high as 4.4 mg/kg/ 24 hours. In older children, the overall mortality rate was not lowered significandy by the use of diazepam, but, as in die neonates, the drug did relieve tonic spasm. It had little effect on reflex convulsions following minor stimuli. Aldiough diere were no toxic effects attributable to diazepam, hypodiermia tended to occur when it was given to neonates. A further report by Femi-Pearse (1966) refers to die use of diazepam in 42 adolescents and young adults widi tetanus. In 17 patients it was given alone, and in die remaining 25 was combined widi varying doses of barbiturates. Apart from an initial intramuscular or intravenous injection, die diazepam was given by a nasogastric tube in doses ranging from 2.4 to 9.3 mg/kg for 24 hours, depending on die severity of die tetanus. In some instances the dose was extremely high, e.g. a 3-kg neonate was given 40 mg/kg daily for 3 days, while a 75-kg man received 30 mg/kg of diazepam plus a barbiturate daily. This audior also found diat diazepam was very effective in controlling muscle rigidity, but was less effective in reducing reflex muscle spasms, and this failure was responsible for 3 of die 6 deaths in die series. Toxic effects were minimal even after very large doses, and diere was no respiratory or circulatory depression. Four patients developed severe behavioural changes during recovery, but these changes disappeared widiin 2-3 days of stopping diazepam. Diazepam is a very useful sedative, not only in patients widi tetanus, but for odier patients requiring prolonged artificial ventilation. Here amnesia is a very prominent feature of its action and doses can be as high as 10 mg/hour if required. For long-term use die intravenous route is preferred, because of die risks of tissue damage from large doses of organic solvent. The authors have given it by continuous infusion—50 mg added to each 0.5 litre infusion solution—for 30 days (total dose of over 6 g) widi no obvious ill effects. However, tolerance developed to its soporific action, but despite diis it remained a useful sedative diroughout the period of its use. The drug can also be given orally early in mild tetanus in doses similar to those employed intravenously, or by nasogastric tube in more severe or in curarized cases.

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it is difficult to decide how much of this is attributable to its soporific effect. Caution should be exercised in its use too early in the postoperative phase, particularly in patients who have received heavy opiate medication before or during anaesthesia. The long-term use of diazepam in the postoperative period is possibly indicated in patients with overriding fractures. Its muscle-relaxant properties overcome the spasm associated with this type of injury (Kestler, 1963).

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Parsonage and Norris (1967) employed diazepam in the treatment of severe status epilepticus in 9 patients. Immediate control of convulsions was obtained in 7 of these with an initial dose of 10 mg of diazepam, and this was followed by intravenous infusion of 100 mg in 500 ml of saline solution, given as required. In the earlier cases doses were restricted to about 30 mg of diazepam daily, given by intravenous or intramuscular injection, but this achieved only temporary control of convulsions. A hypnotic effect was noted in most of these patients when more dian 10 mg diazepam were given. Tolerance usually became evident widiin 24 hours of beginning an intravenous infusion, and appeared to be related to the total dose of diazepam given. Both chlordiazepoxide and diazepam have been used in die management of eclampsia, and their

actions have been compared by Lean, Ratnam and Sivasamboo (1968). Their initial intravenous dose of diazepam was 40 mg followed by an infusion of 40 mg in 500 ml dextrose, with supplementary doses of 20 mg as required. This apparently produced good sedation and control of convulsions, although the authors preferred chlordiazepoxide because that drug was less variable in its action. DIAZEPAM IN OBSTETRICS

Diazepam has been widely used for sedation in labour, for induction of anaesthesia, and as a sole agent during certain obstetric procedures. Rouchy and his colleagues (1966) employed 10 mg intravenously during labour and commented favourably on die relief of anxiety and tension and on die amnesia it produced. They also used it for induction of anaesdiesia for such operations as Caesarean section. Blanc and Miliani (1966) have described its use prior to simple perineal repairs and curettages, while Bepko, Lowe and Waxman (1965) gave 20-40 mg diazepam intramuscularly or intravenously to 81 women in labour. The drug produced no untoward effects upon the mothers or infants and markedly reduced apprehension and pain. Furthermore, it blurred die memory for die event. In diese doses diazepam had no apparent influence on die Apgar score of die neonates or upon the lengdi of labour. As equilibrium between maternal and foetal blood levels is complete widiin a few minutes (Bepko, Lowe and Waxman, 1965), it is conceivable that large doses may lead to drowsiness in die newborn. This has not been reported to date, but is a potential hazard, as is hypotonia of die infant. OXAZEPAM

Oxazepam is a breakdown product of diazepam and it has been suggested that it is die active constituent through which the latter exerts its action. It is not surprising diat the effects of the two benzodiazepines are very similar. However, die use of oxazepam has been limited almost entirely to psychiatric practice, and its potential use in anaesthetic practice does not appear to have been investigated. (This may in part be due to its being available only in tablet form.) It is generally claimed that oxazepam, like diazepam, has die ability to alter emotional reac-

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Other convulsive states. The anticonvulsant action of the benzodiazepines has already been discussed. As diazepam will abolish the seizure discharge in the electroencephalograph within a few seconds of administration, it is not surprising that there have been numerous reports on its efficacy as an anticonvulsant agent in the treatment of status epilepticus (Gastaut et al., 1965; Lombroso, 1966) both in adults and in children. Gastaut and his colleagues reported complete relief of status epilepticus in 12 of 15 patients, following the intramuscular or intravenous administration of diazepam 10 mg, repeated as necessary. Control of the seizures was usually complete within 20 seconds of intravenous injection, or within a few minutes when die drug was given intramuscularly. However, diazepam was less effective in the treatment of status epilepticus due to traumatic or cerebral vascular lesions. To keep control of diese patients, they also used doses of up to 100 mg daily given by slow intravenous infusion. There were no toxic effects due to the drug except in die case of a 9-mondis-old infant who developed respiratory insufficiency following the injection of 6 mg of diazepam. Electroencephalographic monitoring was carried out by Lombroso who employed diazepam in the treatment of various forms of status epilepticus in 27 children, using intravenous doses varying from 2.5 to 10 mg. His results were encouraging, and again he found few side effects attributable to the diazepam.

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THE BENZODIAZEPINES

NITRAZEPAM

This is die most recent of die benzdiazepines in clinical use and it shares many of die properties of die otiier compounds. Like die odier members of diis group, it has been employed in psychiatry, because of its anxiolytic and tension-reducing properties, and also to facilitate communication in anxious patients. It has also been used in combination widi mediylamphetamine for major abreactive reactions (Bediune et al., 1966). However, die major clinical use of nitxazepam is as a hypnotic. A number of workers have studied its efficacy in comparison widi odier hypnotics and concluded diat 5-10 mg nitrazepam compares favourably widi 200 mg sodium amylobarbitone and 250 mg glutediimide (Peck and Shervington, 1966; Haider, 1968). When given at night it did not cause die morning hangover associated widi die odier compounds, although, in a few patients, it produced a resdess sleep during which pleasant dreams were experienced. The

greatest advantage of nitrazepam, in relation to odier hypnotics is its safety in overdosage. Matthew et al. (1969) report 27 instances of acute overdose widi no untoward effects, even when 80 tablets (400 mg) were consumed. These experienced workers carried out a double-blind comparison of 5 mg nitrazepam widi 100 mg butobarbitone and concluded diat die former was a safe hypnotic and as effective as die barbiturate. In contrast to die odier benzdiazepines, which are useful anticonvulsants, nitrazepam may induce grand mal and petit mal in patients who are prone to diese attacks (Zbinden and Randall, 1967). Its premedicant use has been described by many workers, mainly for "pre-premedication", given on die night before operation in order to ensure a sound night's sleep. This seems to be produced by an anxiolytic radier than direct soporific effect (Alder, 1965; Troch, 1965). More recendy Norris and Telfer (1969) studied die efficacy of 5 and 10 mg doses, given at least 1 hour before operation, widi diat of a tablet containing 250 mg mediaqualone and 25 mg diphenhydramine (Mandrax). Bodi doses of nitrazepam and Mandrax appeared to be equally effective and useful as hypnotic premedicants. They comment diat die use of nitrazepam, belonging to a class of drugs claimed specifically to relieve anxiety, produces sedation no better and no worse dian a drug used specifically as a hypnotic. Odier uses of nitrazepam include prevention of travel sickness, when odier sedatives have failed, particularly in children (Bediune et al., 1966). Its muscle-relaxant properties have also been used therapeutically for symptomatic relief in neuromuscular disease and disseminated sclerosis (Zbinden and Randall, 1967). CONCLUSION

The benzodiazepines represent a group of new drugs whose full potentialities in anaesdiesia have yet to be realized. Chlordiazepoxide is, however, already established as a tranquillizer but may well be superseded, in anaesdietic practice at least, by diazepam. This latter more powerful agent is not only of value in providing profound sedation, it has also found an assured place in die treatment of status epilepticus. Nitrazepam is an established hypnotic. The realization of such odier potentialities as it may have has so far been

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tions and is effective in controlling a wide range of stress symptoms in all patients, without affecting their mental faculties or physical activity. Many controlled and uncontrolled trials of oxazepam have been carried out, comparing it with either a placebo, chlordiazepoxide or diazepam, and the conflicting findings of these will not be discussed in detail here. The lack of agreement is illustrated by die study of Nesselhof et al. (1965) who found that neidier oxazepam nor diazepam was better than a placebo in helping psychoneurotic patients who had anxiety as a predominant symptom, and by the work of Le Gassick and MePherson (1965) who found similar doses of oxazepam to be significandy better than a placebo in die same circumstances. Other workers (Tobin, Lorenz and Brousseau, 1964) could not readily distinguish between die effects of oxazepam and comparable doses of chlordiazepoxide but bodi of these were better than a placebo. As stated previously, die main claim for oxazepam is diat it produces its tranquillizing action widi fewer side effects dian comparable doses of diazepam or chlordiazepoxide. However, complications are rare widi die doses of diese latter two drugs which are used in anaesdietic practice, and die need for a safer substitute is doubtful.

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hindered by the lack of an injectable preparation. Whether oxazepam will be of value in anaesthesia remains to be seen. REFERENCES

Klin. Wschr., 76, 884. Bush, G. H. (1968). Diazepam as a premedication in children; in Knight, P. F., and Burgess, C. G. (eds.), Diazepam in anaesthesia, p. 33. Bristol: Wright. Buskop, J. J., Price, M., and Molnar, I. (1967). Untoward effect of diazepam. New Engl. J. Med., 277, 316. Campan, L., and Espagno, M. T. (1964). Note sur le diaz:pam en anesthesiologie. Ann. anesth. franc., 5, 711. Cavanagh, D., and Condo, C. S. (1964). Diazepam: a pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood. Curr.

Therap. Res., 6, 122. Cormier, A., Goyette, M., Ke£ri-Szint6, M., and Rheault, J. A. (1966). A comparison of the action of meperidine and diazepam in anaesthetic premedication. Canad. Anaesth. Soc. J., 13, 368. Cushman, R. P. A. (1966). Diazepam in intravenous anaesthesia. Lancet, 1, 1042. Davidau, A. (1966). La premedication pour les malades difEciles ou sur les seances de soins tres longues. Rev. Stomat. (Paris), 67, 589. De Silva, J. A. F., D^Arconte, L., and Kaplan, L. (1964). The determination of blood levels and the piaccntal transfer of diazepam in humans. Curr therap. Res., 6, 115.

Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on November 16, 2014

Alder, A. (1965). Mogadon in premedication for anaesthesia. Praxis, 54, 365. Aquado, M. A., and Aquerreta, M. L. E. (1964). Neuroleptanalgesia with Valium Plus Dextromoramide (71 clinical observations). Ann. anesthes. Franc., 5, 722. Baker, A. B. (1969). Induction of anaesthesia with diazepam. Anaesthesia, 24, 388. Bepko, F., Lowe, E., and Waxman, B. (1965). Relief of the emotional factor in labour with parenterally administered diazepam. Obstet. and Gynec, 26, 852. Bethune, H. C , Burrell, R. H., Culpan, R. H., and Ogg, G. J. (1966). Preliminary notes on nitrazepam. N2.. med. J., 65, 409, 613. Blanc, B., and Miliani, P. (1966). Utilisation of valium in obstetrics. Gynec. Obstet. (Paris), 18, 296. Brandt, A. L., Lui, S. C. Y., and Briggs, B. D. (1962). Trial of chlordiazepoxide as a pre-anesthetic medication. Anesth. Analg. Curr. Res., 41, 557. Oakes, F. D. (1965). Pre-anesthesia medication: double blind study of a new drug, diazepam. Anesth. Analg. Curr. Res., 44, 125. Brown, P. R. H., Main, D. M. G., and Murray Lawsoo, J. I. (1968) Diazepam in dentistry. Brit. dent. J., 125, 498. Brown, S. S., and Dundee, J. W. (1968). Clinical studies of induction agents. X X V : Diazepam. Brit. J. Anaesth., 40, 108. Bruce, I. S. (1968). Postoperative use of diazepam; in Knight, P. F., and Burgess, C G. (eds.), Diazepam in Anaesthesia, p. 89. Bristol: Wright. Bruha, H. (1964). Ein Bitrag zur vorberutung der patienten bei augenarzthschen eingriffen. Wien.

Dowell, T. (1966). Diazepam in intravenous anaesthesia. Lancet, 1, 369. Du Cailar, J., Gestin, Y., and Galibert, A. M. (1966). Utilisation du diazepam (Valium) comme agent narcotique d'induction au cours de narco-ataralgesie. Arm. anesth. franc., 7, 203. Rioux, J., Bellanger, A., and Grolleau, D. (1964). Utilisation of diazepam (Valium) in premedication. Ann. anesth. franc., 5, 706. Dundee, J. W., Haslett, W. H. K., Keflty, S. R., and Pandit, S. K. (1970). Studies of drugs given before anaesthesia. X X : Diazepam-containing mixtures. Bra. J. Anaesth., 42, 143. Isaac, M., Clarke, R. S. J. (1969). Use of alcohol in anaesthesia. Anesth. Analg. Curr. Res., 48, 665. Taggart, J., and Howard, P. J. (1969). Antagonism to intravenously administered ethanol by chlordiazepoxide (Librium). Proceedings of the 5th International Congest on Alcohol and Traffic Safety, Freiburg, 1969. Keilty, S. R. (1969). Diazepam; chapter in The Newer Intravenous Anesthetics (ed. R. S. J. Clarke). International Anesthesiol. d i n . , 7, 91. Loan, W. B., and Morrison, J. D . (1970). Studies of drugs given before anaesthesia. X I X : The opiates. Brit. J. Anaesth., 42, 54. Farb, H. H. (1963). Intravenous diazepam as preinterview medication fa clinical note). Dis. nerv. Syst., 24, 233. Femi-Pearse, D. (1966). Experience with diazepam in tetanus. Brit. med. J., 2, 862. Fox, G. S., Synands, J. E., and Bhambhami, M. (1968). A Hiniral comparison of diazepam and thiopentone as induction agents to general anaesthesia. Canad. Anaesth. Soc. J., 15, 281. Gastaut, H., Naquet, R., Pire, R., and Tassinari, C. A(1965). Treatment of status epilepticus with diazepam (Valium). Epilepsia, 6, 167. Grogono, A. Q. (1963). Anaesthesia for atrial defibrillation. Effects of quinidine on muscle relaxation. Lancet, 2, 1039. Haider, I. (1968). A double-blind controlled trial of a non-barbiturate hypnotic nitrazepam. Brit. J. Psychiat., 114, 337. Haq, I. U., and Dundee, J. W. (1968). Studies of drugs given before anaesdiesia. X V I : Oral diazepam and trimeprazine for adenotonsiUectomy. Brit. J. Anaesth., 40, 972. Haslett, W. H. K., and Dundee, J. W. (1968). Studies of drugs given before anaesthesia. XIV: Two benzdiazepine derivatives chlordiazepoxide and diazepam. Brit. J. Anaesth., 40, 250. Healy, T. E. J. (1969). Intravenous diazepam for cardiac catheterisation. Anaesthesia, 24, 537. Hendrickse, R. G., and Sherman, P. M. (1966). Tetanus in childhood: report of a therapeutic trial of diazepam. Brit. med. J., 2, 860. Howard, F. M. jr. (1963). A new and effective drug in the treatment of the stiff-man syndrome: preliminary report. Proc. Mayo Clin., 38, 203. Huguenard, J., and Margelidon, L. D . (1964). Deux indications particulieres du diazepam injectable (induction de la neuroplegie—complement dc 1 analgesic peripherique). Ann. anesth. franc., 5, 731. Hunter, A. R. (1967). Diazepam (Valium) as a muscle relaxant during general anaesthesia: a pilot study. Brit. J. Anaesth., 39, 633.

THE BENZODIAZEPINES

233

Inglis, J. M., and Barrow, M. E. H. (1965). Predemica-

Norris, W., and Telfer, A. B. M. (1969). Nitrazepam in premedkation. Brit. J. Anaesth., 41, 877. 29. Nutter, D. O., and Massumi, R. A. (1965). Diazepam Jaquenoud, P., and Sauvan, A. (1966). Premedkation in cardioversion. Neto. Engl. J. Med., 273, 650. orale Le Mogadon (Ro 4-5360). Arm. anesth, O'Neill, R., and Verrill, P. J. (1969). Intravenous franc., 7, 37. diazepam in minor oral surgery. Brit. J. oral Jorgensen, N. B., Bums, A. E., and Gamboa, G. (1963). Surg., 7, 12. A rlinirnl report on premedication from the oral Aellig, W. H., and Laurence, D. R. (1970). surgery clinic of Loma Linde University School of dentistry. J. Sth. Cdif. St. dent. Ass., 31, 7. Further studies of intravenous diazepam in minor Leffingwell, F. (196l). Premedication in dentistry. oral surgery. Brit. dent. J. (in press). Dent. Clin. N. Amer., 5, 299. Parsonage, M. J., and Norris, J. W. (1967). Use of Kahler, R. L., Burrow, G. N., and Felig, P. (1967). diazepam in treatment of severe convulsion status Diazepam-induced amnesia for cardioversion. J. epilepticus. Brit. med. J ., 3, 85. Amer. med. Ass., 200, 997. Katz, J., Finestone, S. C , and Pappas, M. T. (1967). Peabody, J. B. (1965). Premedicating petodontic Circulatory response to tilting after intravenous patients. Tex. dent. J., 83, 12. diazepam in volunteers. Anesth. Analg. Curr. Res., Peck, J. E., and Shervington, P. C (1966). Trial of a 46, 243. new sleep-inducing agent. J. Therap., 1, 25. Keilty, S. R., and Blackwood, S. (1969). Sedation for conservative dentistry. Brit. J. din. Pract., 23, 365. Poswillo, D. (1967). Intravenous amnesia for dental Kemohan, R. S. (1966). Diazepam in cardioversion. and oral surgery. N.Z. dent. J., 63, 265. Lancet, 1, 718. Randall, L. O., Heise, G. A., Schallek, W., Bagdon, Kestler, O. C. (1963). The effect of diazepam in the R. E., Banziger, R., Boris, A., Moc, R. A., and treatment of over-riding fractures. West. Med., 4 Abrams, W. B. (1961). Pharmacological and (•Supplement). clinical studies on Valium, a new psychotheraLanot, G. (1964). Note sur les effects "Protecteurs" du peutic agent of the benzdiazepine class. Curr. diazepam. Ann anesthes. franc., 5, 731. therap. Res., 3, 405. Lean, T. H., Ratnam, S. S., and Sivasamboo, R. (1968). Schallek, W., Heise, G. A., Keith, E. P., Use of benzdiazepines in the management of and Bagdon, R. E. (1960). The psychosedative eclampsia. J. Obstet. Gynaec. Brit. Comm., 75, properties of methaminodiazepoxide. J. Phar856. macol, exp. Ther., 129, 163. Le Gassicke, J., and McPherson, F. M (1965). A Rogers, W. K., Waterman, D. H., Domm, S. E., and sequential trial of Wy 3498 (Oxazepam). Brit. J. Sunay, A. C1965). Efficacy of a new psychotropic Psychim., I l l , 521. drug in bronchoscopy. Dis. Chest, 47, 280. Lombroso, C T. (1966). Treatment of status Rollason, W. N. (1968). Diazepam as an intravenous epilepticus with diazepam. Neurology (Mirmeap.), induction agent for general anaesthesia; in Knight, 16, 629. P. F., and Burgess, C. G. (eds.), Diazepam in Marsh, H. O. (1965). Diazepam in incapacitated Anaesthesia, p. 70. Bristol: Wright. cerebral-palsied children. J. Amer. med. Ass., 191, Rouchy. R., Blondeau, P., Le CanneUer, R., Creze, J., 797. and Grosieux, P. (1966). Diazepam by the intraMatthew, H., Proudfoot, A. T., Aitken, R. C B., venous route in obstetrics. Presse med., 74, 312. Raeburn, J. A., and Wright, N. (1969). NitrazeSadove, M. S., Balagot, R. C , and McGrath, J. M. pam: a safe hypnotic. Brit. med. J., 3, 23. (1965). Effects of chlordiazepoxide and diazepam McQish, A. (1966). Diazepam as an intravenous inon the influence of meperidine on the respiratory duction agent for general anaesthesia. Canad. response to carbon dioxide. J. New Drugs, 5, 121. Anaesth., Soc. J., 13, 562. Andrew, D., and Tetrault, L. (1968). Intravenous Shershin, P. H., and Katz, S. S. (1964). Diazepam in the treatment of tetanus: report of a case followdiazepam for psychiatric reactions following opening tooth extraction. Clin. Med., 71, 362. heart surgery. Canad. Anaesth. Soc. J., 15, 63. Morris, H. J., Nelson, A. A., and Calvery, H. O. (1942). Sorabjee, S. E. (1967). A case of trismus following dental extraction treated with diazepam. E. Afr. Observations on the chronic toxicities of propylene med. J., 44, 186. glycol, ethylene glycol, diethylene glycol, ethylene glycol mono-ethyl-ether, and diethylene glycol Steen, S. N., and Hani, D. (1969). Controlled evaluamono-ethyl-ether. J. Pharmacol, exp. Ther., 74, tion of parenteral diazepam as preanesthetic 266-273. medication. Anesth. Analg. Curr. Res., 48, 4, 549. Muenster, J. J., Rosenberg, M. S., Carleton, R. A., Weitznel, S. W., Amaha, K., and Martinez, and Graettinger, J. S. (1967). Comparison between L. R. (1966). The effect of diazepam on the diazepam and sodium thiopental during DC respiratory response to carbon dioxide. Canad. countershock. J. Amer. med. Ass., 199, 758. Anaesth. Soc. J., 13, 374. Murray, W. J., Bechtoldt, A. A., and Bennan, L. Stock, R. J. (1963). Cardioversion without anesthesia. (1968). Efficacy of oral psychosedative drugs for New. Engl. J. Med., 269, 534. preanesthetic medication. J. Amer. med. Ass., Stovner, J., and Endresen, R. (1965). Diazepam in 203, 327. intravenous anaesthesia. Lancet, 2, 1298. Nesselhof, W. jr., Gallant, D. M., and Bishop, M. P. (1966). Intravenous anaesthesia with dia(1965). A double-blind comparison of WY-3498, zepam (Proc. 2nd European Congress of Anaesdiazepam and placebo in psychiatric outpatients. thesiology). Acta anaesth. scand., Suppl. 24, 223. Amer. J. Psychiat., 121, 809. Svenson, S. E., and Gordon, L. E. (1965). Diazepam: a progress report. Curr. Therap. Res., 7, 367. tion:

a reassessment PTOC. roy. Soc. Med., 58,

Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on November 16, 2014

234

BRITISH JOURNAL OF ANAESTHESIA Touchard, P., and Bobin, P. (1966). Contribution a l'etude deg Diazepam en Anaesthesiologie. Anesth. Analg. Reanxm., 23, 599. Towler, M. L. (1962). The clinical use of diazepam in anxiety states and depression. J. Neurol. Psychiat., 3, 568. Troch, E. (1965). Comparative study of Mogadon and other sedatives given in the evening before surgical intervention. Acta anaesth. belg., 16, 111. Weinberg, W. A. (1964). Control of the neuromuscular and convulsive manifestations of severe systemic tetanus: case report with a new drug, Valium (diazepam). Clm. Pediat., 3, 226. Zbinden, G., and Randall, L. O. (1967). Pharmacology of benzdiazepines: laboratory and clinical correlations. Advanc. Pharmacol., 5, 213. Zsigmond, E. K. (1969). Diazepam. Paper read at Symposium on diazepam. Jersey City Medical Center, New Jersey, November 1969.

FACULTY OF ANAESTHETISTS, ROYAL COLLEGE OF SURGEONS IN IRELAND, STEPHENS GREEN, DUBLIN 2 Scientific Meeting: Saturday, May 23, 1970 PROVISIONAL PROGRAMME

9.45 a.m.

Introduction, by the Dean, Dr. Raymond Davys.

9.55 ajn.

"The Story of Oxygen", Professor Ethna Gaffney (Dublin).

10.15 ajn. 11.00 ajn.

"The Basis of Oxygen Therapy including Hyperbaric Oxygen", Dr. Iain McA. Ledingham (Glasgow). COFFEE

11.30 ajn.

"Operative and Postoperative Oxygen Tensions", Dr. S. Morrell Lyons (Belfast).

12.15 p.m.

"Oxygen Tensions in Infants", Dr. Peter McGovern (Dublin).

12.45 pjn.

2.15 pjn.

LUNCH

"Underwater Medicine", Surgeon Commander E. E. P. Barnard, R.N. (Alverstoke).

2.55 pjn.

"Oxygen Therapy and Equipment", Dr. David Seigne (Cork).

3.25 pjn.

Panel Discussion—Chairman: Professor Robert D. Dripps (Philadelphia). TEA

The Symposium fee will be £1 11s. 6d. which includes Lunch, Tea, and Coffee. Tickets may be obtained on application to the Secretary, Faculty of Anaesthetists, Royal College of Surgeons in Ireland, Stephens Green, Dublin 2. RAYMOND DAVYS, Dean

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Thornton, J. A. (1970). Methohexitone and its application in dental anaesthesia. Brit. J. Anaesth., 42, 255. Thuries, J., and Poncet, M. fl964). Etude dinique d'un nouveau rranquillisant le diazepam ou Ro 5-2807 (Valium) en medication pre-anaesthesique. Arm. anesthesiol. franc., 5, 389. Ticktin, H. E., and Trujillo, N. P. (1965). Evaluation of diazepam for pre-endoscopy medication. Amer. J. dig. Dis., 10, 979. Tobin, J. M., Lorenz, A. A., and Brousseau, E. R. (1964). Clinical evaluation of oxazepam for the management of anxiety. Dis. nerv. Syst., 25, 689. Tornetta, F. J. (1963). Clinical evaluation of injectable librium in pre-anesthetic medication. Anesth. Analg. Curr. Res., 42, 463. (1965). Diazepam as pre-anesthetic medication: a double-blind study. Anesth. Analg. Curr. Res., 44, 449.