Comparison of the efficacy of chlormethiazole and diazepam as i.v. sedatives for supplementation of extradural anaesthesia.

The clinical efficacy of two sedative agents was compared in 21 young healthy patients undergoing surgery under extradural blockade. A state of sedation and amnesia in which patients lapsed into a sleep-like state when left undisturbed, yet spontaneously opened their eyes to make comments and co-operate with verbal commands, was sought. This was achieved readily by careful titration of responses and required a diazepam loading dose of 20 (+/- 15) mg given at a rate of 1 mg min-1 or 0.8% chlormethiazole edisylate infusion 10 ml min-1 given over 16 (+/- 6) min. Control of this state was easier with chlormethiazole (by varying the rate of infusion) than by giving repeated doses of diazepam. Both agents provided good anterograde amnesia; there was no retrograde amnesia. Considerable postoperative somnolence with a high incidence of relapse into amnesic and sedated states were noted with both agents. However, if the total volume of chlormethiazole infused was less than 300 ml, then a distinct advantage of abrupt and lucid recovery was apparent. Blood concentrations producing the desired clinical state were more variable for diazepam than for chlormethiazole.

Failure of IV atropine to abolish nasal irritation caused by chlormethiazole infusion in elderly patients undergoing spinal anaesthesia.

The efficacy of intravenous atropine in abolishing the nasal irritation of chlormethiazole was assessed. Forty elderly patients undergoing transurethral resection of prostate under spinal anaesthesia were studied. One ml of either atropine sulphate (0.6 mg) or normal saline was administered intravenously in a double-blind fashion 10 minutes prior to infusion of 0.8% chlormethiazole edisylate. A loading infusion of 5 ml X min-1 of the chlormethiazole solution was followed by a variable rate of infusion in order to maintain a predetermined state of sedation--i.e. where the patient lapsed into sleep but was easily awakened to obey commands. Sneezing was the commonest side-effect occurring in 45% and 70% of patients in atropine and saline groups respectively. This was not effectively abolished by IV atropine in incremental doses of 0.6 mg up to 1.8 mg. Because of the sneezing and restlessness, four patients in the atropine group required general anaesthesia to improve operating conditions. These side-effects of chlormethiazole may limit its use as a sedative for surgery in this elderly age group.

Effect of lateral posture on epidural blockade for surgery.

In a prospective double-blind study, single-dose lumbar epidural blockade was administered to 60 healthy patients undergoing lower abdominal surgery, the patients lying in the lateral position only during the time of injection of the local anaesthetic. Solutions used were bupivacaine HCl 0.5%, lignocaine HCl 2% and lignocaine-bupivacaine mixtures in the ratios of 1:3, 1:1 and 3:1 by volume. Data were pooled and analysed for the effects of posture on epidural blockade. Using skin temperature as a criterion of sympathetic blockade, onset of blockade was more rapid and there was more prolonged blockade on the dependent side. Initial onset of sensory blockade was faster on the dependent side by 1 minute and 3.1 minutes for partial and complete blockade, respectively. Mean duration of sensory blockade was longer in the dependent dermatomes for partial (14, SD 7, minutes, T6-L4) and complete blockade (20, SD 6, minutes, T8-L3) respectively. Initial onset of complete motor blockade was 5 minutes more rapid on the dependent side, with mean myotome score consistently greater at all time intervals on the dependent side. Our study therefore suggests that a more efficacious sensory and motor blockade could be achieved by lying the patient on the operative side during the administration of the epidural and injection of the local anaesthestic solution close to the operative dermatomes.

Minimal haemolytic effects from 0.8% chlormethiazole infusion in volunteer subjects. Chlormethiazole infusion and haemolysis.

A solution of 0.8% chlormethiazole ethanedisulphonate was infused into the antecubital vein of 14 healthy volunteers for periods ranging from 60 to 120 minutes to examine any haemolytic effects in vivo. Plasma haptoglobin and haemopexin concentrations were measured before, during and after infusion. No evidence of intravascular haemolysis of any clinical significance was found.

Lidocaine and bupivacaine mixtures for epidural blockade.

In a prospective double-blind clinical study, single-dose lumbar epidural blockade was instituted in 60 healthy patients undergoing lower abdominal surgery. Patients were randomly assigned to one of five groups. Each group received treatment with a different local anesthetic solution containing 1:200,000 epinephrine. Local anesthetic solutions used were 0.5 per cent bupivacaine HCl, 2 per cent lidocaine HCl, and lidocaine-bupivacaine mixtures in the ratios of 1:3, 1:1 or 3:1 by volume. Onset and complete spread of sensory blockade were similar in all five groups. Time to regression to two segments of partial and complete sensory blockade was positively correlated (P less than 0.05) with increasing dose of bupivacaine in the solutions and ranged from 84 min (partial) and 70 min (complete) for lidocaine, to 128 min (partial) and 101 min (complete) for bupivacaine. Using skin temperature as a criterion of sympathetic blockade, all three mixtures demonstrated a duration of action intermediate between the two single drugs, lidocaine (124 +/- 13 min) and bupivacaine (286 +/- 32 min). Onset of complete motor blockade was fastest and the degree of motor blockade was most profound with the mixture containing equal proportions of lidocaine and bupivacaine. Pharmacokinetics of individual drugs were unaltered in any of the mixtures.

Two-stage infusion of chlormethiazole for basal sedation.

The effectiveness of chlormethiazole in providing basal sedation was studied using a two-stage infusion regimen consisting of an initial loading dose of 60 mg min-1 for 25 min (in the lateral position) followed by a maintenance constant-rate infusion of 10 mg min-1 for 60 min (in the supine position). The regimen was evaluated in five healthy young volunteers who were all moderately sedated throughout most of the infusion, lapsing into sleep when left undisturbed, yet awakened easily to obey commands. Varying periods of amnesia, corresponding with a mean chlormethiazole ethanedisulphonate blood concentration of 10.3 mg litre-1 (SD 3.8) were obtained. Light sedation occurred during the first 10 min and the last 20 min of the total infusion period, corresponding to chlormethiazole blood concentrations of 7.9 mg litre-1 (SD 1.9) and 7.4 mg litre-1 (SD 2.3) respectively. Adverse side-effects were transient nasal irritation, flushing and a coryza-like syndrome. Other side-effects of tachycardia and hypertension may be beneficial in counteracting cardiovascular depression associated with central neural blockade. A high total body clearance of chlormethiazole (mean 1.39 litre min-1, SD 0.58) was found and would contribute to the brief duration of action after termination of the infusion.

Minaxolone, clinical effects and pharmacokinetics. Subanaesthetic infusion regimen.

Minaxolone, infused at a constant rate of 0.01 mg/kg/min produced drowsiness followed by a sleep-like state from which subjects could be easily awakened. After the infusion was stopped, initial recovery was rapid, and completed within 45 minutes. The ability to produce this state rapidly and reversibly would have great value in outpatient surgery, short operative procedures and for basal sedation during procedures performed under regional anaesthesia. In common with many intravenous induction agents, involuntary skeletal muscle movement and twitching during the latter part of the infusion regimen was observed in some subjects. The rapid recovery was consistent with the pharmacokinetic characteristics of Minaxolone, i.e. high total body clearance (near or even exceeding that of indocyanine green) and rapid redistribution. However, renal clearance of unchanged Minaxolone was negligible.

An integrated study of pharmacokinetics and pharmacodynamics of chlormethiazole in healthy young volunteers.

Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n = 5) and 113 min (Phase 2, n = 5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.151 . min-1, SD 0.49; and 1.051 . min-1, SD 0.49; and 1.051 . min-1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (1371, SD 62; and 1251, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (3081, SD 91; and 2241, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg . 1(-1) (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.

Clinical evaluation of etidocaine in continuous caudal analgesia for pelvic floor repair and post-operative pain relief.

A randomized double-blind trial compared 1-0% etidocaine and 1-5% lignocaine (both with 1/200,000 adrenaline), for caudal anaesthesia for pelvic floor repair. Etidocaine was highly effective for the surgical procedure, with rapid onset of action, adequate muscle relaxation and longer duration of action. Its use for post-operative analgesia may be hindered by the concomitant immobilization of the legs. The problem of tachyphylaxis with etidocaine needs further investigation.