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Anaesthesia-induced malignant hyperthermia (MH) may be caused by specific gene defects in the skeletal muscle ryanodine receptor. We have studied the frequency of occurrence of the C1840T mutation, analogous to the porcine mutation, and three mutations associated both with MH and central core disease (G7301A, C487T and C1209G). We investigated skeletal muscle specimens from up to 137 patients testing negative and 101 patients testing positive for MH susceptibility by the North American MH Group protocol. The presence or absence of the mutations was determined by polymerase chain reaction and restriction enzyme digestion. The frequencies of occurrence of the C1840T and C487T mutations were 2% and 1%, respectively, in MH-positive subjects and were the only two mutations identified. One subject with central core disease did not have any of the three mutations examined associated with this disorder. Therefore, the porcine and central core disease-associated mutations examined in the ryanodine receptor account for a small proportion (approximately 3%) of MH-positive diagnoses. The mutations examined did not occur in any of the MH-negative patients, supporting an association between defects in the ryanodine receptor and a positive diagnosis for MH.(ABSTRACT TRUNCATED AT 250 WORDS)

We have compared two groups (n = 22) of unpremedicated patients to determine if the pain caused by injection of propofol could be modified by alfentanil. In group I, alfentanil 1 mg was given as a bolus i.v. injection 15 s before administration of propofol i.v., while group II received saline. Propofol was given in 20-mg increments every 4 s. All injections were given through the same i.v. cannula on the dorsum of one hand. We found that alfentanil pretreatment reduced pain on injection of propofol (P = 0.001).

We have examined the phenotypic expression of several parameters associated with malignant hyperthermia (MH) susceptibility in three groups (homozygous normal, homozygous abnormal and heterozygous) of Yorkshire/Duroc swine genotyped by a mutation in the ryanodine receptor. Subgroups of homozygous abnormals were classified further by the appearance or absence of muscle rigidity on prolonged in vivo challenge with halothane and suxamethonium. Four swine heterozygous for the proposed MH mutation were indistinguishable from five homozygous normal swine in temperature, heart rate, lactate concentrations, base excess and pH determined during the prolonged halothane and suxamethonium challenge. Resting creatine kinase concentrations, the in vivo barnyard challenge, the in vitro contracture response of skeletal muscle to 3% halothane and the threshold for Ca(2+)-induced Ca2+ release were also similar for subgroups of homozygous normals and heterozygotes. Therefore, inheritance of only one allele carrying the defect in the ryanodine receptor does not significantly alter phenotypes associated with MH susceptibility in this strain of swine. As four swine homozygous for the proposed MH defect did not exhibit rigidity and three of these had no other signs of MH on prolonged halothane and suxamethonium challenge, we conclude that the reported mutation in the ryanodine receptor may be necessary, but is not sufficient, for consistently eliciting the malignant hyperthermia syndrome. These findings suggest that a modulator of the syndrome may explain variability within individuals in human MH.

In this double-blind study, we have allocated randomly 40 ASA I-III patients to one of four groups. After a standard anaesthetic induction, patients received vecuronium 0.08 mg kg-1 or 0.10 mg kg-1, or atracurium 0.4 mg kg-1 or 0.5 mg kg-1. Using an electromyogram (Datex Relaxograph) the train-of-four (TOF) response was measured during onset of and recovery from neuromuscular block. A greater degree of fade of TOF was observed with atracurium during onset of neuromuscular block than with equivalent doses of vecuronium. During recovery of neuromuscular transmission, vecuronium was associated with more fade than atracurium. The differences in the TOF profiles of these two drugs may be important when judging the adequacy of antagonism of neuromuscular block using the TOF response.

Plasma beta-endorphin-like immunoreactivity (beta-ELI) was measured at intervals during labour in 42 patients. An increase in beta-ELI occurred during labour and increased to a maximum during the second stage. The increase in beta-ELI paralleled dilatation of the cervix. A correlation existed between the duration of labour and second stage beta-ELI in patients with labours of more than 4 h duration. Analgesic drugs were associated with changes in beta-ELI. The patients who received Entonox had greater plasma beta-ELI concentrations than those who received pethidine. A significant difference in the second stage beta-ELI existed between those who received only Entonox and those who received only pethidine. Induction and augmentation of labour were also associated with differences in beta-ELI. Patients in spontaneous labour had significantly lower beta-ELI than patients who had either artificial rupture of membranes or Syntocinon augmentation of labour.

The role of lipolysis in halothane-induced contractures of human skeletal muscle was examined using three inhibitors of phospholipase A2 (PLA2) activity (quinacrine, spermine and indomethacin) and exogenously administered PLA2. In addition, we examined the effects of the same PLA2 inhibitors on contractures induced by halothane in combination with suxamethonium. The studies were conducted on directly stimulated muscle strips isolated from biopsies from patients diagnosed as MH susceptible, or not susceptible, by the halothane contracture test. The liberation of fatty acids from skeletal muscle homogenates was examined to determine whether PLA2 activity might be increased in MH susceptible patients. The three PLA2 inhibitors antagonized halothane-induced contractures of muscle from MH susceptible patients as well as induction of contractures by suxamethonium and halothane. Pre-exposing preparations that were previously unresponsive to halothane to bee venom PLA2 caused the muscle strips to respond with contractures upon subsequent challenge with halothane, but not with suxamethonium. Free fatty acid production during an in vitro incubation of skeletal muscle homogenates was greater in preparations from MH susceptible patients than in those from patients who were not susceptible. These results suggest that excess liberation of fatty acids may be involved in halothane-induced contractures of muscle from MH susceptible individuals, in the synergism observed between halothane and suxamethonium, and in human MH.

The rat diaphragm was used as an in vitro model for studies of contractures synergistically-induced by halothane and suxamethonium. The effects of three agents reported to inhibit phospholipase A2 activity (quinacrine, spermine and indomethacin), tubocurarine and dantrolene were examined on these contractures. Contractures induced by 1% halothane (0.26 +/- 0.02 g) (mean +/- SEM) were increased (0.60 +/- 0.04 g) if suxamethonium 50 mmol litre-1 was also in the bathing medium. Suxamethonium-induced contractures (0.22 +/- 0.03 g) were also enhanced when halothane was present (0.51 +/- 0.03 g). Spermine, indomethacin and dantrolene antagonized both halothane- and suxamethonium-induced contractures. Quinacrine potentiated contractures induced by either halothane or suxamethonium. Contractures induced by suxamethonium were antagonized by tubocurarine; however, contractures induced by halothane were not antagonized by tubocurarine. These results suggest that free fatty acids may be involved in contractures induced synergistically by halothane and suxamethonium. Different mechanisms are involved in the induction of contractures by suxamethonium than by halothane.