Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis

Fatigue mechanisms in normal intercostal muscle and muscle from patients with myasthenia gravis (MG) were evaluated by monitoring the compound muscle action potential (CMAP) and tetanic tension responses to repetitive nerve or muscle stimulation in vitro. When fatigue was induced by nerve stimulation at 30 Hz for 0.5 s every 2.5 s, about half of the original tension decreased after 30 min in normal muscle and 5 min in MG muscle. Analysis of the changes in area of CMAPs and tension indicated that impairment of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 40%, 29%, and 31% of fatigue in normal muscle, and 83%, 0%, and 17% of fatigue in MG muscle. When fatigue was induced by muscle stimulation at 30 Hz, tension declined by a quarter after 30 min in normal muscle, but by a half after 17 min in MG muscle. Impairment of muscle membrane excitation and E-C coupling and contractility accounted for 58% and 42% of fatigue in normal muscle, and 22% and 78% of fatigue in MG muscle. Thus, fatigue of normal muscle is caused by impairment of at least four processes, and enhanced fatigue of MG muscle is caused by greater impairment of neuromuscular transmission, E-C coupling, and contractility. © 1993 John Wiley & Sons, Inc.     

Analysis of anticholinesterase-induced neuromuscular transmission failure

To define the underlying mechanism of neuromuscular transmission failure induced by anticholinesterases, we simultaneously performed surface recordings of compound muscle action potentials (CMAPs) and intracellular recordings of miniature end-plate potentials (MEPPs), miniature end-plate current (MEPCs), and end-plate potential (EPPs) in rat diaphragms exposed in vitro to 1 × 10^?4 to 2 × 10^?2 mmol/L neostigmine methylsulfate. At low concentrations of neostigmine, repetitive stimulation of the phrenic nerve resulted in decrement followed by complete recuperation of CMAP amplitudes. This bimodal pattern was associated with maximal end-plate depolarization at the beginning of the stimulation period, increased MEPP amplitudes, and prolonged time constants of MEPC decays. Higher concentrations of neostigmine resulted in a unimodal decline of amplitudes of CMAPs and EPPS, reduced MEPP amplitudes, and a double exponential time course of MEPC decays. These results indicate that low concentrations of anticholinesterases impaired neuromuscular transmission by producing transient depolarization of the end-plate region. Higher concentrations induced desensitization and direct blockade of the end-plate receptor channel, probably in its open conformation. © 1993 John Wiley & Soncs, Inc.     

Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium

The intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required.     

Effect of estradiol and progesterone on muscle weight and acetylcholine receptors in “myasthenic” rats

Summary Clinical evidence suggests that endocrinal factors are involved in fluctuations of the symptoms of women with myasthenia gravis. We studied the effect of estradiol and progesterone in an animal model for myasthenia gravis in rats. Although it was found that the mass of muscles was dependent on sex, and in female rats affected by estradiol, the number of acetylcholine receptors in these muscles was independent of sex and hormone administration. Sex hormones failed to influence the severity of muscle weakness in myasthenic rats.     

Quantifying the interaction of vecuronium with enflurane using closed-loop feedback control of vecuronium infusion

The influence of different levels of enflurane anaesthesia on infusion requirements of vecuronium was studied in 40 adult surgical patients. Ninety percent neuromuscular block was maintained by computer controlled infusion of vecuronium. During the first 90 min study period all patients received fentanyl-nitrous oxide-oxygen (2:1) anaesthesia. For the following 90 min the patients were randomly assigned to receive enflurane at different end-tidal concentrations: group I, control, fentanyl-nitrous oxide anaesthesia; group II, enflurane 0.3%-nitrous oxide; group III, enflurane 0.6%-nitrous oxide; group IV, enflurane 0.9%-nitrous oxide. Every patient served as his/her own control and the changes of vecuronium infusion requirements were determined individually. When the administration of enflurane was started, vecuronium infusion requirements decreased progressively until 90 min. In group II the infusion rate lowered from 80±28 to 56±20 μg . kg^-1 . h ^-1, in group III from 61 ±29 to 34±17 μg . kg^-1 . h^-1 and in group IV from 65±20 to 30± 14 μg . kg^-1 . h^-1. In the control group the infusion rate decreased during the three hour study period from 69± 17 (first 90 min period) to 59± 16 μg . kg^-1 . h^-1 (second 90 min period). Enflurane reduces the dose requirements of vecuronium administered by continuous infusion in a dose- and time-dependent manner.     

Mivacurium in infants and children

Mivacurium is the only available short-acting nondepolarizing muscle relaxant in clinical use. It is a bis-quaternary benzylisoquinolinium ester hydrolysed by plasma-cholinesterase into inactive compounds. The ED₅₀ and ED₉₅ in children are about 50 μg·kg^?1 and 90 μg·kg^?1 respectively. In infants, they have a tendency to be lower. A standard intubating dose of 0.25 mg·kg^?1 causes complete neuromuscular depression in 1.5–2 min, recovery to 5% in 6–10 min, and complete recovery in 15–20 min. The recent tendency is to use 0.3 mg·kg^?1 to obtain better intubating conditions with slight prolongation of effect. Since the recovery profile of mivacurium is independent of the dose and duration, it is most suitable for administration by continuous infusion. The infusion requirement in children is 10–16 μg·kg^?1 min^?1, which is about twice that of adults. Cutaneous flushes from histamine release are commonly seen with the larger doses of mivacurium; however, the associated hypotensive effects are minimal and counteracted by the tracheal intubation. The duration of action of mivacurium is prolonged in patients with cholinesterase deficiency. Mivacurium's neuromuscular effects can be satisfactorily antagonized by edrophonium or neostigmine.     

Influence of anaesthesia and muscle relaxation on intubating conditions and sympathoadrenal response to tracheal intubation

Background : The study aimed to assess the relative influence of anaesthesia and muscle relaxation on intubating conditions and the haemodynamic and catecholamine responses to tracheal intubation.
Methods : Sixty ASA 1 or 2 patients were randomly assigned to one of four groups (15 patients each) that differed in the depth of anaesthesia (thiopentone plus fentanyl 2.5 μg kg^-1 or thiopentone alone) and the degree of vecuronium–induced neuromuscular block (100% or _>: 65%) at intubation. Muscle relaxation was measured at 0.1 Hz by means of mechanomyography. Heart rate (HR) and mean arterial blood pressure (MAP) were measured before and after induction of anaesthesia, and 1 min and 5 min following intubation, while adrenaline (A) and noradrenaline concentrations (NA) were determined from arterial blood samples.
Results : Intubating conditions were improved primarily by providing complete muscle relaxation at the adductor pollicis muscle (P<0.001) and to a lesser extent by adding fentanyl to thiopentone (P=0.04). The response of HR and MAP to tracheal intubation was attenuated mainly by fentanyl (P<0.001). Complete muscle relaxation further diminished the response of MAP to intubation (P=0.03). Changes in A and NA were dependent on the depth of anaesthesia only (P =>0.01).
Conclusion : The results of the study demonstrate that the sympathoadrenal response to intubation is attenuated by adding fentanyl (2.5 kg^-1) to an induction regimen with thiopentone, whereas provision of complete muscle relaxation at the adductor pollicis muscle is necessary to attain smooth intubating conditions.     

Intubating conditions provided by propofol and alfentanil - acceptable, but not ideal

Background: The use of muscle relaxants to facilitate intubation is associated with several side effects regardless of whether depolarizing or non-depolarizing drugs are used. In the present study we compared the intubating conditions, haemodynamic responses and changes in oxygen saturation following induction with alfentanil and propofol or alfentanil, thiopental and suxamethonium.
Methods: Eighty patients (ASA I or II) were in a double-blind manner assigned to receive either of the two induction methods. Intubating conditions were assessed on the basis of jaw relaxation, ease of insertion of the endotracheal tube and coughing on intubation. Heart rate, systolic arterial pressure and oxygen saturation were monitored throughout the procedure.
Results: The use of alfentanil and propofol resulted in significantly lower scored intubation points. Systolic arterial pressure decreased and heart rate increased significantly in the alfentanil-thiopental-suxamethonium group as compared to the alfentanil-propofol group. There were no significant changes in oxygen saturation.
Conclusion: The results show that propofol and alfentanil in combination provides haemodynamic stability and unaltered oxygen saturation but less optimal intubating conditions.