Comparative recovery from three nondepolarizing neuromuscular blockers in a patient before and after chronic anticonvulsant therapy: a case report

We describe a 51-year-old patient undergoing a second neurosurgical procedure after being prescribed anticonvulsant therapy. The patient had significant changes in the duration of action of identical doses of nondepolarizing muscle relaxants and we were able to compare the duration of action of neuromuscular blockers before and after the chronic administration of anticonvulsant therapy. A brief review of the possible mechanisms of action of the acceleration of the patient's recovery profile is also presented.     

Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37-52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors.     

Drug interactions with neuromuscular blockers

Drugs administered to patients undergoing anaesthesia may complicate the use of the neuromuscular blockers that are given to provide good surgical conditions. The various sites of interaction include actions on motor nerve conduction and spinal reflexes, acetylcholine (ACh) synthesis, mobilisation and release, sensitivity of the motor end plate to ACh and the ease of propagation of the motor action potential. In addition, many drugs affect the pharmacokinetics of neuromuscular blockers, especially as most drugs depend to a greater or lesser extent upon renal excretion. The clinically significant interaction between nondepolarisers and depolarisers may be due to blockade of the pre-synaptic nicotinic receptors by the depolarisers, leading to decreased ACh mobilisation and release. Synergism between nondepolarisers probably results from post-synaptic receptor mechanisms. Volatile anaesthetic agents affect the sensitivity of the motor end-plate (post-synaptic receptor blockade) in addition to having effects on pre-synaptic nicotinic function. The effects of nondepolarisers are likely to be potentiated and their action prolonged by large doses of local anaesthetics due to depression of nerve conduction, depression of ACh formation, mobilisation and release, decreases in post-synaptic receptor channel opening times and reductions in muscular contraction. Most antibacterials have effects on pre-synaptic mechanisms. Procainamide and quinidine principally block nicotinic receptor channels. Magnesium has a marked inhibitory effect on ACh release. Calcium antagonists could theoretically interfere with neurotransmitter release and muscle contractility. Phenytoin and lithium decrease ACh release, whilst corticosteroids and furosemide (frusemide) tend to increase the release of the transmitter. Ecothiopate, tacrine, organophosphates, propanidid, metoclopramide and bambuterol depress cholinesterase activity and prolong the duration of the neuromuscular block. The probability of clinically significant interactions increases in patients receiving several drugs with possible effects on neuromuscular transmission and muscle contraction.     

Adverse effects of neuromuscular blockers and their antagonists

Among all the drugs used for general anaesthesia, neuromuscular blockers appear to play a prominent role in the incidence of severe adverse reactions. It now seems likely that most serious adverse drug reactions occurring during anaesthesia are immunological in type. The frequency of life-threatening anaphylactic or anaphylactoid reactions occurring during anaesthesia has been estimated to be between 1 in 1000 and 1 in 25,000 anaesthetic procedures, with the neuromuscular blockers being involved in 80% of cases. The mortality from such serious reactions is reported to be in the range of 3.4 to 6%. The highly immunogenic drug, suxamethonium chloride (succinylcholine), was found to be the most hazardous agent. Drug-specific immunoglobulin E antibodies to suxamethonium chloride and other neuromuscular blockers have been demonstrated. This sensitivity to neuromuscular blockers seems to be a long-lasting phenomenon. During anaesthesia, the clinical features of an allergic reaction are often masked. Tachycardia and circulatory collapse may be the only signs of an allergic reaction, and they are easily misdiagnosed. Bronchospasm is reported to be present in about 40% of cases. Successful management of these patients includes stabilisation during the acute reaction and avoidance of future reactions. The latter is based on the identification of the causative drug and potentially cross-reacting compounds. The use of suxamethonium chloride is associated with many other adverse effects, such as fasciculations, myalgia, potassium release, changes in the heart rate, increases in intragastric and intraocular pressures, and malignant hyperthermia. Because of the dangers of hyperkalaemic cardiac arrest after suxamethonium chloride administration in children with unrecognised muscular dystrophy, there have now been moves to limit the use of this drug in children. Although neuromuscular blockers are designed to specifically block nicotinic cholinergic receptors at the neuromuscular junction, many bind to muscarinic cholinergic receptors on ganglia and smooth muscle, and alter parasympathetically mediated heart rate and airway calibre. Most benzylisoquinolinium muscle relaxants can induce histamine release, especially when they are administered rapidly, which can lead to disturbances of cardiovascular function. In addition, nondepolarising neuromuscular blockers have been implicated in causing generalised weakness following their long term administration to patients on an intensive care unit. The problem with these adverse drug reactions is their unpredictable nature. Therefore, prompt recognition with appropriate therapy can help to improve the outcome.     

Clinical, neurophysiological and hemodynamic effects of a new nondepolarizing myorelaxant mivacurium in heart surgery patients]

Thirty patients aged 23 to 65 years with ASA class III operated on the heart under total intravenous anesthesia were examined after the Good Clinical Practice protocol. Mivacurium in bolus dose of 0.2 mg/kg was injected for intubation of the trachea; neuromuscular blocking (NMB) was maintained by a repeated injection of the drug in a dose of 0.15 mg/kg, after which it was infused at a rate of 1 to 10 micrograms/kg/min. Accelerometric control of neuromuscular conduction was carried out by the Organon (Belgium) TOF-Guard device. Central and peripheral hemodynamics was monitored. Side effects of the drug were recorded. Bolus injection of mivacurium in a dose of 0.2 mg/kg caused T1 suppression (90%) after 2.6 +/- 0.7 min. Maximal (97.7 +/- 4.5%) suppression was observed after 4.17 +/- 2.5 min. The conditions of intubation of the trachea after 3.9 +/- 1.8 min in the presence of 78 to 100% T1 suppression (97.7 +/- 4.5%) were considered excellent or good in 96.6% of cases. Clinically and neurophysiologically sufficient muscle relaxation after the first injection of the drug persisted for 27.7 +/- 7.3 min. Minimal rate of infusion for maintaining the NMB at 95 +/- 4% level of T1 suppression was 6.3 +/- 1.7 micrograms/kg/min. Bolus injection of mivacurium in a dose of 0.2 mg/kg for 60 sec involved a 1-3-min drop of the mean arterial pressure by 10.5% and a 10.3% decrease of heart rate. Repeated bolus injection of the drug in a dose of 0.15 mg/kg and its infusion did not change the peripheral and central hemodynamics. The most typical side effect of the drug in a dose of 0.2 mg/kg is short-term reversible reddening of the skin of the face and neck, observed in 20% of patients. The results permit us to consider mivacurium as an effective, safe, and controllable agent, which can be used in cardiosurgical patients.     

Carvedilol: the new role of beta blockers in congestive heart failure

The prognosis remains poor for patients with congestive heart failure (CHF), despite reduced mortality rates resulting from the addition of angiotensin converting enzyme inhibitors to traditional treatment regimens. Because much of the myocardial damage that occurs in patients with CHF may be related to sympathetic activation, interest in the use of beta blockers has grown. Recent studies have shown the benefits of beta blocker therapy in many patients with heart failure. Carvedilol, the first beta blocker labeled in the United States specifically for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality.     

Calcium channel blockers and hypertension: 2. Safety issues

As the safety of calcium channel blockers continues to be debated, it is important to realize that not all calcium channel blockers are alike. Safety, and efficacy, depend on the kinetic as well as the pharmacologic properties of the drug.     

Formation of the neuromuscular junction: molecules and mechanisms

The vertebrate skeletal neuromuscular junction is the site at which motor neurons communicate with their target muscle fibers. At this synapse, as at synapses throughout the nervous system, efficient and appropriate communication requires the formation and precise alignment of specializations for transmitter release in the axon terminal with those for transmitter detection in the postsynaptic cell. Classical developmental studies demonstrate that synapse formation at the neuromuscular junction is a mutually inductive event; neurons induce postsynaptic differentiation in muscle cells and myofibers induce presynaptic differentiation in motor axon terminals. More recent experiments indicate that Schwann cells, which cap axon terminals, also play an active role in the formation and maintenance of the neuromuscular junction. Here, we review recent advances in the identification of molecules mediating such inductive interactions and the mechanisms by which they produce their effects. Although our discussion concerns events at developing neuromuscular junctions, it seems likely that similar molecules and mechanisms may act at neuron-neuron synapses in the peripheral as well as the central nervous system.     

Animal models of neuromuscular diseases: pathophysiology and implications for rehabilitation

This article explains how animal models can be utilized to develop rehabilitation approaches to minimize the pathophysiology of neuromuscular diseases (NMD). Homologous animal models can be used to understand the pathogenesis of each NMD and the effect of physical interventions. Much of the current work using animals has been conducted to show how gene therapy could be used to ameliorate these diseases. Although we applaud this work, animal models should also be used to determine how the phenotypic expression of the disease can be modified by such physical interventions as exercise, stretching, and immobilization. Methods that can be experimentally applied to animals but not to humans can be used to determine the underlying causes of the pathologic process and to identify potential therapies for NMD.     

Electromyographic biofeedback and neuromuscular rehabilitation.

Electromyographic biofeedback has now been used with apparent success, although most often in an uncontrolled fashion, in the rehabilitation treatment of a wide range of neuromuscular disorders. These have included peripheral nerve-muscle damage, spasmodic torticollis, the stroke hemiplegias, and cerebral palsy. Studies of these applications are reviewed, and some specific problems that should be the topic of further controlled research are outlined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders

Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.     

Vacuolar changes in neuromuscular disorders: a morphometric study

BACKGROUND: Vacuoles in muscle represent a nonspecific alternation and are found in a variety of neuromuscular disorders. To understand their significance, a morphometric study of the vacuolar formation in muscle biopsies from 340 patients was reviewed. METHODS: Vacuolar changes in muscles were found in 24 out of 340 patients with muscle biopsies. The specimens were prepared for histopathological, histochemical and electron microscopic examinations. The location, size, shape, number and content of the vacuoles were recorded. The number of fibers containing vacuoles was also assessed. RESULTS: Observed after modified Gomori trichrome stain, there were rimmed and non-rimmed vacuoles. Rimmed vacuoles were found in limb-girdle myopathy with rimmed vacuoles (5), oculopharyngeal muscular dystrophy (1). inclusion body myositis (2) and neurogenic disorder (1). These vacuoles were usually cleft-like in shape in 5-16% of muscle fibers with a diameter of 3-20 microns. An elevation of acid phosphatase activities and the presence of cytoplasmic debris suggested an autophagic process. In 15 patients with non-rimmed vacuoles, round and oval shapes with variable sizes and numbers were noted. Four with acid maltase deficiency (AMD) had numerous vacuoles containing glycogen, while three with lipid storage disease contained lipid. Interestingly, in AMD the size of the vacuoles was usually more than 10 microns in diameter, but less than 5 microns in lipid storage disease. In other diseases including polymyositis (5), Duchenne muscular dystrophy (2) and hypokalemic periodic paralysis (1), the numbers of vacuoles were usually fewer than three in each fiber. CONCLUSIONS: Vacuolar changes were not specific, but morphometric analysis of the vacuoles may provide some clues in differential diagnosis. The vacuoles were usually numerous in glycogen and lipid storage diseases, while rimmed vacuoles may be found in limb-girdle myopathy with rimmed vacuoles, oculopharyngeal muscular dystrophy, and inclusion body myositis.     

Alkoxypsoralens, novel nonpeptide blockers of Shaker-type K+ channels: synthesis and photoreactivity

A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.     

Approaches to short-acting neuromuscular blocking agents: nonsymmetrical bis-tetrahydroisoquinolinium mono- and diesters

Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.