Cholinesterase inhibition by potato glycoalkaloids slows mivacurium metabolism.

BACKGROUND: The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), alpha-solanine and alpha-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro. METHODS: Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis. RESULTS: SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30-100 nm) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 +/- 12% of control; n = 12). CONCLUSIONS: These findings support the hypothesis that inhibition of endogenous enzyme systems by dietary factors can influence anesthetic drug metabolism and duration of action. Diet may contribute to the wide variation in recovery time from neuromuscular blockade seen in normal, healthy individuals.

Comparison of the intubation conditions provided by rapacuronium (ORG 9487) or succinylcholine in humans during anesthesia with fentanyl and propofol.

BACKGROUND: Currently, the only approved muscle relaxant with a rapid onset and short duration of action is succinylcholine, a drug with some undesirable effects. Rapacuronium is an investigational nondepolarizing relaxant that also has a rapid onset and short duration and consequently should be compared with succinylcholine in its ability to facilitate rapid tracheal intubation. METHODS: This prospective, randomized clinical trial involved 336 patients. Anesthesia was induced with fentanyl and propofol and either 1.5 mg/kg rapacuronium or 1.0 mg/kg succinylcholine. The goal was to accomplish tracheal intubation by 60 s after administration of the neuromuscular blocking drug. Endotracheal intubation was performed, and conditions were graded by a blinded investigator. Recovery of neuromuscular function was assessed by electromyography. RESULTS: Intubation conditions were evaluated in 236 patients. Intubation by 60 s after drug administration occurred in 100% of patients with rapacuronium and in 98% with succinylcholine. Intubation conditions were excellent or good in 87% of patients with rapacuronium and in 95% with succinylcholine (P < 0.05). The time (median and range) to the first recovery of the train-of-four response was 8.0 (2.8-20.0) min with rapacuronium and 5.7 (1.8-17.7) min with succinylcholine (P < 0.05). The overall incidence of adverse effects was similar with both drugs. CONCLUSIONS: A 1.5-mg/kg dose of rapacuronium effectively facilitates rapid tracheal intubation. It can be considered a valid alternative to 1.0 mg/kg succinylcholine for this purpose.

Caffeine- or halothane-induced contractures of masseter muscle are similar to those of vastus muscle in normal humans.

BACKGROUND: Skinned fibers from normal human masseter muscle have greater caffeine and calcium sensitivity than skinned fibers from vastus muscle. We examined sensitivity to caffeine and halothane in fresh, cut muscle bundles (non-skinned) from human masseter muscle. METHODS: Masseter bundles (caffeine, n=25, halothane, n=19) excised from 10 humans under general anesthesia had tension measured in 37 degrees C baths during the addition of caffeine (0.5, 1, 2, 4, 8, 32 mM) or 3% halothane. Results were compared to those of our previous studies (1989, 1997, 25 patients) of vastus bundles (caffeine, n=71, halothane, n=63) using the same protocol, technicians, and equipment. RESULTS: Baseline force in the caffeine test was 2.10+/-1.57 for masseter, and 2.02+/-1.68 and 1.82+/-1.29 respectively for vastus muscle. Force at 32 mM caffeine concentration was 11.2+/-9.9 g for masseter, 11.0+/-5.4 and 13.5+/-7.5 g for vastus. Concentration-response curves were virtually identical. In the halothane group, neither baseline values (masseter 1.47+/-1.30, vastus 1.91+/-1.32 and 2.15+/-1.71) nor contractures in response to 3% halothane were different. Most bundles had no contracture in response to 3% halothane; 3 masseter bundles and 2 vastus bundles (1989) developed contractures of less than 0.05 g. Three vastus bundles (1997) developed contractures >0.2 g. CONCLUSION: Contracture responses of intact cut masseter and vastus bundles (non-skinned) do not differ with respect to caffeine and halothane. Responses of skinned fibers might demonstrate greater sensitivity under certain conditions, but they do not reflect those of intact cut bundles.

Deep sedation and mechanical ventilation without paralysis for 3 weeks in normal beagles: exaggerated resistance to metocurine in gastrocnemius muscle.

BACKGROUND: Patients in the intensive care unit may have muscle weakness in the recovery phase, and disuse atrophy may play a role in this weakness. To assess this problem, the authors measured changes in the potency of the nondepolarizing neuromuscular blocking agent metocurine in a canine model that involved 3 weeks of intensive care, nonparalyzing anesthesia with pentobarbital, and positive-pressure ventilation. METHODS: Six dogs were anesthetized with pentobarbital to a sufficient depth that spontaneous and reflex muscle movements were absent. Their tracheas were intubated, their lungs were mechanically ventilated, and they received round-the-clock intensive medical and nursing care for 3 weeks. Transduced gastrocnemius muscle responses to metocurine were determined weekly. A 4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater concentrations on progressive weeks) yielded more than 80% paralysis. Serial metocurine plasma concentrations during the onset of the block and recovery provided data to determine pharmacokinetics using NONMEM. Metocurine plasma concentrations and the degree of paralysis were used to model the effect compartment equilibration constant, and the Hill equation was used to yield the slope factor and potency within the effect compartment. RESULTS: The metocurine effect compartment concentration associated with a 50% diminution of twitch height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was significantly different from 257+/-34 ng/ml, the value on day 0. There were no pharmacokinetic differences. CONCLUSION: The absence of muscle tone and reflex responsiveness for 3 weeks was associated with exaggerated resistance to the neuromuscular blocker metocurine.

Malignant hyperthermia: advances in diagnostics and management.

Real-time monitoring of end-tidal carbon dioxide during anaesthesia aids in the early detection of malignant hyperthermia and the occurrence of a rapid increase in end-tidal carbon dioxide, associated with unexplained persistent tachycardia, well before the core temperature begins to rise. Should malignant hyperthermia occur, however, dantrolene permits the dependable reversal of skeletal muscle hypermetabolism.

Plasma electrolyte and metabolite concentrations associated with pentobarbital or pentobarbital-propofol anesthesia during three weeks' mechanical ventilation and intensive care in dogs.

Propofol and pentobarbital were used for deep sedation during prolonged mechanical ventilation (3 weeks) and nutritional supplementation in 17 clinically normal dogs in an intensive care setting. Tolerance developed to both drugs. Propofol, in combination with pentobarbital, at an infusion rate of 75 micrograms/kg of body weight per minute was preferred. Pentobarbital infusion alone, begun at the rate of 5 to 6 mg.kg-1.h-1, was satisfactory. The combination of both drugs provided smooth, stable anesthesia and required minimal interventions by intensive care unit personnel. Blood gas tensions and electrolyte, parathyroid hormone (PTH), and metabolite concentrations were generally stable throughout, unless condition of the dog deteriorated (e.g., infection, pneumothorax). Hematocrit and red blood cell count decreased with time, likely attributable principally to multiple blood sample collections. White blood cell count, alkaline phosphatase, phosphate, fibrinogen, cholesterol, and triglyceride values increased with time, in association with pentobarbital and the combination of pentobarbital and propofol. Some of these changes appear to have been related to generic responses to stress and inflammation, some to altered metabolism, and some to the lipid solvent of propofol. The increase in triglyceride concentration was greater when propofol was used. Mortality was 47%, with death occurring between days 2 and 18.

Effect of temperature variation (22 degrees C-44 degrees C) on halothane and caffeine contracture testing in normal humans.

BACKGROUND: Malignant hyperthermia (MH) susceptibility is diagnosed using halothane-caffeine contracture testing of a muscle sample maintained at 37 degrees C. However, there has not been a systematic study that examines the effect of different temperatures on the response of normal muscle to halothane and caffeine. We hypothesized that altering bath temperature would modify the contracture responses. METHODS: We obtained muscle samples from 20 patients undergoing surgical procedures of the lower extremities. The samples were dissected into 245 bundles and the bundles were exposed to halothane 3% or incremental caffeine, according to the North American MH group protocol. Several bundles from each patient were simultaneously studied at four different temperatures (22 degrees C, 30 degrees C, 37 degrees C and 44 degrees C). Each bundle was studied at only one temperature, the muscle samples of 3 patients were simultaneously studied at all four temperatures for halothane and caffeine. RESULTS: Maximum contracture to caffeine (32 mM) was highest at 37 degrees C; however, at lower caffeine concentrations (2-4 mM), there was no consistent effect of temperature on contracture response. Likewise, temperature did not alter contracture responses to halothane. The extremes of temperature (22 degrees C and 44 degrees C) were associated with lack of twitch in response to electrical stimulation. For the bundles exposed to halothane at 22 degrees C, the absence of a twitch was associated with the presence of a contracture, although these were never above the diagnostic threshold. CONCLUSIONS: We conclude that temperature has little effect on responses of normal muscle to halothane and caffeine.

Masseter muscle rigidity and nondepolarizing neuromuscular blocking agents.

Masseter muscle rigidity has been identified as a possible risk factor for malignant hyperthermia (MH) and is usually noted in children receiving intravenously administered succinylcholine chloride after mask induction with halothane. Nondepolarizing muscle relaxants are considered safe for persons susceptible to MH. In this article, we present a case of clinically recognized jaw rigidity in the absence of succinylcholine after administration of a non-depolarizing muscle relaxant that was reported to the Malignant Hyperthermia Association of the United States hot line. The patient had recurrent jaw rigidity during subsequent anesthesia when a different non-depolarizing muscle relaxant was given. The North American MH Registry was then reviewed for similar cases. Three cases of masseter muscle rigidity in the presence of nondepolarizing muscle relaxants were discovered. Two of the patients were not found to be susceptible to MH; however, the third patient had positive findings on muscle biopsy. These cases do not provide enough information to confirm the ability of nondepolarizing muscle relaxants to cause jaw rigidity in the absence of MH.

Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies.

In 1992, the Malignant Hyperthermia Association of the United States and The North American Malignant Hyperthermia Registry received reports of cardiac arrest in apparently healthy children given succinylcholine. Using data from 1990 to 1993, this study analyzes: (1) etiology of all reported pediatric arrests and (2) whether survival was associated with certain patient or treatment variables. We reviewed retrospectively all reports of pediatric (age < 18 years) arrests occurring within 24 hours of anesthesia. Etiology of arrests and presence of myopathy were determined. Twenty-five patients (92% male, median 45 months old) arrested; 23/25 (92%) were scheduled for minor surgery. Before receiving a potent inhalational anesthetic (92%) and/or succinylcholine (72%), these patients were evaluated by the anesthesiologist as being healthy with no personal or family history of myopathy. Serum potassium during arrest was measured in 18/25 (72%) patients; hyperkalemia (mean [K+] = 7.4 +/- 2.8, median 7.5 mmol/L) was detected in 13/18 (72%) patients. Postarrest resuscitations lasted a median of 42 minutes (range 10-296). Ten (40%) patients died, 1 (4%) is vegetative, and 14 (56%) returned to baseline neurologic function. A previously unrecognized Duchenne dystrophy (n = 8) or unspecified myopathy (n = 4) was diagnosed in 12 (48%) patients. Eight of these 12 patients' arrests were associated with hyperkalemia. Ten (40%) patients had no postarrest evaluation to exclude occult myopathy. No patient or treatment variables were statistically associated with survival. We conclude that, whenever possible, pediatricians should evaluate their patients (especially male infants and children) preoperatively for the presence of occult myopathy. During perianesthetic resuscitations, the pediatric advanced life support protocol should be modified to detect and treat hyperkalemia, a potentially reversible state even after prolonged resuscitation efforts. Following anesthetic deaths, pathologists should examine body fluid electrolytes and skeletal muscle for myopathy and dystrophin. If a preanesthetic creatine kinase screen for myopathy in male patients and restrictions on succinylcholine had been used, 64% of arrests and 60% of deaths might have been prevented. A formal prospective risk/benefit analysis for preventive measures is needed.