Possible Effect of Muscle-relaxant Anaesthetics on Invasion, Adhesion and Migration of Breast Cancer Cells.

BACKGROUND: Aggressive surgical removal of the primary tumour is the preferred treatment, but with tumour progression, some tumours cannot be completely removed surgically. Anaesthetics are administered to facilitate surgery. However, anaesthetics act as a potential factor in tumour recurrence or metastasis. MATERIALS AND METHODS: Normal breast cells and cancer breast cells were treated with different doses of muscle-relaxant anaesthetics. The effects on breast cancer cell invasion, adhesion and migration of these anaesthetics were then investigated using in vitro models. RESULTS: With increasing dose of rocuronium bromide and suxamethonium chloride CRS, the number of MCF-10A and MCF-7 cells, but not that of MDA-MB-231 cells, decreased. There was almost no difference in the number of cells when the three cell lines were treated with different doses of vecuronium bromide. The study also demonstrated that rocuronium bromide promoted the invasion, adhesion and growth of MDA-231 cells, while suxamethonium chloride CRS had no effect. Interestingly, vecuronium bromide did not affect the motility and invasion of breast cancer cells significantly. CONCLUSION: An understanding of the effect of anaesthetics and their impact on tumour metastasis is important, thus using an appropriate aesthetic strategy could improve long-term survival in some patients.

The effect of succinylcholine on malignant hyperthermia events in susceptible swine.

BACKGROUND: While the impact of volatile anaesthetics to induce malignant hyperthermia (MH) is abundantly clear, the role of succinylcholine still remains controversial. To evaluate the influence of succinylcholine on porcine MH events, the authors investigated the hemodynamic and metabolic responses in MH susceptible (MHS) and non-susceptible (MHN) swine following either succinylcholine or halothane application alone or a combination of both substances. METHODS: With approval of the local animal care committee 27 MHS and 30 MHN pigs were anaesthetized and mechanically ventilated. Fiberoptic probes for continuous PCO2 measurement were inserted into the femoral vein and the triceps muscle. Group A received succinylcholine 4 mg/kg, group B incremental doses of halothane (0.5, 1.0 vol%) and group C succinylcholine and halothane simultaneously. Vital signs were recorded continuously. RESULTS: Prior to drug application measured values did not differ between MHS and MHN. While MHN pigs did not show relevant alterations, succinylcholine, halothane and the combination of both lead to significant hemodynamic and metabolic changes in MHS swine. CONCLUSIONS: Hemodynamic and metabolic alterations following succinylcholine were similar to halothane in MHS pigs. The combination of both pharmacological agents potentiated the observed effects. According to these results succinylcholine acted as an independent and supportive factor during onset of an MH episode.

Reversal of succinylcholine induced apnea with an organophosphate scavenging recombinant butyrylcholinesterase.

BACKGROUND: Concerns about the safety of paralytics such as succinylcholine to facilitate endotracheal intubation limit their use in prehospital and emergency department settings. The ability to rapidly reverse paralysis and restore respiratory drive would increase the safety margin of an agent, thus permitting the pursuit of alternative intubation strategies. In particular, patients who carry genetic or acquired deficiency of butyrylcholinesterase, the serum enzyme responsible for succinylcholine hydrolysis, are susceptible to succinylcholine-induced apnea, which manifests as paralysis, lasting hours beyond the normally brief half-life of succinylcholine. We hypothesized that intravenous administration of plant-derived recombinant BChE, which also prevents mortality in nerve agent poisoning, would rapidly reverse the effects of succinylcholine. METHODS: Recombinant butyrylcholinesterase was produced in transgenic plants and purified. Further analysis involved murine and guinea pig models of succinylcholine toxicity. Animals were treated with lethal and sublethal doses of succinylcholine followed by administration of butyrylcholinesterase or vehicle. In both animal models vital signs and overall survival at specified intervals post succinylcholine administration were assessed. RESULTS: Purified plant-derived recombinant human butyrylcholinesterase can hydrolyze succinylcholine in vitro. Challenge of mice with an LD100 of succinylcholine followed by BChE administration resulted in complete prevention of respiratory inhibition and concomitant mortality. Furthermore, experiments in symptomatic guinea pigs demonstrated extremely rapid succinylcholine detoxification with complete amelioration of symptoms and no apparent complications. CONCLUSIONS: Recombinant plant-derived butyrylcholinesterase was capable of counteracting and reversing apnea in two complementary models of lethal succinylcholine toxicity, completely preventing mortality. This study of a protein antidote validates the feasibility of protection and treatment of overdose from succinylcholine as well as other biologically active butyrylcholinesterase substrates.

A comparison of the effects of sarin and succinylcholine on respiratory parameters in anesthetized domestic swine.

Differences in the "respiratory paralysis" caused by sarin (GB) and succinylcholine (SDC) were observed in a domestic swine model using a bedside pulmonary dynamics monitor. GB was administered intravenously (9 micrograms/kg/30 min) and compared with SDC administered intravenously (20 mg/30 min). All animals developed respiratory insufficiency indicated by decreased respiratory frequency. Minute ventilation was relatively maintained in animals that received GB by increasing tidal volume, whereas both of these parameters decreased in animals that received SDC. GB animals showed an increase in airway resistance and work of breathing. The former was unchanged and the latter was decreased in animals that received SDC. Mouth occlusion pressure at 100 milliseconds and tidal volume were relatively maintained in GB animals but decreased in SDC animals, suggesting a central mechanism for respiratory paralysis with GB and a peripheral mechanism for respiratory paralysis with SDC.

Hemodynamic and metabolic manifestations of acute endotoxin infusion in pigs with and without the malignant hyperthermia mutation.

BACKGROUND: The hypermetabolic state induced by acute endotoxemia and malignant hyperthermia (MH) may be indistinguishable. The aims of this study were (1) to investigate the differences between MH and sepsis, (2) to determine whether acute endotoxemia can trigger MH, and (3) to establish the effects of dantrolene in these two disorders. METHODS: Three groups of swine were studied. All pigs were invasively monitored and initially anesthetized with nontriggering agents. A placebo MH-susceptible group (n = 5) received normal saline whereas the endotoxin groups (MH-susceptible, n = 6; MH-negative, n = 4) received intravenous endotoxin (250 microg/kg total) during 2.5 h. Halothane (1.5%) and succinylcholine (2-4 mg/kg) were then administered, followed by two doses of dantrolene (4 mg/kg total). RESULTS: Endotoxin infusion resulted in pulmonary hypertension and systemic hypotension in pigs with and without the MH mutation, but did not trigger MH. Halothane and succinylcholine triggered MH, evidenced by a markedly higher oxygen consumption in the MH-susceptible pigs that received endotoxin (325+/-196 ml/min) and those that did not (374+/-110 ml/min) compared to the MH-negative pigs (69+/-15 ml/min, P<0.0009), as well as muscular rigidity in the susceptible animals. Dantrolene reversed these changes. Three of the six MH-susceptible pigs that received endotoxin died; two died soon after triggering and one after dantrolene administration. In contrast, none of the MH-negative pigs or the MH-susceptible pigs that did not receive endotoxin died (0 of 9 vs. 3 of 6, P = 0.044). CONCLUSION: Endotoxemia does not trigger MH, but may worsen outcome if it occurs.

Organophosphorus pesticide-induced butyrylcholinesterase inhibition and potentiation of succinylcholine toxicity in mice.

Succinylcholine is the most important rapid-acting depolarizing muscle relaxant during anesthesia. Its desirable short duration of action is controlled by butyrylcholinesterase, the detoxifying enzyme. There are two reported cases of prolonged paralysis from succinylcholine in patients poisoned with the organophosphorus insecticides parathion and chlorpyrifos. The present study examines the possibility that other organophosphorus and methylcarbamate pesticides might also prolong succinylcholine action by inhibiting butyrylcholinesterase using mice treated intraperitoneally as a model and relating inhibition of blood serum hydrolysis of butyrylthiocholine to potentiated toxicity (mouse mortality). The organophosphorus plant defoliant tribufos (4 h pretreatment, 160 mg/kg) and organophosphorus plant growth regulator ethephon (1 h pretreatment, 200 mg/kg) potentiate the toxicity of succinylcholine by seven- and fourfold, respectively. Some other pesticides or analogs are more potent sensitizers for succinylcholine toxicity with threshold levels of 0.5, 1.0, 1.7, 8, 10, and 67 mg/kg for phenyl saligenin cyclic phosphonate, profenofos, methamidophos, tribufos, chlorpyrifos, and ethephon, respectively. Enhanced mortality from succinylcholine is generally observed when serum butyrylcholinesterase is inhibited 55-94%. Mivacurium, a related nondepolarizing muscle relaxant also detoxified by butyrylcholinesterase, is likewise potentiated by at least threefold on 4 hour pretreatment with tribufos (25 mg/kg) or profenofos (10 mg/kg).

Antagonism of suxamethonium-induced jaw muscle contracture in rats.

Masseter muscle rigidity (MMR) induced during general anaesthesia by suxamethonium is a clinical problem that may interfere with tracheal intubation. We have investigated the relation between twitch tension and contracture response to suxamethonium in rats. Rats were anaesthetized with 1% halothane (1.35 MAC). Jaw muscle temperature was maintained at either 37 or 41 degrees C while rectal temperature was kept at 37 degrees C by radiant heat. Twitch tension was produced by nerve stimulation at 0.2 Hz. Rats were pretreated with either a low dose of vecuronium (0.03 mg kg-1) or dantrolene (0.8 mg kg-1). Thereafter suxamethonium 750 micrograms kg-1 was administrated i.v. Low-dose vecuronium pretreatment significantly (90%) decreased suxamethonium-induced jaw muscle contracture (JMC) with minimal (3%) twitch block during local hyperthermia. Low-dose dantrolene pretreatment also reduced JMC (81% at 37 degrees C and 82% at 41 degrees C) while decreasing twitch by 30% at 37 degrees C and 31% at 41 degrees C. Both vecuronium and dantrolene at doses that minimally depressed the twitch response antagonized suxamethonium-induced JMC. We speculate that pretreatment with low-dose vecuronium decreases suxamethonium-induced MMR clinically.

Prolonged d-tubocurarine infusion and/or immobilization cause upregulation of acetylcholine receptors and hyperkalemia to succinylcholine in rats.

BACKGROUND: Hyperkalemic cardiac arrest after the administration of succinylcholine (SCh) to critically ill intensive care patients has been attributed to changes in the acetylcholine receptors (AChRs) at the muscle membrane. The current study attempts to characterize the contributory roles of chronic administration of nondepolarizing muscle relaxants typified by d-tubocurarine (dTC) and/or of immobilization on AChR upregulation and the relationship of these AChR changes to SCh-induced hyperkalemia. METHODS: Rats received chronic subparalytic infusion of saline or dTC for 28 days via subcutaneous osmotic pumps inserted while they were under anesthesia. Approximately half of the saline- or dTC-treated rats underwent bilateral hind-limb immobilization with plaster casts for the same duration as the infusion. After 4 weeks, the osmotic pumps were removed, and 24-48 h later, the blood potassium concentrations were measured at baseline and at 1, 3, 5, 7, and 10 min after SCh (3 mg/kg). At the end of this period, the gastrocnemius muscle was excised for quantitation of AChR number using (125)I-alpha-bungarotoxin. RESULTS: At 28 days, the weight gain in mobile animals receiving saline or dTC infusion did not differ, nor did that in immobilized animals receiving saline or dTC infusion, confirming that infusion of dTC did not unduly affect the ability of the animals to feed. The maximal potassium change after SCh occurred at 5 min. Potassium responses to SCh changed (mean +/- SE): (1) from 3.9 +/- 0.04 to 4.5 +/- 0.1 mEq/1 in the mobile saline- treated control group, where the AChR concentration was 18.4 +/- 2 fmol/mg protein; (2) from 3.9 +/- 0.03 to 5.1 +/- 0.1 in the mobile dTC-infused group (AChRs = 48.6 +/- 7); (3) from 3.8 +/- 0.1 to 5.5 +/- 0.3 in the immobilized saline- treated group (AChRs = 107.4 +/- 14); and (4) from 3.8 +/- 0.1 to 6.3 +/- 0.2 in the immobilized-dTC-treated group (AChRs = 183.5 +/- 23). There was a significant positive correlation between maximal change in blood potassium concentration and the respective AChR concentration in the gastrocnemius of the same animal (r = 0.81, P<0.01). CONCLUSIONS: Subtherapeutic (subparalytic) doses of chronic infusion of dTC (with no immobilization) or immobilization alone (with no dTC) independently increased number of AChRs. The infusion of dTC with immobilization caused the greatest upregulation of AChRs. The magnitude of the increase in blood potassium to SCh was directly dependent on AChR number. This study shows direct evidence and confirms previous speculation that AChR number plays an important role in the magnitude of the hyperkalemic response to SCh. Presuming this represents an appropriate model for patients who are immobilized and/or receiving nondepolarizing muscle relaxants for prolonged periods, exaggerated blood potassium responses to SCh are possible when either or both of these perturbations are present in patients.

Cardiovascular and metabolic responses to anesthetic-induced malignant hyperthermia in swine.

BACKGROUND: Several cardiovascular disturbances, such as tachycardia and hypotension, are observed during human and porcine malignant hyperthermic (MH) crises. However, the pathophysiologic mechanisms responsible for the deterioration of cardiovascular function during MH are not completely known. The purpose of this study was to elucidate the changes in left ventricular (LV) function and metabolism and the systemic and regional hemodynamics during anesthetic-induced MH in swine. METHODS: The study was carried out in 12 open-chest MH-susceptible pigs and in 8 healthy control (non-MH-susceptible) pigs under the same conditions. The cardiovascular and metabolic responses to halothane (1% inspired) and succinylcholine (3 mg.kg-1 intravenously 15 min after the start of halothane administration) were studied. Global hemodynamic and LV variables (expressed as means +/- SEM) were determined over a period of 90 min after the beginning of halothane exposure. Simultaneous investigations were performed on hindleg and cardiac muscle to compare the regional functional and metabolic changes in these tissues. RESULTS: MH was triggered in all MH-susceptible pigs. Early (10-30 min) cardiovascular changes during the development of MH consisted of a rapid increase in heart rate (from 86 +/- 4 to 204 +/- 8 beats.min-1), cardiac index (+84%), and peak rate of change in LV pressure (+150%); stroke volume index (-24%) and mean aortic pressure (-13%) decreased progressively even in the early stage of MH. These alterations were accompanied by an early and persistent reduction in systemic vascular resistance (maximally -57%) with an increase in aortic pressure amplitude. Early changes in coronary and peripheral hemodynamics during the development of MH consisted of a three-fold increase in coronary blood flow in conjunction with a marked decrease (-77%) in coronary vascular resistance. The early circulatory changes were associated with a fourfold increase in myocardial and a 2.5-fold increase in peripheral O2 consumption. The ratio of the LV stroke work index (LVWI) to myocardial O2 consumption (MVO2) was significantly decreased, by a factor of 5. Increased catecholamine concentrations and myocardial lactate and H+ production could be demonstrated throughout the MH crisis. In the late stage of MH (> 30 min), pronounced hypotension and a subsequent decrease in cardiac index were noted. These changes were associated with a significant reduction in LV end-diastolic pressure, from 9 +/- 1 to 6 +/- 1 mmHg (P < 0.05), and in the rate of change in LV pressure, by a maximum of -25%. Coronary vascular resistance remained reduced while coronary blood flow decreased. Peripheral (hind-leg) blood flow initially increased by 48% while peripheral vascular resistance decreased by 42%, followed by a fivefold increase in peripheral vascular resistance with a marked decrease in peripheral blood flow (-88%) in the late phase of MH. CONCLUSIONS: The current findings indicate that metabolic status during MH is characterized by a demand ischemia of the heart and of the skeletal muscle. Insufficient coronary blood flow and increased metabolism as a result of tachycardia and increased concentrations of catecholamines are the dominant factors contributing to the dramatic alteration in cardiac performance during porcine MH. Acidosis, hypovolemia, and hyperkalemia, especially in the late phase of MH, are additional essential factors responsible for the progressive cardiovascular deterioration and cardiac death.

Facilitation of nicotinic receptor desensitization at mouse motor endplate by a receptor-operated Ca2+ channel blocker, SK&F 96365.

When acetylcholinesterase was inhibited by neostigmine, SK&F 96365 (1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) at 10 microM caused no effect on the amplitude of single endplate potentials (e.p.p.s) but shortened the decay time in mouse phrenic nerve-diaphragm preparations. However, SK&F 96365 inhibited high-frequency stimulation-evoked long-lasting depolarization of the endplate region and accelerated the run-down of trains of e.p.p.s which were eliminated within 1 s. After a train of stimulation, SK&F 96365 produced a post-tetanic depression of single e.p.p.s. The post-tetanic effect gradually dissipated with full restoration in 10-15 s. During a train of stimulation, SK&F 96365 also depressed miniature endplate potentials (m.e.p.p.s), which were restored after termination of stimuli in parallel with the recovery of e.p.p. The decay times of miniature endplate currents during recovery phases changed slightly. In control preparations not treated with neostigmine, however, SK&F 96365 did not alter the amplitude and decay time of m.e.p.p.s or e.p.p.s but accelerated the decay of succinylcholine-induced endplate depolarizations. The results suggest that SK&F 96365 facilitates nicotinic receptor desensitization in addition to blocking receptor-operated Ca2+ channels.

Pathogenesis of suxamethonium-induced muscle damage in the biventer cervicis muscle in the chick.

Muscle damage induced by suxamethonium, and the influence of halothane on it, has been examined by measuring the efflux of creatine kinase (CK) in the biventer cervicis muscle of the chick. Whereas halothane and suxamethonium alone did not increase the enzyme efflux significantly, the combination of the two was associated with significant increase in the concentration of CK in the bathing medium by 59-157%. The increase in CK was prevented by adding chlorpromazine 100 mumol litre-1 to the medium, suggesting the involvement of phospholipases in the pathogenesis of suxamethonium-induced muscle damage.

Paraben preservatives do not increase intracranial pressure in cats.

It has been hypothesized recently that succinylcholine-associated increases in intracranial pressure (ICP) are caused by the paraben preservatives contained in multidose vials. We tested that hypothesis in a standard feline model to determine the effects on ICP of equal-volume injections of preservative-free succinylcholine, succinylcholine with preservatives from multi-dose vials that contain both propylparaben and methylparaben, these preservatives alone at five times the dose contained in the succinylcholine, and normal saline. The preservatives alone increased ICP by 0.08 +/- 0.08 mmHg (+/- standard error; not significant). Normal saline had no effect on ICP. Preservative-free succinylcholine and succinylcholine with preservatives increased ICP by 4.2 +/- 0.10 and 3.8 +/- 0.07 mmHg respectively (P less than 0.01 compared to the preservatives alone and normal saline). The 99% upper confidence limit for the increase in ICP induced by the preservatives alone was 0.42 mmHg. This result suggests that parabens do not cause or substantially augment the ICP increase associated with succinylcholine administration.

Suxamethonium and hyperkalaemia.

Severe life-threatening hyperkalaemia may occur following administration of suxamethonium during certain periods after burns, neurological injuries, and in certain other conditions. Although this response is well-known, there is disagreement about when it may occur. This review describes the normal hyperkalaemic response to suxamethonium, the factors affecting it, the conditions in which it may be exaggerated, and the periods of high risk.

Suxamethonium-induced histamine release from the heart of naïve and suxamethonium-sensitized guinea-pigs: evidence suggesting spontaneous sensitization in naïve animals, and relevance to anaphylactoid reactions in man.

A guinea-pig model for anaphylactic and anaphylactoid reactions to suxamethonium was evaluated. 'Sensitization' to that drug was demonstrated both by cardiac anaphylaxis in the Langendorff preparation, and by serum antibody studies. Spontaneous sensitization to cross-reacting chemicals in a proportion of control animals is strongly suggested, somewhat akin to spontaneous sensitization in patients with anaphylactoid reactions to neuromuscular blockers on first exposure, and in whom IgE antibodies are detected.

Comparison of the effects of succinylcholine and atracurium on intracranial pressure in monkeys with intracranial hypertension.

The effects of succinylcholine (1.5 mg X kg-1 IV) administered five minutes after a defasciculating dose of curare (0.05 mg X kg-1 IV), were compared with the effects of atracurium (0.5 mg X kg-1 IV) on intracranial pressure (ICP) in 13 cynomolgus monkeys with intracranial hypertension (ICP approximately 25 mmHg). Neither succinylcholine nor atracurium increased ICP during general anaesthesia with 60 per cent N2O/O2, 0.5-1 per cent halothane. During a rapid sequence induction and intubation with thiopentone 5 mg X kg-1 IV, ICP increased equally with intubation following both atracurium (25 +/- 1 to 32 +/- 2 mmHg) and succinylcholine (25 +/- 1 to 31 +/- 2 mmHg) (p less than 0.05). Intubation was also associated with significant increases in PaCO2, CVP and MAP. We conclude that in this primate model of intracranial hypertension, neither atracurium nor succinylcholine (when given following a defasciculating dose of curare) elevates ICP. In terms of the elevation of ICP associated with intubation, atracurium was found to offer no advantage over succinylcholine.

Suxamethonium chloride and malignant hyperpyrexia.

Pure suxamethonium chloride does not produce in vitro contracture of skeletal muscle from swine which are susceptible to malignant hyperpyrexia (MH), but does induce MH in vivo. It is suggested that suxamethonium chloride induces MH because the fasciculations which it causes lead to an increase in the myoplasmic calcium concentration.

Changes in heart rate and impulse conduction after a single dose of succinylcholine.

The effect of 1 and 2 mg/kg b.w. succinylcholine on changes in cardiac rate and rhythm was studied in 40 fit, adult patients undergoing non-emergency surgery. Induction of anaesthesia consisted of atropine 0.007 mg/kg b.w., pancuronium 0.015 mg/kg b.w., thiopental 5 mg/kg and succinylcholine 1 or 2 mg/kg b.w. Succinylcholine 1 mg/kg b.w. intravenously resulted in a significant decrease in heart rate after 1 min. This decrease persisted after 2 min. The heart rate was unchanged 1 and 2 min after succinylcholine 2 mg/kg b.w. When the two groups were compared, no significant difference was found. No serious cardiac arrhythmias were seen. These results suggest that the larger single dose of succinylcholine is not more likely to cause severe bradycardia or asystole.

The combined effects of pregnancy and repeated plasma exchange on serum cholinesterase activity.

Fourteen patients are described in whom repeated plasma exchange was performed as part of their treatment for Rh alloimmunisation during pregnancy. Despite administration of fresh frozen plasma at frequent intervals during therapy, serum cholinesterase activity was shown to be reduced to levels sufficient to put many of them at risk from suxamethonium sensitivity. It is recommended that if short-acting muscle relaxants are intended to be used during the delivery of such patients, a careful investigation of cholinesterase status should be undertaken beforehand.

[Muscle-relaxant effects of intravenously administered micronomicin].

Pharmacological effects, mainly on its muscle-relaxant of micronomicin (MCR) were studied. Intravenous infusion of MCR at a dose of 20 mg/kg/hour did not influence on both respiration rate and cardiovascular functions in anesthetized rabbits. When MCR was injected to anesthetized rabbit at an intravenous dose of 100 mg/kg, a respiratory arrest followed by a cardiac arrest was observed. This effect was antagonized by either treatment with CaCl2 or artificial respiration. In slant test, MCR at a dose of 100 mg/kg (i.v.) in mice induced muscle relaxation. This effect was weakened by slowing the injection speed of the drug. Intravenous injection of MCR potentiated the lethality induced by either d-tubocurarine or succinylcholine. Intravenous injection of MCR influenced on neither pentobarbital sodium-, ethyl ether-, nor halothane-induced anesthesia in mice. From these results, intravenous infusion of MCR at a dose of 20 mg/kg/hour that is considered as 5 approximately 10 times of clinical dose (120 approximately 240 mg/day) did not influence on both respiration and cardiovascular functions.

Failure to induce malignant hyperthermia in myotonic goats.

Six goats with myotonia congenita were exposed for 1 h to 1% halothane and a single injection of suxamethonium i.v. in an attempt to induce malignant hyperthermia. No evidence of malignant hyperthermia occurred. Suxamethonium did produce a myotonic response in each goat, lasting 10-20s, which was accompanied by a transient increase in aerobic metabolism as indicated by a decrease in PvO2 from 6.6 to 5.7 kPa, an increase in PaCO2 from 5.1 to 6.1 kPa and an increase in PVCO2 from 5.5 to 6.3 kPa. There was no evidence of any metabolic acidosis since the transient changes in pH and buffer base were consistent with the increase in carbon dioxide tension. It is concluded that in goats myotonia congenita does not predispose to susceptibility to malignant hyperthermia.