Anesthesiologist suicide with atracurium.

Atracurium is a nondepolarizing skeletal muscle relaxant used to facilitate endotracheal intubation and to induce skeletal muscle relaxation during surgery or mechanical ventilation. The drug undergoes a spontaneous non-enzymatic biotransformation, yielding laudanosine and an acrylate moiety. This report documents the case of a 45-year-old anesthesiologist who was found dead at the hospital where he worked. The victim was known to be depressed and undergoing treatment with venlafaxine. An empty syringe was found near the body. Toxicological analysis revealed the presence of laudanosine in the syringe, 0.6 mg/L of laudanosine in heart blood, 0.3 mg/L in urine, and 0.02 mg/L in vitreous humor. Meanwhile, concentrations of venlafaxine and O-desmethyl-venlafaxine, its active metabolite, were 0.7 and 1.1 mg/L in heart blood, 1.7 and 5.2 mg/L in urine, 0.5 and 0.7 mg/L in vitreous humor, and 400 and 20 mg in gastric content, respectively. All drugs and metabolites involved in the case were detected using gas chromatography with nitrogen-phosphorus detection (GC-NPD) and confirmed using GC-mass spectrometry in full scan mode after solid-phase extraction using Bond-Elut Certify columns. Additional high-performance liquid chromatography coupled to diode-array detection screening also obtained the same results. Quantitation of laudanosine and venlafaxine together with its metabolite was carried out using GC-NPD. No other drugs, including ethanol, were detected. Recoveries for laudanosine and venlafaxine were 89% and 86%, respectively, at 0.5 mg/L; intraday and interday precisions were 2% and 6%, and 3% and 7%, respectively; and limits of detection and quantitation were 6 and 20 ng/mL and 18 and 59 ng/mL, respectively. The linearity of the blood calibration curves was excellent for both drugs with r(2) values of > 0.999 (range 0.1-2.0 mg/L). Based on the autopsy findings, case history, and toxicology results, the forensic pathologists ruled that the cause of death was an overdose of atracurium, and the manner of death was suicide.

cis-Atracurium in dogs with and without porto-systemic shunts.

OBJECTIVE: To evaluate the non-depolarizing neuromuscular blocking drug cis-atracurium in dogs with porto-systemic shunts, and to compare it in clinically normal animals. ANIMALS: Thirteen dogs of mixed breed and sex, aged between 3 and 31 months old, weighing 2.2-25.5 kg, with ASA physical status II-IV, and undergoing surgical attenuation of porto-systemic shunt. A control group of 11 bitches of mixed breed, between 8 and 60 months old, and weighing 4.5-41.0 kg, all ASA physical status I, undergoing routine ovarohysterectomy were also studied. MATERIALS AND METHODS: Pre-anaesthetic medication was an opioid analgesic, given either alone or in combination with acepromazine. Following induction of general anaesthesia with intravenous (IV) propofol and oro-tracheal intubation, anaesthesia was maintained using isoflurane in either oxygen or oxygen and nitrous oxide. Ventilation was controlled. The train of four (TOF) technique was used to monitor neuromuscular blockade. An initial dose of 0.1 mg kg(-1)cis-atracurium was given IV and additional doses of 0.03 mg kg(-1)cis-atracurium were administered when at least one twitch of the TOF was present. RESULTS: Except for one dog that was killed during surgery because its anomaly was inoperable, all animals recovered satisfactorily from anaesthesia and surgery. In dogs with porto-systemic shunt, onset of neuromuscular blockade was 3.1 +/- 1.1 minutes (mean +/- SD) and in control dogs was 3.4 +/- 0.7 minutes (not significantly different). Neuromuscular blockade lasted 34 +/- 13 minutes in dogs with porto-systemic shunt and 29 +/- 17 minutes in control dogs (not significantly different). CONCLUSIONS: The presence of porto-systemic shunt did not affect the rate of onset or duration of action of cis-atracurium. CLINICAL RELEVANCE: cis-Atracurium may have a use in veterinary anaesthesia for producing neuromuscular blockade in dogs with hepatic insufficiency, including those with porto-systemic shunt.

The human heart as a shock organ in anaphylaxis.

Human mast cells, by elaborating vasoactive mediators and cytokines, are the primary effector cells of anaphylaxis. A body of evidence implicates human heart mast cells (HHMCs) in anaphylaxis. These cells have been identified perivascularly, in dose proximity to myocytes and in the arterial intima in human heart tissue. The membrane surface of mast cells from human heart tissue of patients undergoing cardiac transplantation expresses the high affinity receptors for IgE (FcepsilonRI) and C5a receptors. Activation of HHMCs in vitro with anti-IgE or anti-FcepsilonRI induced the release of preformed mediators (histamine, tryptase and chymase) and the de novo synthesis of LTC4 (approximately equal to 18 ng/10(6) cells) and PGD2 (approximately equal to 18 ng/10(6) cells). Complement activation and anaphylatoxin formation occur during anaphylaxis in human. C5a caused rapid release of histamine and tryptase from HHMCs. These cells are activated in vitro by therapeutic (general anaesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.) that may cause non-IgE-mediated anaphylactic reactions. Administration of low concentrations of histamine and cysteinyl leukotrienes in subjects undergoing diagnostic catheterization caused significant systemic and coronary haemodynamic effects. Taken together, these results indicate that the human heart can be both the site and the target of anaphylactic reactions.

Laudanosine, an atracurium and cisatracurium metabolite.

Laudanosine is a metabolite of the neuromuscular-blocking drugs atracurium and cisatracurium with potentially toxic systemic effects. It crosses the blood-brain barrier and may cause excitement and seizure activity. Its interest in recent years has increased because of the recognized interaction with gamma-aminobutyric acid, opioid and nicotinic acetylcholine receptors. It has been shown to produce analgesia in animals. In the cardiovascular system, high plasma concentrations produce hypotension and bradycardia. In hepatic failure, its elimination half-life is prolonged but only moderate accumulation occurs in adults, whereas in infants and children plasma concentration are greater. In patients undergoing liver transplantation, laudanosine concentrations are increased during preanhepatic, anhepatic and postanhepatic stages. Patients with renal failure have higher plasma concentrations and a longer mean elimination half-life. In pregnancy, laudanosine crosses the placental barrier. The mean transplacental transfer is 14% of maternal blood concentrations. Except for prolonged administration of atracurium in intensive care units, laudanosine accumulation and related toxicity seem unlikely to be achieved in clinical practice. When cisatracurium is used, plasma concentrations of laudanosine are lower. Further studies are needed, especially around the interactions with gamma-aminobutyric acid, opioid and nicotinic acetylcholine receptors.

[Carboxyperitoneum and clinical efficacy of nondepolarizing relaxants with different types of metabolism]. / Karboxyperitoneum i klinicheskaia éffektivnost' nedepoliarizuiushchikh relaksantov s razlichnymi tipami metabolisma.

A total of 108 patients operated on the abdominal cavity were examined with laparoscopic equipment or via laparotomic assess. The recovery time of neuromuscular conduction was defined for a myorelaxant with organ-depended metabolism (pipecuronium) and, predominantly, nonorgan-depended metabolism (athracurium and cisathracurium) in relation to the type of surgical technique (laparoscopy and laparotomy). It is concluded that carboxyperitoneum prolongs the recovery of neuromuscular conduction for pipecuronium without affecting this parameter in athracurium and cisathracurium. It is more expedient to use these myorelaxants during laparoscopic operations than pipecuronium, a myorelaxant having organ-dependent metabolism.

Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine.

BACKGROUND: Curaremimetic nondepolarizing muscle relaxants are widely used in clinical practice to prevent muscle contraction either during surgery or during intensive care. Although primarily acting at the neuromuscular junction, these compounds can cause adverse effects, including modification of cardiac rhythm, arterial blood pressure, and in the worst cases, triggering of seizures. In this study, we assessed the interaction of atracurium and its metabolite, laudanosine, with neuronal nicotinic receptors. METHODS: The human neuronal nicotinic receptors alpha4beta2, alpha3beta4, alpha3alpha5beta4, and alpha7 are heterologously expressed in Xenopus laevis oocytes, and the effect of atracurium and its degradation product, laudanosine, were studied on these receptors. RESULTS: Atracurium and laudanosine inhibited in the micromolar range the major brain alpha4beta2 receptor and the ganglionic alpha3beta4 or alpha3beta4alpha5 and the homomeric alpha7 receptors. For all four receptors, inhibition was rapid and readily reversible within less than 1 min. Atracurium blockade was competitive at alpha4beta2 and alpha7 receptors but displayed a noncompetitive blockade at the alpha3beta4 receptors. Inhibition at this receptor subtype was not modified by alpha5. Laudanosine was found to have a dual mode of action; first, it competes with acetylcholine and, second, it blocks the ionic pore by steric hindrance. At low concentrations, these two drugs are able to activate both the alpha4beta2 and the alpha3beta4 receptors. CONCLUSION: Adverse effects observed during atracurium administration may be attributed, at least partly, to an interaction with neuronal nicotinic receptors.

Cisatracurio: farmacodinamica, farmacocinetica e uso clinico / Cisatracurium: pharmacodynamics, pharmacokinetics, and clinical use

Cisatracurio e o mais recente bloqueador neuromuscular (BNM) nao-despolarizante benzoisoquinolinico disponivel para uso medico em nosso meio. Trata-se de um dos dez isomeros do atracurio, apresentando potencia tres vezes maior e a mesma via de metabolizacao, a Via de Hoffmann, sendo eliminado de forma independente da funcao renal e hepatica do paciente...

Clinical pharmacokinetics of cisatracurium besilate.

Cisatracurium besilate, one of the 10 stereoisomers that comprise atracurium besilate, is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. Following a 5- to 10-sec intravenous bolus dose of cisatracurium besilate to healthy young adult surgical patients, elderly patients and patients with renal or hepatic failure, the concentration versus time profile of cisatracurium besilate is best characterised by a 2-compartment model. The volume of distribution (Vd) of cisatracurium besilate is small because of its relatively large molecular weight and high polarity. Cisatracurium besilate undergoes Hofmann elimination, a process dependent on pH and temperature. Unlike atracurium besilate, cisatracurium besilate does not appear to be degraded directly by ester hydrolysis. Hofmann elimination, an organ independent elimination pathway, occurs in plasma and tissue, and is responsible for approximately 77% of the overall elimination of cisatracurium besilate. The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.28 L/h/kg (4.7 ml/min/kg), 0.145 L/kg and 25 minutes, respectively. The magnitude of interpatient variability in the CL of cisatracurium besilate is low (16%), a finding consistent with the strict physiological control of the factors that effect the Hofmann elimination of cisatracurium besilate (i.e. temperature and pH). There is a unique relationship between plasma clearance and Vd because the primary elimination pathway for cisatracurium besilate is not dependent on organ function. There are minor differences in the pharmacokinetics of cisatracurium besilate in various patient populations. These differences are not associated with clinically significant differences in the recovery profile of cisatracurium besilate, but may be associated with differences in the time to onset of neuromuscular block.

Effects of neuromuscular blocking agents on excitatory transmission and gamma-aminobutyric acidA-mediated inhibition in the rat hippocampal slice.

BACKGROUND: Although neuromuscular blocking agents do not cross the blood-brain barrier, they may penetrate the central nervous system under particular circumstances and eventually cause neurotoxic consequences. METHODS: The effects of neuromuscular blocking agents on excitatory and inhibitory transmission in area CA1 of rat hippocampal slices were investigated using extracellular and intracellular recording techniques. RESULTS: Application of atracurium in the perfusion medium resulted in a dose-dependent enhancement of excitatory synaptic responses averaging 48.7 +/- 4.3% at a concentration of 10 nM. This effect was correlated with an increase in the size of the presynaptic fiber volley. Laudanosine, but not pancuronium bromide or vecuronium bromide, produced similar changes. In addition, atracurium and laudanosine blocked inhibitory transmission and reduced intracellularly recorded gamma-aminobutyric acidA receptor-mediated potentials. These effects were observed only at concentrations >1 microM and were not reproduced by pancuronium bromide and vecuronium bromide. CONCLUSIONS: Atracurium and its metabolite, laudanosine, contrary to pancuronium bromide and vecuronium bromide, produce two distinct effects on hippocampal slices. They enhance excitatory transmission and neuronal excitability and they block inhibitory gamma-aminobutyric acidA-mediated synaptic responses.

Resistance to atracurium in rats with experimental inflammation: role of protein binding.

The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil. Doses of atracurium ranging from 0.45 to 1.5 mg.kg-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min). The dose-intensity of the effect relationship was modelled using a sigmoid Emax model. The ED50 (effective dose eliciting 50% of the maximum effect) was significantly increased (P < 0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg.kg-1). This change was reflected in a shift of the dose-response curve to the right in the pretreated rats. For equipotent doses ED95 (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of alpha 1-acid glycoprotein (AAG) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats. Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.

Pharmacokinetics and pharmacodynamics of the benzylisoquinolinium muscle relaxants.

The benzylisoquinolinium class of drugs comprises atracurium, 51W89, doxacurium, and mivacurium. Atracurium can be used as a pharmacokinetic benchmark; it has at least two distinct metabolic pathways, of which Hofmann elimination and ester hydrolysis are the most significant. The relative importance of each of these two routes is still a matter of speculation, and this, coupled with the fact that atracurium is a mixture of 10 isomers, has led to the development of many innovative pharmacokinetic modelling concepts. 51W89 is a cis-cis-isomer of atracurium and probably has a pharmacokinetic profile very similar to that of atracurium. Doxacurium, a long-acting benzylisoquinolinium, has a small apparent volume of distribution and an elimination half-time similar to that of pancuronium, and is excreted by the kidneys. Mivacurium is a short-acting benzylisoquinolinium that is rapidly hydrolysed by plasma cholinesterases. Two isomers of mivacurium are very similar, whereas the third isomer differs greatly in both pharmacological activity and elimination half-time, so that analysis requires complex pharmacokinetic methods.

Spontaneous recovery or evoked reversal of neuromuscular block.

Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.

Interaction of gentamycin and atracurium in anaesthetised horses.

Evoked hind limb digital extensor tension (hoof twitch) was maintained at 40% of baseline for 1 h by atracurium infusion in 7 horses anaesthetised with halothane. After 1 h, atracurium was discontinued and hoof twitch allowed to recover to 75%. Atracurium was again given by infusion to maintain 40% twitch for a second hour, then 2 mg gentamycin/kg bwt were given i.v. Atracurium infusion was continued for a third hour, and then hoof twitch was again allowed to recover spontaneously to 75%. Gentamycin reduced twitch strength from 40 +/- 1% (mean +/- sem) to 29 +/- 4% within 7.0 +/- 1.5 min (P = 0.02). Twitch gradually returned to pre-gentamycin strength over the course of the next hour. Recovery of hoof twitch from 50% to 75% took 7.7 +/- 0.7 min for atracurium alone and 11.5 +/- 2.7 min for atracurium plus gentamycin (P = 0.03). Recovery from 50% twitch to 75% fade recovery took 13.8 +/- 0.8 min for atracurium alone and 13.7 +/- 1.2 min for atracurium plus gentamycin. At 75% recovery of fade, hoof twitch was 87 +/- 3% for atracurium alone and 82 +/- 4% for atracurium plus gentamycin. Reversal of the block with edrophonium and subsequent recovery of the horses from anaesthesia were uneventful. It was concluded that, although gentamycin did augment the neuromuscular blockade of atracurium, the effect was minimal.

Influence of incubated atracurium on rat liver function.

Degradation of atracurium by Hofmann elimination and ester hydrolysis depends mainly on pH and temperature and is said to be independent of liver and kidney function. Consequently atracurium is used widely in patients with liver failure. However, there is evidence that incubation of atracurium at 37 degrees C and pH 8 leads to leakage of LDH from hepatocyte cell cultures. We have tested the hepatotoxic effects of incubated atracurium in an isolated perfused rat liver model. After equilibration, atracurium 2010 mumol ml-1 (preincubated at pH 8 and 37 degrees C for 120 min) was administered over a period of 10 min followed by perfusion of Krebs-Henseleit bicarbonate buffer for 60 min. We found that incubation resulted in considerable degradation of atracurium and formation of laudanosine. Administration of incubated atracurium did not produce either biochemical or morphological damage to liver cells, but caused considerable increase in bile flow. We conclude that administration of preincubated atracurium did not produce impairment of liver cell function. The increase in bile flow could be beneficial if it occurs clinically.

Atracurio mas alcuronio en anestesia / Atracurio and alcuronio in anesthesia

Con el presente trabajo se busca demostrar los beneficios del ejemplo alternado en un mismo paciente de dos relajantes musculares no despolarizantes, en este caso atracurio y alcuronio, obteniendose condiciones optimas mas o menos rapidas de intubacion endo-traqueal, adecuada relajacion quirurgica, sin la necesidad de revertir a estos relajantes al finalizar el acto quirurgico. Disminuyendo de esta forma la dosis total de ambos relajantes, probabilidad de depresion respiratoria por relajacion residual post anestesica.