Interrupted (self -)medication with pancuronium(bromide) and fatal outcome.

Pancuronium(bromide) is used because of its relaxing effect on striated muscles and usually requires artificial respiration. A 52-year-old woman suffered from long-standing "generalized dystonia", which had become resistant to conventional therapy. Therefore, an anesthetist established a permanent medication scheme with pancuronium using a PCA pump. This pump had been controlled by the patient herself ensuring an acceptable quality of life with broad personal autonomy. Finally, the woman was found dead in her flat by a member of a home nursing service. The infusion hose showed a fixed knot and further blocking by a clamp. The autopsy findings were non-specific, except for the presence of opioid tablets in the colon. Toxicological analyses showed 72ng/ml pancuronium and 21 ng/ml oxycodone (therapeutic) in the femoral venous blood. The range of published pancuronium levels varies from approx. 80 to 2,000 ng/ml. Thus it had to be assumed that the pancuronium level was too low (72 ng/ml) so that symptoms of dystonia recurred. Based on extensive literature research, the described case can be qualified as unique. The therapy concept had been innovative, sufficient and effective for more than 10 years. It allowed the patient to enjoy a maximum of autonomy. Ultimately, death was due to the blocked pancuronium infusion. The relatively low pancuronium level had provoked the dystonia to return with generalized spasms also involving the respiratory muscles resulting in respiratory arrest. During the police investigations, two previous suicide attempts came to light.

Comparative pharmacodynamics of pancuronium, cisatracurium, and CW002 in rabbits.

Pancuronium is a long-duration neuromuscular blocking drug (NMBD) that has been used in anesthetized rabbits at 0.1 mg/kg. However, there are limited data regarding the time course for recovery from this dose either spontaneously or with pharmacologic reversal. Here we defined the potency, onset, and recovery characteristics for the intermediate-duration NMBD cisatracurium and CW002 (a novel cysteine-inactivated molecule) in the rabbit, and test the hypothesis that these drugs may be alternatives to 0.1 mg/kg pancuronium for survival procedures. New Zealand white rabbits anesthetized with isoflurane were studied in a cross-over design. Potencies of cisatracurium and CW002 were defined as the effective dose for 95% depression of evoked muscle twitch (ED95). Responses to 3×ED95 were used to define onset (time to maximal effect), recovery index (RI; time from 25% to 75% recovery of twitch), and duration (time to complete recovery). Responses to all drugs were determined with and without reversal by neostigmine-glycopyrrolate or L-cysteine. CW002 was 4-fold more potent than was cisatracurium, but their onset, RI, and duration were similar. Pancuronium had similar onset and RI but longer duration, compared with cisatracurium and CW002. Reversal shortened the recovery index and duration for all 3 drugs. At 3×ED95, cisatracurium and CW002 had the same onset as did standard-dose pancuronium, but durations were shorter and more predictable. In addition, CW002 can be reversed without the potential side effects of cholinergic manipulation. We conclude that cisatracurium and CW002 are viable alternatives to pancuronium for survival studies in rabbits.

Neuromuscular blockade in cardiac surgery: an update for clinicians.

There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

Role of cholinesterase activity on pharmacodynamics of mivacurium preceded by pancuronium in elderly and young adults.

Mivacurium- pancuronium combination proved to be more potent than either drug given alone. The goal of this study was to evaluate the safety and efficacy of this combination in elderly group and its correlation to plasma butyryl cholinesterase (Bche) activity. Forty patients, ASA I or II scheduled for elective open cholecystectomy were allocated into two groups of twenty patients each: young group (18- 55 years) and elderly group (60-75 years). Anesthesia was induced with midazolam, fentanyl, and propofol then maintained with isoflurane and opioid supplementation. Neuromuscular blockade (NMB) was monitored by train-of-four (TOF) stimulation of the ulnar nerve. After calibration, NMB was achieved by 16 microg kg(-1) pancuronium followed by 32 microg kg(-1) mivacurium. The following parameters were recorded: The onset time, clinical duration, recovery index and the total dose of mivacurium and pancuronium together with hemodynamic data. Three blood samples for Bche activity were collected: before pancuronium injection, 3 min. and 30 min. afterwards in both groups. The onset time and the recovery index of NMB were comparable in both groups. The duration of action was significantly prolonged in elderly group (49.8 +/- 10.48 min.) compared to young one (37.13 +/- 7.81 min.). The total dose of mivacurium was significantly less in the elderly group (22.56 +/- 2.39 microg kg(-1) hr(-1)) when compared to the young group (25.78 +/- 3.05 microg kg(-1) hr(-1)). For all patients, the preoperative Bche activity was within the normal range. After pancuronium injecttion, it showed a significant reduction in both groups at three and thirty minutes except a non significant value in young at thirty minutes. This reduction showed a significantly higher percent change in the elderly group (30.37 +/- 22.01) than the young group (8.60 +/- 19.19) at thirty minutes. There were significant intra operative variations in the percent changes of hemodynamic data compared to the preoperative values, yet, still within the clinically acceptable range. So, the use of a small dose of pancuronium followed by a small dose of mivacurium with a ratio of 1:2 can produce synergism without affecting either the recovery profile of mivacurium or the clinical hemodynamic stability even in the elderly group.

Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model.

BACKGROUND: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. METHODS: Functional acetylcholine receptors were reduced by administration of alpha-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. RESULTS: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the alpha-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. CONCLUSION: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.

Pancuronium bromide (Pavulon) isolation and identification in aged autopsy tissues and fluids.

The isolation and detection of pancuronium bromide was developed for aged autopsy samples to identify and confirm this compound in questioned tissue samples. A novel protocol was optimized for the isolation of the target drug in highly decomposed tissues. Solid-phase extraction (SPE) cartridges containing styrene-divinylbenzene were investigated. This polymer retained quaternary drugs and facilitated sequential elution upon washing with commonly available solvents. The semi-purified SPE samples were prescreened by pyrolysis GC-MS. A candidate specimen was then confirmed by microbore high-performance liquid chromatography/electrospray-ionization/mass spectrometry (microHPLC-ESI-MS/MS) with a triple-quadrupole mass spectrometer. The developed procedures provided a qualitative or semiquantitative (at best) basis for the investigation of difficult cases involving overdoses of polar drugs.

The application of pancuronium bromide (Pavulon) forensic analyses to tissue samples from an "Angel of Death" investigation.

The case report of a serial killer who worked at several hospitals as a respiratory therapist is presented. The suspect was initially labeled a benevolent Angel of Death who ended the suffering of elderly patients through mercy killing. However, his subsequently declared motive for homicide was very different from other similar cases in medical settings. The application of new analysis techniques for the detection of pancuronium bromide in a series of aged exhumation tissues gave positive results and led to the resultant conviction of the therapist.

Interaction between mivacurium and pancuronium: impact of the order of administration.

INTRODUCTION: Potentiation of mivacurium by low-dose pancuronium is mostly due to an inhibition of plasma butyryl cholinesterase (BchE) resulting in a decreased rate of hydrolysis of mivacurium. Nevertheless, an interaction at the receptor site could not be ruled out. By changing the order of the muscle relaxant injections, we may lessen the pharmacokinetic interaction and assess the impact at the acetylcholine receptor level. METHODS: Twenty patients scheduled for general anesthesia with propofol and fentanyl, and isoflurane were randomized into two groups receiving, mivacurium 100 microg kg-1 followed by pancuronium 15 microg kg-1 (group 1) or pancuronium 15 microg kg-1 followed by mivacurium 100 microg kg-1 (group 2). BchE before and after injection of each relaxant was measured. Neuromuscular block was assessed with a force transducer at the adductor pollicis measuring the elicited twitch to ulnar nerve stimulation. RESULTS: The neuromuscular block was greater when pancuronium was administered before mivacurium (100% versus 96+/-3%; P<0.05). Times to recovery of the elicited twitch response to 25% and 75% of control value were increased by 100% (P<0.05). After pancuronium, decreases in BchE of 11% and 14% in groups 1 and 2 were observed, respectively. CONCLUSION: Interaction between mivacurium and low dose pancuronium is significant only when mivacurium is injected after pancuronium.

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study.

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

Ventajas del uso de dosis de cebado / Advantages of the use of priming doses

Introducción: En la práctica clínica se han ensayado diversas formas de administrar los relajantes muculares con vistas a lograr menores tiempos y mejores condiciones de intubación. Objetivos: Determinar las condiciones y el tiempo de intubación que se lograron al utilizar el principio de dosis de cebado en los pacientes quirúrgicos, y evaluar los valores de la altura del twicht en ese período. Material y método: Se realizó una investigación tipo ensayo clínico en 120 pacientes sometidos a cirugía laparoscópica, subdivididos en 2 grupos. La técnica de dosis de cebado se realizó en 60 pacientes. Los relajantes musculares utilizados fueron: pancuronio (Grupo I) dosis de 0,1 mg/kg, vecuronio (Grupo II) 0,1 mg/kg y atracurio (Grupo III) 0,5 mg/kg. A los pacientes de este grupo se les administró el 10 por ciento de la dosis total calculada en los 4 minutos previos a la administración de la dosis restante. Resultados: Al monitorizar la FNM durante la intubación se observó que el tiempo óptimo de intubación, cuando se utilizaron dosis de cebado con atracurio y vecuronio, fue de 112,12 ñ 3,2 y 118ñ1,4 seg. respectivamente, menores al del grupo pancuronio. Las condiciones de intubación obtenidas según los criterios de Lund y Stouner presentaron un 95 por ciento de condiciones excelentes en los grupos II y III y un 60 por ciento en el grupo I. La altura del twitch en igual período fue semejante para los grupos II y III. Al usar dosis de cebado fue de 28,5 ñ 3,1 y 33,1 ñ 0,8 por ciento respectivamente y de 48,1 ñ 1,5 y 49,1 ñ 2,6 por ciento cuando ésta no se utilizó. Estas diferencias resultaron ser estadísticamente significativas (p<0,05). Como consecuencia de esta técnica, en el Grupo II se encontraron, en un 10 por ciento del total, dificultades para respirar y otro 10 por ciento refirió experiencia subjetiva de parálisis respiratoria y en el 20 por ciento del Grupo III se observaron dificultades respiratorias. Tres pacientes del Grupo I y dos de cada Grupo II y III presentaron diplopia. Conclusiones: Las condiciones de intubación fueron más rápidas cuando se empleó dosis de cebado para los tres fármacos, que cuando no se la utilizó. La laringoscopía y la intubación tuvieron mejores condiciones con los fármacos de acción intermedia (vecuronio y atracurio). La altura del twitch disminuyó más cuando se emplearon dosis de cebado en los tres fármacos que cuando no se utilizaron...(AU)

Fuzzy logic for model adaptation of a pharmacokinetic-based closed loop delivery system for pancuronium.

In this paper, we investigate the ability of fuzzy to adapt the parameters of a pharmacokinetic and pharmacodynamic model-based controller for the delivery of the muscle relaxant pancuronium. The system uses the model to control the rate of drug delivery and uses feedback from a sensor which measures muscle relaxation level to adapt the model using fuzzy logic. The control strategy administers mini-bolus doses of pancuronium and modulates the magnitude and time interval between the bolus doses to maintain a patient's muscle relaxation within an allowable range specified by the user. Before each new dose is given, the fuzzy logic adaptation scheme uses the error between the predicted patient response and the measured response to adapt the model. The system was tested using computer simulation by varying the parameters of the model by 50% from their nominal values. It was also evaluated in a clinical trial of five patients undergoing surgical procedures lasting 5 h or longer.

Uso de bloqueantes neuromusculares y su monitoreo en pediatría / Use of neuromuscular blocking agents and its monitoring in pediatrics

El actual arsenal farmacológico, en cuanto a relajantes musculares ha hecho necesario la constante actualización y desarrollo de técnicas para las indicaciones adecuadas y el correcto control de los mismos. El aumento de la utilización de estos fármacos en pediatría, sobre todo los relajantes musculares no despolarizantes ha facilitado la tarea médica del anestesiólogo, obligándolo a una constante actualización en el conocimiento sobre el desarrollo de estos fármacos y el monitoreo clínico e instrumental sobre el paciente.

Uso de bloqueantes neuromusculares y su monitoreo en pediatría / Use of neuromuscular blocking agents and its monitoring in pediatrics

El actual arsenal farmacológico, en cuanto a relajantes musculares ha hecho necesario la constante actualización y desarrollo de técnicas para las indicaciones adecuadas y el correcto control de los mismos. El aumento de la utilización de estos fármacos en pediatría, sobre todo los relajantes musculares no despolarizantes ha facilitado la tarea médica del anestesiólogo, obligándolo a una constante actualización en el conocimiento sobre el desarrollo de estos fármacos y el monitoreo clínico e instrumental sobre el paciente. (AU)

[The pharmacokinetics of pancuronium bromide in infants, children and adults].

Twenty-four patients scheduled for elective plastic surgery were selected to study the pharmacokinetics of pancuronium bromide under enflurane anesthesia. The patients were divided into three groups by their ages; Group 1 consisted of 5 infants (0.75-2.95 years); Group 2 contained 13 children (4-14 years); Group 3 included 6 adults (16-27 years). An improved fluorimetric assay was used to measure the plasma concentrations of pancuronium bromide after administration of pancuronium bromide at a dose of 100 micrograms/kg. The results showed that the disposition of pancuronium bromide may be best described mathematically by a two-compartment open model in all patients. The younger the patients, the larger the distribution volumes and the higher the Cl. There were significant differences among the three groups with regard to V1, V2, Vdss, Cl, AUC. The T1/2 beta and MRT were longer in Group 1 than in Group 2 and Group 3.

Disposition decomposition analysis for pharmacodynamic modeling of the link compartment.

An approach based on disposition decomposition analysis (DDA) and the hysteresis minimization principle has been developed for pharmacodynamic modeling. It allows calculation of the mean transit time and the ratio of distribution clearance to biophase distribution volume of drug, and determination of the drug concentration-time function at the biophase (Cb(t)). The proposed method extends the DDA approach to drug distribution to a possibly heterogeneous effect compartment of a generalized pharmacokinetic/pharmacodynamic model. The application of this DDA-dynamics method is demonstrated using published data for pancuronium.

Effects of enflurane and isoflurane anesthesia on the pharmacokinetics of pancuronium in adult patients.

OBJECTIVE: To evaluate the effects of 1 MAC of enflurane or isoflurane anesthesia on the pharmacokinetics of pancuronium. METHODS: Eighteen adult patients undergoing the elective plastic surgery were randomly divided equally into 3 groups, namely, Group 1 (control group), Group 2 (enflurane group) and Group 3 (isoflurane group). Anesthesia was maintained with thiopental and 67% N2O-O2 in Group 1, 1 MAC enflurane in Group 2 and 1 MAC isoflurane in Group 3. After administration of a bolus of pancuronium 100 micrograms/kg, an improved fluorimetric assay was used to determine the serum concentrations of pancuronium and the pharmacokinetic variables of pancuronium were calculated with a 3P87 program. RESULTS: The disposition of pancuronium may be well described mathematically by a two-compartment open model. The results showed that in comparison with the control group, patients in Group 2 and Group 3 had a longer T1/2 beta and MRT. The patients in Group 2 had the slower K10 and lower CL than those in the control group. There were no significant differences among the three groups in T1/2 alpha, V1, V2, Vdss, V beta, K21, K12 and AUC. CONCLUSION: During enflurane and isoflurane anesthesia, CL of pancuronium decreased, and T1/2 beta and MRT of pancuronium were prolonged in our patients, so duration of the effective plasma concentrations of pancuronium was much longer. As a result, the effects of enflurane and isoflurane of the pharmacokinetics of pancuronium may be part of reason why two drugs extended the duration of neuromuscular depression produced by pancuronium.

Relajantes musculares en pediatría / Muscle relaxants in pediatrics

Desde el nacimiento, en el organismo ocurren cambios anatómicos y fisiológicos. Es en la primera etapa de la vida donde estas variaciones son más marcadas y ocurren más rápidamente. Así, la respuesta a los fármacos administrados en pediatría depende principalmente de estos cambios. Los relajantes musculares no escapan a esta regla, por tal motivo, para su uso correcto es necesario conocer las variables farmacocinéticas y farmacodinámicas en el recién nacido, lactante y niño

Relajantes musculares en pediatría / Muscle relaxants in pediatrics

Desde el nacimiento, en el organismo ocurren cambios anatómicos y fisiológicos. Es en la primera etapa de la vida donde estas variaciones son más marcadas y ocurren más rápidamente. Así, la respuesta a los fármacos administrados en pediatría depende principalmente de estos cambios. Los relajantes musculares no escapan a esta regla, por tal motivo, para su uso correcto es necesario conocer las variables farmacocinéticas y farmacodinámicas en el recién nacido, lactante y niño