Atracurium during induced hyperthermia.

During hyperthermic intraperitoneal chemotherapy (HIPEC), we observed a partial recovery from neuromuscular block in a hyperthermic patient after hours of monitored adequate surgical relaxation and continuous infusion of atracurium during normothermia. This recovery is indicative of the higher clearance of atracurium during hyperthermia. This case report emphasizes the clinical relevance of the well-known temperature dependence of the Hofmann elimination of atracurium. Moreover, this report illustrates the importance of monitoring muscle relaxation during HIPEC. Clinicians should be aware that the usual continuous infusion rate of atracurium at 0.3 mg.kg(-1).h(-1) may be inadequate in hyperthermic patients.

The development of ultrashort acting neuromuscular relaxant tropane derivatives.

There is a need for neuromuscular relaxant (NMR) agents that are of the "nondepolarizing type" and produce rapidly developing and short-lasting skeletal muscle relaxation in anesthesiology. Many efforts have been directed to produce such agents. Our research focused on the design, synthesis, and evaluation of numerous "bisquaternary" derivatives of the cyclic aminoalkanes: tropane and granatane. Through systematic "steric structure-activity relationship" studies, we arrived at some new bisquaternary tropine and granatanol diesters, which in laboratory studies appeared to be the fastest and shortest acting NMRs recognized so far. Their ultrashort duration action-mechanism was, however, linked to the formation of nephrotoxic metabolites, precluding further development. Even so, we believe that the scientific information gained from more than a thousand such agents, will be useful toward developing the "ideal," ultrashort-acting NMR that could be clinically successful without the use of "reversing" agents, at least until "new biotechnology" may solve all problematic aspects of "transient" muscle relaxation.

Phenobarbital influence on neuromuscular block produced by rocuronium in rats / Influência do fenobarbital no bloqueio neuromuscular produzido pelo rocurônio em ratos

PURPOSE: To evaluate in vitro and in vivo neuromuscular blockade produced by rocuronium in rats treated with Phenobarbital and to determine cytochrome P450 and cytochrome b5 concentrations in hepatic microsomes. METHODS: Thirty rats were included in the study and distributed into 6 groups of 5 animals each. Rats were treated for seven days with phenobarbital (20 mg/kg) and the following parameters were evaluated: 1) the amplitude of muscle response in the preparation of rats exposed to phenobarbital; 2) rocuronium effect on rat preparation exposed or not to phenobarbital; 3) concentrations of cytochrome P450 and cytochrome b5 in hepatic microsomes isolated from rats exposed or not to phenobarbital. The concentration and dose of rocuronium used in vitro and in vivo experiments were 4 µg/mL and 0,6 mg/kg, respectively. RESULTS: Phenobarbital in vitro and in vivo did not alter the amplitude of muscle response. The neuromuscular blockade in vitro produced by rocuronium was significantly different (p=0.019) between exposed (20 percent) and not exposed (60 percent) rats; the blockade in vivo was significantly greater (p=0.0081) in treated rats (93.4 percent). The enzymatic concentrations were significantly greater in rats exposed to phenobarbital. CONCLUSIONS: Phenobarbital alone did not compromise neuromuscular transmission. It produced enzymatic induction, and neuromuscular blockade in vivo produced by rocuronium was potentiated by phenobarbital.

OBJETIVO: Avaliar in vitro e in vivo o bloqueio neuromuscular produzido pelo rocurônio em ratos tratados com fenobarbital e determinar as concentrações de citocromo P450 e b5 em microssomos hepáticos. MÉTODOS: Trinta ratos foram incluídos no estudo e distribuídos em seis grupos de cinco animais cada. Ratos foram tratados por sete dias com fenobarbital (20 mg/kg) e avaliou-se: 1) amplitude das respostas musculares em preparação de ratos expostos ao fenobarbital; 2) o efeito do rocurônio em preparações de ratos expostos ou não ao fenobarbital; 3) as concentrações de citocromo P450 e b5 em microssomos isolados de fígados dos ratos expostos ou não ao fenobarbital. A concentração e dose de rocurônio utilizadas nos experimentos in vitro e in vivo foram respectivamente de 4 µg/mL e 0,6 mg/kg. RESULTADOS: In vitro e in vivo, o fenobarbital não alterou a amplitude das respostas musculares. In vitro, o bloqueio produzido pelo rocurônio foi significativamente diferente (p=0.019) entre expostos (20 por cento) e não expostos (60 por cento); in vivo o bloqueio foi significativamente maior (p=0.0081) nos ratos tratados (93,4 por cento). As concentrações enzimáticas foram significativamente maiores nos ratos expostos ao fenobarbital. CONCLUSÕES: O fenobarbital isoladamente não comprometeu a transmissão neuromuscular. Ocasionou indução enzimática, e in vivo o bloqueio com o rocurônio foi potencializado pelo fenobarbital.

Phenobarbital influence on neuromuscular block produced by rocuronium in rats.

PURPOSE: To evaluate in vitro and in vivo neuromuscular blockade produced by rocuronium in rats treated with Phenobarbital and to determine cytochrome P450 and cytochrome b5 concentrations in hepatic microsomes. METHODS: Thirty rats were included in the study and distributed into 6 groups of 5 animals each. Rats were treated for seven days with phenobarbital (20 mg/kg) and the following parameters were evaluated: 1) the amplitude of muscle response in the preparation of rats exposed to phenobarbital; 2) rocuronium effect on rat preparation exposed or not to phenobarbital; 3) concentrations of cytochrome P450 and cytochrome b5 in hepatic microsomes isolated from rats exposed or not to phenobarbital. The concentration and dose of rocuronium used in vitro and in vivo experiments were 4 microg/mL and 0,6 mg/kg, respectively. RESULTS: Phenobarbital in vitro and in vivo did not alter the amplitude of muscle response. The neuromuscular blockade in vitro produced by rocuronium was significantly different (p=0.019) between exposed (20%) and not exposed (60%) rats; the blockade in vivo was significantly greater (p=0.0081) in treated rats (93.4%). The enzymatic concentrations were significantly greater in rats exposed to phenobarbital. CONCLUSIONS: Phenobarbital alone did not compromise neuromuscular transmission. It produced enzymatic induction, and neuromuscular blockade in vivo produced by rocuronium was potentiated by phenobarbital.

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.

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.

Risk of recurarization during retransfusion of autologous blood withdrawn after injection of muscle relaxants: a comparison of rocuronium and mivacurium.

STUDY OBJECTIVES: In the context of acute normovolemic hemodilution (ANH) recurarization, defined as significant decrease of train-of-four ratio (TOFR) during retransfusion of autologous blood withdrawn after induction of anesthesia, has been described for vecuronium and atracurium. The present study for the first time examined this risk for rocuronium and mivacurium. DESIGN: Prospective, randomized, unblinded clinical study. SETTING: University Hospital in Zurich/Switzerland. PATIENTS: 20 ASA physical status I and II patients undergoing general anesthesia for major maxillofacial surgery. INTERVENTIONS: Anesthesia was induced and maintained with propofol and remifentanil, and rocuronium (0.9 mg kg(-1)) or mivacurium (0.25 mg kg(-1)) was given to facilitate intubation. Thereafter, ANH was started with the removal of 500 mL autologous blood and the subsequent replacement by the same amount of 6% hydroxyethyl starch. The withdrawn blood was stored at 4 degrees C until retransfusion at the end of surgery. MEASUREMENTS: To estimate the risk of recurarization during retransfusion, the degree of recurarization during retransfusion of the autologous blood was assessed mechanomyographically. Plasma levels of rocuronium and mivacurium in the patients' plasma and the autologous blood were determined after its removal and before retransfusion. MAIN RESULTS: The TOFR before retransfusion was 0.97 (range: 0.96 to 0.98) for rocuronium (n = 10) and 0.98 (range: 0.96 to 1.0) for mivacurium (n = 8); n.s. During retransfusion, a slight, but statistically significant reduction of TOFR occurred in one patient in each group. In the mivacurium group, this recurarization occurred 10 minutes after the start of retransfusion; in the rocuronium group, it occurred 20 minutes after retransfusion. The plasma levels of rocuronium and mivacurium in the autologous blood did not change during storage. The plasma concentration of mivacurium in the autologous blood after its removal was 420 +/- 142 microg/L; before retransfusion, it was 384 +/- 147 microg/L. The respective concentrations for rocuronium were 2930 +/- 516 microg/L and 2660 +/- 464 microg/L. CONCLUSIONS: Recurarization during retransfusion may occur with both neuromuscular blocking drugs, mivacurium and rocuronium, when these drugs were injected before the removal of the autologous blood.

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.

The effect of vecuronium is enhanced by a large rather than a modest dose of gentamicin as compared with no preoperative gentamicin.

UNLABELLED: We compared the effect of two doses of gentamicin versus no gentamicin (NG) given before surgery on the neuromuscular relaxant effect of vecuronium. Seventy patients (intraabdominal procedures) were randomly allocated to receive preoperative large-dose (4 mg/kg) gentamicin (LD), a modest dose (1.2 mg/kg) of gentamicin (MD), or NG. No more than one dose of gentamicin was given before the vecuronium administration. Serum gentamicin levels, the time for 25% recovery of the first twitch in the train-of-four after a bolus of vecuronium, and the time from cessation of the vecuronium infusion to extubation of the trachea were estimated. Serum gentamicin levels were higher (P < 0.001) for LD than MD. The time for 25% recovery of the first twitch after the vecuronium bolus was slightly longer with LD than MD (P = 0.06) and longer in LD than NG (P = 0.001) (42.9 +/- 23.6 min versus 36.2 +/- 17 min and 27.4 +/- 9 min, respectively). The time to extubation was similar with LD and MD and longer for LD than NG (P = 0.008) (34.7 +/- 19.2 min versus 27.4 +/- 19.3 min and 19.4 +/- 10.1 min, respectively). The differences in these times were insignificant between MD and NG. Gentamicin administered as a LD rather than MD enhanced the neuromuscular blockade of vecuronium as compared with NG given before surgery. IMPLICATIONS: We demonstrated that the neuromuscular relaxant effect of vecuronium is enhanced by a large (4 mg/kg) rather than a modest (1.2 mg/kg) dose of gentamicin as compared with no gentamicin given before surgery.

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.

[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.

Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

BACKGROUND: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED(95). METHODS: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. RESULTS: The clearances (5.28 +/- 1.23 vs. 4.66 +/- 0.67 ml x min(-1) x kg(-1) and terminal elimination half-lives (22.4 +/- 2.7 vs. 25.5 +/- 4.1 min) were not statistically different between patients receiving 0.1 mg x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-1), respectively. Monoquaternary acid was not quantified in any plasma sample. CONCLUSIONS: Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg x kg(-1).

Pharmacokinetics of 51W89: preliminary data.

The pharmacokinetics of the 1R cis-1'R cis-isomer of atracurium (51W89) and its metabolite, laudanosine, were studied in 11 healthy patients with normal renal function and in 12 patients with chronic renal failure undergoing regular dialysis. A bolus dose of 51W89 (0.1 mg/kg) was given, and the plasma concentration was measured at regular intervals for 480 min. The elimination half-life of 51W89 was significantly longer in renal failure patients than in healthy controls (38.9 min vs 30.6 min; P < 0.05). The plasma laudanosine levels were lower than those reported after an equipotent dose of atracurium besylate. 51W89 may have a prolonged effect in renal failure patients.

Clinical pharmacology of the neuromuscular blocking agents.

Neuromuscular blocking agents are among the most commonly used drugs during general anesthesia. They compete with acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal muscle relaxation. Based on their mechanism of action, neuromuscular blocking agents are classified as either depolarizing or nondepolarizing. Succinylcholine is a short-acting depolarizing agent. Commonly used nondepolarizing agents are curare (long-acting), pancuronium (long-acting), atracurium (intermediate-acting), and vecuronium (intermediate-acting). Neuromuscular blocking agents are used clinically to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery. This article provides an overview of the physiology of the neuromuscular transmission and summarizes our current knowledge on the use of these agents during general anesthesia.

Comparative potency of pipecuronium bromide and pancuronium bromide.

Cumulative dose-response curves were constructed to determine the comparative potency of pipecuronium and pancuronium. From these, the ED50 and ED95 values were calculated. These were 24.96 micrograms kg-1 and 44.96 micrograms kg-1, respectively, for pipecuronium and 30.42 micrograms kg-1 and 61.12 micrograms kg-1, respectively, for pancuronium.