[New developments in neuromuscular blocking agents].

Curare was clinically used in a patient with acute appendicitis by Griffith and Johnson in January 1942. From the day on, the development of new muscle relaxants went on in the world. Since pancuronium was synthesized by Savage in 1964, it was widely used in clinical cases because it provided sufficient muscle relaxation during operation. At present, pancuronium, vecuronium and rocuronium are routinely used in the world. In the future, we expect development of new muscle relaxants with rapid onset, intermediate duration of action, rapid recovery and without side effects.

[Reversal of neuromuscular blockade and complications of remaining blocking effect].

We Japanese anesthesiologists can now use rocuronium as well as vecuronium. Although the onset of rocuronium is more rapid, the non-depolarizing neuromuscular blocking (NMB) agent has similar characteristics of duration and recovery compared to vecuronium. Reversal of NMB is therefore essential to recover patients safely. Conventional standard of reversal of NMB [train of four (TOF) >0.7] is not enough to have sufficient vital capacity and inspiratory force, resulting in pulmonary regurgitation or atelectasis. Even though the reversal of NMB cannot sufficiently be completed by anti-cholinesterase (ChE) agents such as neostigmine, it is needed to reverse the NMB because of their late spontaneous recovery. We also have to take care of patients with neuromusclar diseases such as Duchenne-type muscle dystrophy, when we use anti-ChE agents. Sugammadex is a novel and unique compound designed as an antagonist of rocuronium and possibly other steroid NMB agents. Sugammadex exerts its effect by forming very tight water-soluble complexes at a 1 : 1 ratio with steroid NMB agents (rocuronium>vecuronium>>pancuronium). PhaseIII trials in Japan as well as Europe and the US have just been finished, and it is expected to be used clinically in the near future.

Effect of anaesthetic and choice of neuromuscular blocker on vagal control of heart rate under laboratory animal experimental conditions.

Neuromuscular-blocking agents are commonly used in laboratory animal research settings. Due to actions of cholinergic receptors at locations other than the motor end-plate, these agents have a strong propensity to modulate autonomic outflow and may therefore not be desirable in studies examining autonomic function. This study aimed to compare the effect of two non-depolarizing neuromuscular-blocking agents, pancuronium and cisatracurium, on blood pressure, heart rate and non-invasive indices of autonomic function (heart rate variability, systolic blood pressure variability and baroreflex sensitivity) under two different types of anaesthesia in Lewis rats. Pancuronium produced a profound vagolytic response characterized by tachycardia, reduction in heart rate variability and baroreflex sensitivity under urethane anaesthesia, and with minimal effect under isoflurane anaesthesia. Conversely, cisatracurium produced no evidence of vagolytic action under either urethane or isoflurane anaesthesia. Therefore, for studies interested in examining autonomic function, particularly baroreflex or vagal function, neuromuscular blockade would be best achieved using cisatracurium.

Myopathy following mechanical ventilation for acute severe asthma: the role of muscle relaxants and corticosteroids.

BACKGROUND: Acute myopathy following mechanical ventilation for near-fatal asthma (NFA) has been described recently, and some researchers have suggested that this complication is related to the use of neuromuscular blocking agents (NMBAs) and corticosteroids (CSs). OBJECTIVES: To determine the incidence of acute myopathy in a group of patients and to examine the most important predictors of its development. DESIGN AND METHODS: A retrospective cohort study over a 10-year period (1985 to 1995) of all asthma patients who received mechanical ventilation at two centers in Vancouver (designated center 1 and center 2). RESULTS: In center 1, there were 58 patients who had 64 episodes of NFA, and in center 2, there were 28 patients who had 30 episodes. NMBAs were used in 30 of 86 admissions for acute severe asthma (35%). The mean (+/- SD) duration of muscle paralysis was 3.1+/-2.3 days. A total of 9 patients (10.4%) developed significant myopathy. The incidence of myopathy was 9 of 30 (30%) among patients who received NMBAs. In a multiple logistic regression model, the development of myopathy was only significantly associated with the duration of muscle relaxation. The odds ratio for the development of myopathy increased by 2.1 (95% confidence interval, 1.4 to 3.2) with each additional day of muscle relaxation. The dose and the type of the CS were not significantly associated with the myopathy in the multiple logistic regression analysis. CONCLUSION: Our study showed that there is a high incidence of acute myopathy when NMBAs are used for NFA. The incidence of myopathy increases with each additional day of muscle relaxation.

Anesthesia related muscle paralysis in renal failure.

We present 3 patients with chronic renal failure who had postoperative paralysis due to the administration muscle relaxants. One of them received gallamine, a non-depolarizing blocking agent that is mainly excreted by the kidney (70--90%). Two of them received pancuronium bromide, also a non-depolarizing blocking agent which is partially excreted by the kidneys (37--44%). All of them received succinylcholine. Succinylcholine is hydrolyzed by the serum cholinesterase into succinylmonocholine and choline. These active metabolites are excreted by the kidney. These patients serve as examples of the importance of considering the route of excretion of drugs and their metabolites in clinical situations involving the renal failure patient. The pharmacology of drugs administered relative to surgical procedures is reviewed.

Neuromuscular blockade and lung function during resuscitation of infants with congenital diaphragmatic hernia.

BACKGROUND: There is no consensus or evidence as to whether a neuromuscular blocking agent should be used during the initial resuscitation of infants with congenital diaphragmatic hernia (CDH) in the labour ward. OBJECTIVE: To determine if administration of a neuromuscular blocking agent affected the lung function of infants with CDH during their initial resuscitation in the labour ward. METHODS: Fifteen infants with CDH were studied (median gestational age 38 weeks, range 34-41; birth weight 2,790 g, range 1,780-3,976). Six infants had undergone feto-endotracheal occlusion (FETO). Flow, airway pressure, tidal volume and dynamic lung compliance changes were recorded using a respiratory function monitor (NM3, Respironics). Twenty inflations immediately before, immediately after and 5 min after administration of a neuromuscular blocking agent (pancuronium bromide) were analysed. RESULTS: The median dynamic lung compliance of the 15 infants was 0.22 ml/cm H2O/kg (range 0.1-0.4) before and 0.16 ml/cm H2O/kg (range 0.1-0.3) immediately after pancuronium bromide administration (p < 0.001) and remained at a similar low level 5 min after pancuronium bromide administration. The FETO compared to the non-FETO infants had a lower median dynamic compliance both before (p < 0.0001) and 5 min after pancuronium administration (p < 0.001) and required significantly longer durations of ventilation (p = 0.004), supplementary oxygen (p = 0.003) and hospitalisation (p = 0.007). CONCLUSIONS: Infants with CDH, particularly those who have undergone FETO, have a low lung compliance at birth, and this is further reduced by administration of a neuromuscular blocking agent.

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.

Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers.

BACKGROUND: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs). METHODS: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs. RESULTS: The maximal nonreactive concentrations were 10 m for suxamethonium; 10 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice. CONCLUSION: The aminosteroidal NMBAs pancuronium, vecuronium, and rocuronium and the benzylisoquinoline cisatracurium have a similar potency to induce a nonspecific skin reactivity. If the criteria for positivity and the maximal concentrations of the commercially available compounds recommended by French practice guidelines are used, the risk of false-positive results is limited, and only minor modifications of these recommendations could be suggested. A slight reduction in the maximal concentration used for rocuronium from 1:100 to 1:200 and an increase from 1:1,000 to 1:200 for mivacurium can be proposed.

Prolonged neuromuscular blockade following vecuronium. A case report.

Vecuronium was used to provide muscle relaxation in a patient who subsequently developed prolonged neuromuscular blockade (8 h) after anaesthesia. The aetiology of this condition, and the possible role of vecuronium, are discussed.

Cutaneous sensitivity to atracurium and vecuronium in patients suffering anaphylactoid reactions to neuromuscular blockers.

Using an ordinal measure of cutaneous sensitivity to intradermal injections of atracurium and vecuronium, 40 nonreacting subjects were compared with a group of 24 patients previously suffering life-threatening anaphylactoid reactions to other muscle relaxants. Enhanced cutaneous sensitivity to vecuronium was found in three, and to atracurium in two of the previously reacting group. With the exception of those showing abnormal reactivity, no significant difference was found in the distribution of cutaneous sensitivity in the control and reacting group. A concentration of vecuronium 8.75 times that of atracurium was required to produce an equivalent intradermal wheal response.

Precurarization--a hazard to the patient?

Four case histories are presented illustrating the unpleasant and serious reactions that may follow precurarization with small doses of non-depolarizing muscle relaxants. The importance of preoperative information, the necessity of relating the dose of the precurarizing drug to the weight of the patient and the possibility of hypersensitivity to this drug are emphasized.

Reversible paralysis with status asthmaticus, steroids, and pancuronium: clinical electrophysiological correlates.

Prolonged neuromuscular weakness has been identified after neuromuscular blockade in intensive care unit patients on mechanical ventilation. Previously reported electromyographic studies in these patients documented both neurogenic features and features consistent with a myopathy. We recorded sequential electrophysiological parameters during recovery from neuromuscular blockade in 5 patients with clinical weakness. An evolving pattern was identified. The early features were in keeping with previous reports of neurogenic changes, and this evolved into features consistent with a primary myopathy. Several potential underlying mechanisms are discussed.

Vecuronium and atracurium in the elderly: a clinical comparison with pancuronium.

The intubating conditions, time to complete block and duration of clinical relaxation were observed in a group of 101 elderly patients (aged over 65 years) following pancuronium 0.1 mg kg-1, vecuronium 0.1 mg kg-1 or atracurium 0.5 mg kg-1. The intubating conditions in the three groups were similar when assessed at 2 min following relaxant administration. The time to complete block was shortest with vecuronium (4.3 min) in comparison to atracurium (5.0 min) and pancuronium (6.0 min), but the differences were not statistically significant. The duration of clinical relaxation, however, was significantly shorter with vecuronium (37 min) and atracurium (35 min) in comparison to pancuronium (99 min).

[Pharmacodynamics of vecuronium. A clinical study]. / Pharmakodynamische Untersuchungen mit Vecuronium. Eine klinische Studie.

54 Patients (ASA I + II) were paralysed with different doses of vecuronium during neuroleptanesthesia. Time course of action was registered by means of mechanical twitch response. ED 95 as calculated by linear regression amounted to 63 micrograms/kg (ED 50: 27 micrograms/kg). After administration of ED 95 about 3/4 of the patients are completely paralysed. After administration of 70 micrograms/kg 9/10 of the patients are completely paralysed. Mean duration of action of these two doses is 28 and 35 min respectively. Vecuronium doses from 60 micrograms/kg on are suitable for orotracheal intubation. However onset time of action is 3-4 min. Circulatory side effects after administration of vecuronium were not observed.

The use of fetal neuromuscular blockade during intrauterine procedures.

Advances in fetal therapy have led to the utilization of such techniques as intravascular transfusion of the Rh-affected fetus, bladder shunt placement in the fetus with obstructive uropathy, and percutaneous umbilical blood sampling. Fetal movement makes these procedures technically more difficult while increasing the risk of fetal injury. However, maternal sedation rarely results in adequate suppression of fetal activity. Thus we tested the sedative effects of intramuscular d-tubocurarine (3 or 1.5 mg/kg) or pancuronium bromide (0.3 mg/kg) injected into the fetal gluteal region under ultrasound guidance in conjunction with 70 invasive in utero procedures. Short-term paralysis of the fetus was induced in all cases. No deleterious effects of this technique were noted on initial examination of the neonates. Neuromuscular blockade was found to be a very useful adjunct to both diagnostic and therapeutic procedures involving the fetus.