Nondepolarizing Relaxants Research Articles

Is succinylcholine appropriate or obsolete in the intensive care unit?

Muscle relaxants in intensive care unit (ICU) patients are predominantly administered to facilitate intubation. The adverse effect profile of succinylcholine is such that its use in the ICU must be considered obsolete. Suitable alternatives are the intermediately long-acting nondepolarizing relaxants, of which rocuronium is probably preferable.

Comparison of the Intubation Conditions Provided by Rapacuronium (ORG 9487) or Succinylcholine in Humans During Anesthesia with Fentanyl and Propofol

FLEMING, NEAL W.; CHUNG, FRANCES; GLASS, PETER S.A.; KITTS, JOHN B.; KIRKEGAARD-NIELSEN, HANS; GRONERT, GERALD A.; CHAN, VINCENT; GAN, TONG J.; CICUTTI, NICHOLAS; CALDWELL, JAMES E. Author Information

Neuromuscular Effects of Mivacurium in 2- to 12-yr-old Children with Burn Injury

Background: Burned patients are usually resistant to the neuromuscular effects of nondepolarizing relaxants, mostly because of receptor changes. The magnitude of the resistance is related to burn size and time after burn. Mivacurium is a muscle relaxant, degraded by plasma cholinesterase, whose enzyme activity is decreased in burns. The present study tested the hypothesis that burn-induced depressed plasma cholinesterase activity counteracts the receptor-mediated resistance, resulting in a lack of resistance to mivacurium. Methods: Burned patients (n = 23), aged 2-12 yr, subclassified into burns of 10-30% or > 30% of body surface, were studied at ≤ 6 days and again at 1-12 weeks after burn if possible. Thirteen additional patients served as controls. Neuromuscular variables monitored included onset and recovery following bolus dose, continuous infusion rates required to maintain 95 ± 4% paralysis, and recovery rates following infusion. Results: The onset times of maximal twitch suppression were not different between burns and controls, but recovery to 25% of baseline twitch height was prolonged in patients with > 30% burn irrespective of time after injury. The continuous infusion rates to maintain twitch suppression at 95 ± 4% were not different between groups. The recovery indices, including train-of-four to > 75%, 25-75%, or 5-95% in burned patients, were similar or prolonged compared with controls. The prolonged recovery in burned patients was inversely related to plasma cholinesterase activity (R 2 = 0.86, r = - 0.93, P < 0.001), and the decreased plasma cholinesterase activity was related to burn size and time after burn. Conclusions: A normal mivacurium dosage (0.2 mg/kg) effects good relaxation conditions in burned patients, with an onset time similar to that in controls. This finding contrasts with the response seen with other nondepolarizing drugs, higher doses of which are required to effect paralysis. The decreased metabolism of mivacurium, resulting from depressed plasma cholinesterase activity, probably counteracts the receptor-mediated potential for resistance. Because succinylcholine is contraindicated in burned patients, larger doses of nondepolarizing agents are advocated to effect rapid onset of paralysis. This generalization does not hold for mivacurium.

Room 224-226, 10/16/2000 9: 00 AM - 10: 30 AM (PD) The Ultra-Short Acting Nondepolarizing Relaxant GW280430A Undergoes Rapid Degradation by Chemical Mechanisms

<b>Room 224-226, 10/16/2000 9: 00 AM - 10: 30 AM (PD) The Ultra-Short Acting Nondepolarizing Relaxant GW280430A Undergoes Rapid Degradation by Chemical Mechanisms</b>

Rocuronium Is the Best Non-Depolarizing Relaxant to Prevent Succinylcholine Fasciculations and Myalgia

ied. They were divided into six groups of 20 according to the non-depolarizing pretreatment used: NaCl 0.9%(control), 0.05 mg'kg -I d-tubocurarine, 0.01 mg'l~ I vecuronium, 0.05 mg'kg -I atracurium, 0.02 mg'kg -I mivacurium and 0.06 mg.kg -I rocuronium. Four minutes after the pretreatment, 1.5 mg.kg -I succinytcholine was injected. Side effects of the pretreatment, the presence and magnitude of fasciculations, the ease of tracheal intubation, myalgia I, 24 and 48 hr after surgery were observed. A Puritan Bennett Datex TM 221 NMT Relaxograph monitor was used to evaluate the neuromuscular block. Results: Muscle fasciculations were observed in 19 of the 20 patients in the control group and in 3 of the 20 patients in the rocuronium group, the best of the pretreatments in that aspect. Four patients in the mivacurium group were unable to sustain more than four seconds head-lift after pretreatment (P < 0.05). Tracheal intubation conditions were better and the onset of block was faster and longer after succinylcholine in the control group (P < 0.05). Myalgias were present in 71% of the patients 24 hr postoperatively and the frequency was not different among the groups. Conclusion: Among the pretreatments tested, 0.06 mg'kg -~ rocuronium was the best to prevent muscular fasciculations following succinylcholine injection. In the population studied, pretreatment did not prevent postoperative myalgia. Succinylcholine 1.5 mg-kg -~ was more effective without a non-depolarizing pretreatment. Objectif : D&erminer quel myorelaxant non d~polarisant, dont la d-tubocurarine, le v&uronium, I'atracurium, le mivacurium et le rocuronium, saura le mieux pr~venir ~les myofasciculations et les myalgies qui suivent I'utilisation de succinylcholine.

Clinical pharmacology of neuromuscular blocking agents.

The clinical pharmacology of neuromuscular blocking agents is described. During neuromuscular blockade, succinylcholine attaches to receptors in the motor end plate and depolarizes the neuromuscular junction, making the end plate refractory to acetylcholine. The nondepolarizing relaxants have a structure similar to that of succinylcholine and bind to the same receptors. Instead of depolarizing the junction, they block acetylcholine from binding to the receptor and cause channel blockade. As the concentration of nondepolarizing relaxant increases relative to acetylcholine, neuromuscular transmission is compromised. This relationship is used clinically to facilitate recovery from nondepolarizing agents. Succinylcholine is popular because its onset is faster than that of the nondepolarizing relaxants and metabolism by pseudocholinesterase clears it quickly. It is commonly given as an i.v. bolus to facilitate tracheal intubation. The onset of these agents varies widely and is dose dependent. Large doses are usually given to hasten the onset of paralysis; subsequent doses are adjusted according to response. The nondepolarizing agents interact with inhaled anesthetics, magnesium, and many antimicrobials. Drugs like neostigmine, edrophonium, and pyridostigmine antagonize neuromuscular blockade; an anticholinergic drug is typically administered to counteract the cardiovascular effects. The most serious adverse effects of succinylcholine are malignant hyperthermia syndrome, masseter muscle rigidity, and bradycardia. Some nondepolarizing relaxants (atracurium, mivacurium, and pancuronium) are associated with histamine release, occasionally causing serious hypotension and tachycardia. Neuromuscular blocking agents are essential to anesthesia. Older compounds produce greater toxicity than newer compounds, and several of these older compounds therefore are no longer in clinical use.

Recent advances in neuromuscular blocking agents

Factors driving the development of neuromuscular blocking agents are discussed. The goal of recent development of neuromuscular blocking agents is to develop agents with fewer adverse effects than succinylcholine and greater control. Greater control can be achieved through a short duration of action and a fast onset, similar to that found with succinylcholine. Duration control can be achieved through rapid, reliable metabolism that is organ independent, as with cisatracurium, or that occurs in the liver, because this will fail only in patients with severe hepatic disease. Rapid onset can be achieved by giving higher doses of drugs that have a fast, reliable metabolism or a rapid distribution to tissue. This has been done with succinylcholine, cisatracurium, and mivacurium. It has been shown that a low-potency drug has a faster onset than a higher-potency drug, even at the same relative dose. Rocuronium was the first neuromuscular blocking agent marketed that was developed specifically as a low-potency drug for achieving a rapid onset. In a comparison with two other intermediate-duration neuromuscular blocking agents at equipotent doses, rocuronium's onset was about one minute, which was two minutes faster than that of either vecuronium or atracurium. Rapacuronium is an investigational intermediate-duration agent and is even less potent than rocuronium. Clinical studies have shown it to have a very rapid onset (about 50 seconds) and a short duration of action (15-25 minutes, depending on the dose). Its short duration of action will make it potentially useful for short surgical procedures and procedures in which nerve integrity must be monitored. At the same time, its onset time approaches that of succinylcholine. Recent advances have made the administration of neuromuscular blocking agents much easier because the newer nondepolarizing relaxants offer faster onset and greater control.

Widespread Application of Topical Steroids to Decrease Sore Throat, Hoarseness, and Cough After Tracheal Intubation

Widespread Application of Topical Steroids to Decrease Sore Throat, Hoarseness, and Cough After Tracheal Intubation

A comparative study of the dose-response and time course of action of rocuronium and vecuronium in anesthetized adult patients

Study Objectives: (1) To compare the dose-response relations of rocuronium and vecuronium in healthy adult patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental; and (2) to evaluate the time-course of action of two drugs following equipotent doses. Design: Prospective, randomized, clinical comparison. Setting: Operating room, Plastic Surgery Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College. Patients: 60 ASA physical status I patients, aged 17–51 years, scheduled for elective plastic surgery. Interventions: All patients were randomly assigned to either the rocuronium or vecuronium group. General anesthesia was induced with thiopental 4 to 6 mg/kg and fentanyl 2 to 4 μg/kg intravenously (IV), and maintained with 60% nitrous oxide (N 2O) in oxygen. Further increments of thiopental or fentanyl were given as required. The dose-response relations of rocuronium and vecuronium were determined by the cumulative dose-response technique. Measurements and Main Results: Neuromuscular function was assessed mechanomyographically with train-of-four (TOF) stimulation at the wrist every 12 seconds. The percentage depression of first twitch (T 1) was used as the study parameter. The cumulative dose-response curve of vecuronium was shifted to the left in a parallel fashion compared with that of rocuronium. As assessed by linear regression, the potency ratio of vecuronium:rocuronium was 1:7.2. There were significant differences in the ED 50, ED 90, and ED 95 between the two drugs. After IV administration of equipotent doses of both drugs (2 × ED 90), the duration of peak effect, clinical duration, recovery index, and total duration were not significantly different between the two drugs. Conclusions: Compared with vecuronium, rocuronium is a low-potency, nondepolarizing relaxant, and its neuromuscular blocking potency is approximately 15% that of vecuronium in adult patients anesthetized with N 2O and fentanyl. Following equipotent doses, the time-course of recovery for rocuronium is similar to that of vecuronium.

Monitoring the onset of neuromuscular blockade with double burst stimulation (DBS)

The present study was undertaken to evaluate the suitability of the DBS mode in the determination of the proper time to perform tracheal intubation following cisatracurium muscle relaxation. The DBS3.3 pattern was administered to the ulnar nerve at the wrist in 45 patients paralyzed with cisatracurium 0.15 mg.kg-1 and tracheal intubation was attempted immediately after the disappearance of both palpable contractions of the adductor pollicis. Intubation conditions were assessed with a standard four-graded scoring system and the onset time of the relaxant was determined. Forty-two patients (93%) exhibited acceptable intubation conditions as soon as both responses to DBS were absent and the estimated apparent onset time, according to the stimulation mode applied, was 114.68 +/- 13.2 sec. Our data suggest that disappearance of both palpable responses to DBS3.3 may be used as an accurate predictor of acceptable intubation conditions, following nondepolarizing relaxants such as cisatracurium.

Mivacurium for caesarean section in hypertensive parturients receiving magnesium sulphate therapy

The interaction between mivacurium and magnesium sulphate was investigated in a group of parturients undergoing caesarean section under general anaesthesia. Thirty parturients were studied; 10 normotensive controls (group NT), 10 hypertensive controls (group HT) and 10 hypertensives who received magnesium sulphate (group HTM). At induction group HT received 30 μg/kg of alfentanil and group HTM 10 μg/kg of alfentanil and 30 or 60 mg/kg of magnesium sulphate. Neuromuscular function was monitored by electromyography. Mivacurium 0.15 mg/kg was given after 60% recovery of T 1 following succinylcholine. Magnesium concentrations and plasma cholinesterase activity were significantly elevated in group HTM (1.57 ± 0.53 mmol/1 and 4.60 ± 1.27 kU/1) compared with group HT (0.71 ± 0.18 mmol/1 and 3.44 ± 0.97 kU/1) and group NT (0.60 ± 0.07 mmol/1 and 2.86 ± 0.82 kU/1) ( P < 0.005). Time to maximal recovery, and time from 25–75% of maximal recovery from mivacurium, were significantly prolonged in group HTM (60.9 ± 15.3 min and 16.8 ± 5.6 min) compared with group HT (34.9 ± 7.6 min and 7.6 ± 3.6 min) and group NT (37.4 ± 14.4 min and 8.5 ± 3.4 min) ( P < 0.01). Time to 25% recovery was prolonged in group HTM (35.1 ± 7.4 min) compared with the other two groups (HT: 21.6 ± 6.4 min and NT: 22.8 ± 10.2 min) ( P < 0.01). Whilst the duration of action of mivacurium, determined by electromyography, is prolonged by subtherapeutic serum magnesium concentrations, of the available non-depolarizing relaxants mivacurium would seem to be most appropriate for caesarean section.

Indicators of Recovery of Neuromuscular Function

Department of Anesthesiology, St. Vincent Hospital, Room NR408, 153 W. 11th Street, New York, New York 10011, akopman@aol.com.In Reply:-We thank Dr. Jones for bringing his publication of 1963 to our attention. [1] In that report, he observed that after the injection of 20 mg of gallamine into his right femoral artery, almost complete paralysis of the ipsilateral leg soon followed. The only other sign or subjective symptom of neuromuscular block that he experienced was ocular in nature, and these persisted for 2 h. It should be noted that the ED95of gallamine is 2.4 mg/kg, and thus the dose he administered to himself was small. [2] We certainly do not want to claim primacy for the observation that vision may be impaired by very small doses of nondepolarizing relaxants. It is a common observation that patients often complain of blurred vision after the usual d-tubocurarine precurarizing dose of 0.05 mg/kg.The only publications of Draper and Whitehead that we have been able to locate were done using a canine model. We would welcome any help in tracking down the citation of total body paralysis in humans to which Dr. Jones refers. Nonetheless, Dr. Jones is correct in stating that the observation that subjective symptoms of residual weakness may be long-lasting is not a new one. A study that deserves to be read by all clinicians is the 1947 paper by Smith et al. [3] In that report, Smith (an 80-kg male) received 500 U (75 mg) of d-tubocurarine over 33 min while fully awake. Despite the administration of 3.5 mg of neostigmine over the following 100 min (last dose, 4:30 P.M.), symptoms of residual weakness persisted throughout the evening.Aaron F. Kopman, M.D.Pamela S. Yee, B.A.George G. Neuman, M.D.Department of Anesthesiology; St. Vincent Hospital; Room NR408; 153 W. 11th Street; New York, New York 10011akopman@aol.com(Accepted for publication August 21, 1997.)

Reply

Department of Anesthesiology, Saint Vincent's Hospital and Medical Center, 153 West 11th Street, New York, New York 10011.In Reply:-Dr. Lam's inability to antagonize residual diplopia with neostigmine after atracurium administration is fascinating because we have had a similar experience. Before the 10 cases that we reported, [1] we did a pilot study using rocuronium as the test drug. One individual (a man aged 26 years and weighing 70 kg) complained of pronounced visual disturbances despite a measured train-of-four (TOF) fade ratio of 0.93 at the end of the study. At this time, the subject was given 0.4 mg of atropine and 5.0 mg of edrophonium intravenously. The TOF ratio promptly returned to a value of 1.00, but the subject reported that if anything his vision got worse. Blurred vision persisted for an additional 60 min.This observation, if it can be reproduced, raises several questions. What is the effect (if any) of intravenous atropine, glycopyrrolate, neostigmine, and edrophonium alone or in combination on visual acuity and extraocular muscle function? Is it advisable to attempt to reverse diplopia if that is the sole residual effect of an administered relaxant? Is it even possible to do so? Certainly this is an area deserving of further investigation.The question of whether persistent visual disturbances after the use of nondepolarizing relaxants represents “residual weakness” or something else is probably best left to semanticists. I would not dismiss the importance of these symptoms as lightly as Dr. Lam. The issue is not simply our comfort with the extent of neuromuscular recovery. Should not patient satisfaction enter into the equation as well?Aaron F. Kopman, M.D.Pamela S. Yee, B.A.George G. Neuman, M.D.Department of Anesthesiology; Saint Vincent's Hospital and Medical Center; 153 West 11th Street; New York, New York 10011(Accepted for publication July 7, 1997.)

The Train-of-Four Count and Kinetic-Dynamic Modelling

The intraoperative monitoring of neuromuscular blockade usually involves measurement of the muscular responses to motor nerve stimulation. Although researchers have the time and technology to obtain predrug control measurements of the twitch responses, these are seldom available to the clinician. During surgically useful relaxation, there is progressive inhibition of responses to train-of-four (TOF) stimulation in the presence of a nondepolarizing relaxant, and the clinician can count the number of responses to predict the likely time-course of paralysis. At the extremes, a count of four (of four) responses may indicate a need for further relaxant, whereas with profound paralysis, the absence of responses may suggest that reversal with an anticholinesterase may be ineffective. Concentrations in the effect compartment associated with these two extremes of the TOF count are combined with concentration-time profiles of vecuronium with various dose regimens. This study models the effect compartment concentrations associated with vecuronium-induced paralysis, combining them explicitly with the range of concentrations associated with the TOF count to demonstrate the kinetic mechanisms underlying the time-course of paralysis.

A Mixture of Mivacurium and Rocuronium Is Comparable in Clinical Onset to Succinylcholine

Comment: This study supports prior evidence that the addition of mivacurium to rocuronium accelerates the onset of neuromuscular block while not unduly prolonging the duration of block. The relatively fast onset of rocuronium and the relatively short duration of mivacurium make them well suited for use in combination. Although onset times equivalent to those after succinylcholine are difficult to obtain with a single nondepolarizing relaxant (unless one is willing to accept marked prolongation or side effects such as histamine release), combinations of moderate doses of drugs with different dose-related side effects may provide the clinician with a much needed alternative. The ablation of T1 twitch height occurred at 47 ± 7 sec after succinylcholine and only 51 ± 13 sec after mivacurium plus rocuronium. Similarly, good to excellent intubating conditions were obtained to approximately the same degree. However, it can be seen that the variability was greater in the combination group. Moreover, 8 of 10 patients in the succinylcholine group had excellent conditions (and possibly even a better outcome would have been obtained if >1 mg/kg had been used); only 21 of 30 patients had excellent conditions in the combination group. Although such subtle differences might not be important in most clinical settings, they could be extremely important if one really wishes to intubate as soon as possible, especially if one needs to avoid any movement or coughing.

Comparative recovery of 50-Hz and 100-Hz posttetanic twitch following profound neuromuscular block

To determine if posttetanic twitch following 100-Hz tetanic stimulation enables titration of a nondepolarizing relaxant infusion to a greater depth of block than that achieved with posttetanic twitch following 50 Hz. Prospective, observational study. Operating rooms of a university tertiary care center. 10 ASA physical status II and III patients free of known neuromuscular disease and undergoing general endotracheal anesthesia for routine elective surgery. Following induction of general anesthesia, neuromuscular block was maintained with a continuous intravenous vecuronium infusion. Depth of neuromuscular block was assessed by tactile evaluation of the evoked responses of the adductor pollicis muscle following supramaximal stimulation of the ulnar nerve via surface electrodes. The vecuronium infusion was titrated to loss of posttetanic twitch following 100-Hz tetanic stimulation, at which point the infusion was discontinued. 100-Hz tetanic stimulation was repeated every two minutes until recovery of the first posttetanic twitch, at which point 50-Hz tetanic stimulation was repeated every two minutes until recovery of the first posttetanic twitch. The median time (interquartile range) from discontinuation of the vecuronium infusion to recovery of the first posttetanic twitch following 100-Hz tetanic stimulation was 27% faster than the corresponding time to recovery of the first posttetanic twitch following 50-Hz tetanic stimulation [19 (10 to 24) min and 26 (20 to 30) min respectively, p < 0.002]. Posttetanic twitch following 100-Hz tetanic stimulation enables titration of a vecuronium infusion to a greater depth of block than posttetanic twitch following 50-Hz tetanic stimulation. The present findings should enable more effective titration of this relaxant, thereby reducing the likelihood of unwanted patient movement or unduly prolonged recovery due to relaxant overdosing.

Neuromuscular transmission and its pharmacological blockade. Part 2: Pharmacology of neuromuscular blocking agents.

Clinically, neuromuscular blockade is induced with either depolarizing or non-depolarizing relaxants. Suxamethonium is the only depolarizing relaxant still in use. It is hydrolysed in the plasma by pseudo-cholinesterase (plasma cholinesterase). In some patients and in particular diseases the plasma cholinesterase activity is low and hence the effect of suxamethonium prolonged. Suxamethonium is characterized by side-effects such as myalgia, fasciculations and increase in intraocular, intracranial and intragastric pressure. More serious adverse reactions are masseter muscle spasm and potassium release, in patients with some neuromuscular diseases and increase in extrajunctional acetylcholine receptors. As non-depolarizing muscle relaxants benzylisoquinolines and steroidal compounds are mainly used. Each relaxant has its own pharmacological characteristics. The effect of most relaxants depends on liver and renal function because the pharmacokinetic behaviour is strongly dependent on these organs. Also, acid base balance disturbances, change in temperature, and neurological diseases have an effect on the profile of the relaxants. A number of drugs (anaesthetics, antibiotics, antiepileptics, etc.) have an effect on neuromuscular transmission, and thus interact with the relaxants. Some non-depolarizing relaxants cause histamine release and cardiovascular effects.

The view of the glottis at laryngoscopy after unexpectedly difficult placement of the laryngeal mask.

In 12 patients to whom a non-depolarising neuromuscular relaxant had been given and in whom placement of the laryngeal mask had failed unexpectedly, the view of the larynx at laryngoscopy and the ease of tracheal intubation were examined. The glottis was only partially seen at laryngoscopy in three patients and was not seen at all in another three patients. Tracheal intubation was difficult in three of them. It would appear that in some patients both placement of the laryngeal mask and tracheal intubation are difficult. It is thus inadvisable to paralyse patients electively and rely on the laryngeal mask to secure a clear airway when tracheal intubation is predicted to be difficult.

Future developments of non-depolarizing relaxants

Future developments of non-depolarizing relaxants

Clindamycin-Induced Neuromuscular Blockade

The purpose of this article is to report the case of a patient who developed prolonged neuromuscular block after a large dose of clindamycin (2400 mg). A 58-yr-old, 65 kg woman with severe rheumatoid arthritis was admitted for wrist arthrodesis. After d-tubocurarine (3 mg) and fentanyl (1.5 micrograms.kg-1), anaesthesia was induced with thiopentone (4 mg.kg-1) followed by succinylcholine (1.5 mg.kg-1) and was maintained with N2O in O2 and isoflurane (0.75-1.0% end tidal) and ventilation was controlled. No further neuromuscular relaxants were given although full return of neuromuscular activity in response to train-of-four and 100 Hz tetanic stimulation was observed after succinylcholine. An overdose of clindamycin (2400 mg, instead of the intended 600 mg) was given i.v. soon after the start of surgery. At the end of surgery, 75 min later, the patient made no attempt at spontaneous ventilation, was unresponsive to painful stimuli and naloxone (0.2 mg i.v.) was ineffective. Controlled ventilation was continued in the Recovery Room where neuromuscular testing showed a train-of-four ratio of 0.27 which improved to only 0.47 five minutes after calcium chloride (1.5 mg.kg-1 i.v.), and to 0.62 after edrophonium (20 mg) and neostigmine (2 mg). Nine hours later the patient began to cough, the TOF had returned to 1.0 and two hours later the trachea was extubated and spontaneous ventilation was resumed. Large doses of clindamycin can induce profound, long-lasting neuromuscular blockade in the absence of non-depolarizing relaxants and after full recovery from succinylcholine has been demonstrated.