Nondepolarizing Relaxants Research Articles

Sensitivity to curare in patients with upper and lower motor neurone dysfunction

Sensitivity to the action of nondepolarising relaxants was compared in muscles of upper and lower limbs in four syringomyelic patients undergoing elective neurosurgical procedures. It was observed that muscles with signs of lower motor neurone dysfunction are supersensitive to the action of nondepolarising relaxants. Terminal sprouting of motor axons and the occurrence of newly formed neuromuscular junctions may be responsible for a low synaptic efficacy and may explain the high sensitivity to factors that reduce the safety margin of neuromuscular transmission.

The onset of disuse-related potassium efflux to succinylcholine.

Disuse atrophy of skeletal muscle produces resistance to nondepolarizing relaxants and increased potassium efflux after the administration of succinylcholine. These changes appear to be due to development of perijunctional and/or extrajunctional receptors (up-regulation). In this study, the authors searched for the earliest detectable appearance of increased potassium efflux in beagles in whom disuse atrophy was simulated. Seven beagles underwent unilateral cast immobilization of a hind limb. Between 4 and 42 days, they periodically received succinylcholine 0.25 mg/kg while anesthetized with thiamylal and nitrous oxide. Sequential bilateral femoral venous samples showed that the casted limb did not manifest potassium release greater than the upper limit of normal (1 mEq/l) until cast immobilization periods of 14 days or longer. When this occurred, the increase in the potassium concentration in the femoral venous blood of the casted limb exceeded that from the noncasted limb by at least 0.7 mEq/l (P less than 0.01). The range for the onset of this response after casting was 14-42 days, the mean 27.2 days, and the standard deviation 9.8 days. These findings imply that up-regulation of skeletal muscle receptors, associated with exaggerated potassium efflux after administration of succinylcholine, is dependent on progressive development of extrajunctional receptors over surface membrane areas beyond the endplate.

Effects of Succinylcholine on the Pharmacodynamics of Pipecuronium and Pancuronium

To study the effects of succinylcholine on subsequent pharmacodynamics of nondepolarizing muscle relaxants, a comparative pharmacodynamic study was carried out in patients having balanced anesthesia (thiopental, fentanyl, nitrous oxide/oxygen) in whom equipotent doses of pipecuronium (80 micrograms/kg) and pancuronium (100 micrograms/kg) were given with or without prior administration of succinylcholine (1 mg/kg). Fifty-two patients were randomly assigned to one of the following four groups: 1, pancuronium (100 micrograms/kg); 2, pipecuronium (80 micrograms/kg); 3, succinylcholine (1 mg/kg) plus pancuronium (100 micrograms/kg); and 4, succinylcholine (1 mg/kg) plus pipecuronium (80 micrograms/kg). In groups 3 and 4, the nondepolarizing relaxant was given after succinylcholine when the twitch height recovered to 75% of its control value. For maintenance of neuromuscular blockade, additional increments of pancuronium (20 micrograms/kg) or pipecuronium (15 micrograms/kg) were given. Neuromuscular function was monitored throughout induction, maintenance, spontaneous recovery, and pharmacologic reversal of the neuromuscular block. Mean onset times for pancuronium (group 1) and pipecuronium (group 2) given without succinylcholine were (mean +/- SEM) 2.5 +/- 0.3 and 2.8 +/- 0.2 min, respectively. Mean onset times (times to maximum twitch depression) of the two drugs given after succinylcholine (groups 3 and 4) were significantly shorter (1.4 +/- 0.4 and 1.6 +/- 0.1 min, respectively). Clinical durations (i.e., until 25% twitch recovery of pancuronium and pipecuronium) were not significantly different among the four groups, varying from 81.1 +/- 5.4 (group 4) to 107.0 +/- 17.0 (group 2) min.(ABSTRACT TRUNCATED AT 250 WORDS)

Myasthenia Gravis in Children and its Anaesthetic Implications

Myasthenia gravis, a rare disease in children, occurs in a variety of forms. The aetiology and clinical presentations are reviewed. Eight patients who were studied with electromyography are presented. The results show that, in general, patients with the usual pattern of disease are resistant to suxamethonium (ED95 3-4 times normal) and are sensitive to nondepolarizing relaxants. When the latter are used it is advisable to administer small increments with neuromuscular monitoring. One patient with the disease localised to the eyelid had normal EMG responses when monitored on the hand with ulnar nerve stimulation.

Doxacurium and Mivacurium Do Not Trigger Malignant Hyperthermia in Susceptible Swine

The role of succinylcholine in the precipitation of malignant hyperthermia (MH) necessitates the testing of new neuromuscular relaxants for their ability to trigger MH in MH-susceptible swine before general human use. We tested doxacurium and mivacurium, two new nondepolarizing bis-benzylisoquinolinium neuromuscular relaxants, at ED95 and at four times ED95 doses in swine previously documented to be MH-susceptible. In none of the 16 animals was MH triggered after administration of these relaxants, whereas all animals developed fatal MH after administration of halothane or halothane plus succinylcholine. Muscle biopsy specimens taken before administration of the relaxant confirmed that all animals had increased sensitivity to halothane, caffeine, or both. Thus, we conclude that doxacurium and mivacurium are not triggering agents of malignant hyperthermia in MH-susceptible swine.

Pharmacology of depolarizing and non-depolarizing relaxants

Pharmacology of depolarizing and non-depolarizing relaxants

Pharmacology of depolarizing and non-depolarizing relaxants

Institute for Anaesthesiology, University of Nijmegen, Nijmegen, The Netherlands Current Opinion in Anaesthesiology 1990, 3:620-624

Anesthetic management for surgical removal of renal carcinoma with caval or atrial tumor thrombus using deep hypothermic circulatory arrest

Twenty cases of renal carcinoma with tumor thrombus extending into the vena cave or atrium, in which cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) were used, are reviewed. Arterial, central venous (n = 9), or pulmonary artery catheters (n = 11), ECG, and rectal or bladder and pharyngeal temperatures were used for monitoring. The anesthetic was a high-dose narcotic supplemented with a nondepolarizing relaxant and a volatile agent. The surgery consisted of mobilization of the kidney followed by CPB via strial and aortic cannulae, cooling via CPB, axsanguination, and removal of thrombus during DHCA. Duration of cooling was 21 ± 7 minutes to a pharyngeal temperature of 15.8° ± 2.6°C with α-stet pH management; DHCA lasted 26 ± 10 minutes, and rewarming was continued to a mean pelvic temperature of 36.2°C. Duration of surgery was 8.1 ± 1.6 hours. The mean initial hematocrit was 33.5%, mean lowest Hct during CPB was 16.9%, and mean Hct at the end of surgery was 30%. Intraoperatively, 9.0 ± 6.4 units of blood were used, and most patients received component therapy. Average crystalloid use was 7 L, and albumin or hetastarch (1.3 ± 0.9 L) was used in 13 patients. One patient with severe cardiac disease could not be weaned from CPB. In the 19 operative survivors, there were no neurological deficits. There was one late death from pulmonary complications. The use of thiopental (n = 13), dexamethasone (n = 11), or mannitol (n = 19) was not clearly related to outcome. Hypothermia, hemodilution, α-stet pH management, and normoglycemia are believed to be important aspects of perioperative care. Practical problems included blood loss, coagulopathy, and temperature decrease after CPB.

Exercise Produces Sensitivity to Metocurine

Chronic muscle disuse decreases the sensitivity of skeletal muscle to nondepolarizing relaxants, such as metocurine (MTC). In this study, the authors determined whether chronic conditioning would produce the opposite effect and increase the sensitivity of skeletal muscle to MTC. Five dogs were exercised by daily running over a period of 5 weeks. At the conclusion of this training period, a pharmacokinetic and pharmacodynamic study of the MTC dose-response relationship was performed. The same analysis was performed on four dogs housed in the same kennel who did not undergo conditioning. Neuromuscular blockade was measured and recorded bilaterally in both gastrocnemius muscles while the animal was anesthetized with nitrous oxide and pentobarbital, 30 ml.kg-1. Plasma concentrations of MTC were measured by radioimmunoassay. The MTC concentration estimated in the effect compartment which produced 50% paralysis was 0.114 +/- 0.008 micrograms.ml-1 (mean +/- SD) in exercised dogs and 0.189 +/- 0.038 micrograms.ml-1 in nonexercised dogs, which was significant at P less than 0.005). The MTC concentration versus response curves were parallel. This supports the authors' hypothesis that exercise increases sensitivity to the nondepolarizing muscle relaxant metocurine.

A Comparison of the Neuromuscular Blocking and Autonomic Effects of Two New Short-acting Muscle Relaxants with Those of Succinylcholine in the Anesthetized Cat and Pig

The actions of two new steroidal nondepolarizing neuromuscular blocking agents, structurally related to vecuronium, have been compared with those of succinylcholine in anesthetized cats and pigs. Both new compounds (Org 7617 and Org 9616) exhibited properties typical of nondepolarizing relaxants in each species. Org 9616 was one-fifth (ED50 cat tibialis 154 micrograms.kg-1) and Org 7617 was one-tenth (ED50 cat tibialis 287 micrograms.kg-1) as potent as vecuronium as a neuromuscular blocking drug. Both compounds produced rapidly developing muscle relaxation in cats that, like that of succinylcholine, was transient in time course (onset/duration of action--tibialis anterior muscle: Org 7617 1.6/3.9 min; Org 9616 1.5/4.3 min; succinylcholine 1.7/5.7 min). In pigs that were used as a predictor of duration of action in humans, both Org 7617 and Org 9616 also produced short-lived neuromuscular blockade. The neuromuscular blocks produced by Org 7617 and Org 9616 were readily reversed by neostigmine. Both compounds blocked the heart rate responses to vagal stimulation at doses higher than those required to produce neuromuscular block. The vagal:neuromuscular blocking ratio for Org 7617 was 10, and for Org 9616 was 17. These compare to approximate published values for vecuronium, atracurium, and pancuronium of 60, 25, and 3, respectively. Ganglion block was only seen at 30-60 times the neuromuscular blocking doses. Both compounds produced a decrease in arterial blood pressure. This was more pronounced with Org 7617. In addition, Org 9616 produced a slight increase in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketamine Potentiates Nondepolarizing Neuromuscular Relaxants in a Primate

Ketamine has many neuromuscular effects in vitro. Its neuromuscular effects in vivo have been controversial and inconsistent. To systematically examine its neuromuscular effects over a wide dose range and its interaction with all popular nondepolarizing neuromuscular relaxants, the effects of ketamine 2, 5, and 10 mg/kg IV were studied on a continuous but incomplete (50%) neuromuscular block preestablished by an IV infusion of d-tubocurarine, atracurium, vecuronium, and pancuronium. Indirectly stimulated adductor pollicis muscle response of monkeys anesthetized with 0.5-1.0% halothane in oxygen were quantified. Ketamine in the absence of a neuromuscular relaxant had no effect on the thumb twitch. In a dose-dependent manner, ketamine significantly enhanced the 50% depression of the thumb twitch preestablished by a constant IV infusion of each of the four muscle relaxants studied. Ketamine 2 mg/kg potentiated the neuromuscular relaxants in the following order of magnitude: vecuronium greater than atracurium greater than d-tubocurarine greater than pancuronium. However, with a 10 mg/kg dose of ketamine, pancuronium became as potentiated as was vecuronium, i.e., pancuronium = vecuronium greater than atracurium greater than d-tubocurarine. It is concluded that in the primate, ketamine potentiates all nondepolarizing muscle relaxants in a dose-dependent manner.

A comparison of computer-controlled versus manual administration of vecuronium in humans.

The short elimination half-life of vecuronium suggests it may be delivered more efficiently by continuous infusion than by traditional bolus injections. The objective of this study was to compare manual administration with computer-controlled administration. Anesthesia was induced in 22 patients (American Society of Anesthesiologists [ASA] physical status I and II) with fentanyl and sodium thiopental and maintained with halothane and nitrous oxide in oxygen. Neuromuscular function was assessed at the hypothenar eminence and the adductor pollicis (train-of-four stimulation). A bolus of 0.1 mg/kg of vecuronium was given to obtain 100% twitch depression for tracheal intubation. After twitch height returned to 25% of control, relaxation was maintained by traditional bolus injections (group 1, n = 7), manually controlled continuous infusion (group 2, n = 7), or computer-controlled continuous infusion (group 3, n = 8). In all three groups the desired level of relaxation was 90% twitch depression. Variability of relaxation differed significantly among the three groups (group 1: 10.5%, group 2: 12.4%, group 3: 7.1%). Twitch height was more constant with computer control than with either bolus injections or manual infusion (P less than 0.05). There was no statistically significant difference in the drug requirement (group 1: 1.60 microgram/kg/min, group 2: 1.51 microgram/kg/min, group 3: 1.45 microgram/kg/min). Variability in the mechanomyogram (n = 12) was much higher than in the electromyogram (n = 10). Computer-controlled infusion may be a useful adjunct for the anesthesiologist who desires a stable level of patient relaxation when using short-acting, non-depolarizing relaxants.

Myalgia and biochemical changes following intermittent suxamethonium administration. Effects of alcuronium, lignocaine, midazolam and suxamethonium pretreatments on serum myoglobin, creatinine kinase and myalgia.

One hundred gynaecological patients for laparoscopy divided into five groups were studied to determine the effects of a number of pretreatments on serum myoglobin, creatinine kinase and myalgia following intermittent suxamethonium administration. One group acted as controls, while the other groups were given intravenous pretreatments of alcuronium 2 mg, midazolam 0.15 mg/kg, lignocaine 1.5 mg/kg and suxamethonium 7 mg. Serum myoglobin was determined by radio-immunoassay. The mean increases in the control group were 167 micrograms/litre myoglobin at 20 minutes and 196 IU creatinine kinase at 24 hours; 13 out of 20 patients responded with a marked increase of serum myoglobin at 20 minutes and of creatinine kinase at 24 hours. Only alcuronium pretreatment prevented myoglobin increase at 20 minutes, abolished creatinine kinase increase at 24 hours and reduced 24-hour myalgia. The other pretreatments slightly reduced myoglobin increase at 20 minutes and 24-hour creatinine kinase but did not reduce myalgia. Only one patient in the whole study had markedly elevated serum myoglobin at 24 hours. We conclude that only non-depolarising relaxant pretreatment is effective in the reduction of some of the adverse effects of suxamethonium administration.

Hand grip force as an assessment of recovery from neuromuscular block.

A simple hydraulic hand dynamometer was used to assess the hand grip force before and after general anesthesia. Eight patients received a general anesthetic of nitrous oxide and oxygen and an inhalational agent without relexants (non-relaxant group). Ten patients received a similar anesthetic of nitrous oxide and oxygen and an inhalational agent with non-depolarizing relaxants (relaxant group). The patients in the nonrelaxant group showed a mild depression to 77% of initial hand grip force by the time they could hold up their heads for 5 seconds. Patients in the relaxant group had a mean of only 29% of initial hand grip force when they could lift their heads. One hour later, hand grip force increased to 76% of preoperative force in the relaxant group. Hand grip force appears to be a sensitive measurement of residual relaxant effect.

Myasthenia gravis and thymic surgery—anaesthetic considerations

Summary Myasthenia gravis is an uncommon condition but it is of particular interest to the anaesthetist because it involves the neuromuscular junction causing a decrease in the margin of safety of neuromuscular transmission. Early thymectomy is the treatment of choice for most patients with MG but the surgical approach to the thymus (transcervical or transsternal) remains controversial. The anaesthetic technique for thymectomy must consider the sensitivity of MG patients to certain drugs used in anaesthesia. While potent inhalational agents are probably the most popular approach, competitive muscle relaxants may be safely used, provided that reduced doses are carefully titrated against effect with the aid of a neuromuscular transmission monitoring system. Of the non-depolarizing relaxants, atracurium would seem to be the ideal because of its short duration of effect and reliable pharmacokinetics. Elective tracheotomy, once routine in all MG patients undergoing thymectomy, is now the exception. Attempts to identify those MG patients who will require prolonged mechanical ventilation postoperatively have produced inconsistent results and each patient must therefore be treated on her/his own merit. Thymectomy averts the progression of disease in most MG patients, speeds the onset of remission, and appears to exert a protective effect against the development of certain extrathymic neoplasms.

Clinical Pharmacology of Muscle Relaxants in Patients With Burns

Pathophysiologic changes accompanying burn trauma can alter the pharmacokinetics and pharmacodynamic responses to neuromuscular relaxants. Pathophysiologic changes that can potentially affect kinetics in the hypermetabolic phase of burn injury include increased hepatic blood flow, increased glomerular filtration, and increased protein binding. Except for D-tubocurarine, the pharmacokinetics of neuromuscular relaxants relative to burn trauma have not been studied. The unbound volume of distribution, clearance, and half-life of D-tubocurarine were not significantly different from controls, but the plasma binding and renal elimination at 24 hours was increased in burn patients. The aberrant pharmacodynamic responses to neuromuscular relaxants in burn patients include the potential for lethal hyperkalemia with the administration of depolarizing relaxant, succinylcholine, and a 2.5- to 5.0-fold increase in the dose or plasma concentration requirement for nondepolarizing relaxant, including D-tubocurarine, metocurine, pancuronium, and atracurium. The altered pharmacodynamic responses are probably related to an increase in nicotinic acetylcholine receptor number. An alternative to succinylcholine to produce rapid-onset neuromuscular paralysis include the administration of 3XED95 doses of pancuronium and metocurine in combination (but recovery from paralysis is prolonged). Vecuronium and atracurium have good cardiovascular stability and faster recovery times even in high dosages in healthy patients, but the pharmacokinetics and pharmacodynamics of these drugs in patients with burns have not been fully characterized.

Interaction between atracurium and suxamethonium in the dog

The depolarising muscle relaxant suxamethonium (0.3 mg kg-1) and the non-depolarising relaxant atracurium (0.6 mg kg-1) were administered to four dogs. In the first series of experiments atracurium was administered, followed at 50 per cent return of neuromuscular activity by suxamethonium. At 50 per cent return of activity atropine and neostigmine were administered to reverse the block. In the second series of experiments the sequence was reversed and atracurium was administered after suxamethonium. At 50 per cent recovery atropine and neostigmine were given. In the first series of experiments it was demonstrated that the prior administration of atracurium reduced the duration of action of suxamethonium. However, in the second series it was shown that the prior administration of suxamethonium had no significant effect on the duration of action of atracurium.

Intraocular pressure--physiology and implications for anaesthetic management.

The major factors controlling intraocular pressure during surgery are the dynamic balance between aqueous humour production in the ciliary body and its elimination via the canal of Schlemm; the auto-regulation and chemical control of choridal blood volume; the extraocular muscle tone and vitreous humour volume. Prior to surgical incision of the anterior chamber in open intraocular procedures, a low-normal intraocular pressure is mandatory to avoid the hazards of iris or lens prolapse and vitreous loss associated with sudden decompression. In general, the central nervous system depressant drugs, hypnotics, narcotics, major tranquillizers, volatile anaesthetic agents are associated with a reduction in intraocular pressure, with the exception of ketamine and possibly trichloroethylene. The mechanism of action of anaesthetic agents in reducing intraocular pressure may involve a direct effect on central diencephalic control centres, reduction of aqueous production, facilitation of aqueous drainage or relaxation of extraocular muscle tone. Succinylcholine administration is associated with a significant rise in intraocular pressure, with a peak increase between two to four minutes following administration and a return to base line values after six minutes. The intraocular hypertensive effect may be due to a tonic contraction of the extraocular muscles, choroidal vascular dilatation or relaxation of orbital smooth muscle. Despite many claims to the contrary, no reported method to date has been shown to consistently prevent the intraocular hypertensive response to intravenous succinylcholine administration. Because the non-depolarizing relaxants are associated with a reduced intraocular pressure, a barbiturate-non-depolarizing relaxant technique utilizing preoxygenation and cricoid pressure has evolved as the most commonly employed induction technique for the emergency repair of a penetrating eye injury. The alternative non-depolarizing relaxant pretreatment-barbiturate-succinylcholine technique may offer the advantages of more rapid onset of relaxation with only minor increases in intraocular pressure and in a carefully controlled rapid sequence induction technique may be the most acceptable method of handling emergency penetrating eye injuries.

MONITORING TECHNIQUE AFFECTS MEASUREMENT OF RECOVERY FROM SUCCINYLCHOLINE

To compare recovery time from neuromuscular blockade after the administration of a single intravenous bolus of succinylcholine (1 mg/kg), we measured, both mechanically and electromyographically, the evoked twitch responses in the hand muscles of 10 patients. Electromyographic data were obtained, electronically integrated, and recorded by a newly available clinical monitoring device. Using both the mechanical and the electromyographic devices, we recorded the times for first return of twitch, as well as for 25% and 75% recovery of twitch height compared with prerelaxant twitch baseline values and compared the values by calculating least-squares regression lines. Times given by the electromyographic device for these measures of returning neuromuscular function were notably longer than those given by the mechanical evoked force monitor. No such findings have been reported in previous studies that compared these two techniques for monitoring of muscle recovery from nondepolarizing relaxants. The specific reasons for the differences found in this study are unknown.

Neonatal Anaesthesia

The techniques of neonatal anaesthesia detailed in this chapter reflect the practice at the Hospital for Sick Children in London where approximately 500 newborns undergo surgery each year. Surgery is usually to correct congenital disease, often life-threatening and commonly in babies born prematurely or of low birth-weight. The development of sophisticated transport systems for newborns means that sick babies can be moved to regional Centres for neonatal surgery where expertise exists to treat such conditions as congenital diaphragmatic hernia or tracheo-oesophageal fistula. The reserves of all physiological systems of the newborn are limited so respiratory, cardiac or renal failure may be a sequel to any surgical condition at this age. An immature liver and central nervous system make the baby very sensitive to all anaesthetic drugs. Techniques using specialized equipment almost always involve intubation and controlled ventilation using nondepolarizing relaxants and small doses of inhalational agents. All techniques of intraoperative monitoring apply equally to the neonate and for the preterm baby care must be taken to limit arterial oxygenation to prevent damage to the developing retina. Pre- and postoperative monitoring must involve detection of apnoea, changes in blood volume and maintenance of body temperature and blood sugar levels. Intraventricular cerebral haemorrhage is a risk associated with prematurity, surgery and anaesthesia, but with care the risk can be minimized so that the child may develop without handicap.