EFFECTS OF ANAESTHETICS AND THEIR INTERACTIONS WITH NEUROMUSCULAR BLOCKING AGENTS IN CATS

In cats lightly anaesthetized with chloralose, ventilation with75 per cent nitrous oxide did not affect arterial blood pressure,heart rate or the responses of gastrocnemius muscles to indirectstimulation; blockade by tubocurarine and gallamine was significantlyenhanced but that by suxamethonium was almost unchanged. Ventilationwith approximately 0.5 per cent halothane caused hypotensionand bradycardia and slightly depressed the responses of themuscles to indirect tetanic stimulation leaving the single twitchesunimpaired. The intensity and duration of paralysis by tubocurarinewere significantly increased but a similar tendency for gallaminpdid not achieve significance; the action of suxamethonium wasvirtually unaltered. Infusion of thiopentone, 8–10 mg/kgi.v., lowered arterial blood pressure and heart rate and slightlyincreased the tetanic contractions of the muscles without alteringthe twitch responses; blockade by tubocurarine and gniiaminf;was significantly enhanced, whereas that by suxamethonium wasunchanged. Halothane and thiopentone potentiated the hypotensiveaction of tubocurarine.     

EFFECT OF HALOTHANE ON TUBOCURARINE AND SUXAMETHONIUM BLOCK IN MAN

The effect of halothane 2 per cent on neuromuscular transmissionand its interaction with both tubocurarine and suxamethoniumwas investigated in twenty patients undergoing surgery, usingthe twitch response to ulnar nerve stimulation. Ventilationwas constantly controlled throughout the procedure. Halothanedid not cause any depression of the twitch response in the absenceof tubocurarine; a slight increase was even observed. On theother hand, when halothane was inhaled during tubocurarine block,a marked depression of the twitch was observed. Suxamethoniumproduced intense fasciculations when injected during halothaneanaesthesia, but no significant difference in the degree ofblock was observed.     

Anaesthesia for Friedreich''s ataxia

A patient with Friedreich's ataxia was anaesthetised on two occasions. The neuromuscular blocking agent was atracurium 0.5 mg/kg on the first occasion and tubocurarine 0.5 mg/kg on the second. The effect of each was monitored using the train-of-four twitch technique. Friedreich's ataxia has been reported to cause a marked sensitivity to non-depolarising muscle relaxants and hyperkalaemia, with resulting cardiac dysrhythmias after suxamethonium. This patient did not demonstrate an abnormal response to either relaxant; the operating conditions were satisfactory and recovery was not delayed. These drugs may be safely used in this condition provided that monitoring is adequate.     

A COMPARISON OF THE EFFECTS OF SUXAMETHONIUM AND TUBOCURARINE IN PATIENTS IN LONDON AND NEW YORK

The effects of suxamethonium and tubocurarine were studied inLondon and New York patients anaesthetized with thiopentone,nitrous oxide and halothane. The action of tha muscle relaxantswere assessed by measurement of the twitch respone of the adductorpollicis muscle to supramaximal stimulation of the ulnar nerve.The duration of action of suxamethonium (1 mg/kg) was less inLondon patients than in a comparable group of New York patients.With tubocurarine (0.1 mg/kg) the magnitude and duration ofaction was less in London than in New York patients. In a groupof Amercian patients at a United States Air Force (USAF) hospitalthe magnitude and duration of action of tubocurarine (0.1 mg/kg)was similar to that seen in New York patients. It was also observedthat the response to tubocurarine (0.1 mg/kg) was affected bythe prior administration of suxamethonium (1 mg/kg). Both themagnitude and duartion of action of tuborcurarine were greaterin patients who had previously received suxamethonium than inthose who had not.     

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK BY SUXAMETHONIUM IN DOGS

The effects of intravenously administered calcium chloride onpartial neuromuscular block produced by small and large dosesof suxamethonium, tubocurarine and gallamine have been studiedin dogs. Calcium chloride brought about an improvement in twitchtension, and this depression lasted for 5–15 minutes.The possible mechanisms of the block produced by small dosesof suxamethonium. In the presence of a complete phase II blockproduced by suxamethonium, however, calcium chloride depressedthe twitch tension, and this depression lasted for 5—15minutes. The possible mechanism of the varying effects of calciumon different types of neuromuscular block are discussed andit is suggested that the depression of twitch by calcium inthe presence of desensitization block may be due to a "membranestabilizing action". It is possible that this observation mayprove useful clinically in differentiating desensitization blockfrom other varieties of neuromuscular block. ^*S.M.S. Medical College, Jaipur, India. ^*College of Medical Sciences, Banaras Hindu University,Varanasi, India     

ANTAGONISM OF NEUROMUSCULAR BLOCK BY PHYSOSTIGMINE IN MAN

In 20 adult patients undergoing inguinal herniorhaphy neuromuscularblock was induced with tubocurarine 10 mg. In 10 patient, neostigmine1–2 mg antagonized the block and restored the twitch responseto its baseline value. Physostigmine, up to 4 mg, did not producesignificant antagonism of the neuromuscular block.     

Pretreatment with pancuronium before suxamethonium administration in patients heterozygous for the usual and the atypical plasma cholinesterase gene

The object of this study was to investigate whether pretreatment with pancuronium before i.v. injection of suxamethonium could cause prolonged neuromuscular blockade in patients heterozygous for the usual and the atypical plasma cholinesterase gene (E1uE1a). Forty-three patients, 23 with genotype E1uE1a and 20 with normal genotype (E1uE1u), were pretreated with pancuronium 0.01 mg.kg-1 followed by suxamethonium 1.5 mg.kg-1, and received either neurolept anaesthesia or halothane anaesthesia. Seven patients (E1uE1a) were given suxamethonium 1.5 mg.kg-1 without pretreatment. The duration and type of neuromuscular block were evaluated using train-of-four (TOF) nerve stimulation. Type of anaesthesia did not significantly influence the results. The duration of block following pretreatment was significantly longer in heterozygous patients than in normal patients. Time to 90% twitch height recovery was 10.7 +/- 1.2 min (mean +/- s.d.) in genotypically normal patients, and 18.0 +/- 4.2 min in patients with genotype E1uE1a. Pretreatment with pancuronium caused a significantly slower recovery of the TOF ratio (phase II block). Thus, a TOF ratio of 0.7 was always reached within 13 min in genotypically normal patients. In genotypically abnormal patients, the same TOF ratio was reached within 20 min in all but three patients. In these three patients time to 90% twitch height recovery was prolonged (18-31 min), and TOF ratio did not return to normal, but stabilized at about 0.35, 0.50, and 0.65, respectively. Injection of edrophonium restored normal neuromuscular function in 10 min. It is concluded that in patients heterozygous for the usual and the atypical gene, pretreatment with pancuronium in combination with an increased dose of suxamethonium may cause a phase II block and thus a prolonged neuromuscular block.     

Twitch augmentation and train-of-four fade during onset of neuromuscular block after subclinical doses of suxamethonium

We have studied the train-of-four (TOF) response mechanomyographically during onset of neuromuscular block produced by subclinical doses of suxamethonium in order to follow the augmentation of the first twitch of the TOF (T1) and TOF fade compared with control TOF responses before the drug was given. In the groups given suxamethonium 0.05, 0.1, 0.2 and 0.3 mg kg-1, the increments in T1 after administration of the drug were observed before twitch depression occurred; these were mean 22.3 (SEM 8.1)%, 19.2 (3.3)%, 10.8 (2.0)% and 4.2 (2.2)%, respectively. This effect was more marked with the lower doses (P < 0.05). The degree of TOF fade was moderate during onset of neuromuscular block and depended on the dose of drug. The results of this study suggest that low doses of suxamethonium produced transient increase in muscle tension and twitch depression with significant TOF fade. We conclude that suxamethonium was associated with presynaptic effects as a consequence of brief stimulation of acetylcholine release followed by progressive diminution at the neuromuscular junction.      

Onset of neuromuscular block after tourniquet inflation: comparison of suxamethonium with vecuronium

To determine the influence of circulatory factors on onset of neuromuscular block, we have measured twitch height in an arm with a tourniquet inflated during onset and compared this with data from a control arm in 20 patients under fentanyl-thiopentone-nitrous oxide- isoflurane anaesthesia. Patients were allocated randomly to receive either vecuronium 0.1 mg kg-1 (n = 10) or suxamethonium 1 mg kg-1 (n = 10). The EMG response of the first dorsal interosseous to single twitch stimulation of the ulnar nerve every 10 s was recorded in both arms. When neuromuscular block was 20% (i.e. twitch height was 80% of control), the tourniquet was inflated to a pressure of 250 mm Hg. It was deflated 5 min later. In the vecuronium group, the rate of onset did not differ in both arms and mean maximum block was 95 (SD 4)% in the tourniquet arm, which was not different from 99 (2)% in the perfused arm. In the suxamethonium group, the presence of a tourniquet decreased the rate of onset by 66%. Maximum block was only 74 (20)% in the tourniquet arm compared with 97 (5)% in the perfused arm (P < 0.05). The difference in maximum neuromuscular block between arms was 4 (3)% in the vecuronium group and 22 (17)% in the suxamethonium group (P < 0.01). We conclude that during onset, neuromuscular block continued to increase in spite of interruption of blood flow, and this increase was greater with vecuronium than with suxamethonium. These results suggest that redistribution of free molecules of drug from extra-junctional to junctional areas is one of the factors governing onset of action of neuromuscular blocking drugs.      

DUAL BLOCK AFTER INTERMITTENT SUXAMETHONIUM

The production of dual block is part of the normal action ofdepolarizing agents if their presence at the neuromuscular junctionis prolonged. Dual block was demonstrated in fifteen out oftwenty patients who received suxamethonium 200 mg in divideddoses. Gallamine 5 mg was given at the end of surgery and theeffect on respiratory minute volume was measured by spirometryand by the ergograph recording of finger twitch response toelectrical stimulation of the median nerve. It is suggestedthat dual block occurs more readily when suxamethonium is givenintermittently than when it is infused at a constant rate. Thenature and possible clinical importance of dual block are discussed.It is concluded that suxamethonium is unsuitable if paralysisfor more than 20 minutes is required.     

NEUROMUSCULAR BLOCKADE BY NEOSTIGMINE IN ANAESTHETIZED MAN

The tetanic and single twitch responses of the adductor pollicismuscle were used to study the neuromuscular effects of neostigminein 26 patients anaesthetized with thiopentone and nitrous oxide.Neostigmine 2.5 mg i.v. given 5 min after exposure to halothaneantagonized non-depolarizing neuromuscular block, whereas asecond dose given 2–5 min later depressed the peak tetaniccontraction and re-established tetanic fade. In the absenceof halothane the second dose of neostigmine had less effect.Recovery of the single twitch was not impaired by the seconddose. A single dose of neostigmine 5 mg rapidly antagonizedthe competitive block of the tetanic response but the subsequentslight depression of the peak contraction and the brief reappearanceof fade were less than after 5 mg given in two doses of 2.5mg. In patients who were not given neuromuscular blocking drugs,one or two injections of neostigmine 2.5 mg caused a substantialreduction in the peak tetanic contraction and severe tetanicfade which persisted for about 20 min; the single twitch wasslightly potentiated. The neostigmine block of the tetanic responsecould be antagonized by galla-mine and potentiated by suxamethonium.These findings indicate that neostigmine in clinical doses canproduce an acetylcholine-induced block which would be a potentialhazard in anaesthetic practice. ^* Present address: Pharmacology Department, The Wellcome ResearchLaboratories, Langley Court, Beckenham, Kent.     

Comparison of the neuromuscular effects of mivacurium and suxamethonium in infants and children

We compared both the time course of neuromuscular blockade and the cardiovascular side-effects of suxamethonium and mivacurium during halothane and nitrous oxide anaesthesia in infants 2–12 months and children 1–12 years of age. Equipotent doses of mivacurium and suxamethonium were studied; 2.2×ED₉₅ was used in four groups of infants and children, while 3.4×ED₉₅ was used in two groups of children. Onset of neuromuscular block in infants was not significantly faster with suxamethonium than with mivacurium ( P =0.2). In all infants given suxamethonium, intubating conditions were excellent, while, in 6/10 infants given mivacurium, intubating conditions were excellent. Onset of complete neuromuscular block in children was significantly faster with suxamethonium, 0.9 min compared with mivacurium, 1.4 min ( P ×0.05). Increasing the dose of suxamethonium or mivacurium in children to 3.4×ED₉₅ did not change the onset of neuromuscular block. Recovery of neuromuscular transmission to 25% of initial twitch height (T₂₅) in infants and children was significantly faster after suxamethonium than after mivacurium, at 2.5 and 6 min, respectively ( P ×0.05). In children given 3.4×ED₉₅ of suxamethonium or mivacurium, recovery from neuromuscular block was almost identical with the dose of 2.2×ED₉₅, with spontaneous recovery to T₂₅ prolonged by only 0.5 min. No infant or child had hypotension after the mivacurium bolus dose.     

IN VITRO MUSCLE CONTRACTURES INDUCED BY HALOTHANE AND SUXAMETHONIUM: I: The Rat Diaphragm

The rat diaphragm was used as an in vitro model for studiesof contractures synergistically-induced by halothane and suxamethonium.The effects of three agents reported to inhibit phospholipaseA₂ activity (quinacrine, spermine and indomethacin), tubocurarineand dantrolene were examined on these contractures. Contract-uresinduced by 1% halothane (0.26±0.02g) (mean±SEM)were increased (0.60±0.04g) if suxamethonium 50 mmollitre^–1 was also in the bathing medium. Suxamethonium-inducedcontractures (0.22±0.03g) were also enhanced when halothanewas present (0.51±0.03g). Spermine, indomethacin anddantrolene antagonized both halothane- and suxamethonium-inducedcontractures. Quinauced by either halothane or suxamethonium.were antagonized by tubocurarine; however, Contractures inducedby halothane were not antagonized by tubocurarine. however,contractures induced by halothane were not antagonized by tubocurarine.These results suggest that free fatty acids may be involvedin contractures induced synergistically by halothane and suxamethonium.Different mechanisms are involved in the induction of contracturesby suxamethonium than by halothane.     

PRETREATMENT WITH NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS AND SUXAMETHONIUM-INDUCED INCREASES IN RESTING JAW TENSION IN CHILDREN

We have studied the effect of prior administration of non-depolarizingneuromuscular blocking drugs on suxamethonium-induced increasesin masseter muscle tension in 21 children aged 3–10 yr,anaesthetized with nitrous oxide and halothane using supramaximalstimulation of the ulnar nerve and the nerve to masseter. Restingtension and isometric force of contraction were measured inthe adductor pollicis and masseter muscles. A sub-paralysingdose of tubocurarine 0.05 mg kg^–1, a paralysing dose ofatracurium 0.5 mg kg^–1 or saline was given, followed 3min later by suxamethonium 1 mg kg^–1. Onset times of suxamethoniumand atracurium block were shorter in the masseter than in theadductor pollicis muscle. When preceded by a sub-paralysingdose of tubocurarine, suxamethonium produced an increase inmasseter tension (47 (SEM 15) g) similar to that produced bysuxamethonium alone (59 (13) g). Prior administration of a paralysingdose of atracurium almost abolished this increase in tension(2.5 (2.5) g) (P < 0.05 vs saline). The tension increasein adductor pollicis was 0, 3.2 (2.2) and 5.9 (1.1) g in theatracurium, tubocurarine and saline groups, respectively. Tubocurarineand atracurium prevented muscle fasciculations in all patients.It was concluded that increased muscle tone is a normal responseto suxamethonium and is greater in the masseter than adductorpollicis. Sub-paralysing doses of non-depolarizing neuro-muscularblockers have little effect, in contrast with paralysing doses.This suggests that the effect is mediated via postsynaptic receptors.     

Succinylcholine apnoea: attempted reversal with anticholinesterases

Anticholinesterases were administered in an attempt to antagonize prolonged neuromuscular blockade following the administration of succinylcholine in a patient later found to be homozygous for atypical plasma cholinesterase. Edrophonium 10 mg, given 74 min after succinylcholine, when train-of-four stimulation was characteristic of phase II block, produced partial antagonism which was not sustained. Repeated doses of edrophonium to 70 mg and neostigmine to 2.5 mg did not antagonize or augment the block. Spontaneous respiration recommenced 200 min after succinylcholine administration. It is concluded that anticholinesterases are only partially effective in restoring neuromuscular function in succinylcholine apnoea despite muscle twitch activity typical of phase II block.     

Antagonism of suxamethonium-induced jaw muscle contracture in rats

Masseter muscle rigidity (MMR) induced during general anaesthesia by suxamethonium is a clinical problem that may interfere with tracheal intubation. We have investigated the relation between twitch tension and contracture response to suxamethonium in rats. Rats were anaesthetized with 1% halothane (1.35 MAC). Jaw muscle temperature was maintained at either 37 or 41 degrees C while rectal temperature was kept at 37 degrees C by radiant heat. Twitch tension was produced by nerve stimulation at 0.2 Hz. Rats were pretreated with either a low dose of vecuronium (0.03 mg kg-1) or dantrolene (0.8 mg kg-1). Thereafter suxamethonium 750 micrograms kg-1 was administrated i.v. Low- dose vecuronium pretreatment significantly (90%) decreased suxamethonium-induced jaw muscle contracture (JMC) with minimal (3%) twitch block during local hyperthermia. Low-dose dantrolene pretreatment also reduced JMC (81% at 37 degrees C and 82% at 41 degrees C) while decreasing twitch by 30% at 37 degrees C and 31% at 41 degrees C. Both vecuronium and dantrolene at doses that minimally depressed the twitch response antagonized suxamethonium-induced JMC. We speculate that pretreatment with low-dose vecuronium decreases suxamethonium-induced MMR clinically.      

PROLONGED SUXAMETHONIUM INFUSION DURING NITROUS OXIDE ANAESTHESIA SUPPLEMENTED WITH HALOTHANE OR FENTANYL

The neuromuscular blockade produced by a prolonged infusionof suxamethonium was studied using train-of-four stimulationin 40 patients receiving either halothane-nitrous oxide or fentanyl-nitrousoiide anaesthesia. Initially, a depolarizing (phase I) blockwas observed in all patients followed by phase II block whichwas associated with tachyphylaxis to suxamethonium; the latterchanges occurring more rapidly in the halothane group. Infusionswere continued for more than 150 min in 17 patients and therewas a late decrease in suxamethonium requirement in those whoreceived halothane, but not fentanyl. Ten minutes after thesuxamethonium infusion was stopped, most patients received neostigminewhich was followed by rapid recovery of neuromuscular transmission.     

Cholinesterases and the resistance of the mouse diaphragm to the effect of tubocurarine

BACKGROUND: The diaphragm is resistant to competitive neuromuscular blocking agents. Because of the competitive mechanism of action of tubocurarine, the rate of hydrolysis of acetylcholine at the neuromuscular junction may modulate its neuromuscular blocking effect. The authors compared the neuromuscular blocking effect of tubocurarine on isolated diaphragm and extensor digitorum longus (EDL) muscles and quantified the acetylcholinesterase activity in hetero-oligomers. METHODS: Adult Swiss-Webster and collagen Q-deficient (ColQ) mice were used. The blocking effect of tubocurarine on nerve-evoked muscle twitches was determined in isolated diaphragm and EDL muscles, after inhibition of acetylcholinesterase by fasciculin-1, butyrylcholinesterase by tetraisopropylpyro-phosphoramide, or both acetylcholinesterase and butyrylcholinesterase by neostigmine, and in acetylcholinesterase-deficient ColQ muscles. The different acetylcholinesterase oligomers extracted from diaphragm and EDL muscles were quantified in sucrose gradient. RESULTS: The EC50 for tubocurarine to decrease the nerve-evoked twitch response was four times higher in the diaphragm than in the EDL. The activity of the different acetylcholinesterase oligomers was lower in the diaphragm as compared with the EDL. Inhibition of acetylcholinesterase by antagonists resulted in an increased dose of tubocurarine but an unchanged resistance ratio between the diaphragm and the EDL. A similar diaphragmatic resistance was found in ColQ muscles. CONCLUSION: The current study indicates that, despite differences in acetylcholinesterase activity between the diaphragm and EDL, the diaphragmatic resistance to tubocurarine cannot be explained by the different rate of acetylcholine hydrolysis in the synaptic cleft.     

Does suxamethonium influence the subsequent dose requirements of alcuronium and its reversibility in children?

Suxamethonium is often used for intubation prior to the use of a nondepolarizing muscle relaxant. This study was performed to determine whether suxamethonium altered the dose of alcuronium required to produce neuromuscular block. The findings were that suxamethonium 1.0 mg/kg did not alter the depth, duration or reversibility of block if given before alcuronium 0.3 mg/kg. Reversal with neostigmine was more rapid following 50 micrograms/kg than after 25 micrograms/kg. If recovery from neuromuscular block was greater than 25 per cent, the lower dose produced satisfactory reversal, whether or not suxamethonium had been given previously.     

Cholinesterases and the Resistance of the Mouse Diaphragm to the Effect of Tubocurarine

Background: The diaphragm is resistant to competitive neuromuscular blocking agents. Because of the competitive mechanism of action of tubocurarine, the rate of hydrolysis of acetylcholine at the neuromuscular junction may modulate its neuromuscular blocking effect. The authors compared the neuromuscular blocking effect of tubocurarine on isolated diaphragm and extensor digitorum longus (EDL) muscles and quantified the acetylcholinesterase activity in hetero-oligomers.

Methods: Adult Swiss-Webster and collagen Q-deficient (ColQ-/-) mice were used. The blocking effect of tubocurarine on nerve-evoked muscle twitches was determined in isolated diaphragm and EDL muscles, after inhibition of acetylcholinesterase by fasciculin-1, butyrylcholinesterase by tetraisopropylpyro-phosphoramide, or both acetylcholinesterase and butyrylcholinesterase by neostigmine, and in acetylcholinesterase-deficient ColQ-/- muscles. The different acetylcholinesterase oligomers extracted from diaphragm and EDL muscles were quantified in sucrose gradient.

Results: The EC50 for tubocurarine to decrease the nerve-evoked twitch response was four times higher in the diaphragm than in the EDL. The activity of the different acetylcholinesterase oligomers was lower in the diaphragm as compared with the EDL. Inhibition of acetylcholinesterase by antagonists resulted in an increased dose of tubocurarine but an unchanged resistance ratio between the diaphragm and the EDL. A similar diaphragmatic resistance was found in ColQ-/- muscles.