EARLY DIAGNOSIS OF ANAPHYLACTIC REACTIONS TO NEUROMUSCULAR BLOCKING DRUGS

Neuromuscular blocking drugs (NMB) are involved in most of theanaphylactic reactions occurring during anaesthesia. Patientsare evaluated usually 6 weeks after the reaction, by skin testing.In order to obtain an earlier diagnosis, we have measured plasmaconcentrations of histamine, tryptase and NMB-specific IgE antibodiesin 14 patients after an anaphylactoid reaction. We have comparedthe results with those of skin tests and specific IgE obtained8 weeks later. Good agreement was observed in all subjects betweenthe results of skin tests and the values for histamine and tryptase,provided that both markers were measured simultaneously. Furthermore,there was no significant difference between the concentrationsof NMB-specific IgE antibodies observed at the time of the reactionand 8 weeks later. Thus anaphylaxis to neuromuscular blockingdrugs can be demonstrated at the time of the reaction by measuringplasma concentrations of histamine, tryptase and specific IgE.In the event of the patient's death, such measurements may beuseful in identifying the likely cause.     

EFFECT OF EXPERIMENTAL CHOLESTASIS ON NEUROMUSCULAR BLOCKING DRUGS IN CATS

Pancuronium, Org 6368 and gallamine were compared in controlcats and in cats with experimental cholestasis. A decrease inthe plasma clearance and a prolongation of neuromuscular blockadewith Org 6368 and pancuronium were found in the latter; no significantdifference was detected in the biotransformation pattern ofOrg 6368 and pancuronium compared with controls. Inhibitionof hepatic uptake of Org 6368 and pancuronium in extrahepaticcholestasis might explain the significant alterations in thepharmacokinetics of the two steroid neuromuscular blocking drugs.The pharmacokinetics of gallamine were normal during cholestasis.The results suggest that, under pathological conditions involvingincreased plasma concentrations of bile salts, neuromuscularblocking agents that are cleared from the plasma by the livermay have an impaired hepatic uptake and consequently a prolongedduration of action.     

PLATELET SEROTONIN IS A MEDIATOR POTENTIALLY INVOLVED IN ANAPHYLACTIC REACTION TO NEUROMUSCULAR BLOCKING DRUGS

A platelet serotonin release test was performed on blood from10 patients who had suffered from an IgE-dependent allergicreaction to a neuromuscular blocking drug. The results werecompared with those of a leukocyte histamine release test. Theupper limit of serotonin release induced by neuromuscular blockerswas estimated to be 2.3% in non-allergic patients. The testwas positive in six patients and was consistent with histaminerelease in five. Serotonin re/ease induced by neuromuscularblockers comprised 2.9–25% of total platelet serotonincontent. We conclude that serotonin is one of the mediatorsassociated with histamine release during anaphylaxis to neuromuscularblockers. Platelet serotonin release tests may be useful forthe investigation of anaphylactic responses to neuromuscularblocking drugs. (Br. J. Anaesth. 1993; 70: 322–325)     

SELF-ANTAGONISM: A POSSIBLE MECHANISM OF TACHYPHYLAXIS IN SUXAMETHONIUM-INDUCED NEUROMUSCULAR BLOCK IN MAN

Twelve adults receiving halothane-nitrous oxide anaesthesiafor elective surgery were investigated during suxamethonium-inducedneuromuscular block, using the train-of-four twitch for measurementof both the degree of block and the magnitude of fade (decreasein fourth-to-first ratio). The residual neuromuscular blockresulting from prolonged exposure to suxamethonium could beantagonized by bolus injections of suxamethonium itself, indoses which increased the block in Phase I. When self-antagonismwas demonstrated, larger doses were necessary to increase theresidual block, but only after overcoming the self-antagonizingeffect. A biphasic response, first antagonizing then increasingthe block, was observed following injection of a single bolusof suxamethonium. The self-antagonizing effect was more obviousin the fourth twitch of the train-of-four, resulting in a markeddecrease in train-of-four fade (increase in train-of-four ratio).It was concluded that self-antagonism may be an important causeof tachyphylaxis in suxamethonium-induced neuromuscular blockin man.     

RELATIONSHIP BETWEEN DECAY OF PLASMA CONCENTRATION OF FAZADINIUM AND RECOVERY FROM ITS NEUROMUSCULAR BLOCKING EFFECT

The relationship of the time-course of the decay of plasma concentrationof fazadinium and neuromuscular block has been investigatedafter i.v. administration ofO.75mgkg^–1 to six anaesthetizcdpatients. The phar acokinctic of fazadinium were analysed accordingto a two-compartment open model. A significant correlation wasfound between the plasma concentration of fazadinium and thetwitch height (TH) values during recovery from the block (P<0.001). The mean total plasma concentrations for 25,50and75%THrecoverywere: 1.90±0.17; 1.44±0.l8and 1.08±0.l2µgm^–1,respectivcly.Elapsed time between fazadinium administrationand the Th recovery to 50% (0-TH and the recovery period TH_25–75were 47±4mm and 25±2mm, respectively. Plasma logdecay rate of fazadinium during TH_25–75 period (K_{app 25–75})was: 0.0249±0.0032min^–1. Significant correlations(P<0.01) were observed between the elimination rate constant(k₁₀ ) of the pharmacokinetic model, K_{app 25 –75} (P<0.01)and the pharmacodynamic parameters: time interval 0-TH₅₀ andrecovery rate TH _25-73. These results showed that part of theindividual pharmacodynamic variation had its origin in the interindividualpharmacokinenc variation.     

IN VITRO STUDY OF INTERACTIONS BETWEEN I.V. ANAESTHETICS AND NEUROMUSCULAR BLOCKING AGENTS

The interactions of four anaesthetic drugs (ketamine, propanidid,Althesin and methohexitone) with two neuromuscular blockingagents (suxamethonium and pancuronium) have been investigated.On the isolated rat phrenic nerve—diaphragm preparation,all the anaesthetic drugs examined potentiated suxamethoniummore than they potentiated pancuronium. The anticholinesteraseagent, ecothiopate, had no significant effect on the potentiationof suxamethonium caused by the anaesthetic drugs. At low concentrationsthe anaesthetic drugs increased the twitch tension elicitedby stimulation of the phrenic nerve, whilst at high concentrationsthis potentiation was followed by blockade of neuromusculartransmission. With the exception of Althesin, all the anaestheticsdecreased the sensitivity of the frog rectus preparation toacetylcholine. The possible sites and mechanisms of these interactionsare discussed.     

IN VITRO COMPARISON BETWEEN THE NEUROMUSCULAR AND GANGLION BLOCKING POTENCY RATIOS OF ATRACURIUM AND TUBOCURARINE

Results from in vitro experiments, using the hypogastric nerve-vas deferens preparation, and the phrenic nerve - hemidiaphragmpreparation of the guineapig, have been used to determine theseparation between the neuromuscular and ganglioruc blockingeffects of atracunum and tubocurarine. Regression lines wereused to calculate the concentrations of each drug (99% confidencelimits) which would produce a 50% blockade (EC50) of ganglionicand neuromuscular transmission. The equipotent molar ratio,using EC50 values, for ganglionic/neuromuscular blockade was48 for atracunum and 9.4 for tubocurarine.     

IN VITRO INVESTIGATION OF THE PRIMING PRINCIPLE FOR RAPID NEUROMUSCULAR BLOCK

The priming principle was investigated in the rat phrenic nerve-diaphragmpreparation stimulated continuously at 0.2 Hz. Tubocurarinewas added to the organ bath as either a single (non-primed)or a divided (primed) dose. Priming consisted of 15% or 20%of the final dose, with priming intervals of 5 or 10 min. Primingdecreased significantly the time to 80% block and was associatedwith mild neuromuscular block. A simple model adequately predictedthe time to 50% and 80% block, using the same diffusion constantfor both primed and non-primed conditions. The onset of neuromuscularblock, with and without priming, depended mostly upon the distributionof the drug to its site(s) of action. Present address: Department of Anesthesiology, The Johns HopkinsHospital Baltimore, Md, U.S.A. Accepted for Publication: October3, 1988.     

INTERACTION OF MIDAZOLAM WITH TWO NON-DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS IN THE RAT IN VIVO SCIATIC NERVE-TIBIALIS ANTERIOR MUSCLE PREPARATION

Studies of the possible interactions between the water-solublebenzodiazepine, midazolam, and two non-depolarizing neuromuscularblocking drugs, vecuronium and tubocurarine, were performedin the rat in vivo sciatic nerve-tibialis anterior muscle preparation.Midazolam 0.5 and 5 mg kg^–1 caused 17% and 34% depressionof the twitch height, respectively, once a steady-state blockadeof the twitch height had been induced by vecuronium. The potentiationof the tubocurarine steady state blockade by midazolam 5 mgkg^–1 was quantitatively equal to that of vecuronium, butwas slower in onset. The buffer solvent of midazolam 5 mg kg^–1did not change the steady-state blockade of vecuronium. Midazolam5 mg kg^–1 caused a shift to the left of the cumulativedose-response curves of vecuronium.     

DISPLACEMENT OF SOME BASIC DRUGS FROM HUMAN SERUM PROTEINS BY ENFLURANE, HALOTHANE AND THEIR MAJOR METABOLITES

The influence of volatile anaesthetics (halothane, enflurane)on the serum protein binding of three highly bound basic drugshas been studied in vitro by equilibrium dialysis. Radioactivelabelled isotopes were used for the determination of drug concentrations.Enflurane, halothane and the halothane metabolite trifluoroaceticacid (TFA) inhibited the binding of diazepam to serum and toits main binding protein, albumin. The binding of diazepam toalbumin was inhibited in a competitive manner and was not relatedto the anaesthetic potency of the vapours. Thus the observeddisplacement of diazepam should be regarded as a side-effectof the volatile anaesthetics. The binding of propranolol andprazosin in serum was not significantly influenced by the investigatedanaesthetics. At clinically relevant concentrations of the anaesthetics,diazepam was displaced significantly only by enflurane withan increase in free fraction of 60% in serum. TFA in concentrationsseen after operation significantly increased te free fractionof diazepam up to 90%. We conclude that enflurane anaesthesiamay temporarily potentiate the pharmacological effect of diazepamand that, in the postoperuative period following halothane anaesthesia,a more rapid elimination of diazepam could be expected.     

CLINICAL STUDY OF PANCURONIUM BROMIDE AS A NEUROMUSCULAR BLOCKING AGENT IN ANAESTHESIA

Pancuronium bromide has proved to be a useful non-depolarizing long-acting neuromuscular blocking agent which is nearly three times (2.42) as potent as alcuronium chloride. Pancuronium bromide blockade can be reversed fairly quickly by anticholinesterase agents, and die patient recovers to the 90% level of muscle tone in 15-20 minutes.

ZUSAMMENFASSUNG

Pancuroniumbromid hat sich als brauchbarer nicht-depolarisierender langwirkender neuromuskulärer Blocker erwiesen, der fast dreimal so stark (2,42) ist als Alcuroniumchlorid. Die Blockade durch Pancuroniumbromid kann mittels Anticholinesterasen ziemlich rasch aufgehoben werden; der Patient erreicht innerhalb von 15 bis 20 Minuten wieder 90% seines Muskeltonus.     

CROSS-REACTIVITY OF METOCURINE, ATRACURIUM, VECURONIUM AND FAZADINIUM WITH IgE ANTIBODIES FROM PATIENTS UNEXPOSED TO THESE DRUGS BUT ALLERGIC TO OTHER MYONEURAL BLOCKING DRUGS

An inhibition assay was used to determine quantitatively theallergenic cross-reactivity of some myoneural blocking drugsnot yet released for use in Australia, in the sera of patientswho had experienced anaphylactic reactions to neuromuscularblocking drugs. Two of the compounds, metocurine and atracuriumwere highly cross-reactive with the currently used myoneuralblockers; fazadinium was weakly cross-reactive and vecuroniumintermediate in potency between these two extremes. From theseresults, we predict that anaphylactic reactions to these compounds,and particularly to metocurine and atracurium, will occur insome patients allergic to the currently used neuromuscular blockingagents.     

A METHOD FOR PRODUCING CONSTANT PLASMA CONCENTRATIONS OF DRUGS: Application to Methohexitone

A delivery system in which a dilute in fusion of methohexitoneis continuously added to a smaller volume of more concentratedsolution has been used to infuse exponentially decreasing drugconcentrations at a constant rate of infusion. The constantsfor calculation of concentrations and infusion rate are described.It was possible to achieve and maintain the target plasma concentrationrequired to produce anaesthesia in conjunction with nitrousoxide in oxygen. Methohexitone is the only available drug suitablefor this technique, but it requires frequent opioid supplementationand is not the ideal drug for such a technique.     

THE EFFECTS OF ANAESTHESIA WITH THIOPENTONE, NITROUS OXIDE, NARCOTICS AND NEUROMUSCULAR BLOCKING DRUGS ON RENAL FUNCTION IN NORMAL MAN

Changes in renal haemodynamics, water and electrolyte excretionwere determined in 10 healthy male volunteers before and afterthe administration of narcotic and atropine sulphate intravenously,and after anaesthesia with thiopentone, nitrous oxide in oxygen,neuromuscular blocking drugs and in some instances intermittentnarcotic. A significant reduction in glomerular filtration rate(13 per cent) without change in renal plasma flow with an increasedrenal vascular resistance was observed following narcotic andatropine premedication. No alteration in urine volume or osmolalityfollowed narcotic premedication suggesting failure of ADH release.Administration of anaesthesia resulted in a further reduction(11 per cent) in glomerular filtration rate, a 31 per cent reductionin renal plasma flow and maintained increase in renal vascularresistance. A profound antidiuresis characterized by low urinevolume, increased urine osmolality, and negative free waterclearance was observed during anaesthesia. This could not bereversed by ethanol infusion, unlike the response in previousstudies with cyclopropane and halothane. ^*Present address: Michael Reese Hospital andMedical Center,Chicago, Illinois 60616.     

ACUTE AND SUBCHRONIC NEUROMUSCULAR BLOCKING CHARACTERISTICS OF STREPTOMYCIN: A COMPARISON WITH NEOMYCIN

The characteristics of the neuromuscular block produced by streptomycinin vivo were studied on the sciatic-tibialis anterior nerve-musclepreparation of eight anaesthetized cats. The lungs of the animalswere ventilated mechanically and normocarbia was maintained.During acute exposure to streptomycin (within 2 h), ED₅₀ forblockade of the twitch was 56 (SEM ± 5) mg kg^–1of the base. The characteristics of block were similar to thoseof neomycin-induced block in some aspects. There was absenceof train-of-four fade and tetanic fade, partial sparing of theresponses elicited at 10 Hz and 20 Hz, and total sparing ofthe 50 Hz tetanus, as well as the post-tetanic twitch. In contrastto neomycin-induced neuromuscular block, however, post-tetanicexhaustion was not observed and prolonged exposure to streptomycin(22–28 h) did not change the characteristics of the block.We conclude that, despite their chemical similarities, streptomycinand neomycin block neuromuscular transmission differently. ^*An abstract was presented at the 1978 Annual Meeting of theAmerican Society of Anesthesiologists, October 1978, under thetitle "Antibiotic-induced neuromuscular block: phenomenologicaldifferences between streptomycin and another aminoglycosideneomycin".     

EVALUATION OF GLYCOPYRROLATE AND ATROPINE AS ADJUNCTS TO REVERSAL OF NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS IN A "TRUE-TO-LIFE" SITUATION

Glycopyrrolate, a quaternary ammonium anticholinergic compound,and atropine were evaluated in combination with neostigminefor antagonism of non-depolarizing neuromuscular block. A totalof 641 patients were investigated in a "true-to-life" situation.The patients receiving glycopyrrolate with neostigmine had smallerchanges in heart rate than those who received atropine. Thiswas particularly apparent in patients with cardiovascular disease. ^* Present address: Department of Anaesthesia, University CentralHospital, 00290 Helsinki, 29, Finland.     

USE OF THE POST-TETANIC COUNT TO MONITOR RECOVERY FROM INTENSE NEUROMUSCULAR BLOCKADE IN CHILDREN

The post-tetanic count was investigated as a method of monitoringintense neuromuscular blockade in children. One of five myoneuralblockers (atracurium, vecuronium, pancuronium, tubocurarineor alcuronium) was given to groups of six children during nitrousoxide-oxygen-halothane anaesthesia. During recovery, the firstpost-tetanic response always preceded the first train-of-fourresponse. The interval between the appearance of the first post-tetanicresponse and the first train-of-four response was typically5–10 min for the intermediate-acting agents vecuroniumand atracurium, and 20–30 min for the long-acting agentspancuronium, alcuronium and tubocurarine. A post-tetanic countof 6 with alcuronium and tubocurarine, or 7 with vecuronium,atracurium and pancuronium indicated that recovery of the firsttrain-of-four response was imminent.