Anaphylaxis due to suxamethonium in a 7-year-old child: a 14-year follow-up with allergy testing

In 1973 a 7-year-old girl had anaphylactic reactions after two general anaesthetics. In-vitro testing with the leucocyte challenge histamine release test showed a strong response to suxamethonium, and other tests indirectly suggested an allergic mechanism. The conclusion was that this was an allergy to suxamethonium. Further blood was sent for testing against a range of neuromuscular blockers, but the patient was 'lost' until she re-appeared 14 years later as an antenatal patient. In-vitro testing was repeated against suxamethonium and all the available neuromuscular blockers after delivery. The radio-allergosorbent test for allergen-specific IgE antibodies was performed on newly collected serum and that which had been stored for 13-14 years. Skin testing was also performed. The results remain positive and suggest a degree of allergy to all the neuromuscular blockers with the possible exception of vecuronium. The radio-allergosorbent test was negative in the patient's baby.     

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.     

Suspected malignant hyperthermia reactions in New Zealand

Early clinical signs, triggering agents, time to onset of reaction, mortality and methods of treatment were identified in 123 suspected malignant hyperthermia reactions. In vitro contracture test results were compared with clinical signs and the Malignant Hyperthermia Clinical Grading Scale. Increased end-tidal carbon dioxide is the earliest sign when not preceded by masseter spasm. Earlier diagnosis reduces the incidence of rigidity and severe metabolic acidosis. The combination of suxamethonium and a potent volatile anaesthetic agent triggers an earlier reaction compared with a volatile agent alone. There has been zero mortality since 1981, essentially due to a combination of advanced monitoring capability, increased anaesthetist awareness of malignant hyperthermia, and dantrolene availability. DNA analysis has identified nine New Zealand families with ryanodine receptor gene mutations. A positive DNA test indicates malignant hyperthermia susceptibility with "causative" mutations but discordance requires that negative DNA tests are confirmed with in vitro contracture test. This test also demonstrated the shortcomings of the Malignant Hyperthermia Clinical Grading Scale.     

Neuromuscular blockade induced by flunarizine alone and in combination with pancuronium, suxamethonium or neomycin: studies in isolated rat phrenic-hemidiaphragm preparations

The in vitro effects of flunarizine on indirectly- and directly-elicited contractions in rat phrenic-hemidiaphragm preparations were studied. The interactions of flunarizine with non-depolarizing and depolarizing neuromuscular blocking drugs (pancuronium and suxamethonium) and with an aminoglycoside antibiotic (neomycin) were also evaluated. Flunarizine induced a slowly developing concentration-dependent reduction of indirectly-elicited diaphragm twitch height, but only slightly reduced directly-elicited contractions. Flunarizine 1 and 5 mumol.l-1 produced a concentration-dependent enhancement of pancuronium-induced neuromuscular blockade, whereas suxamethonium blockade was significantly increased by flunarizine 5 mumols.l.-1 only. Moreover, both flunarizine 1 and 5 mumols.l-1 also increased the neuromuscular blockade induced by neomycin. In conclusion, flunarizine induced neuromuscular blockade and enhanced the effects of several neuromuscular blocking agents to varying degrees in vitro.     

An anaphylactic reaction to succinylcholine. A clinical case

A case of severe anaphylactic reaction provoked by suxamethonium during the induction of general anaesthesia is reported. Diagnosis of reaction and the trigger effect of suxamethonium was identified by intradermal testing. Diagnosis of anaphylactic reaction was confirmed on serial blood estimations of IgE and C3-C4 of complement fractions.     

NEUROMUSCULAR EFFECTS OF HALOTHANE, SUXAMETHONIUM AND TUBOCURARINE IN A MYASTHENIC UNDERGOING THYMECTOMY

The neuromuscular effects of halothane, suxamethonium, and tubocurarinewere observed in a female patient undergoing thymectomy becauseof myasthenia clinically localized to extraocular muscles. Thetwitch response was compared with that obtained in a controlgroup of five non-myasthenic patients. In the control non-myasthenicgroup, halothane 2 per cent increased the twitch response, suxamethonium20 mg produced complete neuromuscular block, whilst tubocurarine3 mg produced partial block which rapidly recovered. On theother hand, in the myasthenic patient, halothane did not affectthe twitch response, suxamethonium only produced partial neuromuscularblock, whilst tubocurarine produced severe block associatedwith marked tetanic fade and post-tetanic facilitation. Thisaltered response to halothane, resistance to depolarizing agents,and sensitivity to antidepolarizing agents were demonstratedin muscles of the body that did not show clinical weakness.     

Leucocyte migration: effects of in vitro exposure to anaesthetic agents: possible potentiation of effects by adrenaline.

The effect on in vitro migration of leucocytes and lymphocytes of various drugs used in anaesthesia have been determined in the concentration range 10(-2) to 10(-6) M. The drugs included, thiopentone, bupivacaine, lignocaine, adrenaline, noradrenaline, hydrocortisone, morphine (with and without preservative), lorazepam, suxamethonium, pancuronium and atropine. Toxicity and effect on random mobility after incubation for 1 and 18 h were also determined. Thiopentone depressed leucocyte function at a concentration of 10(-5) M which is comparable to clinical plasma concentrations. Increasing the duration of exposure of the cells to the drugs significantly lowered the concentrations at which depression of function was observed. At concentrations used during local infiltration in clinical practice, bupivacaine and lignocaine were toxic to both leucocytes and lymphocytes. Adrenaline, whilst having no direct effect on cell function, potentiated the effect of lignocaine. Morphine showed no effect at 10(-4) M, a level 1,000 times greater than the reported toxic plasma levels. However, this level falls within the range reported for drug addicts. No effects were found for the other drugs.     

Screening for mast cell tryptase and serum IgE antibodies in 18 patients with anaphylactic shock during general anaesthesia

BACKGROUND: In the perioperative setting multiple agents can cause anaphylaxis. Often the reactions are dramatic, and due to their lifethreatening potential it is crucial that the responsible agent is identified in order to avoid future adverse reactions. The aim of the present study was to measure the concentration of serum mast cell tryptase (MCT), to investigate the prevalence of serum IgE antibodies against ammonium groups, choline, morphine, suxamethonium, thiopentone and latex and to perform skin prick tests (SPTs) in 18 patients experiencing an anaphylactic reaction during induction of general anaesthesia. METHODS: Serum samples from 18 patients with an anaphylactic reaction during general anaesthesia were analyzed for MCT and specific IgE against ammonium groups, choline, morphine, suxamethonium, thiopentone and latex. Skin prick tests were performed in 11 out of 18 patients. RESULTS: Ten patients had elevated MCT levels and specific IgE against ammonium ion, morphine and (with the exception of patient nos 3, 9 and 10) suxamethonium. Seven of these patients had positive SPTs to suxamethonium. One of the patients tested positive to latex in addition to suxamethonium. Two patients showed elevated MCT, while specific IgE against the drugs tested was not detected. Three patients tested positive to ammonium ion, morphine and suxamethonium, but negative to MCT. Three patients tested negative to both MCT and specific IgE. CONCLUSIONS: Fifteen out of 18 sera tested positive for MCT and/or specific IgE against neuromuscular blocking drugs (NMBDs). Ten of the 18 patients experienced an IgE-mediated anaphylactic reaction to NMBDs during anaesthesia, verified by detection of specific IgE and elevated levels of MCT.     

Comparison of muscle relaxants in clinical use.

A prospective clinical comparison of d-tubocurarine, alcuronium, gallamine and pancuronium was performed in 400 surgical patients. Various parameters usually followed during clinical anaesthesia were recorded from the beginning of, to the recovery from anaesthesia. Endotracheal intubation was performed with or without suxamethonium. Intubation was always possible in 1-3 min when different muscle relaxants were used in the following initial doses: d-tubocurarine 0.4 mg/kg, alcuronium 0.3 mg/kg, gallamine 1.8 mg/kg, and suxamethonium 0.8 mg/kg. However, there was a statistically significant inferiority of the d-tubocurarine and gallamine groups. The use of suxamethonium seemed to shorten the duration of the initial dose of the nondepolarising agents and also to increase especially the dose of gallamine when calculated as mg/kg/h. It should be mentioned that the non-depolarising agents were given soon after suxamethonium without waiting for the return of spontaneous respiration. Pancuronium and alcuronium caused least changes in the cardiovascular parameters. Erythematous skin reactions were seen mostly after the use of d-tubocurarine and suxamethonium. This could depend on histamine liberating potency of these muscle relaxants.     

Spinal block, after dantrolene pretreatment, for resection of a thigh muscle herniation in a young malignant hyperthermia susceptible man

We describe a young man who experienced malignant hyperpyrexia, probably triggered by suxamethonium and/or enflurane during his second operation for an epigastric hernia. His malignant hyperthermia susceptibility was later verified using the caffeine/halothane contracture test in vitro. Subsequently, a tumorous mass, consisting of herniated and hypertrophied muscle grew in his thigh, and was resected under spinal anaesthesia. Whereas dantrolene (2.5 mg/kg i.v.) pretreatment produced impaired swallowing, the subsequent high spinal block, in addition, resulted in laboured breathing. It is stressed that respiratory power should be monitored when patients pretreated with dantrolene are given spinal anaesthesia. The muscular symptoms and test results in the patient's relatives are also discussed.     

A case of rhabdomyolysis associated with suxamethonium

A boy presenting for oesophagoscopy developed myoglobinuria during convalescence from the procedure. A susceptibility to malignant hyperpyerexia was considered in the differential diagnosis but was felt to be unlikely on the basis of in vitro testing of muscle biopsy specimens. A review of relevant papers suggests that rhabdomyolysis of significant degree following suxamethonium administration may be more common than generally appreciated, particularly in children.     

SUXAMETHONIUM-INDUCED MUSCLE CONTRACTURE FOLLOWING TRAUMATIC DENERVATION IN MAN

The effects of the systemic and of the i.v. regional administrationof suxamethonium were investigated in 23 patients with traumaticnerve injury. Following the systemic administration of suxamethonium100 mg, normally innervated muscles showed muscle fasciculationsinitially, followed by muscular relaxation. On the other hand,denervated muscles did not fasciculate and, in 21 patients,manifested suxamethonium-induced contractures. In the othertwo patients no response was observed. In 10 of the patients,the i.v. regional administration of suxamethonium 5 mg was followedby a contracture of the denervated muscle which was maintaineduntil the tourniquet was deflated. No systemic reaction to suxamethonium,other than mild ptosis, followed the release of the tourniquet.     

Fatal anaphylactic reaction to suxamethonium: new screening test suggests possible prevention

A 40-year-old woman suffered cardiovascular collapse, cardiac ischaemia and arrest during induction of anaesthesia. Severe cerebral ischaemic damage was sustained during this episode and the patient died 4 days later. This fatal reaction was shown to be anaphylactic in origin; the causative agent was suxamethonium. High levels of IgE antibodies specific to the quaternary ammonium group (two of which are present in suxamethonium) were detected by the radioallergosorbent test. Results of the leucocyte histamine release test were less clear, partly as a result of steroid treatment. The two most relevant points were the absence of a history of previous anaesthesia, and involvement of the heart as the principal target of the reaction. This unfortunate and extreme case indicates the necessity for allergy testing (screening) before anaesthesia, and the need for organisation and funding of this procedure, if these fatal or near-fatal reactions are to be prevented. It is a timely reminder that action should be taken, since neuromuscular blockers have been confirmed as the most common culprits, and that specific tests for IgE antibodies are now available against haptenic groups generally common to all neuromuscular blockers.     

Malignant hyperthermia

Malignant hyperthermia (MH) is a rare but potentially life-threatening emergency characterized by a hypermetabolic state which leads to pyrexia and muscle rigidity. It is a genetic disorder that displays autosomal dominant inheritance. Defects of the RyR1 and CACNA1S genes cause dysregulated calcium release within skeletal myocytes on exposure to triggering agents, causing tetanic contraction of the myocyte. Triggering agents are the halogenated volatile anaesthetic agents and suxamethonium chloride. Diagnosing MH involves genetic testing and an in-vitro contracture test. This is performed at specialist MH centres.An unexplained rise in end-tidal CO₂ and tachycardia should prompt the anaesthetist to consider an MH crisis. This can occur at any time during an anaesthetic or within the ensuing hours. A previous uneventful general anaesthetic does not rule out a crisis happening on subsequent anaesthetics. Crisis management comprises of stopping the offending triggering agent and provision of a clean volatile-free anaesthetic circuit. Activated charcoal filters are useful for the sequestration of halogenated vapours. Dantrolene is the only available treatment and should be immediately available in every area providing anaesthetic assistance. Active body cooling should be implemented to target core body temperatures below 38.5°C. Supportive measures should be instigated until the reaction has subsided. Guidelines produced by the Association of Anaesthetists of Great Britain and Ireland and the European Malignant Hyperpyrexia Group are available to aid in the management of the MH-susceptible patient and an MH crisis.     

SUXAMETHONIUM CHLORIDE AND MALIGNANT HYPERPYREXIA

Pure suxamethonium chloride does not produce in vitro contractureof skeletal muscle from swine which are susceptible to malignanthyperpyrexia (MH), but does induce MH in vivo. It is suggestedthat suxamethonium chloride induces MH because the fasciculationswhich it causes lead to an increase in the myoplasmic calciumconcentration. ^*Department of Biochemistry, University of Oxford, South ParksRoad, Oxford, OX1 3QU.     

Urogenital inflammation: changes of leucocytes and ROS

The presence of excess leucocytes in the semen has been associated with male infertility. According to the WHO, concentrations of more than 106 leucocytes ml-1 are considered as leucocytospermia, indicating genital tract infections. Up to now, no consensus has been achieved on how leucocytes should be quantified in semen. Using the peroxidase staining and monoclonal antibodies to CD15, CD45 and CD68, we found significant differences between the detection methods. Only 47.4% of the semen samples that were assessed as leucocytospermic by CD45 were identified as such by peroxidase staining. The concentration of peroxidase-positive cells was significantly correlated with polymorphonuclear granulocyte (PMN) elastase (P < 0.0001). However, a negative correlation of peroxidase-positive cells with the sperm concentration was only found in oligozoospermic patients (P < 0.0001). Moreover, the slightly positive correlation with normal sperm morphology seems to be applicable only in cases of oligozoospermia. Significant negative correlation of the number of peroxidase-positive cells were found for both maximal inducible acrosome reaction (P = 0.0219) and the inducibility of acrosome reaction (P = 0.0370), indicating a rather deleterious effect of leucocytes on this important sperm function. Concerning the result in the in vitro fertilization programme, none of the examined parameters (PMN elastase, concentration of round cells and peroxidase-positive cells) showed a correlation with either fertilization or pregnancy. This result seems to be reasonable as severely damaged spermatozoa and leucocytes are eliminated from the ejaculate by different sperm separation methods. Interestingly, a significant negative correlation of the TUNEL assay as a measure of sperm DNA fragmentation was found only with pregnancy (P = 0.006) but not with fertilization. As DNA fragmentation can also be caused by ROS that are generated by leucocytes, this causality should not be neglected.     

Oral dantrolene prevents rise of myoglobin due to suxamethonium

Forty patients were studied in a randomised trial to investigate the effect of pre-operative oral dantrolene on the increase of serum myoglobin and creatinine kinase due to suxamethonium administration. Twenty patients in the treatment group were given 1.5 mg/kg dantrolene orally 4 hours pre-operatively. Blood was drawn immediately pre-induction and 5, 10 and 20 minutes after suxamethonium 1.2 mg/kg administration, following which surgery could commence. Myoglobin was measured by radioimmunoassay. The increase in mean myoglobin values was greatly reduced following suxamethonium in the treatment group (10.6 micrograms/litre at 20 minutes) compared to the control group (54.8 micrograms/litre at 20 minutes), (p less than 0.01). Total fasciculation score was not significantly reduced by the dantrolene pretreatment. No increase in creatinine kinase values occurred in any patient and the changes in mean potassium values in both groups were negligible. The only side effect attributed to dantrolene was pre-operative nausea in two patients. No interference with the action of suxamethonium, or difficulty with reversal was noticed. Oral dantrolene may be almost as effective as pretreatment with non-depolarising neuromuscular blocking drugs in preventing suxamethonium-induced increase in myoglobin with less interaction with other anaesthetic agents.     

IDENTIFICATION OF SUSCEPTIBILITY TO MALIGNANT HYPERPYREXIA IN SWINE

In vitro muscle contracture responses in swine susceptible tomalignant hyperpyrexia (MH) were similar to those found in musclefrom humans susceptible to this anaesthetic complication, confirmingthe suitability of the pig as an animal model for studying MH.The results suggest that there are different degrees of susceptibilityto MH. Whichever drug was used, there was some overlap in thecontracture responses between susceptible animals and controls,suggesting that the most accurate way of identifying susceptibilityto MH is to use a variety of chemical agents, the best of whichseem to be halothane, caffeine, suxamethonium and potassiumchloride. Thymol, which is used as a preservative in commercialpreparations of halothane, potentiates halothane contractures,but it is not known if this is significant clinically. ^*Present address: Department of Anaesthesia, Shiga Medical College,Shiga, Japan.     

SUXAMETHONIUM AND SERUM CHOLINESTERASE Comparative Studies in vitro and in vivo on the Catabolism of Suxamethonium

From in-vitro and in-vivo studies and from earlier publicationsthe following conclusions may be drawn concerning the pharmacologyof suxamethonium. The serum cholinesterase plays a decisiverole in the splitting of suxamethonium. With a purified concentratedenzyme preparation (3000 u) cleavage was proved in vitro. Inthe case of genetic enzyme variants hydrolysis is diminished.Cbolinesterase-free serum is unable to split suxamethonium.Spontaneous hydrolysis may be neglected; it may play some rolein the rare case of anenzymia. In vivo the serum cholinesteraseis most inhibited in the third minute after the administrationof suxamethonium. Spontaneous respiration recurs as soon asthe activity of the serum cholinesterase has returned to itsinitial value. In the case of extremely low cholinesterase activitythe hydrolysis of suxamethonium after a single dose of 50–70mg is prolonged by a few minutes.     

Comparison of the effects of neostigmine and edrophonium on the duration of action of suxamethonium

Rapid sequence induction of anaesthesia necessitating the use of suxamethonium may occasionally be needed soon after antagonism of neuromuscular block with anticholinesterase agents. The onset and duration of action of 1 mg kg^-1 of suxamethonium was recorded in groups of 10 patients each, 5 or 10 min after the administration of edrophonium 1 mg kg^-1 or neostigmine 40 μg kg^-1 given for the antagonism of atracurium-induced neuromuscular block. Plasma cholinesterase activity was measured before, and 5 and 10 min after the administration of the anticholinesterases. A further 10 patients received suxamethonium 1 mg kg^-1 without prior atracurium or anticholinesterase administration to serve as controls. The onset of action of suxamethonium was significantly prolonged when administered 5 min after both anticholinesterases, compared to the control group ( P <0.01). Recovery of suxamethonium block was delayed significantly after neostigmine, compared to both the edrophonium and the control groups ( P <0.05–0.001). Plasma cholinesterase activity was significantly reduced with the use of neostigmine but not with edrophonium ( P <0.001).