Dorota Pyra-Łatkiewicz, Agnieszka Chruścicka, Jacek Krysa, Monika Olewińska-Okońska, Krzysztof Przesmycki
Malignant hyperthermia during anaesthesia for strabismus surgery
II Department of Anaesthesiology and Intensive Therapy,
Head: K. Przesmycki, M.D., Ph.D. Department of Anaesthesiology and Intensive Therapy, Children's Hospital,
Head: Z. Winiarczyk, M.D., Ph.D. Chair and I Department of Ophtalmology,
Head: prof. Z. Zagórski Medical Academy of Lublin, Poland
Malignant hyperthermia symptoms: hyperthermia (42.5°C), tachycardia (160 bpm) and muscle rigidity was observed 45 minutes after induction of anaesthesia in the 6-yr-old boy during strabismus surgery. Anaesthesia was induced with thiopental/fentanyl/suxametonium and maintained with N2O/O2, halothane and atracurium. Surgery was stopped, superficial cooling started, halothane and nitrous oxide disconnected and dandrolene sodium (2 x 30 mg) given (30 minutes after beginning of the episode). Immediately after dandrolene sodium all symptoms have eased and another 20 mg was given 10 hours after. The child recovered completely and was transferred to the low-dependence area 72 hrs after the episode.
Malignant hyperthermia (MH) is a life-threatening condition resulting from an abrupt increase in skeletal muscles tone. Suxamethonium and different anaesthetic agents may provoke this phenomenon. The incidence of MH is estimated at 1 per 250 000 cases of general anaesthesia. In patients anaesthetised with halogenated volatile anaesthetics or /and suxamethonium the rate is as high as 1 per 62 000 procedures .
MH is five times more frequent in paediatric patients, than in adults (from 1:10000  to 1:15000  anaesthesias). The typical age of development of MH is between 4 and 14 years . Relatively more frequent development of MH in children undergoing strabismus surgery has been explained by the speculation, that strabismus may be an early sign of undiagnosed congenital myopathy . In children with strabismus, after administration of halothane and suxamethonium, an isolated spasm of the masseter muscles is observed 4 times more frequently, than in other children (2.8% and 0.82%, respectively) . The role of suxamethonium in provoking masseter spasm was emphasised by Schwartz et al. . The authors did not observe a muscular spasm in children in whom pancuronium was used for tracheal intubation in strabismus surgery. Rosenberg and Fletcher  stated that in about 50% (40-60%) of patients in whom MH developed, masseter muscles stiffness was observed at induction of anaesthesia. These observations suggest that children operated on for strabismus are at greater risk of postoperative MH . As compared with the adult population, one can estimate that this risk may be as high as 1 per 3000 anaesthesias (i.e. 20-fold greater).
The authors present the case report of a child in whom symptoms of MH developed during anaesthesia for strabismus surgery.
A 6-year-old boy (body weight: 22 kg) after preoperative examination (ASA goup I) was qualified for bilateral strabismus surgery under general anaesthesia. On the day of surgery he received as premedication midazolam 6 mg p.o., 30 minutes before transfer to the operating theatre. After preoxygenation, atropine 0.3 mg, fentanyl 0.1 mg thiopentone 125 mg and suxamethonium 40 mg were injected intravenously. Tracheal intubation was performed; no masseter spasm was observed. Artificial ventilation was performed manually (20/min) with a Kühn set. An O2/N2O mixture 1:2, at a flow of 6 L/min was used. Anaesthesia was maintained with halothane (1.5-0.5 v%) and atracurium (20 mg). Monitoring included ECG, non-invasive blood pressure and pulsoxymetry. The course of anaesthesia during the first 40 minutes of surgery was uneventful. At the end of strabismus correction on the right side (about 40-45 minutes of anaesthesia), a spasticity of the left arm occurred. Additional doses of atracurium (5 and 4 mg) had no effect; on the contrary, the spasticity increased, including masseter muscles. Hyperaemia of the skin, hyperthermia and tachycardia occurred. As malignant hyperthermia was being suspected of anaesthesia and surgery were immediately interrupted.
Artificial ventilation was continued manually at an increased rate (>30/min), with oxygen flow of 8 L/min, until the transfer of the child to the ITU. Tachycardia (160/min) and hyperthermia (superficial temperature: 42.5°C) were observed. External cooling was instituted. Dantrolene i.v. (20 mg t.i.d.) was started about 30 minutes after MH diagnosis (i.e. 75 min. from the start of anaesthesia). This resulted in the immediate muscle relaxation and heart rate decrease. Before transfer to the ITU, the boy received an additional dose of fentanyl 1 mg and midazolam 5 mg i.v. for sedation.
On admission to the ITU the body temperature was 35°C and bradycardia was observed. Dantrolene was continued at previous dose. The boy was ventilated with a Bird 8400 STi ventilator, SIMV mode (MV 6 L/min; RR 20/min; FI O2 0,25). After 6 hours, the endotracheal tube was removed. At hour 9 from admission an additional dose of 20 mg Dantrolene was administered i.v. because of the rise in body temperature to>37.7°C. The following 2 days in ITU were uneventful, and the boy was discharged to the ophtalmology department.
During the ITU stay, immediately after admission, creatinine phosphokinase (CPK) activity and WBC count were elevated 4430 IU/L (normal range: 22-269) and 16.3 T/L, respectively. Seven hours later, a slight decrease in arterial blood pH (7.33), pCO2 (33.7 mmHg; 4.5 kPa) and negative base excess (-7) persisted. On the 7th day of hospitalisation, CPK activity decreased to 3531 IU/L.
After the first 45 minutes of anaesthesia, to this point uneventful, the first warning sign was the increase of muscle tone of the upper extremity, persisting despite additional doses of atracurium. MH develops most frequently during the induction of anaesthesia, although it may manifest itself in the later period (recovery or postoperative) . In the described case, an additional factor contributing to the late onset of MH, might be the influence of atracurium, administered at the beginning of anaesthesia at a relatively high dose. Hall et al.  stated that non-depolarising muscle relaxants may delay the onset of MH symptoms, both in experimental animals and in humans. Lack of muscle relaxation, after administration of a repeated dose of atracurium may additionally reflect the refractoriness of muscular spasm to non-depolarising relaxants, characteristic of MH .
Independently of the time of MH development, its course may be rapid. In the case presented in this report, the full clinical picture of MH developed within 5 minutes. It consisted of progressive spasm of all skeletal muscles (including masticators) leading to generalised extensor muscle stiffness, and unnatural skin hyperaemia accompanied by hyperthermia and tachycardia. According to Larach et al.  the main clinical features of MH are: skeletal muscles stiffness, tachycardia and fever. Two out of these 3 signs are relevant for the diagnosis of MH . In the described case all 3 clinical signs were observed during anaesthesia. An early finding confirming the diagnosis of MH may be the abrupt rise in the end-tidal CO2 concentration. In this case, however, capnography was not a part of intraoperative monitoring, so the assessment of PECO2 and metabolic rate increase were not possible.
The main factor contributing to the increased metabolic rates (both aerobic and anaerobic) of skeletal muscles in MH is their rapidly increasing tone. Progressive increase of muscle stiffness is observed in 75% of patients with MH . As skeletal muscles constitute about 40-50% of the body mass, the increase in their metabolism influences the overall body homeostasis. The increasing stiffness of skeletal muscles in MH results from the loss of intracellular control of release and uptake of calcium from the sarcoplasmatic reticulum. In normal conditions, calcium released from the sarcoplasmatic reticulum during muscle contraction flows back into it during relaxation. An increase in CO2, lactate and heat production (hyperthermia) is a consequence of muscle rigidity and increased metabolism. It is often observed that the body temperature in few minutes and may exceed 43°C . It must not be forgotten that MH is primary to disturbed muscle function, leading to their abnormally increased metabolism. These changes are not always accompanied by a rise in body temperature .
It is very likely, that the cause of MH is an autosomal genetic error, concerning chromosome 19. This hereditary defect leads to the increased metabolism triggered by inhalation anaesthetic agents and depolarising muscle-relaxants .
During the first stage of MH increase of ionised calcium, CPK activity, myoglobin potassium and sodium concentrations in plasma are observed. In the later stage, when the muscular spasm and oedema develop, the serum concentration of calcium and sodium decrease . In more than 70% of patients the increase in CPK activity is proportional to the degree of the muscle cells damage . At the final stage, MH leads to cellular metabolic insufficiency caused by increased permeability of cellular membranes, leading to oedema (including acute brain oedema). Myoglobinuria, disseminated intravascular coagulation, acute renal failure and cardiac insufficiency may also occur.
Dantrolene (sodium salt) specifically inhibits the release of calcium ions, without interfering with its reuptake. In 1975, Harrison  reported the effectiveness of dantrolene in prevention and treatment of MH in pigs. This was confirmed by Kolb et al. in 1982  in a multicentre study in humans. Dantrolene administrated in the early stage of MH (when the normal blood flow through muscle tissue is preserved) causes an immediate decrease of muscle stiffness and metabolism, as well as normalisation of plasma concentrations of catecholamines and potassium. This is why Dantrolene was called "the miraculous drug" in the treatment of MH, giving hope for diminishing mortality even to 0% .
In Polish medical literature (up to 1982) , only 3 cases of MH during general anaesthesia in patients aged 13, 17 and 41 years were presented [16,17]. Two of these patients died. A fatal case of MH happened in 1973 in a child given general anaesthesia with halothane (unfortunately the case report was not published). It is very likely, that the number of cases of MH which have happened in Poland is greater then reported. Since 1982, in Poland, one case of prophylactic use of dantrolene during anaesthesia, in a patient in whom MH occurred during previous surgery, has been described .
During the first 7 years from the initial report of Kolb et al. , at least 12 cases of MH have resulted in death or permanent brain damage, despite dantrolene administration [15, 19, 20, 21, 22, 23, 24, 25, 26]. In only 2 cases hyperthermia was the leading clinical sign. Apart from muscle rigidity, the most frequent signs were tachycardia and arrhythmia. As capnography and pulsoxymetry were in that time not available during anaesthesia, the diagnosis of MH was delayed. Corticosteroids, lidokaine, calcium channel blockers, fentanyl, benzodiazepines, muscle relaxants and antipyretic drugs were introduced, but later claimed ineffective . In 6 patients early cardiac arrest occurred, and in 10 permanent damage to the central nervous system was found. In majority of cases dantrolene was administered too late (more than 30 minutes from the first symptoms). In 10 cases dantrolene was given in minimal dose (far from the recommended maximal dose of 10 mg/kg of body weight) and treatment was terminated too early. It can be assumed that the cause of treatment failure was the delay in dantrolene administration. According to current knowledge, early introduction of dantrolene to the treatment of MH leads to decrease of mortality from 70% (observed before introduction of dantrolene) to less than 10% .
At present the overall number of cases of surgery for strabismus in our regional ophtalmological wards is difficult to estimate. Since 1992 the number of patients operated on in the Medical Academy of Lublin for strabismus significantly increased to 1447. We estimated that 1500 paediatric patients underwent strabismus surgery in other regional centres. The estimated overall strabismus surgery procedures, which average 3000, may reflect the possibility of the risk of MH in children with strabismus (1:3000).
1. The family history of children qualified for strabismus correction must not be underestimated. It may be the first signal of unrecognised hereditary myopathy, which increases the risk of malignant hyperthermia.
2. As the risk of MH development in children with strabismus may be greater than the risk of general anaesthesia itself, anaesthetic routine must include:
a) continuous monitoring of PECO2
b) availability of dantrolene (it must be administered 20-30 min after the onset of symptoms of MH) in sufficient quantity (36 packs for adults and 12 packs for children)
c) elimination of all potential MH triggering anaesthetic drugs such as suxamethonium and halogenated inhalation agents.
Originally published in Anestezjologia Intensywna Terapia 31; (3), 183-186, 1999.
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