No response to trigger agents in a malignant hyperthermia-susceptible patient

B. A. Claxton*,1, M. H. Cross2 and P. M. Hopkins3

1Department of Anaesthesia, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, 2Department of Anaesthesia, Leeds General Infirmary, Leeds and 3Malignant Hyperthermia Unit, University of Leeds, Leeds LS1 3EX, UK*Corresponding author

Accepted for publication: February 11, 2002


    Abstract
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Malignant hyperthermia susceptibility is an inherited disorder, where a life-threatening condition can result from exposure to a trigger agent or agents. Succinylcholine and volatile anaesthetic agents are well established to be trigger agents in anaesthetic practice. We describe a case of a previously investigated malignant hyperthermia-susceptible patient who did not declare his status and was exposed to both succinylcholine and isoflurane, without any detectable reaction. Possible explanations for the lack of reaction include a subnormal temperature when exposed to isoflurane, and a significant interval between exposure to succinylcholine and isoflurane. Absence of a reaction to trigger agents on this occasion is not thought to indicate an incorrect diagnosis and labelling.

Br J Anaesth 2002; 88: 870–3

Keywords: complications, malignant hyperthermia; anaesthesia, general; complications, adverse reaction


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Malignant hyperthermia (MH) is an inherited myopathic disorder where contact with specific agents can trigger an abnormal calcium release into the cytoplasm causing myofibrillar contraction, accelerated metabolic rate, and increased carbon dioxide and heat production.1 Identifiable trigger agents include succinylcholine and volatile anaesthetic agents.13 The main feature of the reaction gave this condition its name in 1960, where the principal effect was a progressive febrile reaction leading to death.4

Other signs include unexplained tachycardia, rising end-tidal carbon dioxide concentration, and decreasing oxygen saturation. Sustained jaw rigidity after succinylcholine is reported to be an early indicator of MH susceptibility (MHS).5 Preoperative diagnosis of MH is usually impossible unless a previous reaction has occurred, or a family history is evident. Despite subsequent laboratory testing to confirm the diagnosis of MHS, there have been retrospective studies which identified patients who had apparently unremarkable anaesthetics before a reaction during a subsequent anaesthetic, or before the family history became apparent.6 The case reported here differs because the patient, unknown to the medical staff, had been tested and been found to have MHS, but was given trigger agents, and did not develop a reaction.


    Case report
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
A 27-yr-old man was brought to the accident and emergency department of a district general hospital. He had deliberately shot himself in the chest with a crossbow. On arrival he was alert and orientated, with a pulse of 105 beats min–1, and an arterial pressure of 158/80 mm Hg. The bolt was positioned 2 cm below his left nipple, and was noted to be moving in time with his pulse. His arterial oxygen saturation was 95% on oxygen 8 litre min–1. Arterial blood gases on oxygen 10 litre min–1 were PaO2 45.1 kPa, PaCO2 4.2 kPa, and pH 7.36. On questioning he denied any drug intake, and admitted to a past suicide attempt, 2 yr previously, also by a crossbow bolt to the chest, when he required repair of a hole in his left ventricle. He gave no history of drug allergies or problems with past anaesthetics. He denied any family history of anaesthetic concern.

It was decided that transfer to the regional cardiothoracic centre was appropriate, and a left-sided chest drain was inserted before departure. The transferring anaesthetist felt it was safer to electively intubate the patient’s trachea and mechanically ventilate his lungs for transfer, and this was facilitated with a rapid sequence induction using propofol, alfentanil, and succinylcholine. No difficulty with intubation was experienced. Atracurium was used to maintain neuromuscular block, and a propofol infusion was started. Monitoring during transfer included oxygen saturation, invasive arterial pressure measurement, and ECG.

Transfer was uneventful, other than a raised systolic arterial pressure, which varied between 170 and 180 mm Hg, and which was unresponsive to boluses of propofol. The pulse rate remained at approximately 100 beats min–1.

On arrival at the regional cardiothoracic centre 2 h after presentation, the patient was taken directly to the operating theatre. He was given fentanyl 1.5 mg and cefuroxime 1.5 g. The propofol infusion was discontinued and anaesthesia maintained using isoflurane at 1 MAC, measured in the end-tidal gas mixture. He had a median sternotomy, the bolt was removed from the left ventricle, and the resulting hole was sutured. This procedure lasted 75 min. The systolic arterial pressure remained between 90 and 120 mm Hg, and his pulse between 80 and 100 beats min–1. The patient’s oxygen saturation remained at 100%, and the end-tidal carbon dioxide between 3 and 4 kPa. The patient’s temperature was noted intraoperatively to be 35.5°C nasopharyngeal, and 32.3°C on the skin.

The patient’s lungs were ventilated mechanically overnight and his trachea was extubated the following morning after an uneventful night. His postoperative blood results were sodium 140 mmol litre–1, potassium 3.8 mmol litre–1, urea 5.6 mmol litre–1, creatinine 94 µmol litre–1, ALT 14 IU litre–1, bilirubin 23 µmol litre–1, alkaline phosphatase 108 IU litre–1, and calcium 1.81 mmol litre–1. When his old notes arrived, it was discovered that he had been diagnosed previously as susceptible to MH. On questioning, he confirmed that he was tested by muscle biopsy in 1991, and was found to be positive. However, he was unconcerned that he had been given trigger agents in this event, and appeared indifferent to the importance of informing the anaesthetist who had cared for him the previous night.

Further investigation into his family history revealed that his cousin underwent an ENT procedure in 1988. She received thiopental, succinylcholine, and halothane anaesthesia. She developed masseter spasm and then unexplained tachycardia. Managed with dantrolene, she recovered and subsequently tested susceptible to MH. The patient’s father was tested in 1988, and was also found to be susceptible. The patient was tested in November 1991. In all, 20 members of his family were tested, seven of whom were susceptible. The patient did have a past history of a dental procedure under general anaesthesia as a child, with no major complications. His suicide attempt 2 yr previously required a thoracotomy at another hospital. The notes at this hospital clearly labelled him to be MHS and the anaesthetist at that time had avoided MH trigger drugs and the patient was maintained using propofol and remifentanil. The patient was not screened for MHS again after the most recent event.


    Discussion
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
This patient’s lack of response to exposure to known MH trigger agents can be explained by either a misdiagnosis of MHS, or non-triggering in a MHS individual. Testing for MHS is initially carried out in the patient who had a MH reaction (proband), and then their immediate family. Testing is performed according to the European Malignant Hyperthermia Group (EMHG) procedure.7 A muscle biopsy is performed under local anaesthetic and muscle strips are then attached to sensitive strain gauges. Each strip is exposed to various concentrations of halothane and caffeine. A contracture of >=0.2 g at a concentration of <=2 mM caffeine or <=2% halothane is considered pathological. The threshold is the concentration at which an increase in tension of at least 0.2 g is seen.7 A patient can, on the basis of this test, be placed into one of three groups, according to the laboratory diagnosis.

1. MHS. This will be diagnosed if a pathological contracture appears in both the halothane and caffeine tests.

2. Malignant hyperthermia equivocal (MHE). If the pathological contracture occurs in only one of the tests.

3. Malignant hyperthermia negative (MHN). If no pathological contracture occurs.

The diagnosis of MHS from clinical presentation does not in all cases correspond with the laboratory diagnosis. On review of our patient’s actual muscle biopsy, carried out in 1991 according to the European procedure for diagnosis of MH in humans,7 8 there are several points to note. First, on the halothane contracture test, he reached the threshold static contracture of 0.2 g at 1% halothane, and at 2% halothane, 0.7 g of force was reached. This result is clearly abnormal,710 and interestingly this pattern was reproducible in the other family members who tested positive. This reproducible pattern strengthens the diagnosis of MHS, as his pattern of testing has a very similar phenotype to other positive family members, including his cousin who had a clinical reaction.

The static caffeine test reached the required threshold at 3.0 mM, which is not considered to be a strong response, and according to the European procedure would result in a laboratory diagnosis of MHE. Using this procedure of testing, the clinical sensitivity is quoted at 99% and the clinical specificity at 93.6%, when both equivocal and susceptible laboratory results were considered susceptible.7 8 11 12 However, the specificity increases to 98% when MHE results are not included. Could there be a false positive on this patient’s halothane contracture test? Ording and colleagues8 suggest that false positive results are unlikely with halothane contracture of greater than 0.5 g at 2% halothane. Also, the type of situation that leads to suspicion that the test was a false positive, is when an individual has very weak responses to halothane and/or caffeine, whilst other family members have much stronger responses.

On discussion with the regional malignant hyperthermia unit, they believe no repeat testing is necessary, as their current policy, as agreed by the EMHG, is to label any patient whose laboratory diagnosis is equivocal or susceptible, as clinically susceptible.

As there is good evidence from this patient’s family history and muscle biopsy results that a misdiagnosis is highly unlikely, why was there no reaction when he was exposed to two trigger agents? Succinylcholine is quoted as a trigger agent,1 2 10 and is well known to cause masseter spasm in MHS patients. However, it is not fully established whether a single dose of succinylcholine produces the metabolic features of MH, although one reported case did describe a mild reaction to succinylcholine alone.13 A review of 503 published cases of MH in 19933 found that 428 patients ‘received either a volatile anaesthetic, a depolarizing neuromuscular junction blocker, or both’. It is well established that succinylcholine acts to prime the muscle to the abnormal effects of volatile anaesthetic agents.2 Experiments performed on in vitro samples of normal muscle demonstrate that succinylcholine causes an increase in intracellular calcium, and it is postulated that this calcium release is exaggerated in MH muscle.14 The masseter muscle contains a high proportion of type I compared with type II muscle fibres. Halothane and caffeine contracture testing of both types of muscle fibre have found type I to be more sensitive than type II.15 This may in part explain why masseteric spasm can occur in MHS patients.

There is known to be a spectrum of severity of MH reactions, ranging from unexplained pyrexia to multiorgan failure and death.3 In this case, there was a significant delay between the administration of succinylcholine and isoflurane. There may have been an unnoticed pyrexia during transfer, and certainly the hypertension noticed at the time of transfer is suspicious. However, it would be difficult to draw conclusions from this sign as inter-hospital transfer often results in instability of vital signs. It would seem unlikely that any reaction occurred as a result of succinylcholine, as on arrival at the second hospital, the patient’s heart rate and arterial pressure were within the normal ranges.

Isoflurane, although known to be a trigger in MHS patients, may be less potent than the halothane that is used in vitro as a test trigger. Wedel and colleagues16 demonstrated that there could be a significant delay between exposure to isoflurane or desflurane, and onset of a reaction in MHS pigs, compared with halothane. Delays of up to 4 h have been described. However, the significance of this research when applied to our patient is doubtful, as no pyrexia or tachycardia was seen postoperatively on the ICU in the first 24 h. One proposed mechanism for non-triggering in MHS patients, has been when exposure to the volatile agent has been for a short time, and/or at a low concentration.17 However, in this case the procedure lasted 75 min.

Studies conducted on MH susceptible swine,17 have shown that reducing core temperature to 33°C prevented triggering of MH when exposed to succinylcholine and halothane, and cooling to a core temperature of 35°C impairs triggering and reduces the progression of MH. It is interesting to note that at the time of this patient’s surgery, his core temperature was measured at 35.5°C. This is potentially an explanation for his lack of response to trigger agents.

Perhaps the most important factor is that many patients who have an MH reaction have a past history of uneventful anaesthesia. A retrospective analysis of anaesthetics received by patients before they were recognized as MHS was conducted by Halsall and colleagues in 1979.6 This showed that in the 20 probands (patients who subsequently had a MH reaction under anaesthesia), a total of 30 anaesthetics had been administered before a reaction occurred. Of the 38 MHS patients, none of whom had ever developed an MH reaction, a total of 62 general anaesthetics had been administered previously without effect.

There is perhaps no one explanation for the occurrence of uneventful anaesthesia in MHS patients, and this demonstrates that there can be significant intra-patient variation in expression of this genetic disease. The history of patients who eventually develop a MH reaction under general anaesthesia, has demonstrated that it is not uncommon to have had uneventful anaesthesia in the past. There has not as yet been any satisfactory explanation for this occurrence, and although it might be tempting to theorize that there may be some trigger event in the patient that has caused the MHS to become manifest, cases such as these where in vitro but not in vivo reactions have occurred would refute the theory.

This patient is labelled as MHS, and although he may not have reacted on this occasion, this is no guarantee that he will not react in future exposures.


    References
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 Britt BA. Recent advances in malignant hyperthermia. Anesth Analg 1982; 51: 841–50[Medline]

2 Kalow W. Rigidity and malignant hyperthermia associated with anaesthesia. Humangenetik 1970; 9: 237–9[ISI][Medline]

3 Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth Analg 1993; 77: 297–304[Abstract]

4 Denborough MA, Lovell RRH. Anaesthetic deaths in a family. Lancet 1960; ii: 45

5 Christian AS, Ellis FR, Halsall PJ. Is there a relationship between masseteric spasm and malignant hyperpyrexia? Br J Anaesth 1989; 62: 540–4[Abstract]

6 Halsall PJ, Cain PA, Ellis FR. Retrospective analysis of anaesthetics received by patients before susceptibility to malignant hyperpyrexia was recognized. Br J Anaesth 1979; 51: 949–54[Abstract]

7 Islander G, Twetman ER. Comparison between the European and North American protocols for diagnosis of malignant hyperthermia susceptibility in humans. Anesth Analg 1999; 88: 1155–60[Abstract/Free Full Text]

8 Ording H, Brancadoro V, Cozzolino S, et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. Acta Anaesthesiol Scand 1997; 47: 955–66

9 Heiman-Patterson TD, Rosenberg H, Fletcher JE, Tahmoush AJ. Halothane-caffeine contracture testing in neuromuscular disorders. Muscle Nerve 1988; 11: 453–7[ISI][Medline]

10 Aldrete JA. Advances in the diagnosis and treatment of malignant hyperthermia. Acta Anaesthesiol Scand 1981; 25: 477–83[ISI][Medline]

11 Wedel DJ, Nelson TE. Malignant hyperthermia: diagnostic dilemma—false negative contracture responses with halothane and caffeine alone. Anesth Analg 1994; 78: 787–92[ISI][Medline]

12 Allen GC, Larach MG, Kunselman AR, et al. The sensitivity and specificity of the caffeine-halothane contracture test. Anesthesiology 1998; 88: 579–88[ISI][Medline]

13 Laurence AS, Vanner GK, Collins W, Hopkins PM. Serum and urinary myoglobin following an aborted malignant hyperthermia reaction. Anaesthesia 1996; 51: 958–61[ISI][Medline]

14 Ruff RL. Calcium sensitivity of fast- and slow-twitch human muscle fibers. Muscle Nerve 1989; 12: 32–7[ISI][Medline]

15 Adnet PJ, Reyford H, Tavernier BM et al. In vitro human masseter muscle hypersensitivity: a possible explanation for increase in masseter tone. J Appl Physiol 1996; 80: 1547–53[Abstract/Free Full Text]

16 Wedel DJ, Gammel SA, Milde JH, Iaizzo PA. Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine. Anesthesiology 1993; 78: 1138–44[ISI][Medline]

17 Hopkins PM. Malignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth 2000; 85: 118–28[Free Full Text]

18 Iaizzo PA, Kehler CH, Carr RJ, Sessler DI, Belani KG. Prior hypothermia attenuates malignant hyperthermia in susceptible swine. Anesth Analg 1996; 82: 803–9[Abstract]





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