Malignant Hyperthermia
KEYWORDS Anaesthetic complications, Hyperthermia, Hyperpyrexia, Anaesthesia, Calcium, Dantrolene
Malignant hyperthermia (MH) is a rare genetic condition which may manifest for the first time during anaesthesia associated with a routine surgical procedure. Characterised initially by muscle rigidity, increased body temperature and metabolic acidosis, the syndrome may prove fatal unless prompt, effective treatment is administered. The sudden development of MH constitutes a medical emergency; hence it is essential that theatre practitioners are knowledgeable about the presenting symptoms and management of the condition.
Introduction
MH was first described in the literature in 1962 following an incident in which a patient nearly died as a result of hyperpyrexia, while receiving a general anaesthetic. Enquiries were made by the individual’s relatives who had been considerably affected by similar deaths of other family members. Investigations revealed that, of 37 members of the family who had received a general anaesthetic, ten had died as a result.
Within a short period of time similar incidents and histories were being reported in other parts of the world and MH was soon diagnosed as an inherited autosomal dominant disorder of skeletal muscle. This potentially fatal condition is triggered by a variety of anaesthetic agents, and manifests as muscle rigidity followed by a hypermetabolic state associated with a subsequent rapid increase in body temperature of more than 2C an hour in some cases (Aitkenhead & Smith 1991, Carrie et al 1996, Wikipedia 2004a).
The condition must have existed prior to this event, though it had not been recognised as a clinical entity in itself but as an obscure complication of anaesthesia. The sudden and dramatic appearance of similar cases was no doubt due to the advent of two very powerful triggers of the condition, halothane and suxamethonium, which were being introduced into anaesthetic practice at the time, and proving extremely popular (Park & Gempeler 1993, Carrie et al 1996).
The incidence of MH is estimated at between 1:50,000 and 1:100,000 among adult patients receiving a general anaesthetic. It occurs worldwide, affects all racial groups equally and is predominantly seen in children, young males and individuals with a musculoskeletal disorder. Prompt and appropriate treatment has reduced mortality rates from 70% in the 1960s to 5% today (Aitkenhead & Smith 1996, Nagelhout & Zaglaniczny 1997, Neligan 1999, Harmer et al 2004, Wikipedia 2004a).
Ice cubes can be used to cool the patient down
Aetiology
The genetic mutation responsible for MH is located on chromosome nineteen. Although the exact defect at cellular level remains unclear, affected individuals receiving an agent known to trigger MH will experience enhanced release of calcium from the sarcoplasmic reticulum of skeletal muscle, followed by the development of cell membrane permeability. Calcium is utilised within cells to initiate muscle contraction. The abnormality of muscle fibre membranes and problems with the accumulation of calcium associated with the triggering of MH can result in a 500-fold increase of intracellular calcium. As a consequence, sustained muscle contraction occurs which depletes reserves of high energy phosphate within the muscle (Aitkenhead & Smith 1996, Carrie et al 1996, Neligan 1999, Pinnocketal2003).
Adenosine triphosphate (ATP) is referred to as the ‘energy currency’ of the cell and, as muscle tissue contracts, ATP is required for operation of the calcium pump and to power cross bridge activity. Very little ATP can be stored within muscles, only 4-6 seconds worth, and once contractions commence stores are rapidly exhausted.
When there are sudden increased demands for ATP then aerobic breakdown of glucose within the blood stream and glycogen within muscle tissue occurs, releasing carbon dioxide as a waste product. If, however, the delivery of oxygen to the tissues fails to match the requirements for aerobic respiration within muscle tissue, then anaerobic pathways are utilised. While ATP is still produced quickly this less efficient process produces lactic acid rather than carbon dioxide (Marieb 1995).
When MH is triggered, the body’s nutritional requirements are increased. This initiates a rise in metabolic rate with additional body heat produced as a by-product of metabolism. Hence a grave situation can be seen developing (Aitkenhead & Smith 1996, Marieb 1996) in which:
* excess calcium within muscle cells generates constant myofibrillar contraction
* high energy phosphate reserves within the muscle become depleted
* the body’s metabolic rate is increased along with a rapid rise in body heat
* carbon dioxide production and oxygen consumption are increased
* metabolic acidosis ensues.
Unless this situation is reversed, potassium leaking from cell membranes into extracellular fluid causes hyperkalaemia and cell walls become so unstable they eventually rupture. Hence the hyper- rigidity (rhabdomyolysis) of muscle tissue leads rapidly to its destruction and, secondary to this, cell debris may damage the kidneys, resulting in renal failure (Aitkenhead & Smith 1991, Wikipedia 2004b). Severe untreated cases will result in death of the patient (Carrie et al 1996).
Clinical features of MH
Masseter muscle spasm following the use of suxamethonium at intubation may be an early indication of the development of MH, though less than 10% of patients who present in this way will progress to the full MH syndrome (Aitkenhead & Smith 1996). However, Tinker et al (1994) highlight one devastating case in which triggering of the condition did not occur until at least an hour after the patient had entered the recovery room.
The use of nondepolarising muscle relaxants and barbiturates may delay the onset of the condition for up to 24 hours postoperatively. Therefore practitioners should be aware of the symptoms of MH and be alert for development of the syndrome at any time during the perioperative period.
Unexplained and progressive tachycardia is a consistent and early indicator of the condition, while patients who are breathing spontaneously may present with tachypnoea and an increase in end- tidal carbon dioxide concentration (Aitkenhead & Smith 1996, Kirby et al 2002, Hall & Chantigian2003).
A rise in body temperature during anaesthesia should always be investigated, since under normal circumstances heat loss can be expected during anaesthesia and surgical procedures (McNeil 1998a). With MH the temperature can rise by more than 2C an hour and, while this is not always the case, body temperature may exceed 40C in some instances (Aitkenhead & Smith 1996).
Increased muscle tone and muscle rigidity is a common feature of MH (Carrie et al 1996). Other clinical features of MH may vary considerably in their severity and can appear at various stages during the anaesthetic or the early postoperative period (Aitkenhead & Smith 1991, Aitkenhead & Smith 1996, Neligan 1999). These will include:
* tachycardia
* hypoxaemia
* cyanosis
* sweating
* hyperkalaemia
* hypocalcaemia
* arrhythmias
* respiratory and metabolic acidosis
* elevated creatine kiriase
* myoglobinuria
* oliguria
* acute renal and cardiac failure.
Predisposing conditions
MH is a rare condition and although young athletic males are considered to be most at risk of the development of this syndrome, there would also appear to be an uncertain clinical relationship between MH and other myopathies and musculoskeletal disorders (Aitkenhead & Smith 1996). Kumar (1990) particularly highlights the susceptibility of individuals with congenital ptosis, osteogenesis imperfecta, kyphoscoliosis, inguinal hernia and cleft palate to development of MH.
Triggers for MH
MH would appear to be triggered by all volatile anaesthetics, most particularly halothane. A study undertaken by Wedel and Gammel et al in 1993 confirmed that in swine susceptible to MH, exposure to halothane would appear to lead to development of the condition more rapidly than other inhalational anaesthetics (Tinker et all 994).
Suxamethonium is also recognised as a most powerful trigger of MH, and atropine, diazepam, lignocaine, pancuronium, tricyclic antidepressants, phenothiazines, ecstasy, vigorous exercise, heatstroke and even stress have been implicated in development of the condition (Kumar 1990, Aitkenhead & Smith 1996, Carrie et al 1996, Neligan 1999, Kirby et al 2002, Pinnock et al 2003).
Management of patients with MH
Treatment of patients with MH will involve reversal of the condition with dantrolene and commencement of general resuscitative measures dependent upon the nature and severity of the symptoms.
Administration of dantrolene, a skeletal muscle relaxant, brings about muscle weakness when a sufficient dose is delivered. During an episode of MH, dantrolene reverses the calcium accumulation within skeletal muscle sarcoplasm by inhibiting the release of calcium from the sarcoplasmic reticulum without altering the reuptake mechanism.
Initially, dantrolene lmg/kg is administered intravenously and this may be followed by l-2.5mg/kg every ten minutes until the condition is under control. The dosage of dantrolene must not exceed a maximum dose of 10mg/kg.
Dantrolene is stored in powder form and needs to be reconstituted with sterile water. Since it takes some time to dissolve completely, it is best if one person is allocated the task of dantrolene preparation. \Initial administration of dantrolene will be intravenous, however this may be substituted later by oral therapy since dantrolene is recommended for 48 hours after development of the syndrome to prevent relapse of the condition (Aitkenhead & Smith 1996, Neligan 1999, Croft & Upton 2001, Kirby et al 2002).
Young athletic males are most at risk of developing MH
Other treatments for patients with MH (Kumar 1990, Aitkenhead & Smith 1991, Aitkenhead & Smith 1996, Croft & Upton 2001, Wikipedia 2004b, Pinnock et al 2003) will involve the following:
* Assistance should be sought from other members of the theatre team.
* All trigger agents, for example, suxamethonium, volatile gases, should be withdrawn.
* A new breathing circuit should be employed and the lungs hyperventilated with 100% oxygen. If being used, the soda lime should be changed. If a tracheal tube is not in place then tracheal intubation should be undertaken at the earliest opportunity.
* Surgery should be abandoned as quickly as possible.
* Unconsciousness can be achieved or maintained by the administration of a sedative-hypnotic agent.
* Core temperature should be monitored every five minutes along with blood pressure and pulse.
* Intravenous fluids should be given in order to maintain urinary output. Urine should be observed carefully since the production of a dark coloured urine may indicate renal failure.
* Ensure metabolic acidosis is corrected.
* Insulin and glucose may be utilised to correct hyperkalaemia.
* Monitor central venous pressure.
Heat can be lost from the body by conduction, radiation, evaporation and convection (McNeil 1998b). This may be facilitated by both surface and core cooling. Following the removal of all clothing, surface cooling should be initiated using tepid sponging, ice cubes or ice packs, and cold saline bags to the groin, axilla and neck. This will cause considerable amounts of heat to be lost via the aforementioned routes (Edwards 2002).
Thought should be given to lowering the temperature of the operating theatre and additional heat loss by conduction can be achieved by the irrigation of open body cavities with cold or iced fluids. Core cooling can also include rectal, nasogastric and peritoneal lavage and bladder irrigation.
Confusingly, the rapid onset of a rise in temperature may be delayed in MH; at the same time pyrexia minus other symptoms suggestive of the syndrome is insufficient evidence to confirm or imply the condition. Sudden pyrexia intraoperatively may also be the result of a thyroid crisis, metastatic carcinoid, neurologic injury, pheochromocytoma, drug overdose, drug or transfusion reaction (Nagelhout & Zaglaniczny 1997).
However, the maximum temperature attained by the patient during an MH episode will have a direct correlation with the mortality rate (Kirby et al 2002). Generally patients with a hyperpyrexia of 41C will experience convulsions and, at high temperatures, proteins within the body will begin to denature or degrade; brain damage may therefore ensue with 43C appearing to be the upper limit for life (Marieb 1995). Circulating theatre staff should therefore make every effort to reduce body temperature as quickly as possible.
Repeated blood samples should monitor acidbase status, coagulation, serum electrolyte concentrations and arterial blood gas tensions. Disseminated intravascular coagulation is a complication of MH, hence the importance of clotting screening (Aitkenhead & Smith 1996).
Since careful monitoring will now be required, the patient should be transferred to a high dependency or intensive care unit.
Patients requjrmg further surgery
Anaesthesia in the MH-susceptible patient necessitates careful preoperative planning. Procedures should be undertaken on an inpatient basis only, with provision made for extended postoperative monitoring should this be required.
Anticholinergic premedication should be avoided since this interferes with thermoregulation. Wherever possible regional anaesthesia should be undertaken in preference to general anaesthesia. It is also worth noting that MH is known to have developed in patients undergoing spinal nerve blocks. Regarding the use of local anaesthetic agents, bupivicaine is a safer option than lignocaine.
If general anaesthesia is required, total intravenous anaesthesia using propofol and oxygen is recommended. Propofol, etomidate, barbiturates, non-depolarising muscle relaxants, opioids and benzodiazepines are all known to be safe for use in MH-susceptible patients.
The monitoring of end-tidal carbon dioxide concentration, oxygen saturation levels, core temperature, ECG and arterial pressure is advisable. It is no longer thought necessary to flush the anaesthetic machine to be used in the procedure overnight with 100% oxygen. Flushing with highflow oxygen for a period of time, changing the soda lime if used, and attaching a new breathing circuit to the machine prior to commencement of the operation should be sufficient (Kirby et al 2002). Dantrolene and emergency resuscitation equipment should be present within the anaesthetic room (Aitkenhead & Smith 1991, Aitkenhead & Smith 1996, Neligan 1999).
Screening patients and relatives _
Following an episode of hyperpyrexia associated with an anaesthetic, both the patient and his or her family will require screening for MH. A quadriceps muscle biopsy will determine presence of the condition following in vitro exposure of the specimen to halothane and caffeine.
Referral to the Leeds MH Investigation Unit will be necessary since these investigations are highly specialised. Recognition that certain family members may also be susceptible to MH will allow the development of a high-risk patient management plan in the event that these individuals need surgery themselves. It is worth noting, however, that MH-susceptible patients can undergo anaesthesia with agents known to trigger the disease but not develop MH each time (Aitkenhead & Smith 1991, Morton & Peutrell 2003, Harmer et al 2004).
Conclusions
All theatre practitioners are aware of the precise location of the dantrolene emergency kit within their department in the event of MH developing in a patient. However, as this is a rare condition, many will admit to having limited knowledge about the condition itself. As well as being unexpected, the development of MH will often be sudden and dramatic.
As far as control of this condition is concerned, time is of the essence. Hence it is essential that all theatre practitioners are not only aware of the early presenting features of this syndrome, but also have some suspicion if they develop, until other possible causes are excluded. Hopefully this article will have been useful in outlining the early clinical signs of MH, along with providing a brief overview of the aetiology of the condition and guidelines for effective patient management.
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It occurs worldwide and affects all racial groups
As well as being unexpected, the development of MH will often be sudden and dramatic
REFERENCES
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Wedel DJ, Gammel SA, Milde JH, laizzo PA1993 Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine Anesthesiology 78(6)1138-1144
Wikipedia 2004a Wikipedia, the free encyclopedia Available from: http://en.wikipedia.org/wiki/malignantjiyperthermia
Wikipedia 2004b Wikipedia, the free encyclopedia Available from: http://en.wikipedia.org/wiki/hyperpyrexia
About the author
Beverley McNeil MSc, BSc(Hons), RGN
Lecturer in Operating Theatre Practice/Adult Nursing Studies, Canterbury Christ Church University
Copyright National Association of Theatre Nursing Sep 2005