Malignant Hyperthermia: A Life-Threatening Condition in Patients Undergoing Surgical Intervention

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Abstract

INTRODUCTION

Malignant hyperthermia (MH) is a rare genetic disorder, which, if failed to be diagnosed and treated promptly, could be a potentially fatal condition. Though Dr RA Gordon coined the term MH based on its clinical features, the entity was first reported by Michael Denborough and Roger Lovell of Melbourne, Australia1). Denborough and Lovell’s publication (1962) described the case of a young man requiring emergency surgery, with a history of many family members dying unexpectedly during or shortly after anesthesia, entitled “Anesthetic Deaths in a Family”2). Subsequently, many cases were found with similar features from Canada and other countries3). Over the recent years, clinical encounters with MH and related scientific knowledge have increased significantly. In India, Punj et al. reported the first case of MH in 20014). The literature reports only a very small number of cases with successful treatment for MH. Since MH is commonly encountered in children and young adults, surgeons and anesthetists need to stay updated with the current progress on the subject. Hence, the need for a review article like ours is justified.

DEFINITION OF MALIGNANT HYPERTHERMIA

MH is a life-threatening, progressive disorder characterized by an unexplained elevation of expired carbon dioxide despite increased minute ventilation, muscle rigidity and rhabdomyolysis, hyperthermia, tachycardia, acidosis, and hyperkalemia5). This manifest as a hypermetabolic response. It can be triggered by many pharmacological agents such as potent inhalation anesthetics (halothane/ isoflurane/ sevoflurane/ desflurane), the depolarizing muscle relaxant (succinylcholine), and extreme physiological conditions such as vigorous exercise and working excessively in a hot and dry environment6). Mutations of RYR1 and CACNA1S genes are associated with MH7).

CLINICAL DESCRIPTION OF MALIGNANT HYPERTHERMIA

The incidence of malignant hyperthermia episodes during anesthesia is estimated to be between 1 in 10,000 and 1 in 2,50,0001). MH is a life-threatening condition that can lead to multiorgan dysfunction, so it should be recognized as early as possible based on the clinical features. MH may occur from the onset of anesthesia to the early postoperative period, but usually not after an hour of discontinuation of volatile agents8). The cardinal features are a sudden rise in end-tidal expired carbon dioxide concentration (EtCO₂) despite increased minute ventilation, tachycardia, and muscle rigidity, especially following succinylcholine administration. The increase in end-tidal carbon dioxide is a sensitive early sign of MH. However, due to a decreasing trend in the use of succinylcholine in recent years, a more gradual rise in EtCO₂ is noted rather than an abrupt rise, and this gradual rise in EtCO₂ can also be masked by increasing minute ventilation9). Despite stopping the use of warming devices, a gradual increase in core temperature at 1-2 °C every five minutes leads to the suspicion of hyperthermia. Severe hyperthermia (core temperature greater than 44 °C) may occur, leading to increased oxygen consumption, CO₂ production, widespread vital organ dysfunction, hypoxia, metabolic acidosis, and disseminated intravascular coagulation (DIC)10). Indeed, when the body temperature exceeds approximately 41 °C, DIC is the usual cause of death. Larach et al. found that increased body temperature was the first to third earliest sign in 63.5 % of MH cases. So, core body temperature monitoring in patients undergoing general anesthesia for periods lasting more than 30 min is mandatory11). Uncontrolled hypermetabolism first leads to respiratory and, in most cases, to metabolic acidosis, secondary to rapid production of CO₂ and large amounts of lactate. If left untreated, it leads to continuous myocyte death and rhabdomyolysis, resulting in life-threatening hyperkalemia and myoglobinuria, leading to acute renal failure. An irreversible stage is set up if this hypermetabolic state is continued, and it is associated with a combination of histotoxic hypoxia due to mitochondrial failure and stagnant hypoxia leading to muscle ischemia, with increasing intra-compartmental pressures. The additional life-threatening events include DIC, congestive heart failure, bowel ischemia, and compartment syndrome5).

PATHOPHYSIOLOGY OF MALIGNANT HYPERTHERMIA

A defective Ca2⁺ channel in the sarcoplasmic reticulum (SR) membrane underlies the MH susceptibility. This channel is termed the Ryanodine Receptor (RyR1). It is strongly associated with many other proteins, such as the dihydropyridine receptor (DHPR) Ca2⁺ channel, situated in the T-tubule region of the sarcolemma that mediates the transfer of voltage change to the RyR1 receptor. In cases susceptible to MH, exposure to inciting agents leads to dysregulation of excitation-contraction coupling and a sustained calcium release into the cytosol12). Initially, this increased intracellular calcium level needs to be sequestered out of the cell, which requires a high amount of ATP, further increasing the metabolic rate and causing an increase in O₂ consumption and enhanced CO₂ and heat production. Cytosolic calcium accumulates as the release of calcium progresses, sequestration capacity is exceeded, myofilaments are activated, and sustained muscle contraction, which produces enormous heat and develops progressive muscle rigidity, is caused5). The initial acid-base disturbance is reflected in the form of respiratory acidosis. When oxygen consumption exceeds supply, lactate levels rise and superimpose a metabolic component of respiratory acidosis. Sustained contractile activity damages sarcolemma integrity, causing the release of potassium ions, creatine kinase, and myoglobin, leading to hyperkalemia and acute kidney injury. Hyperthermia and rhabdomyolysis predispose to DIC, which is a poor prognostic sign in MH13).

RHABDOMYOLYSIS IN MALIGNANT HYPERTHERMIA

Rhabdomyolysis refers to the breakdown of skeletal muscles. It is usually a late feature of MH. Muscle breakdown leads to the following two physiological alterations-

1. Hyperkalemia, which causes cardiac arrhythmias and cardiac arrest in the later stage and

2. Myoglobin excretion via kidneys leads to acute tubular necrosis (ATN) and renal failure.

The occurrence of this complication secondary to muscle breakdown, leading to dyselectrolemia and renal damage, is associated with poor clinical outcomes. Burns et al. stated that MH should be considered in all patients presenting with rhabdomyolysis where the degree of muscle necrosis exceeds the expectation of the accompanying disorder’s severity14).

CLINICAL DIAGNOSIS METHODS OF MALIGNANT HYPERTHERMIA

The three cardinal diagnostic features with respect to MH are as follows15):

1. Unexplained, unexpected increase in EtCO₂

2. Unexplained, unexpected increase in heart rate

3. Unexplained, unexpected increase in temperature

Diagnosis of MH is mainly clinical, but its clinical features are non-specific and variable in terms of order of appearance and time of onset. So, laboratory investigations are essential for confirmation of the diagnosis. The core clinical features of MH are the unexplained sudden rise of EtCO₂ and temperature, muscle rigidity, tachycardia, acidosis, and hyperkalemia. In cases susceptible to MH, there may be an increased creatine kinase (CK) value and a positive in vitro contracture test. To predict the MH susceptibility in patients and the clinical severity of MH events, Larach et al. came up with a comprehensive grading system (Table 1)16). Various disease processes are scored based on the presence of indicators and summed up to obtain a raw score. Except for other indicator categories, all other disease processes are assigned a score equal to the score of the highest indicator present. MH ranking based on the total raw score describes the likelihood of an MH event (a score >50 almost certainly confirms MH). Four indicators in the grading system are used only to determine MH susceptibility in patients.

Table 1.

Clinical grading system of malignant hyperthermia

LABORATORY DIAGNOSTIC METHODS OF MALIGNANT HYPERTHERMIA

The in vitro contracture test (IVCT) is the gold standard for diagnosing MH. This is based on the contracture of muscle fibres in the presence of halothane or caffeine. Two widely used forms of this test are: 1) IVCT, developed by the European Malignant Hyperthermia Group (EMHG), and

2) the Caffeine-halothane contracture test (CHCT) by the North American Malignant Hyperthermia Group (NAMHG)17). Fig. 1. depicts the algorithm used for evaluating individuals with susceptibility to MH.

Fig. 1.

Algorithm for evaluation of individuals with high susceptibility to malignant hyperthermia (MH). (IVCT- Invitro contracture test; MHS_hc- sensitive to halothane and caffeine; MHS_h- sensitive to halothane only; MHS_c- sensitive to caffeine; MHN- non sensitive to halothane and caffeine).

DIFFERENTIAL DIAGNOSIS OF MALIGNANT HYPERTHERMIA

Several conditions can mimic the features of MH, but because of its nonspecific features, it needs to be differentiated (Table 2).

Table 2.

The comprehensive description of cases reports over the last two decades from Indian Subcontinent

1. Insufficient anesthesia/analgesia: Patients with an inadequate depth of anesthesia/analgesia can have tachycardia, hypertension, and tachypnea in spontaneously breathing patients. In contrast with MH, tachypnea due to light anesthesia would usually be associated with reduced end-tidal carbon dioxide (EtCO₂). Involuntary muscle activity, such as gross tremor with increased muscle tone, may also occur with incomplete muscular blockade with muscle relaxants.

2. Hypoventilation or CO₂ rebreathing: Patients with insufficient ventilation have hypercarbia and respiratory acidosis and may have reflex tachycardia and hypertension. Insufficient ventilation can result from inappropriate ventilator settings or equipment problems (e.g., malfunction of unidirectional valves on the anesthesia breathing circuit, kinked endotracheal tube, etc.). Significant inspired CO₂ on the anesthesia gas analyzer does not occur at the onset of an MH episode before the CO₂ absorbent is exhausted and usually indicates an equipment problem.

3. Increased CO₂ absorption during laparoscopy or GI endoscopy: Hypercarbia, despite an increase in minute ventilation, may be due to continuous CO₂ absorption during laparoscopy or, less commonly, GI endoscopy. The presence of subcutaneous emphysema or known insufflation of CO₂ into tissues makes this a likely explanation. Tachycardia and hypertension are also common during laparoscopy.

4. Fever: No matter how high, fever alone is not a helpful indicator of acute MH. This may occur because of an infectious process (correlated with high total leucocyte count preoperatively and positive culture) or iatrogenic overwarming. Postoperative fever is relatively common, and alternate diagnoses should be sought in the absence of other signs and symptoms of MH.

5. Anaphylactic reaction: It is characterized by hypotension, bradycardia, bronchospasm, flushing, coughing, and rash, followed by desaturation, cyanosis, wheezing, and urticaria. Some inciting agents should be present here, which leads to anaphylaxis. There is no hyperthermia and muscle rigidity, and EtCO₂ is usually expected. Contrast dye injection- Injection of ionic contrast agents into the cerebrospinal fluid and ventricles inducing hyperthermia and vigorous muscle activity.

6. Thyroid storm: It is characterized by an elevated level of T3 and T4 in circulation. Clinical features include tachycardia, hypertension, hyperthermia, and diaphoresis. It is not associated with muscle rigidity and masseter spasms. The EtCO₂ level is maintained during anesthesia. There should be a history or features suggestive of hyperthyroidism, and a definitive diagnosis should be made based on thyroid-stimulating hormone (TSH) and free T4 (fT4) levels.

7. Pheochromocytoma: Phaeochromocytomas may present with a classic symptom triad of headache, palpitations, and sweating. Hypertension is present in around 90% of cases, although it is paroxysmal in 35-50%. Other non-specific presentations include anxiety, lethargy, nausea, weight loss, hyperglycemia, and tremor. Abdominal pain may result from bowel ischemia due to excessive vasoconstriction. Visual disturbance may develop from papilledema induced by malignant hypertension. It differs from MH as it has more BP fluctuation and tachycardia and is not associated with muscle spasms and rhabdomyolysis. Arterial blood gas (ABG) is usually standard in this condition.

8. Neurolept malignant syndrome (NMS): It is a life-threatening idiosyncratic reaction to antipsychotic drugs characterized by hyperthermia, altered sensorium, muscle rigidity, acidosis, rhabdomyolysis, and autonomic dysfunction. It has been associated with all neuroleptics, used for psychiatric conditions like schizophrenia, including newer atypical antipsychotics like haloperidol, as well as a variety of other medications that affect central dopaminergic neurotransmission. Treatment of neurolept malignant syndrome is mainly supportive and stopping the offending drug18).

9. Heat stroke: This clinical condition is noticed primarily outside the operation room (OR) in a hot and humid environment. The individual is found to have dry and hot skin all over the body.

Management of acute malignant hyperthermia crisis (Figs. 2, 3)

Fig. 2.

Emergency management of malignant hyperthermia ACT QUICK14).

Fig. 3.

Checklist for the management of malignant hyperthermia.

The first step in the management of an acute MH crisis is the immediate discontinuation of trigger agents, hyperventilation, call for help, and administration of dantrolene sodium. Successful treatment depends on early diagnosis and aggressive management. The onset of a reaction can be within minutes of induction. Previous uneventful anesthesia DOES NOT exclude MH. The following steps should be initiated on a priority basis as soon as a clinician suspects an individual to be a possible case of malignant hyperthermia14):

1. Call for help, as multiple simultaneous actions will be required to manage the chain of reaction optimally.

2. Notify the surgical team about the condition.

3. Stop potent inhalation agents, flush the circuit with maximum oxygen, change soda lime and manually hyperventilate with 100% oxygen at 15 L/min. During this period, anesthesia should be managed with an intravenous agent.

4. If activated charcoal filters are available, insert them both in the expiratory and inspiratory limbs.

5. Increase minute ventilation to maintain EtCO₂ level within normal limits.

6. Prepare and administer dantrolene sodium:

• 2.5 mg/kg IV initial dose.

• Titrate dantrolene sodium to reduce tachycardia and hypercarbia.

• 10 mg/kg is the maximum dose and there is no evidence of improvement beyond this dose.

• For the preparation of dantrolene, extra staff should be allotted as this is time-consuming. Each 20 mg vial of dantrolene needs to be dissolved by vigorous mixing with 60 mL of water for injection.

• Stop administration of dantrolene sodium once EtCO₂ is < 6Kpa, and temperature is < 38.5 °C.

• Calcium channel blockers should not be used along with dantrolene sodium, as both have a myocardial depressant effect.

7. Monitoring: Continue routine anesthetic monitoring SpO₂, EtCO₂, blood pressure (BP), and electrocardiogram (ECG).

8. Begin cooling measures:

• Switch off active warming devices.

• To prevent hyperthermia, use ice packs on the groin, axilla, and neck.

• Nasogastric lavage with iced solution, urinary bladder flushing with cold saline.

• Stop cooling measures once the temperature reaches 38.5°C to avoid hypothermic overshoot.

9. Treat arrhythmias using Amiodarone. Do not use calcium channel blockers. Treat cardiac arrest according to advanced cardiac life support (ACLS) guidelines.

10. Laboratory tests: Send ABG, electrolytes, creatine kinase, blood and urine for myoglobin, renal function test, liver function test, glucose, and coagulation parameters.

11. Hyperkalemia: The European MH Group guideline suggests 50 IU of insulin in 50 ml 50% dextrose as hyperkalemia may be profound.

12. Acidosis: If pH <7.2, start sodium bicarbonate infusion and increase ventilation to correct respiratory acidosis.

13. Continue dantrolene sodium at 1 mg/kg every 4–8 hours for a duration of 24–48 hours.

14. A diuresis of 2 mL/kg/h should be established primarily with intravenous fluid. Dantrolene sodium contains mannitol which will help in maintaining an adequate urine output. If an adequate diuresis is not maintained in the presence of rhabdomyolysis, then consider adding furosemide (0.5–1 mg/kg) for maintaining the desired rate of urine output.

15. Evaluate the patient for mechanical ventilation and additional invasive monitoring.

16. Evaluation and management of disseminated intravascular coagulation (DIC). In MH, this manifests as a consumptive coagulopathy. Pragmatic administration of platelets and clotting factors is indicated but the coagulopathy is likely to continue until hyperthermia is corrected.

17. Shift the patient to an Intensive Care Unit (ICU) for a period of at least 36 hours.

18. Counsel the family members and refer the patient and family to the MH testing center for contracture or DNA testing.

PREVENTIVE MEASURES FOR MALIGNANT HYPERTHERMIA

As we all know, prevention is better than cure. A thorough anesthetic history should be taken during a pre-anesthetic checkup to exclude the possibility that the patient or a family member has experienced an MH episode. If history is present, avoid the inciting agent, counsel them, and send them for susceptibility testing. MH-susceptible patients should be warned about the possibility of heat stroke in a hot and humid environment. Succinylcholine is contraindicated in patients with any form of muscle disorders/ dystrophies (like hypokalemic periodic paralysis, Duchenne, or Becker’s muscular dystrophies)5). Additionally, inhalational agents should be used cautiously in such cases of muscle disorders/ dystrophies. Every patient receiving general anesthesia should have their core temperature monitored. In young patients (age <12 years), succinylcholine should preferentially be avoided for elective procedures, as the possibility of hyperkalemic response secondary to undiagnosed muscular dystrophy cannot be ruled out5).

CONCLUSION

MH is a severe life-threatening condition for susceptible individuals undergoing general anesthesia using volatile agents. With children and young adults commonly affected, thorough, up-to-date knowledge about the management of MH is necessary, especially for anesthetists and surgeons.

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