Malignant Hyperthermia(MH)

Malignant Hyperthermia is a rare, life-threatening, inherited pharmacogenetic disorder of skeletal muscle. It is characterized by a hypermetabolic crisis triggered by exposure to certain volatile anesthetic gases (e.g., sevoflurane, desflurane, isoflurane) and the depolarizing muscle relaxant succinylcholine. In susceptible individuals, these agents induce an uncontrolled release of calcium from the sarcoplasmic reticulum of muscle cells, leading to a cascade of physiological derangements that, if not promptly recognized and treated, results in multi-organ failure and death.

Pathophysiology

The core of MH pathophysiology lies in a genetic mutation, most commonly in the RYR1 gene (Ryanodine Receptor 1), located on chromosome 19. This gene codes for the ryanodine receptor, a calcium channel on the sarcoplasmic reticulum (SR) in skeletal muscle.

1. Normal Muscle Contraction: Normally, a nerve impulse triggers a small calcium influx, which signals the RYR1 channel to open, releasing a large burst of stored calcium from the SR into the muscle cell cytoplasm. This calcium binds to troponin, leading to muscle contraction. The calcium is then rapidly pumped back into the SR by the SERCA (Sarco/Endoplasmic Reticulum Ca²⁺-ATPase) pump, using ATP, causing the muscle to relax.

2. Abnormal Response in MH: In an MH-susceptible (MHS) individual, the RYR1 channel is abnormal and hypersensitive.

   • Trigger: Exposure to a triggering agent (volatile anesthetic or succinylcholine) causes the RYR1 channel to remain open for an abnormally long time or to open uncontrollably.
   • Uncontrolled Calcium Release: This leads to a massive and sustained release of calcium into the muscle cell cytoplasm.
   • Hypermetabolic Cascade: The sustained high intracellular calcium concentration drives several pathological processes:
     • Sustained Muscle Contraction: Leads to muscle rigidity and immense ATP consumption.
     • Hypermetabolism: The SERCA pump works furiously to clear the calcium, consuming enormous amounts of ATP. This massive ATP demand drives a hypermetabolic state, producing excessive heat (hyperthermia) and carbon dioxide (hypercapnia).
     • Cellular Breakdown (Rhabdomyolysis): The energy depletion and sustained contraction cause muscle cell membranes to break down, releasing intracellular contents like potassium, myoglobin, and creatine kinase (CK) into the bloodstream.
     • Acidosis: The massive production of CO₂ and lactic acid from anaerobic metabolism leads to severe combined respiratory and metabolic acidosis.
     • Systemic Effects: Hyperkalemia can cause fatal cardiac arrhythmias. Myoglobin can precipitate in the renal tubules, causing acute kidney injury. The hypermetabolic state can lead to disseminated intravascular coagulation (DIC).

Clinical Features

The presentation of an MH crisis is highly variable. It can occur within minutes of exposure to a trigger or be delayed for several hours. The earliest and most sensitive sign is often an unexplained, rapid rise in end-tidal carbon dioxide (EtCO₂).

The signs can be categorized into early and late manifestations.

Detailed Management

Management of an MH crisis is a race against time and requires a coordinated, protocol-driven response. The MHAUS (Malignant Hyperthermia Association of the United States) protocol is the internationally recognized standard.

Step 1: Immediate Actions (The First 5 Minutes)

1. Call for Help: Announce an "MH crisis" to mobilize the entire team.
2. Stop Triggers: Immediately discontinue all volatile anesthetic agents. Remove the vaporizer from the anesthesia machine.
3. Hyperventilate: Increase fresh gas flow to 10 L/min and hyperventilate the patient with 100% oxygen to help blow off excess CO₂.
4. Change Circuit: Replace the breathing circuit and CO₂ absorber on the anesthesia machine.
5. Administer Dantrolene: This is the specific antidote.
   • Initial Dose: 2.5 mg/kg IV, administered rapidly.
   • Preparation: Dantrolene sodium is poorly soluble. It must be mixed with sterile water (not saline) and vigorously shaken until fully dissolved. This process is time-consuming, so multiple people should prepare vials simultaneously.
   • Repeat Doses: Continue giving 2.5 mg/kg doses until the signs of MH subside (e.g., heart rate normalizes, EtCO₂ decreases, muscle rigidity resolves). The total dose may exceed 10 mg/kg or even 20-30 mg/kg in severe cases.

Step 2: Supportive and Symptomatic Care

1. Treat Hyperthermia (Cooling Measures): Initiate aggressive cooling immediately, concurrently with dantrolene administration.

   • Surface Cooling: Apply ice packs to the groin, axillae, neck, and head. Use a cooling blanket.
   • Core Cooling: Administer cold (4°C) IV fluids (e.g., normal saline or lactated Ringer's). Perform lavage of the stomach, bladder, and if necessary, the thoracic or peritoneal cavities with cold saline.
   • Stop Cooling: Once the core temperature reaches 38°C (100.4°F), active cooling should be stopped to prevent rebound hypothermia.

2. Manage Acidosis: Hyperventilation with 100% O₂ is the first step. If severe metabolic acidosis (pH < 7.2) persists after adequate ventilation and circulation are restored, treat with sodium bicarbonate.

3. Manage Hyperkalemia: This is a critical, life-threatening step.

   • Treat immediately with standard protocols: calcium chloride/gluconate to stabilize the cardiac membrane, insulin with glucose, sodium bicarbonate, and albuterol to drive potassium intracellularly.
   • CRITICAL CONTRAINDICATION: Do not use calcium channel blockers (e.g., verapamil, diltiazem) in MH. When used with dantrolene, they can produce profound, life-threatening hyperkalemia and myocardial depression.

4. Maintain Circulation: Treat hypotension with aggressive IV fluid resuscitation (to treat dehydration from capillary leak and promote diuresis) and vasopressors (e.g., phenylephrine, norepinephrine) as needed.

5. Induce Diuresis: Once the patient is hemodynamically stable, administer mannitol (0.5-1 g/kg) or furosemide to maintain a urine output of > 1-2 mL/kg/h. This helps flush myoglobin and prevent acute kidney injury.

Step 3: Monitoring and Post-Crisis Care

1. Continuous Monitoring: ECG, core temperature (esophageal or bladder), arterial blood pressure, urine output, and end-tidal CO₂.
2. Laboratory Tests: Frequent arterial blood gases (ABGs), serum electrolytes (especially K⁺, Ca²⁺), creatine kinase (CK), and coagulation profile.
3. ICU Transfer: All patients who have experienced an MH crisis must be transferred to an Intensive Care Unit for a minimum of 24-48 hours of monitoring.
4. Monitor for Recrudescence: MH signs can recur ("rebound MH") for up to 24-36 hours. Continue dantrolene infusion (e.g., 1 mg/kg/hr) or oral dantrolene for 24-48 hours, and continue close monitoring.
5. Patient and Family Counseling: The patient must be informed of their diagnosis. They should be referred to an MH testing center for definitive diagnosis and genetic counseling. All immediate family members (parents, siblings, children) should be tested for MH susceptibility. The patient should wear a medical alert bracelet.

Other Relevant Findings

• Diagnostics:
  • In Vitro Contracture Test (IVCT): The gold standard for diagnosing MH susceptibility. A fresh muscle biopsy (usually from the thigh) is exposed to caffeine and halothane. An MH-susceptible muscle will contract abnormally.
  • Genetic Testing: Can identify the RYR1 mutation or other less common mutations. However, a negative genetic test does not rule out MH, as not all causative genes have been identified.
• Differential Diagnosis: Other conditions can mimic MH, including sepsis, thyroid storm, pheochromocytoma, and neuroleptic malignant syndrome (NMS). The key differentiator is the direct link to triggering anesthetic agents and the rapid response to dantrolene.
• Prevention: The cornerstone of prevention is a thorough pre-anesthetic history. Any patient with a personal or family history of MH-related problems or an unexplained adverse event during anesthesia should be considered MH-susceptible. These individuals must have a "trigger-free" anesthetic using total IV anesthesia (TIVA) and non-depolarizing muscle relaxants. An unopened MH cart with