“Understanding Malignant Hyperthermia: Pathways, Prevention, and Protocols”

Nabil Ebraheim MD. Bruce Heck MD.

Introduction

Malignant hyperthermia (MH) is a severe genetic disorder that triggers a hypermetabolic response to certain anesthetic gases like halothane, isoflurane, and succinylcholine. Notorious for its rapid onset during surgery, MH can result in catastrophic physiological disturbances, including dramatic increases in body temperature and muscle rigidity. This article aims to deliver a detailed overview of MH, emphasizing its pathophysiology, incidence, clinical presentation, and contemporary management strategies.

Pathophysiology and Triggering Factors

MH is primarily linked to mutations in the RYR1 gene, which encodes the ryanodine receptor. These receptors play a crucial role in calcium regulation within muscle cells. In individuals with MH susceptibility, exposure to triggering anesthetics or extreme physical stress can cause an abnormal release of calcium from the sarcoplasmic reticulum, leading to excessive muscle contraction, heat production, and a rapid increase in metabolic rate. Malignant hyperthermia is an autosomal dominant condition affecting 50% of offspring. This disorder can be lethal. The patient will get succinylcholine, halothane, or other inhalation agents to initiate malignant hyperthermia. Anesthetic agents (such as succinylcholine and halothane) impair the function of the sarcoplasmic reticulum and calcium hemostasis.

Incidence and Risk Factors

The incidence of malignant hyperthermia (MH) during anesthesia is relatively low, estimated between 1 in 10,000 and 1 in 250,000 anesthetic procedures. However, children and individuals with specific muscle disorders are at higher risk. MH susceptibility is notably increased in conditions such as Central Core Disease, Multiminicore Disease, King-Denborough Syndrome, and in cases with clinical presentations similar to Neuroleptic Malignant Syndrome. Additionally, exertional heat stroke and rhabdomyolysis are associated with heightened MH risk. Moreover, MH is linked to Duchenne Muscular Dystrophy (DMD) and Arthrogryposis, all of which can predispose individuals to this severe reaction during exposure to certain anesthetic agents. Children are considered to be at higher risk compared to adults. The presentation in children can be particularly challenging to manage due to the rapid progression of symptoms and the severity of the reaction. Children under 15 years of age account for over half of all reported cases of MH.

Clinical Presentation and Diagnosis

Intraoperative Clinical Presentation

Malignant hyperthermia (MH) typically manifests suddenly during anesthesia and is characterized by specific symptoms that include:

• The rapid rise in end-tidal CO2: This early indicator occurs as an unexplained increase in carbon dioxide levels in the patient’s exhaled air, closely monitored during anesthesia.
• Unexpected tachycardia: An unusually fast heart rate that develops without other obvious causes.
• Severe muscle rigidity, notably in the jaw and upper chest, is distinct from normal responses to surgery and anesthesia. Because there is a problem in the ryanodine receptor, there will be uncontrolled release of calcium with sustained muscle contraction, rigidity, spasms, muscle damage, myoglobinuria, rhabdomyolysis, and acute renal failure. Because of all the hypermetabolic activity, patients will get the classic hyperthermia; that’s why they call it malignant hyperthermia (classic findings).
• Hyperthermia: Elevated body temperature; although this is a later sign, it can escalate quickly if the MH is not managed promptly.
• Metabolic acidosis and hyperkalemia occur, which may give the patient dysrhythmia or a marked CO2 production. If CO2 production increases, there will be increased end-tidal CO2 (ETCO2), which can’t be explained, but it is the earliest sign and probably the most specific and sensitive finding. A rise in the end-tidal CO2 concentration is perhaps the earliest indication that the patient may have malignant hyperthermia.

These symptoms are critical for the immediate recognition and management of an MH episode, as they provide direct, observable evidence of the condition unfolding during surgery.

Preoperative Considerations: Patient and Family History

The preoperative assessment for MH includes evaluating the patient’s and their family’s medical history for any signs or previous episodes that suggest susceptibility to MH:

• Previous MH episodes are either personally experienced by the patient or family members during previous surgeries.
• Postoperative muscle symptoms: Unexplained muscle pain or stiffness following anesthesia might indicate subclinical MH episodes.
• Genetic predisposition: A history of MH in family members suggests a genetic risk for the condition.

Role of History in Diagnosis

This historical data is crucial as it helps preoperatively identify patients at risk of MH. Knowing the patient’s and family’s medical history allows healthcare providers to plan adequately for potential MH crises, ensuring that all necessary precautions and emergency interventions are ready if needed. It informs the decision to perform specific diagnostic tests, such as the Caffeine-Halothane Contracture Test (CHCT), and to consider genetic testing for mutations associated with MH.

Diagnostic Tests for MH

• Caffeine-Halothane Contracture Test (CHCT): This test, usually conducted preoperatively for at-risk individuals, involves exposing a small sample of muscle tissue to caffeine and halothane to observe contraction responses indicative of abnormal calcium handling.
• Genetic testing: Used to detect mutations in the RYR1 gene and other genes linked to MH, offering valuable insights into the genetic basis of susceptibility.

These approaches — observational data from the clinical presentation during anesthesia and comprehensive historical assessment — form the basis for diagnosing and managing malignant hyperthermia, ensuring patient safety during and after surgery.

How does this condition of malignant hyperthermia occur? What is going on? What is the physiology of malignant hyperthermia?

For diagnosis of malignant hyperthermia, we need to know three things: sarcolemma, which is in the membrane of the cell, T-tubule which is like a divot in the cell or a cliff; and the sarcoplasmic reticulum, which is storage for calcium. The sarcoplasmic reticulum is a container for calcium when the muscle is relaxed. Larger protein is embedded into the wall that serves as a calcium release channel. After the muscle contracts, the calcium is taken up by the sarcoplasmic reticulum (storage site).

When there is this process of dysregulation because the ryanodine receptor is defective, then ryanodine triggers calcium release to the inside of the cell in large quantities than normal. The intracellular concentration of calcium increases substantially and will cause a sustained contracture of these muscles, which is how you get malignant hyperthermia.

Management and Treatment

Immediate management of MH involves the cessation of triggering agents and administration of dantrolene, a muscle relaxant that mitigates calcium release. Dantrolene is used to help treat malignant hyperthermia. Dantrolene is a lifesaving drug that stops calcium from being released from the sarcoplasmic reticulum into the cell. Dantrolene blocks the calcium, decreases the intracellular calcium, and stabilizes the sarcoplasmic reticulum.

Supportive measures include cooling the patient, administering fluids and electrolytes, and monitoring for complications like kidney failure and cardiac disturbances. Preventive strategies are crucial for known susceptible individuals and involve using non-triggering anesthetic techniques and thorough family and medical history evaluations.

Prognosis and Prevention

With rapid recognition and treatment, the prognosis for MH can be excellent. Preventive measures, including genetic counseling and avoidance of known triggers, can significantly reduce the risk of an MH crisis. Ongoing education for healthcare providers is vital to ensure timely and effective management of this life-threatening condition.

Conclusion

Malignant hyperthermia remains a critical concern in anesthesia and emergency medicine. Through comprehensive understanding and vigilant monitoring, it is possible to manage and prevent this life-threatening condition effectively. This review serves as a resource for healthcare professionals to ensure patient safety during susceptible scenarios.

Quizzes

1: What is the gold standard diagnostic test for susceptibility to Malignant Hyperthermia?

1. Electrocardiogram
2. Muscle biopsy
3. Caffeine-Halothane Contracture Test
4. Full blood count. Answer: 3. Caffeine-Halothane Contracture Test

2: What is the primary genetic mutation associated with malignant hyperthermia?

1. BRCA1
2. CFTR
3. RYR1
4. HBB. Answer: 3. RYR1

3: Which of the following is a common trigger for malignant hyperthermia?

1. Nitrous oxide
2. Sevoflurane
3. Propofol
4. Lorazepam. Answer: 2. Sevoflurane

4: Which medication is used as a first-line treatment for malignant hyperthermia?

1. Epinephrine
2. Dantrolene
3. Morphine
4. Diazepam. Answer: 2. Dantrolene

5: What role do ryanodine receptors play in malignant hyperthermia?

1. They decrease calcium release.
2. They prevent muscle contraction.
3. They facilitate excessive calcium release.
4. They block neuromuscular transmission. Answer: 3: They facilitate excessive calcium release.

6: Which symptom is not typically associated with an MH crisis?

1. Muscle rigidity
2. Hypothermia
3. Tachycardia
4. Elevated end-tidal CO2. Answer: 2. Hypothermia

7: What is the gold standard diagnostic test for MH susceptibility?

1. Electrocardiogram (ECG)
2. Muscle biopsy
3. Caffeine-halothane contracture test (CHCT)
4. Full blood count (FBC). Answer: 3. Caffeine-halothane contracture test (CHCT)

8: What does a positive Caffeine-halothane contracture test indicate?

1. Low risk of blood clots
2. Abnormal calcium handling in muscle cells
3. Resistance to anesthetics
4. Immunity to MH. Answer: 2. Abnormal calcium handling in muscle cells

9: Who should be considered for genetic testing for MH susceptibility?

1. Patients with a history of diabetes
2. Patients with a personal or family history of MH
3. Patients undergoing minor surgery
4. Patients taking beta-blockers. Answer: 2. Patients with a personal or family history of MH

10: During an MH crisis, what physiological change is often the earliest and most specific indicator?

1. Decrease in blood pressure.
2. Increase in end-tidal CO2.
3. Drop in oxygen saturation.
4. Increase in body temperature. Answer: 2. Increase in end-tidal CO2

11: Which of the following is not a treatment for MH?

1. Administration of dantrolene
2. Cooling the patient
3. Hyperventilation
4. Administration of succinylcholine. Answer: 4. Administration of succinylcholine (Succinylcholine is a trigger, not a treatment.)