OVERVIEW
A fatal and severe form of hyperthermia that occurs most often during general anesthesia.
The patient has a sudden and worsening fever that can exceed 40°C, with generalized muscle rigidity.
It is an autosomal dominant disease, triggered by the use of certain anesthetic drugs and intense training in hot environments.
Treatment includes discontinuation of certain anesthetics, use of dantrolene sodium, and physical hypothermia and hemodialysis.
Definition
Malignant hyperthermia (MH) is a rare inherited disorder of skeletal muscle with a predominantly autosomal dominant mode of inheritance.
Malignant hyperthermia is a serious anesthetic complication that occurs in people with this genetic trait when certain general anesthetic drugs are administered.
These anesthetics primarily include inhaled anesthetics (e.g., halothane, isoflurane, sevoflurane, and desflurane) and depolarizing muscle relaxants (succinylcholine).
Typical presentation is a sudden onset of hyperthermia during anesthesia, which continues to worsen and can exceed a temperature of 40°C, with generalized muscle rigidity. Tachycardia, arrhythmias, severe acidosis, and a generalized hypermetabolic state may also occur [1].
The presence of this genetic variant is often referred to as “malignant hyperthermia susceptible”, and the onset of the disease is referred to as “patient”.
Staging or classification
According to the clinical manifestations of malignant hyperthermia, it can be categorized into fulminant type, occlusal spasm type, simple rhabdomyolysis type, and delayed-onset type.
Violent type: It is the most common and typical type, characterized by high fever and generalized reaction.
Occlusal spasm type: patients present with a stiff bite and clenched teeth.
Simple rhabdomyolysis type: most often occurs within 24 hours after surgery, with sudden onset of muscle pain, weakness, and deepening of urine color.
Delayed onset type: uncommon, mostly occurring 1 hour after the end of general anesthesia [2].
Morbidity
There is no authoritative data on the incidence of malignant hyperthermia in China.
According to foreign literature, the incidence rate of adults is about 1/50000, and the incidence rate of children is much higher than that of adults, which is 1/15000, and there are more male patients than female [3-4].
Questions you may be concerned about
What is malignant hyperthermia
Malignant hyperthermia is a hereditary disease of perioperative death due to routine anesthetic drugs.
Malignant hyperthermia is a contraction of skeletal muscle that occurs during exposure to volatile anesthetics and polarizing muscarinic drugs during general anesthesia procedures, and the energy produced as a result leads to an increase in body temperature, and the patient may experience cardiac arrhythmia and hypoxemia. Without control by specific medications, the patient’s temperature will continue to rise, eventually leading to death.
Malignant hyperthermia is a hereditary condition that occurs in the resuscitation room or the operating room. When the patient is exposed to anesthetic drugs, the attack is sudden and the condition presents as malignant, and the patient will develop a sudden high temperature that may result in a temperature of 45°C or more.
The drug used to treat malignant hyperthermia is dantrolene, which has the effect of inhibiting the release of calcium ions and relaxing skeletal muscles, and should be administered under medical supervision.
Causes
Causes
Malignant hyperthermia is an autosomal dominant disorder primarily associated with mutations in the gene encoding the sarcoplasmic reticulum calcium channel protein RYR1 in skeletal muscle.
The regulatory mechanisms of intracellular calcium ions in skeletal muscle of susceptible individuals are abnormal but are not normally triggered, and their skeletal muscle neuromuscular junctions, cellular structures, and intracellular calcium ion concentrations are normal.
When the susceptible person encounters special circumstances such as anesthetic drugs or high-intensity training, this calcium ion regulation disorder is triggered, causing an abnormal increase in intracellular calcium ion concentration, leading to the occurrence of tonic contraction of the skeletal muscle cells, resulting in a large amount of cellular oxygen consumption, heat production, and CO2 over-production, resulting in the occurrence of malignant hyperthermia.
This in turn leads to the manifestations of sharply elevated body temperature, severe acidosis, hyperkalemia, cardiac arrhythmia, disseminated intravascular coagulation, myoglobinuria, and multi-organ functional damage [5-7].
Predisposing factors
Volatile inhalation anesthetics: receiving general anesthesia for various reasons, especially volatile inhalation anesthetics such as halothane, enflurane, isoflurane, sevoflurane, desflurane, etc.
Depolarizing muscle relaxants: intravenous succinylcholine during general anesthesia.
Intense athletic training in high temperature and high humidity environments.
Risk factors or predisposing factors
Some congenital, familial muscle disorders have a higher risk of occurring in patients. Such as idiopathic scoliosis, strabismus, ptosis, umbilical hernia, inguinal hernia, etc [2].
Symptoms
Main Symptoms
Malignant hyperthermia occurs most often during surgical anesthesia and is difficult for non-operating room staff to have the opportunity to observe.
The first symptom is mostly a sharp increase in body temperature, followed by other symptoms such as muscle spasms and ankylosis, and the common manifestations are as follows:
Elevated body temperature: the body temperature rises sharply, which can reach over 40℃.
Bite muscle spasm: manifested as tight teeth, difficult to pry open the mouth.
Tachycardia: the heart rate can be up to 160 to 180 beats per minute or more, often accompanied by severe arrhythmia.
Generalized muscle tonus, difficulty in flexing the joints of the limbs.
Urine becomes dark in color and resembles soy sauce.
Muscle aches and weakness.
Others: shortness of breath, profuse sweating, flushing, sudden rise and fall of blood pressure, bleeding from the mouth and nose, multiple bleeding spots and petechiae on the skin, coma, etc. The patient may die in a few hours to a few days.
Consultation
Department of Anesthesiology
Anesthesiology
Malignant hyperthermia is most commonly seen during general anesthesia, and once it occurs, anesthesiologists and surgeons will treat it as a matter of urgency.
If you have a history of malignant hyperthermia or a family history of malignant hyperthermia, you should inform your doctor during the preoperative anesthesia evaluation so that he or she can assess the risk.
Emergency Department
Rarely, patients with this disease may develop the disease while not under anesthesia, such as during intense athletic training in high temperature and high humidity environments, in which case it is necessary to call the 120 emergency number or send the patient to the Emergency Department for emergency treatment.
Preparation for medical treatment
Consultation: registration, preparation of information, common problems
Tips for medical treatment
If the patient is going to undergo general anesthesia surgery, it is recommended to go to the anesthesia evaluation clinic for consultation.
Prepare relevant medical records before the consultation, especially pay attention to your family medical history.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, specific manifestations, etc.
Is there high fever, tachycardia, generalized rigidity?
Is there any clenching of teeth, darkening of urine color?
Are there any muscle aches, weakness?
Is there any unstable respiratory blood pressure, red face and sweating, generalized bleeding, coma, etc.?
Medical History Checklist
Have you received general anesthesia before? Has there been high fever, tachycardia, rigidity, etc. during anesthesia?
Any congenital or familial muscular disorders such as idiopathic scoliosis, strabismus, ptosis, umbilical hernia, inguinal hernia, etc.?
If the onset of the disease was not during anesthesia, was there any intense training in a hot, high humidity environment prior to the onset of the disease?
Has anyone in the family experienced unexplained deaths during and after anesthesia?
Checklist
Test results of the last six months, which can be brought to the doctor’s office
Routine tests: liver and kidney function, blood electrolytes, blood gas tests, serum myoglobin, coagulation, electrocardiogram, etc.
Other tests: caffeine-fluoroalkane isolated skeletal muscle contraction test, genetic testing.
Medication List
Medications used in the last 3 months, if available in boxes or packages, bring them with you to the doctor’s office
General anesthetic medications: halothane, enflurane, isoflurane, sevoflurane, desflurane, succinylcholine, ketamine, etc.
Diagnosis
Diagnosis is based on
Medical history
Patients tend to have a family history of malignant hyperthermia.
May have a history of malignant hyperthermia.
May have congenital, familial muscle disease.
Patients who develop the disease not during anesthesia may have trained intensely in a hot, high humidity environment.
Symptoms.
The main manifestations are high fever, tachycardia, generalized rigidity, clenching of teeth, darkening of urine, muscle aches and pains, malaise, unstable respiratory blood pressure, redness and sweating, generalized hemorrhage, and coma.
Physical examination
Mainly check the patient’s body temperature, heart rate, respiration, blood pressure, muscle stiffness.
Examination
Routine examination
Blood gas analysis: can show severe hypercapnia, respiratory acidosis.
Myoglobin in serum and urine: patients who develop rhabdomyolysis may have significantly elevated levels of myoglobin in serum and urine.
Renal function: patients may develop severe renal injury, which is manifested by abnormal creatinine and glomerular filtration rate.
Cardiac electric examination: patients may have tachycardia, various arrhythmias and even ventricular fibrillation at the onset of the disease.
Clinical Rating Scale
The Clinical Grading Scale (CGS) is the most commonly used clinical diagnostic criterion for malignant hyperthermia.
The doctor will evaluate several aspects such as muscle rigidity, rhabdomyolysis, respiratory acidosis, elevated temperature, cardiac arrhythmias, and family history. A total score of 50 or more makes the basic diagnosis.
Caffeine-fluoroalkane isolated skeletal muscle contraction test
It is the gold standard test to confirm the diagnosis of malignant hyperthermia.
It is indicated for people over 8 years of age and weighing more than 20 kg and is mostly used for pre-morbid screening and confirming the diagnosis.
The doctor will collect muscle fibers (quadriceps) from the patient’s thigh for testing. The effect of different concentrations of halothane and caffeine on the muscle fiber tone of the collected specimen is determined.
The results of the test are judged by 2 criteria, European and North American.
Genetic testing
Genetic testing cannot be used to directly diagnose malignant hyperthermia because there are multiple genetic variants.
However, it can be used to test clinically confirmed patients, highly suspected patients, and their family members, and a diagnosis of malignant hyperthermia susceptibility can be made if the family member shows the same pathogenic mutation results as the patient [8-9].
Differential diagnosis
Malignant hyperthermia is mainly differentiated from the following diseases.
Antipsychotic malignant syndrome
Similarities: both may present with muscle rigidity, elevated body temperature, unstable blood pressure, tachycardia, tachypnea, and excessive sweating.
Differences: Antipsychotic malignant syndrome is mainly seen after the use of antipsychotic drugs such as haloperidol and haloperidol.
Myotonic dystrophy
Similarities: Both are hereditary disorders that can present with muscle weakness and elevated muscle enzymes.
Differences: Myotonic dystrophy has a childhood onset of symptoms, which gradually worsens and is not related to drugs or exercise.
Rhabdomyolysis induced by non-anesthetic drugs
Similarity: Both patients may present with skeletal muscle damage such as muscle pain, fatigue, and deepening of urine color.
Differences: Patients with non-anesthetic-induced rhabdomyolysis do not have genetic mutations, but suffer from skeletal muscle damage due to medications, which is common in patients using lipid-lowering drugs such as atorvastatin and rivastigmine [1-2].
Treatment
Aim of treatment: to save lives, reduce symptoms, and improve patients’ postoperative quality of life and life expectancy.
Principles of treatment: discontinue the inducing drugs, replace the blank anesthesia machine, use dantrolene sodium as soon as possible, actively lower the temperature physically, correct the disturbance of the internal environment, and protect the function of vital organs.
Rescue measures
Malignant hyperthermia is mostly seen during general anesthesia or within a short time after the end of anesthesia. Once it occurs, the anesthesiologist and surgeon will immediately resuscitate it.
The first step is to immediately discontinue the use of inhalation anesthetics such as halothane, enflurane, isoflurane, sevoflurane, desflurane, or the depolarizing muscle relaxant succinylcholine.
Administer dantrolene sodium intravenously at the same time. Dantrolene sodium is a potent agent in the treatment of malignant hyperthermia and should be used early. Adverse drug reactions include muscle weakness, hyperkalemia, gastrointestinal disturbances, and thrombophlebitis.
The surgeon will end the surgery as soon as possible, and if the surgery cannot be ended in a short period of time, the anesthesia will be changed to a drug that does not induce malignant hyperthermia to maintain anesthesia [1-2].
Symptomatic treatment
Physical hypothermia
The patient’s body temperature > 39 ℃ immediately began to cool down, when the body temperature dropped to about 38 ℃ to stop cooling to avoid hypothermia.
Cooling methods include wearing an ice cap, alcohol bath, intravenous infusion of cold saline, gastric tube and ureter injection of cold saline irrigation, intracorporeal iced saline irrigation, and extracorporeal circulation for cooling.
Stabilization of the internal environment
Patients may develop acidosis, hyperkalemia, etc. Drugs such as sodium bicarbonate, glucose, insulin, etc. should be used early to correct acidosis and electrolyte disorders.
Blood purification treatment
Blood purification treatment is usually called “dialysis treatment”, continuous renal replacement therapy (CRRT) is helpful to maintain the patient’s internal environment and avoid or treat renal failure.
Questions you may be concerned about
What is the most effective medicine for malignant fever?
The specific drug for malignant hyperthermia is generic dantrolene. Malignant hyperthermia is caused by the inhalation of anesthetics and depolarizing muscarinic drugs after triggering mandatory contraction of skeletal muscles, the body a large number of heat production, body temperature continues to rise. Dantrolene is a skeletal muscle relaxant that relieves the forced contraction of skeletal muscle, thereby controlling the abnormal increase in body temperature and relieving the symptoms of malignant hyperthermia.
Dantrolene adverse reactions include nausea and vomiting, weakness and vertigo, dizziness and drowsiness, constipation and diarrhea, abdominal cramping sensation, gastrointestinal bleeding, rash and fever, headache and convulsions, blurred vision and depression, and slurred conversation. Note that it is forbidden to combine with alcohol or central nervous system depressants. Use with caution in patients with severe liver disease, hepatic insufficiency, severe cardiopulmonary insufficiency.
Malignant hyperthermia needs to be rescued under the guidance of specialized physicians, and the medication should be administered in strict compliance with the doctor’s instructions.
Prognosis
Cure
Most patients with malignant hyperthermia have their symptoms subside within a few days after prompt and effective treatment.
However, the disease is hereditary and cannot be cured by current treatments.
When the patient encounters triggering factors such as general anesthesia and high-impact athletic training, there is a possibility of reoccurrence of the disease.
Malignant hyperthermia is characterized by acute onset, rapid progression, and high case fatality rate, and the case fatality rate of malignant hyperthermia in China was about 73.5% before domestic dantrolene sodium was put into clinical use [10-12].
Surviving patients may be left with serious complications such as rhabdomyolysis, renal injury or renal failure.
The prognosis of patients is mainly affected by the timeliness of resuscitation, the patient’s response to drugs, and the underlying condition.
Daily
Daily management
There are no special precautions for daily life before the onset of malignant hyperthermia in susceptible people.
After the onset of the disease, if the patient’s condition is stabilized and serious complications such as rhabdomyolysis, renal injury or renal failure remain, it is necessary to pay attention to avoiding alcohol, using medication cautiously, and reducing physical activity.
Disease monitoring
Patients without complications usually do not need to be re-examined.
Patients left with the above complications need to be rechecked according to the doctor’s recommendation, usually once every 1 to 3 months, and blood tests may be performed during the recheck.
Prevention
The onset of malignant hyperthermia can be prevented, and the following methods can help to avoid the onset of this disease.
The most important preventive measure is to truthfully inform the anesthesiologist at the time of preoperative anesthesia evaluation of one’s genetic history, history of anesthesia procedures, and the presence of any adverse reactions during the procedure.
For those with a clear family history of genetic disease, genetic testing can be performed to screen for susceptibility to malignant hyperthermia.
The diagnosis of malignant hyperthermia susceptibility can be clarified by performing a caffeine-halothane isolated skeletal muscle contraction test before undergoing general anesthesia.
Drugs that can trigger malignant hyperthermia, such as inhalation anesthetics like halothane, enflurane, isoflurane, sevoflurane, desflurane, and succinylcholine, are avoided during general anesthesia in malignant hyperthermia susceptible individuals.
Avoid high-intensity athletic training in malignant hyperthermia susceptible individuals, especially in high temperature and high humidity environments.