Malignant hyperthermia (MH) is a pharmacogenetic disease of skeletal muscle. Characteristically patients with this disease have no signs or symptoms except during an anesthetic. When exposed to inhalational anesthetics (those which are gases ), muscle metabolism increases, and a series of signs and symptoms appear, which if left untreated can lead to death. The earliest findings are an increased production of carbon dioxide and signs of increased sympathetic nervous system activity. 
 

Other MH sites 

Canadian Malignant Hyperthermia Association
Malignant Hyperthermia Association of the U.S.
Gasnet
Neuromuscular Home Page
 
 

Last Updated on January 29, 1998 by Jordan D. Miller M.D.

Malignant Hyperthermia is typically a fulminant life-threatening disease, also referred to as a syndrome, which occurs when a person with malignant hyperthermia susceptibility trait is exposed to triggering factors, which include most inhalational anesthetics (though not Nitrous Oxide), succinylcholine (a muscle relaxant used during surgery) and rarely, stress. Classic Malignant Hyperthermia is characterized by hypermetabolism, (increased oxygen consumption and increased carbon dioxide production) muscle rigidity, muscle injury, and increased sympathetic nervous system activity. Hypermetabolism reflected by elevated carbon dioxide production precedes the increase in body temperature.

At present the most specific and sensitive test for the diagnosis of Malignant hyperthermia susceptibility is the Halothane caffeine contracture test. In this test a small piece of muscle is obtained under regional or general anesthesia and while still viable is placed in a special solution and attached to a device which measures the force of contraction. The muscle strip is then exposed to either Halothane (an inhalational anesthetic) or caffeine and the response measured. A response to Halothane or a response to low concentrations of caffeine are considered diagnostic for malignant hyperthermia susceptible muscle. The UCLA Department of anesthesiology maintains one of the few centers in the US and Canada ( There are 9 centers in the United States and 3 in Canada which perform such biopsies.) where patients suspected of being MH susceptible can be evaluated and if indicated have a diagnostic biopsy performed. All biopsies must be performed at the diagnostic center since the muscle must be fresh when tested.  An abnormal response to the Halothane test and Caffeine test are shown below along with a technical description of the Halothane Caffeine contracture test. 

To schedule a consultation call (310) 825 7850 or email  Jordan D. Miller M.D.

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• Trigger 
• All potent inhalational agents
• Succinylcholine
• Increased Cytoplasmic Free calcium
• Rigidity - may or may not be present
• Masseter spasm
• Total body
• Hypermetabolism
• Increased oxygen consumption
• Increased carbon dioxide production
• Increased heat production
• Cell damage
• Leakage of cell contents
• Potassium
• Myoglobin
• CK (CPK)
• Compensatory mechanisms
• Heat loss
• Sweating
• Cutaneous vasodilatation
• Increased circulating catecholamines
• Increased heart rate
• Cutaneous vasoconstriction
• Increased systemic vascular resistance
• Increased cardiac output - may not keep up with O₂ demand
• Decreased mixed venous oxygen content
• Decreased arterial oxygen content depends on shunt
• Lactic acidosis
• Increased ventilation - may not keep up with need
• Increased respiratory drive
• Increased end tidal carbon dioxide
• Temperature rise
• Severity of stimulus
• Environmental temperature
• Starting temperature
• Amount of vasoconstriction vs vasodilatation
• Secondary systemic manifestations
• Cardiac arrhythmias
• Disseminated intravascular coagulation
• Hemorrhage
• Cerebral edema
• Renal failure

• Definite association
• Central Core Disease
• Possible Association: Muscle destruction occurs with stress
• Duchenne Muscular Dystrophy
• King-Denborough Syndrome
• Other myopathies
• Becker Muscular Dystrophy
• Periodic Paralysis
• Myotonia Congenita
• Schwartz-Jampel Syndrome
• Fukuyama Type of Congenital Muscular Dystrophy
• Mitochondrial Myopathy
• Sarcoplasmic Reticulum Adenosine Triphosphate Deficiency
• Coincidental Association:
• Neuroleptic Malignant Syndrome
• Sudden Infant Death Syndrome
• Osteogenesis Imperfecta
• Glycogen Storage Disease
• Lymphomas
• Heat Stroke

• General Population
• Anywhere from 1:60,000 anesthetics to suspected in 1:4000
• Familial
• Most families - dominant pattern of inheritance
• Variable penetrance and expressivity
• Occurs on second or later triggering anesthetic in 1/3
• But all thought to be picked up by contracture testing
• Genetics
• At least 4 chromosomal locations
• Best defined is the Ryanodine receptor on 19q13
• Also 17, 7, and 3
• For more information Neuromuscular web site

• All potent inhalational agents including the newer agents sevoflurane, and desflurane.
• All depolarizing muscle relaxants Succinylcholine, decamethonium

• All other anesthetic drugs including N₂O, Pentothal, benzodiazepines, droperidol, ketamine, etomidate, propofol, narcotics, non-depolarizing muscle relaxants, anticholinergics, anticholinesterases, local anesthetics

Avoid verapamil, diltiazem potential hyperkalemia if Dantrolene given

• No problem at non toxic doses
• Amide local anesthetics- In vitro prevents calcium uptake into SR
• Caffeine, aminophylline - In vitro potentiates halothane
• Calcium - Plasma calcium decreased during event as calcium goes into cell and poisons the cell
• Epinephrine High sympathetic tone potentiates MH in pig
• Atropine High heart rate and decreased sweating

Let us now enter into the area of differential diagnosis, starting with the most common early symptoms of malignant hyperthermia. The number in parenthesis is the percent of patients exhibiting the symptom in the first 30 minutes of anesthesia ( From Britt, B.A. Malignant hyperthermia a review Handbook of Experimental Pharmacology Volume 60 1982) 

• Tachycardia (90%)
• Light anesthesia - drug tolerant patient
• Hypovolemia
• Febrile patient
• Allergic reaction
• Anoxic pain, prolonged tourniquet time
• Anticholinergic
• Cardiomyopathy with or without skeletal disease
• Hyperthyroid
• Pheochromocytoma
• Withdrawal from beta blocker, clonidine narcotics etc.
• Epinephrine absorption (surgical field epidural etc.)

 
• Hypercarbia (80%) The value is high for the observed minute ventilation excludes hypoventilation induced hypercarbia
• Measurement error, re-check, compare end tidal with arterial
• Has bicarbonate just been given, this will transiently raise the carbon dioxide production
• Previously high CO₂ leading to high body stores
• Problem with unsuspected re-breathing, valves sticking, exhausted CO₂ absorber - check for inspired CO₂
• Alveolar ventilation lower than expected poor pulmonary compliance, increased machine compression volume
• High dead space ventilation, if alveolar dead space, end tidal will be low compared to arterial
• Hypermetabolic state
• Returning core temperature to normal on awakening
• Total parenteral nutrition
• Pyrogen reaction
• Fever pre- operatively
• Shivering
• Seizure
• Pheochromocytoma, hyperthyroidism 

• Rigidity (80%)
•    The problem of Masseter Rigidity
•    Increased masseter tone in 0.3% of those under halothane anesthesia given succinylcholine, 50% of those referred have positive muscle biopsy
•    At least three degrees
•    Poor relaxation - "common" response
•    Mild increase in tone - can intubate and ventilate
•    Jaws of Steel - can't intubate
•    Since incidence malignant hyperthermia susceptible <<< 1:300
•    Those sent for biopsy are selected to be positive, have other findings as well
•    Some biopsies are false positives.
•    Check nerve stimulator to see if relaxant dose is adequate
•    Check muscle tone in extremities
•    Clinical picture does not prospectively predict susceptibility

• Hypertension (75%)
• Light anesthesia - drug tolerant patient
• Hypervolemia
• Hypertensive patient
• Anoxic pain, prolonged tourniquet
• Exogenous catecholamine, aminophylline
• Hypermetabolic state
• Total parenteral nutrition
• Pyrogen reaction
• Fever pre- operatively
• Shivering
• Seizure
• Pheochromocytoma, hyperthyroidism
• Withdrawal from beta blocker, clonidine, narcotic etc.

• Hyperthermia (70%)
• Centrally mediated
• Pyrogen reaction
• Drug
• Blood product reaction
• Bacteremia, sepsis
• Tumor
• Surgery around the thalamus
• Blood or pyrogen in CSF
• Neuroleptic malignant syndrome - patient on neuroleptics
• Lethal Catatonia - patient not on neuroleptics
• Anticholinergic overdose 
• Hypermetabolic state
• Total parenteral nutrition
• Pyrogen reaction
• Fever pre- operatively
• Shivering
• Seizure
• Pheochromocytoma, hyperthyroidism 
• Iatrogenic
• Excessive warming of patients - typically with sensor in wrong location
• Room temperature too high
• External heating - lights, hot air
• Covering patient completely
• Heated humidifier, Bair Hugger etc.
• Wrong location of measurement
• Heated humidifier with measurement in close proximity, or leak with probe in gas stream
• Probe moved- measuring temperature of heated mattress
• Esophageal can vary by 2^o C by moving 4"
• Skin probe - change in vasodilation rapid change in measured temperature
• Solution -Change location of sensor; tympanic, nasopharyngeal, esophageal, axillary, PA catheter
• Defective equipment - check using independent system
• Pyrogenic drug such as prostaglandin 

• Testing and the differential diagnosis
• Blood
• Immediately for arterial blood gas, potassium, CK total. Early elevation of the CK suggests underlying myopathy
• Venous gas may be useful for base excess, Pco₂ and potassium
• Draw blood culture and plasma myoglobin - results useful later
• If possible note minute ventilation, end tidal CO₂ on record
• Fever work up as soon as practical - check blood products, Look for ear infection, URI, UTI, atelectasis, fat emboli
• Save all syringes and drugs used, (for culture remember propofol)
• Continue blood sampling for CK Q 6 h for 24 hours
• Urine preferably spontaneous voiding to avoid trauma
• Test for hemoglobin in the absence of red cells
• If positive may be myoglobin, send for analysis
• Urinalysis and culture 
• Look for EMG activity on EKG R/O shivering, seizure
• Deepening anesthesia with barbiturate or more non depolarizing relaxant may decrease hypermetabolic state if not MH.
• Retake history - frequently can obtain new information on family or about muscle disease.
• Dantrolene is an antipyretic, response is not diagnostic, though it is more convincing if rapid and complete response occurs.
• Interpretation of CK increase may be more difficult since it may be blunted.
• Call for MH consultation - UCLA (310) 825-6831 ask for MH consultant, or Hotline (800) MH HYPER
• Fill out an adverse metabolic response to anesthesia report with the MH registry at Penn. State University, Hershey Penn.
• Episodes which start out like MH but turn out to be something else are important to identify so as to improve our diagnostic acumen. 

A muscle strip is placed in a muscle bath with physiological solution, bubbled with oxygen and carbon dioxide. The strip is attached to an electrical stimulator which produces twitches every 10 seconds. The strength of the contraction is measured electronically and recorded on a piece of paper. The muscle length is adjusted to produce a maximal force of contraction. The muscle is then allowed to stabilize, and when the baseline is stable halothane is added to the gases that bubble through the solution. Normal muscle will not change its baseline by more than 0.5 grams (half a box) during the period that halothane is present.

The strip below is of an abnormal Halothane test

Less than 1 minute after turning on the halothane the muscle starts to contract, and reaches a maximum of >5 grams in less than 2 minutes. Though not present in this example the twitch height may increase with halothane but does not distinguish between normal and abnormal. The muscle will decrease its contracture even though the anesthetic is continued. 

The caffeine test is performed in a similar manner though there is no change in the gas bubbled through the solution. Instead when the baseline is stable caffeine is added to the bath to produce progressively higher concentrations of caffeine in the bath.

The strip below is of an abnormal caffeine test

Caffeine is added to a final concentration of 0.5 mM. a small increase (<0.2 gm) in baseline is seen with an increase in twitch height (this does not distinguish normal from abnormal). When the final concentration is 1 mM the baseline rises by 0.6 gm, and at 2 mM by a further 1.8 gm. Abnormal muscle is any response >0.2 gm over the no drug baseline at 2 mM caffeine. Further additions of caffeine (4, 8, 32 mM) increase the baseline and the scale is changed to allow interpretation (2 gm/box at 8 and 4 gm/box at 32mM). Normal muscle will produce a baseline contracture at 4, 8 and 32 mM. 

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Technical description of Halothane caffeine contracture test

Pharmacogenetic: A genetic abnormality that is brought out by drugs. 

Caffeine: A drug that is found in many beverages including coffee and cola drinks. The dose necessary to trigger malignant hyperthermia is unlikely to be obtained from drinking these beverages. 

Contracture: Muscle shortening 

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