Malignant Hyperthermia

Malignant hyperthermia

Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anaesthesia") is a rare life-threatening condition that is triggered by exposure to certain drugs used for general anesthesia (specifically all volatile anesthetics), nearly all gas anesthetics, and the neuromuscular blocking agent succinylcholine. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body's capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.

Susceptibility to MH is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest,[1] most prominently the ryanodine receptor gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy. MH is usually unmasked by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with dantrolene sodium is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition.

Malignant hyperthermia Signs and symptoms

Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff. Characteristic signs are muscular rigidity, followed by a hypermetabolic state with increased oxygen consumption, increased carbon dioxide production (hypercapnia, usually measured by capnography), tachycardia (fast heart rate), and an increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour; temperatures up to 42°C are not uncommon. Rhabdomyolysis (breakdown of muscle tissue) may develop, as evidenced by red-brown decoloration of the urine and cardiological or neurological evidence of electrolyte disturbances.[citation needed]

Halothane, a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anaesthetics are potential triggers of malignant hyperthermia. Succinylcholine, a neuromuscular blocking agent, is also a trigger for MH. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances.

A proportion of people susceptible to malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described myopathy (muscle weakness due to muscle cell abnormality), short stature, cryptorchidism (undescended testicles), pectus carinatum (a chest wall deformity), thoracic lordosis and lumbar kyphosis (reversed curvature of the spine), and unusual facial characteristics.[2] Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.

Malignant hyperthermia Diagnosis

During an attack

Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes blood tests, which may show a raised creatine kinase level, elevated potassium, increased phosphate (leading to decreased calcium) and - if determined - raised myoglobin; this is the result of damage to muscle cells. Metabolic acidosis and respiratory acidosis (raised acidity of the blood) may both occur. Severe rhabdomyolysis may lead to acute renal failure, so kidney function is generally measured on a frequent basis.[citation needed]

Susceptibility testing

In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test would not mean that the patient is not at further risk of further episodes on future occasions. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as sepsis (severe infection).[citation needed]

The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT. A muscle biopsy is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%.[3] Negative biopsies are not definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.[citation needed]

Less invasive diagnostic techniques have been proposed. Intramuscular injection of halothane 6 vol% has been shown to result in higher than normal increases in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and specificity was 75%. For patients at similar risk to those in this study, this leads to a positive predictive value of 80% and negative predictive value of 100%. This method may provide a suitable alternative to more invasive techniques.[4] A 2002 study examined another possible metabolic test. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.[5]

A 2005 paper proposes a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.[1]

Criteria

A 1994 consensus conference led to the formulation of a set of diagnostic criteria. The higher the score (above 6), the more likely a reaction constituted MH:[6]

Respiratory acidosis (end-tidal CO2 above 55 mmHg or arterial pCO2 above 60 mgHg)
Heart involvement (unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation)
Metabolic acidosis (base excess lower than -8, pH<7.25)
Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l)
Temperature increase (rapidly increasing temperature, T >38.8°C)
Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
Family history (autosomal dominant pattern)

Malignant hyperthermia Treatment

The current treatment of choice is the intravenous administration of dantrolene, the only known antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction. Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.[16]

Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium. After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH.[17]

Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes which may complicate clinical management. Azumolene is a 30-fold more water-soluble analogue of dantrolene that also works to decrease the release of intracellular calcium by its action on the ryanodine receptor. In MH susceptible swine, azumolene was as potent as dantrolene.[18] It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.

Malignant hyperthermia Prevention

In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia.[17] However, multiple retrospective studies, have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. 1082 of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with parenteral dantrolene, and the remaining one recovered with only symptomatic therapy.[19] After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of non-depolarising neuromuscular blocking agents[16]), experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.[17]

Anaesthesia for known MH susceptible patients requires avoidance of triggering agents (all volatile anaesthetic agents and succinylcholine). All other drugs are safe (including nitrous oxide) as are regional anaesthetic techniques. Where general anaesthesia is planned it can be provided safely by removing vaporisers from the anaesthetic machine, placing a new breathing circuit on the machine, flushing the machine and ventilator with 100% oxygen at maximal gas flows for 20-30 minutes, and inducing and maintaining anaesthesia with non triggering agents (eg: propofol).[16]

Malignant Hyperthermia
Norovirus Marfan syndrome Nasal Cancer Marburg Hemorrhagic Fever Malignant Hyperthermia Male Breast Cancer Lyme disease Lung cancer Legionellosis Latex Allergy Lassa Fever Jaundice / Kernicterus Hypothyroidism Kawasaki disease Genetic-Brain-Disorders Gallbladder-Diseases Fetal alcohol syndrome Diabetes Crimean-Congo Hemorrhagic Fever Dengue-and-Dengue-Hemorrhagic-Fever Chikungunya-Fever Cat Scratch Disease Cancer Larynx Cancer Among Children Borderline Personality Disorder Bladder cancer Baylisascaris Infection Benign tumor Skin Cancer African trypanosomiasis Coming Soon	Malignant hyperthermia Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anaesthesia") is a rare life-threatening condition that is triggered by exposure to certain drugs used for general anesthesia (specifically all volatile anesthetics), nearly all gas anesthetics, and the neuromuscular blocking agent succinylcholine. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body's capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly. Susceptibility to MH is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest,[1] most prominently the ryanodine receptor gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy. MH is usually unmasked by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with dantrolene sodium is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition. Malignant hyperthermia Signs and symptoms Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff. Characteristic signs are muscular rigidity, followed by a hypermetabolic state with increased oxygen consumption, increased carbon dioxide production (hypercapnia, usually measured by capnography), tachycardia (fast heart rate), and an increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour; temperatures up to 42°C are not uncommon. Rhabdomyolysis (breakdown of muscle tissue) may develop, as evidenced by red-brown decoloration of the urine and cardiological or neurological evidence of electrolyte disturbances.[citation needed] Halothane, a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anaesthetics are potential triggers of malignant hyperthermia. Succinylcholine, a neuromuscular blocking agent, is also a trigger for MH. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances. A proportion of people susceptible to malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described myopathy (muscle weakness due to muscle cell abnormality), short stature, cryptorchidism (undescended testicles), pectus carinatum (a chest wall deformity), thoracic lordosis and lumbar kyphosis (reversed curvature of the spine), and unusual facial characteristics.[2] Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report. Malignant hyperthermia Diagnosis During an attack Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes blood tests, which may show a raised creatine kinase level, elevated potassium, increased phosphate (leading to decreased calcium) and - if determined - raised myoglobin; this is the result of damage to muscle cells. Metabolic acidosis and respiratory acidosis (raised acidity of the blood) may both occur. Severe rhabdomyolysis may lead to acute renal failure, so kidney function is generally measured on a frequent basis.[citation needed] Susceptibility testing In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test would not mean that the patient is not at further risk of further episodes on future occasions. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as sepsis (severe infection).[citation needed] The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT. A muscle biopsy is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%.[3] Negative biopsies are not definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.[citation needed] Less invasive diagnostic techniques have been proposed. Intramuscular injection of halothane 6 vol% has been shown to result in higher than normal increases in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and specificity was 75%. For patients at similar risk to those in this study, this leads to a positive predictive value of 80% and negative predictive value of 100%. This method may provide a suitable alternative to more invasive techniques.[4] A 2002 study examined another possible metabolic test. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.[5] A 2005 paper proposes a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.[1] Criteria A 1994 consensus conference led to the formulation of a set of diagnostic criteria. The higher the score (above 6), the more likely a reaction constituted MH:[6] Respiratory acidosis (end-tidal CO2 above 55 mmHg or arterial pCO2 above 60 mgHg) Heart involvement (unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation) Metabolic acidosis (base excess lower than -8, pH<7.25) Muscle rigidity (generalized rigidity including severe masseter muscle rigidity) Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l) Temperature increase (rapidly increasing temperature, T >38.8°C) Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels) Family history (autosomal dominant pattern) Malignant hyperthermia Treatment The current treatment of choice is the intravenous administration of dantrolene, the only known antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction. Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.[16] Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium. After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH.[17] Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes which may complicate clinical management. Azumolene is a 30-fold more water-soluble analogue of dantrolene that also works to decrease the release of intracellular calcium by its action on the ryanodine receptor. In MH susceptible swine, azumolene was as potent as dantrolene.[18] It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH. Malignant hyperthermia Prevention In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia.[17] However, multiple retrospective studies, have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. 1082 of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with parenteral dantrolene, and the remaining one recovered with only symptomatic therapy.[19] After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of non-depolarising neuromuscular blocking agents[16]), experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.[17] Anaesthesia for known MH susceptible patients requires avoidance of triggering agents (all volatile anaesthetic agents and succinylcholine). All other drugs are safe (including nitrous oxide) as are regional anaesthetic techniques. Where general anaesthesia is planned it can be provided safely by removing vaporisers from the anaesthetic machine, placing a new breathing circuit on the machine, flushing the machine and ventilator with 100% oxygen at maximal gas flows for 20-30 minutes, and inducing and maintaining anaesthesia with non triggering agents (eg: propofol).[16]
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