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Malignant hyperthermia

Systemic hypermetabolism during or immediately after administration of a general anesthetic which is a triggering agent.

Malignant hyperthermia is due to an autosomal dominant mutation in the ryanodine receptor, which leads to excessive calcium release from the sarcoplasmic reticulum in skeletal muscles upon exposure to halogenated inhalational anesthetic agents and succinylcholine. 

Associated with an increased oxygen consumption via uncontrolled glycolysis and aerobic metabolism which leads to hypoxia, progressive lactic acidosis and hypercarbia.

A type of severe reaction that occurs to particular medications used during general anesthesia, among those who are susceptible.

Occurs in 1 in 25,000 cases of when anesthetic gases are used,

Occurs in between 1:5,000 and 1:100,000 in procedures involving general anaesthesia.

A worldwide phenomena and affects all racial groups.

Inheritance is autosomal dominant with variable penetrance.

The defect is typically located on the long arm of chromosome 19 (19q13.2[9]) involving the ryanodine receptor.

Symptoms include muscle rigidity, high fever, and tachycardia.

Complications can include rhabdomyolysis and hyperkalemia.

Due to volatile anesthetic agents or succinylcholine in those who are susceptible.

Diagnosis is based on symptoms and situation, and the differential diagnosis includes:

Sepsis, anaphylaxis, serotonin syndrome, and neuroleptic malignant syndrome.

Treatment is by the use of Dantrolene, and supportive care.

In the absence of treatment the risk of death is 75%.

With treatment great risk of death falls to 5%.

Susceptibility to malignant hyperthermia can occur due to at least six genetic mutations.

The most common genetic mutation is one of the RYR1 gene.

Susceptibility is often inherited in an autosomal dominant manner.

The process may also occur as a new mutation or be associated with a number of inherited muscle diseases.

In susceptible individuals, medications induce the release of stored calcium ions within muscle cells.

The increased calcium concentrations within the muscle cells cause the muscle fibers to contract, generating excessive heat and results in metabolic acidosis.

Diagnosis is clinical based on symptoms occurring in the appropriate situation.

Family members may be tested for their susceptibility, by muscle biopsy or genetic testing.

The typical signs are due to a hypercatabolic state.

Patients present with high temperature, an increased heart rate and rapid breathing, increased carbon dioxide production, increased oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis.

Clinical signs can develop any time during the administration of the anesthetic triggering agents.

Cases in the postoperative period do not occur more than several minutes after discontinuation of anesthetic agents.

A disorder considered to be the result of a gene-environment interaction.

Susceptible patients have few or no symptoms unless they are exposed to a triggering agent.

Common triggering agents are volatile anesthetic gases, such as halothane, sevoflurane, desflurane, isoflurane, enflurane or the depolarizing muscle relaxants suxamethonium and decamethonium used primarily in general anesthesia.

Rarely, the biological stresses of physical exercise or heat may be the trigger

Avoiding potential triggers is recommended in susceptible people.

The condition affects one in 5,000 to 50,000 cases where people are given anesthetic gases.

Males affected more often than females.

Other anesthetic drugs are considered safe and include local anesthetics, opiates, ketamine, barbiturates, nitrous oxide, propofol,, and benzodiazepines.

The nondepolarizing muscle relaxants pancuronium, cisatracurium, atracurium, mivacurium, vecuronium and rocuronium also do not cause MH.

Some susceptible may develop the process with exercise and/or on exposure to hot environments.

25 different mutations, or more, in this gene are linked with malignant hyperthermia.

Mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2.

Chromosome 7q and chromosome 17 have also been implicated.

In 50–70% of cases, the propensity for malignant hyperthermia is due to a mutation of the ryanodine type 1 receptor located on the sarcoplasmic reticulum.

The sarcoplasmic reticulum is the organelle within skeletal muscle cells that stores calcium.

The ryanodine type 1 receptor opens in response to increases in intracellular Ca2+, resulting in a drastic increase in intracellular calcium levels and muscle contraction.

Caffeine, halothane, and other triggering agents act by drastically increasing the affinity of the RYR1 A-site for Ca2+

Sequestering this excess Ca2+consumes large amounts of adenosine triphosphate (ATP), the main cellular energy carrier, and generates the excessive heat that is the hallmark of the disease.

When the muscle cell is damaged by the depletion of ATP and possibly the high temperatures, potassium, myoglobin, creatine, phosphate and creatine kinase leak into the circulation.

Another causative gene for MH is CACNA1S, which encodes an L-type voltage-gated calcium channel α-subunit.

In most cases the relevant gene remains to be identified.

The earliest signs for diagnosis may include: masseter muscle contracture following administration of succinylcholine, a rise in end-tidal carbon dioxide concentration, unexplained tachycardia, and muscle rigidity.

Elevation of body temperature is often a late sign, but may appear early in severe cases.

Respiratory acidosis is universally present.

Many patients develop metabolic acidosis at the time of diagnosis.

Rapid breathing, cyanosis, hypertension, abnormal heart rhythms, and high blood potassium may also be seen.

Core body temperatures should be measured in any patient undergoing general anesthesia longer than 30 minutes.

Malignant hyperthermia is diagnosed on clinical grounds.

Confirmatory tests include a raised creatine kinase level, elevated potassium, phosphate and myoglobin levels, as a result of damage to muscle cells.

Severe rhabdomyolysis may lead to acute kidney failure.

The main candidates for testing are those with a close relative who has suffered an episode of MH or have been shown to be susceptible.

The procedure for testing close relatives of individuals who have suffered an episode of MH is the “caffeine-halothane contracture test”, CHCT.

A muscle biopsy is performed and it is bathed in solutions containing caffeine or halothane and observed for contraction.

The CHCT has a sensitivity is 97% and the specificity 78%.

As a negative biopsy is not definitive.

A patient suspected of MH by their medical history or that of blood relative is generally treated with non-triggering anesthetics, even if the biopsy was negative.

Genetic testing in people with a family history of MH, RYR1 mutations may be useful.

Diagnostic criteria include:

Respiratory acidosis

Heart involvement, such as unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation.

Metabolic acidosis

Muscle rigidity

Muscle breakdown with elevated CK >20,000/L units, dark colored urine or excess myoglobin in urine or serum, and hyperkalemia.

Rapidly increasing temperature, T >38.8 °C).

Family history, with autosomal dominant pattern.

In the past, the prophylactic use of dantrolene was recommended for MH-susceptible patients.

It is no longer recommend for use prior to trigger-free general anesthesia in MH-susceptible patients.

Anesthesia for people with known MH susceptible requires avoidance of triggering agent concentrations above 5 parts per million of all volatile anesthetic agents and succinylcholine.

Nitrous oxide, and all other agents are safe.

Treatments:

The only available medical treatment for malignant hyperthermia is dantrolene sodium.

Treatment is mainly supportive care and use of dantrolene to decrease calcium release, and subsequent avoidance of triggering medications.

Dantrolene sodium intravenously administered is preferred, and is the only known antidote.

Management includes discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction.

With dantrolene, the mortality of malignant hyperthermia fell from 80% to less than 5%.

Dantrolene remains the only drug known to be effective in the treatment of MH.

If not appropriately and aggressively treated the prognosis is poor.

Http://WWW.MHAUS.org for support.

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