Malignant hyperthermia

# Overview
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.  MH is an autosomal-dominant inherited disorder, children and young adults are most affected, with a significant male predilection. Mutations in the RYR1 gene on chromosome 19q13.1 have been associated with a predisposition to MH. When an MH-susceptible (MHS) individual is exposed to a volatile anesthetic (eg, halothane, isoflurane, enflurane, sevoflurane, desflurane) or succinylcholine, the triggering agent induces prolonged opening of functionally altered ryanodine receptors, causes an uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle rigidity. This may lead to a metabolic crisis which manifests clinically as tachycardia, hypercarbia, hyperpyrexia, kidney failure and eventually death may occur if left untreated. Management of malignant hyperthermia crisis includes administration of dantrolene sodium, which is a postsynaptic muscle relaxant that reduces excitation-contraction coupling in muscle cells, and the avoidance of triggering anesthetic agents or succinylcholine, external and internal cooling until body temperature reaches 38.5C, hemodynamic monitoring in Intensive care unit. This strategy has markedly reduced the mortality from this condition.

# Signs and symptoms
- Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff. 
- Clinical signs and symptoms of patients with malignant hyperthermia are include 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 ~2C per hour; temperatures up to 42C are not uncommon.
- Halothane, a once popular but now rarely used volatile anesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anesthetics 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), lumbar lordosis and thoracic kyphosis (reversed curvature of the spine), and unusual facial characteristics. Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.

# Diagnosis

## 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).
- 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.
- In-vitro contracture response of biopsied muscle is the only reliable procedure for diagnosis of MH in those individuals with a positive family history or previous clinical signs. 
- 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.
- 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.
- Based on the studies done, there is another possible metabolic test for diagnosing MH. 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.
- 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.

# Diagnostic criteria
Diagnosis of malignant hyperhtermia is based on clinical manifestation or laboratory testing. In 1994, a clinical grading scale was developed by Larach and colleagues in order to predict malignant hyperthermia susceptibility. The elements of this grading scales include:
- 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 >38.8C)
- Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
- Family history (autosomal dominant pattern)

# Pathophysiology

## Disease mechanism
- The potential cause of Malignant hyperthermia in large porportion (50-70%) of cases is a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium.
- RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca2+ concentrations: the A-site and the I-site.
- Mg2+ also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for Mg2+ at either one of these sites is greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold.
- The excess Ca2+ must be reabsorbed and this process utilize large amounts of ATP (adenosine triphosphate), this leads to generation of the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine, phosphate and creatine kinase.
- The other known causative gene for MH is CACNA1S, which encodes and L-type voltage-gated calcium channel -subunit. There are two known mutations in this protein, both affecting the same residue, R1086.
- This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in HEK 293 (human embryonic kidney) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5-10mV more hyperpolarized.
- Furthermore, cells expressing these channels have an increased basal cytosolic Calcium concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Calcium, and, thereby, muscle excitability.
- Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.

# Genetics
- At least 70 mutations in the ryanodine receptor have been described, which are transmitted in an autosomal dominant fashion.
- The gene is located on the long arm of the nineteenth chromosome (19q13.1).
- These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Calcium. MH3 is located in the transmembrane forming C-terminus.
- This region is important for allowing Calcium passage through the protein following opening.

# Differential diagnosis of malignant hyperthermia
A number of conditions may present with clinical manifestation similar to those of acute malignant hyperthermia. Although treatment for malignant hyperthermia should be initiated during an acute attack, it is important to consider other causes as an alternative diagnosis. 

# Epidemiology
- The incidence has been reported to be between 1:4,500 to 1:60,000 procedures involving general anaesthesia.
- This disorder occurs worldwide and affects all racial groups.
- Most cases however occur in children and young adults, which might be related to the fact that many older people will have already had surgeries and thus would know about and be able to avoid this condition.

# History
- The syndrome was first recognized in Australia in an affected family by Denborough et al in 1962.
- Similar reactions were found in pigs.
- The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the British Journal of Anaesthesia.
- After further animal studies corroborated the possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.

# Treatment
Management of malignant hyperthermia crisis include the following steps:
- Discontinue the potent Inhaled anesthetic agents,  remove the vaporizer and hyperventilate with 100% oxygen to increase elimination of triggering agent and CO2 and to maximize oxygen delivery.
- If succinylcholine has been given, do not readminister it
- Call for help
- Stop surgery as soon as possible or switch to total IV anesthesia to complete the surgical procedure if it cannot be stopped
- Increase the minute ventilation to decrease end-tidal carbon dioxide (EtCO2)
- Increase fresh gas flow with 100% oxygen to 10 L/min
- Administer IV dantrolene, The starting dose of dantrolene is 2.5 mg/kg, then 2.5 mg/kg every 5-10 minutes until acidosis, tachycardia, pyrexia, and muscular rigidity are resolving. Adult patients will require multiple vials for the starting dose (e.g. 10 vials for a patient of 80 kg). One person should be assisting in preparing the drug.
- Cool patient with IV sodium chloride 0.9% at 4oC, ice packs, and gastric lavage; stop cooling at 38.5oC to prevent rebound hypothermia
- Obtain values for arterial blood gases (ABG), electrolytes, creatine kinase, and blood and urine myoglobin
- Treat arrhythmias and hyperkalemia - Do not use calcium-channel blockers
- Observe the patient in the intensive care unit (ICU) for 24 hours
- Ensure urine output of 2 mL/kg/hr with mannitol, furosemide, or fluids as needed
- Continue dantrolene 2.5 mg/kg if signs or symptoms recur
- Refer the patient and family for MH testing
- Recrudescence of the hypermetabolic reaction can occur for up to 14 h after initial resolution.
- Treatment must be started as early as malignant hyperthermia diagnosed based on clinical suspicion of the onset of symptoms.
- Dantrolene is a post-synaptic muscle relaxant which inhibits Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors directly on the ryanodine receptor to prevent the release of calcium that leads to lesser excitation-contraction of muscle cells.
- After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.
- Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes which may complicate clinical management.
- In MH susceptible swine, azumolene was as potent as dantrolene. It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.

# Prevention
- In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. 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.
- The only sure way to prevent MH is to avoid the use of triggering agents in patients known or suspected of being susceptible to MH.