malignant hyperthermia

Author: Cecilia Pini
Date: 05/12/2012


Malignant hyperthermia (MH), also know as malignant hyperthermia syndrome (MHS) is a condition genetically determined that is clinically characterised by sustained muscle contraction and hyperpyrexia. Hyperthermia malignant is included among the hyperthermia syndromes.
Hyperthermia is characterized by an unchanged (normothermic) setting of the thermoregulatory centre in conjunction with an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. Excessive heat production can easily cause hyperthermia despite physiologic and behavioural control of body temperature. Although most patients with elevated body temperature have fever, there are a few circumstances in which elevated temperature represents not fever but hyperthermia. The table above show possible causes of hyperthermia.
Hyperthermia and malignant hyperthermia should be differentiated from fever. Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point.

MH is an autosomal dominant disorder, commonly defined as a hyper metabolic condition due to the exposure to some enhancing factors. This rare life-threatening condition is usually triggered by exposure to certain drugs used for general anaesthesia: specifically, the volatile anaesthetic agents 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.

In the USA and Europe MH occurs in 1/12000 children and in 1/50000 adults who undergo anaesthesia. The number of malignant hyperthermia crisis is estimated to be 0,5-1/1000000/year. These records probably underestimate the real genetic predisposition to MH in the population, because most of the individuals, who have a genetic susceptibility to develop this disorder, only develop it on the second or third time they are exposed to the enhancing agent.

During excitation-contraction coupling, muscle membrane depolarization induces a conformational change in the dihydropyridine-sensitive L-type voltage-dependent calcium channel (DHPR). This conformational change leads to the activation of the ryanodine receptor type 1 (RYR1) and the rapid release of Ca2+ from its stores in the SR. Released Ca2+ binds to troponin C, causing movement of tropomyosin away from the myosin-binding sites on the thin filament and triggering muscle contraction. Muscle contraction is terminated when Ca2+ is actively pumped back into the SR by the ATP-dependent calcium pump. This process is the fundamental excitation-contraction coupling (ECC) needed for normal skeletal muscle function.

Major defects in the two receptors (RYR1 and DHPR), as well as in other proteins, such as triadin and FK 506 binding protein involved in the myoplasmic calcium regulation, are responsible for the functional changes of calcium regulation in MH. The cause of dysfunctional calcium regulation in skeletal muscle with MHS lies, in more than 50% of cases, in a defective RYR1 in SR.
Korean J Anesthesiol. 2012, November
Up to date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate MHS trait. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein. Functional analysis shows that MHS mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper-and hyposensitive to activating (caffeine and halothane) and inactivating ligands (H+, ruthenium red, Mg2+ and calmodulin).

Caffeine, halothane, and other triggering agents act by drastically increasing the affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant proteins. This cause RyR1 to remain abnormally open and, as the speed at which calcium is released for SR exceed the speed at which it is uptaken and elimated by the calcium pump, the calcium concetration in the myoplasm greatly increases. In the early phase of MH, the muscle cells attempt to restore homeostasis by sequestering calcium through the increase of aerobic and anaerobic metabolism. However, at some point, the cellular capacity to re-establish homeostasis is overpowered by the massive calcium entrance in the myoplasm. This abnormal myoplasmic calcium rise eventually reaches the threshold levels for myofibrillar contraction, and results in sustained muscle contraction. This produces a rapid depletion of adenosine triphosphate (ATP) with a concomitant increase in glucose metabolism, oxygen consumption, carbon dioxide production, and heat production. ATP stores become depleted, which progressively lead to the failure of membrane integrity with leakage of muscle cell contents (including electrolytes, myoglobin and various other sarcoplasmic proteins, like CK into the circulation).

Hum Mutat. 2000;15(5):410-7.
Ryanodine receptor mutations in malignant hyperthermia and central core disease.
McCarthy TV, Quane KA, Lynch PJ.
Department of Biochemistry, University College, Cork, Ireland.

The other known causative gene for MH is CACNA1S, which encodes and L-type voltage-gated calcium channel α-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 human embryonic kidney (HEK 293) 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 Ca2+ concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca2+, and, thereby, muscle excitability.

Signs & symptoms:
Early recognition of an impending MH crisis and its immediate treatment is essential for the patient’s survival. Any patient may develop MH during or shortly after an anaesthetic where trigger agents are used; this can occur even in patients who have had uneventful general anaesthesia previously.
Trigger agents are
• All volatile (inhalation) anaesthetic agents
• Succinylcholine

Clinical signs can be divided in early and later signs:
• Early signs
- Metabolic:
1. Inappropriately elevated CO2 production
2. Increased O2 consumption.
3. Mixed metabolic and respiratory acidosis.
4. Profuse sweating
5. Mottling of skin
- Cardiovascular:
1. Inappropriate tachycardia
2. Cardiac arrhythmias (especially ectopic ventricular beats and ventricular bigemini)
3. Unstable arterial pressure
- Muscle:
1. Masseter spasm if succinylcholine has been used
2. Generalized muscle rigidity

• Later signs:
- Hyperkalaemia
- Rapid increase in core body temperature
- Grossly elevated blood creatine phosphokinase levels
- Grossly elevated blood myoglobin levels
- Dark-coloured urine due to myoglobinuria
- Severe cardiac arrhythmias and cardiac arrest
- Disseminated intravascular coagulation

To summarize, the clinical criteria to diagnose MHS are:

Differential diagnosis
When symptoms compatible with MH are present, the following differential diagnosis should be taken into count:
• Insufficient anaesthesia or insufficient analgesia or both
• Infection or septicaemia
• Insufficient ventilation or fresh gas flow
• Anaesthetic machine malfunction
• Anaphylactic reaction
• Phaeochromocytoma
• Thyroid crisis
• Cerebral ischemia
• Neuromuscular disorders
• Elevated end-tidal CO2 due to laparoscopic surgery
• Ecstasy or other dangerous recreational drugs
• Malignant neuroleptic syndrome

Treatment & therapy
Guidelines of the European Malignant Hyperthermia Group stress the importance to start an appropriate treatment as soon as an MH crisis is suspected. The clinical presentations of MH are variable and treatment should be modified accordingly to them.
The following measures should be taken promptly:
• Stop all trigger agents
• Hyperventilate with 100% O2 at high flow
• Declare an emergency and call for help
• Change to non-trigger anaesthesia (TIVA)
• Inform the surgeon and ask for termination/postponement of surgery
• Disconnect the vaporizer
• Give Dantrolene 2 mg kg -1 i.v.. Dantrolene infusions should be repeated until the cardiac and respiratory systems stabilize. The maximum dose (10 mg kg -1) may need to be exceeded.

Following these immediate measures, monitoring should be continued as indicated below:
• Continue routine anaesthetic monitoring (Sa O2, ECG, NIAP, E′CO2)
• Measure core temperature
• Establish good i.v. lines with wide-bore cannulas
• Consider inserting an arterial and central venous line, and a urinary catheter
• Obtain samples for measurement of K+, CK, arterial blood gases, myoglobin, and glucose
• Check renal and hepatic function and coagulation
• Check for signs of compartment syndrome
• Monitor the patient for a minimum of 24 h (ICU, HDU, or in a recovery unit)

Finally is necessary to treat also:
• Hyperthermia
• Hyperkaleamia
• Acidosis
• Arrhythmias
and maintain urinary output >2 ml kg−1 h-1

Br J Anaesth. 2010 Oct;105(4):417-20.
Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group.
Glahn KP, Ellis FR, Halsall PJ, Müller CR, Snoeck MM, Urwyler A, Wappler F; European Malignant Hyperthermia Group.
Danish Malignant Hyperthermia Centre, Department of Anaesthesia, University Hospital Herlev, Copenhagen, Denmark.

The diagnosis is often made when a MHS develops during a surgery employing the trigger agents. However, there are methods (contracture test and molecular genetic test) to diagnose MH susceptibility before a patient undergoes anaesthesia with halothane or succinylcholine. Indications to the use of these techniques are different in Europe and in the USA.

Contracture test
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 centre, under local anaesthesia. 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%. 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 anaesthetics, 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.

Molecular Genetic Testing
To date, only two MHS-causative genes have been identified:
RYR 1 (MHS1 locus)
CACNA1S (MHS5 locus)
Three additional loci have been mapped; the genes have not been identified:
MHS2, linked to chromosomal locus 17q11.2-q24
MHS4, linked to chromosomal locus 3q13
MHS6, linked to chromosomal locus 5p

Malignant Hyperthermia Susceptibility
Malignant Hyperpyrexia. Includes: CACNA1S-Related Malignant Hyperthermia Susceptibility, MHS2-Related Malignant Hyperthermia Susceptibility, MHS4-Related Malignant Hyperthermia Susceptibility, MHS6-Related Malignant Hyperthermia Susceptibility, RYR1-Related Malignant Hyperthermia Susceptibility
Henry Rosenberg, MD, Nyamkhishig Sambuughin, PhD, and Robert Dirksen, PhD

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