Malignant Hyperthermia and Dantrolene's role in the therapy

Author: Stefano Revello
Date: 11/12/2012



Malignant hyperthermia (MH), also known as malignant hyperthermia syndrome (MHS) is a genetically determined condition that is clinically characterised by sustained muscle contraction and hyperpyrexia. Malignant hyperthermia is included among the hyperthermia syndromes.
Table 16-1 Causes of 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.
Harrison's Principles of Internal Medicine.18th edition

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.
Malignant hyperthermia. 2012

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).

Ryanodine receptor mutations in malignant hyperthermia and central core disease. 2000

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).

ryanodine receptor, ryanodine receptor structure and mutations,pathophysiology of MH

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:
** Inappropriately elevated CO2 production
** Increased O2 consumption.
** Mixed metabolic and respiratory acidosis.
** Profuse sweating
** Mottling of skin
# Cardiovascular:
** Inappropriate tachycardia
** Cardiac arrhythmias (especially ectopic ventricular beats and ventricular bigemini)
** Unstable arterial pressure
# Muscle:
** Masseter spasm if succinylcholine has been used
** Generalized muscle rigidity

Later signs
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:
Table 1. Criteria used in the Clinical Grading Scale for Malignant Hyperthermia

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
Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group.. 2010

How does dantrolene work?
Dantrolene and its molecular structure
The molecular structure of dantrolene (hydrated 1-(((5-(4-nitrophenyl)-2-furanyl)-methylene)amino)-2,4-imidazolidine dione sodium salt), a hydantoin derivative, is planar except for the phenol ring, which is rotated approximately 30° out of the plane of the furane ring) .Dantrolene is highly lipophilic and therefore poorly soluble in water. This created problems for its clinical introduction until the 1980s. Widespread use had to await a suitable intravenous preparation. Today, dantrolene is available for intravenous use in vials containing 20 mg lyophilized dantrolene sodium added to 3 g mannitol to improve water solubility.
Dantrolene – A review of its pharmacology, therapeutic use and new developments. 2004

Dantrolene and its mechanism of action
It is a muscle relaxant that acts directly on skeletal muscle. The only mechanism of action that is currently known is the inhibition of calcium release from the sarcoplasmic reticulum into the myoplasm. The DS has neither effect on neuromuscular transmission, or effects on the myocardium. Recent studies suggest that the receptors for the DS would be located at the RyR1 calcium channel.
Malignant hyperthermia: new developments in diagnosis and clinical management [fr]. 2001

In particular, Nelson and al. tried to work out the mechanism of action of Dantrolene with the following experiment: single ryanodine (Ry1) receptor calcium release channels were incorporated into a planar lipid bilayer for electrophysiologic recording and for subsequent analysis of the channel's gating and conductance properties. The cellular effects of low DS concentrations were investigated by isometric contracture tension responses in biopsied MH human and dog muscle fascicles and in normal, single fibres from human vastus lateralis muscle. With this study, two concentration-dependent dantrolene effects on the isolated Ry sub 1 receptor were discovered, suggesting at least two different binding sites. At nanomolar concentrations, DS activated the channel by causing three- to fivefold increase in open-state probability and dwell times. At micromolar concentrations, dantrolene first increase then reduced activity in the channels, with the dominant effect being reduced activity.

The study results suggest that at least two binding sites for DS exist on the Ry receptor calcium channel: a low-affinity (micro Meter) site is associated with reduced channel gating and open-state dwell time and may relate to the established pharmacologic muscle relaxant effect of DS, and a high-affinity (nM) dantrolene binding site that activates the channel, producing Calcium2+ release to the myoplasm, which, under environmentally adverse conditions, could damage genetically predisposed MH muscle.

Dantrolene Sodium Can Increase or Attenuate Activity of Skeletal Muscle Ryanodine Receptor Calcium Release Channel: Clinical Implications. 1996

Adverse effects of dantrolene
Central nervous system side effects are quite frequently noted and encompass speech and visual disturbances, mental depression and confusion, hallucinations, headache, insomnia and exacerbation or precipitation of seizures, and increased nervousness. Infrequent cases of respiratory depression or a feeling of suffocation have been observed. Gastrointestinal effects include bad taste, anorexia, nausea, vomiting, abdominal cramps, and diarrhea. Hepatic side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal hepatitis. The risk of hepatitis is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far. Pleural effusion with pericarditis (oral treatment only), rare cases of bone marrow damage, diffuse myalgias, backache, dermatologic reactions, transient cardiovascular reactions, and crystalluria have additionally been seen. Muscle weakness may persist for several days following treatment

Drug interaction
Dantrolene may interact with the following drugs:
* Calcium channel blockers of the diltiazem/verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, arrhythmias, myocardial depressions, and hyperkalemia.
* Nondepolarizing neuromuscular blocking agents, such as vecuronium bromide: Neuromuscular blockade is potentiated.
* CNS depressants: Sedative action is potentiated. Benzodiazepines may also cause additive muscle weakness

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.

Table 2. Testing protocols for MH

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. 2003

Stefano Revello, Cecilia Pini

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