Malignant Hyperthermia: A Danger of General Anesthesia
Malignant hyperthermia is a rare inherited skeletal muscle disorder wherein there is an abnormality of the skeletal-muscle sarcoplasmic reticulum. This results in a rapid increase in intracellular calcium levels in response to an exposure to halothane and other potent volatile anesthetics or to succinylcholine (Harrison, 2012). It can also be triggered by stress (exertional or heat) without pharmacologic triggering agents in rare cases (Kim, 2012).
Malignant hyperthermia is inherited in an autosomal dominant manner with variable expression and incomplete penetrance. Susceptibility to malignant hyperthermia is conferred by mutations in the RYR1 gene located on chromosome 19. RyR1 skeletal muscle ryanodine receptor is the calcium release channel in the sarcoplasmic reticulum membrane and is involved in the excitation-contraction process of the muscle cell. This supplies the myoplasmic calcium for contraction (Hirshey Dirksen et al., 2011). When a patient susceptible to malignant hyperthermia is exposed to a triggering agent, there is a destabilization of intracellular calcium regulation (increased calcium levels in skeletal muscle) resulting in malignant hyperthermia. (Gurnaney et al., 2009)
Signs and symptoms of malignant hyperthermia include elevated temperature, increased muscle metabolism, muscle rigidity, rhabdomyolysis, acidosis, and cardiovascular instability that develop within minutes (Harrison, 2012). Severe complications include cardiac arrest, brain damage, internal bleeding or failure of other body systems. This rare condition is often fatal due to a secondary cardiovascular collapse. (MHAUS, 2013)
The exact incidence of malignant hyperthermia is unknown. Epidemiologic studies shows that there is one in about 100,000 surgeries in adults and one in about 30,000 surgical procedures in children. The prevalence of genetic change that predisposes to malignant hyperthermia is about one in 2,000 patients.— United States Malignant Hyperthermia Association
It is important to note that Malignant Hyperthermia (MH) is a pharmacologic disorder affecting the skeletal muscle primarily. This is considered as an adverse drug event following the administration of triggers such as volatile inhalational anesthetics and depolarizing muscular agents such has succinylcholine (Munhoz & Moscovich, 2012). Mutations in the RYR receptor-1 added with environmental factors predispose the patient in the onset of the rapid cycling of excitation-contraction after administration of anesthetic triggers (Hirshey Dirksen et al., 2011).
The RYR1 is the Calcium release channel within the sarcoplasmic reticulum (SR) membrane whose major known function is supplying the myoplasmic Ca for contraction. It is the largest known calcium receptor known to man and it mainly functions in the induction of calcium release (Lanner, Georgiou, Joshi, & Hamilton, 2010). During a normal excitation-contraction coupling, the membrane of muscle cells depolarize and it causes a conformational change in the dihydropyridine –sensitive L-type voltage gated calcium channels. This change causes activation of the RYR-1 and the consequent release of calcium found in the calsequestrin (CSQ) and calcium stores. Calcium binds to troponin C causing movement of the tropomyosin triggering the muscle contraction. Calcium is then pumped out of the membrane by ATPase dependent pumps (Hirshey Dirksen et al., 2011; Kim, 2012). Impairment in the RYR channel is the main proposed cause of MH.
Skeletal Muscle Excitation
The Role of Genetics
The channelopathy is caused by an incomplete penetrance with variable expressivity and this contributes to most, but not all the main causes of the disease condition (Hirshey Dirksen et al., 2011). The impairment in this channel causes a subsequent change in the skeletal muscle’s potential for a calcium-induced calcium release leading to unregulated contraction. This causes the primary signs and symptoms of the condition related to hypermetabolism, lactic acidosis and increase in temperature (Katzung, Masters, & Trevor, 2012).
Aside from the current accepted understanding that the RYR1 receptors are the main culprit for the abnormal response of predisposed patients, the exact mechanism is still debated until today. Most of what we currently know is based from the effect of a prototypical drug, dantrolene, which was discovered 40 years ago for the management of this condition. Several mechanisms have been proposed and evidences points out that the drug causes indirect changes in the RYR1 receptor via the store-operated calcium entry (SOCE) which causes plasma extracellular calcium to be brought into the cell’s plasma membrane. Other proposed mechanism involves the ff.: (1) Excitation-Coupled Calcium Entry (ECCE), a store-independent Ca entry pathway that is activated by repetitive or prolonged depolarization. (2) SOICR (Store Overload Induced Calcium Release), a process triggered by SR Ca overload that leads to spontaneous release of SR Ca into the cytoplasm. It is also proposed that MH-causing mutations in RYR1 serve to lower the channel’s SOICR threshold, in which this is aggravated by the administration of halothane and other volatile anesthetics. (Hirshey Dirksen et al., 2011) The mechanism is caused by the effect of volatile anesthetics and/or succinylcholine to cause and increase in myoplasmic calcium concentration in susceptible patients, resulting in persistent muscle contraction (Brunicardi et al., 2010).
Histologically, it is seen that tissues affected have different functionality as well. This may be due to the presence of heterogenous group of RYR tetramers which have varying capacities for contraction and functionality leading to different responses to calcium stimulation. Furthermore, it is hypothesized that increased stress causes changes in the core regions which may be the result of excessive leak of calcium from the SR. The proposed mechanism causesthe formation of ROS and RNS resulting to oxidation and damage to the cell, disruption of mitochondria and the sarcotubular system, and the eventual degeneration of contractile machinery. When this happens, the myopathic state develops (Hirshey Dirksen et al., 2011).
The diagnosis of MH basing primarily from clinical manifestations or laboratory testing is generally difficulty due to its variable presentation, and the effects vary from person-to-person and differences in dose. Furthermore, the onset of the first sign, and subsequent signs for that matter, has differences as well (Kim, 2012).The episode of MH may be similar with that of Duchenne’s Muscular Dystrophy. However, there is lesser signs of significant rhadbdomyolysis and lactic acidosis in the former (Gurnaney, Brown, & Litman, 2009). A comparison to other movement disorders related to adverse drug events is indicated in the figure below.
Table 1: Recognizing Malignant Hyperthermia
EMHG Guidelines:Recognizing an MH crisis: Clinical Signs
• Inappropriately elevated CO2production (raised end-tidal CO2on capnography, tachypnoea if breathing spontaneously).
• Increased O2consumption.
• Rapid increase in core body temperature
• Mixed metabolic and respiratory acidosis.
• Grossly elevated blood creatine phosphokinase and myoglobin levels
• Profuse sweating.
• Disseminated intravascular coagulation
• Mottling of skin.
• Dark-coloured urine due to myoglobinuria
• Inappropriate tachycardia.
• Severe cardiac arrhythmias and cardiac arrest
• Cardiac arrhythmias (especially ectopic ventricular beats and ventricular bigemini).
• Unstable arterial pressure.
• Masseter spasm if succinylcholine has been used.
• Generalized muscle rigidity.
The clinical presentation ranges from the manifestations attributed from the rapid excitation-contraction cascade in skeletal muscles. There are most severe manifestations which may evolve from rhabdomyolysis, hyperthermia, disseminated intravascular coagulopathy, lactic acidosis and eventually cardiac arrhythmia (Gurnaney et al., 2009). The guidelines of the European Malignant Hyperthermia Group (EMHG)(see table 1) is being used in the investigation for the early recognition of this rare disorder (Glahn et al., 2010).
In the early stages of the condition, the cell membrane tries to restore the homeostasis by sequesterin calcium by increasing aerobic and anaerobic metabolism. However, due to the mutation, there is excessive uncontrolled release of calcium when triggered by anesthetics. It causes a strong and sustained muscular contraction (Kim, 2012). This persistent muscle contraction is the main mechanism involved in the development of the disease process.
The initial effects causing hypermetabolism dis due to several mechanisms mainly: “(i) direct stimulation of glycolytic enzymes by the calcium-calmodulin complex; and (ii) indirectly, through the demand for ATP which is required both to fuel the excessive myofilament interaction and to provide the energy source for various membrane calcium pumps that will be operating maximally in order to try and restore calcium homeostasis (Halsall & Hopkins, 2003).”The earliest signs are tachycardia, rise in end-expired carbon dioxide concentration despite increased minute ventilation, accompanied by muscle rigidity. This is considered as one of the most important earliest signs to watch out for in unexplained cases after the onset of anesthesia(Halsall & Hopkins, 2003; Rosenberg, Davis, James, Pollock, & Stowell, 2007). In cases of administration of succinylcholine, the muscle spasm may often be restricted and labeled as masseter muscle spasm (MMS). This is seen as intense jaw rigidity and it has been document prior to the onset of paralysis. (Halsall & Hopkins, 2003; Rosenberg et al., 2007)
The classic MH crisis involves the triad of hypermetabolic state, tachycardia, and abnormal rise in end-tidal CO2 because of constant minute ventilation. This causes respiratory and metabolic acidosis and muscle rigidity follows. Death of skeletal muscle causes rhadomyolysis as well as electrolyte imbalances due to the release on intracytoplasmiccations, primarily potassium. This predisposes the patient to the development of sudden cardiac arrest. The increase in temperature secondary to hypermetabolic state is already considered as a late sign of the disease progression (Brunicardi et al., 2010).
The skeletal muscle comprises around 40% of the body mass; hence, excessive stimulation leads to heat-production in excess of heat-losing capabilities in which the body temperature may rise > 1C per minute. This is further complicated by the changes in oxygenation and ventilation capacity and increase in CO2 production (Halsall & Hopkins, 2003).
Pharmacology in the Triggering of MH
Potent inhalation anesthetic agents have been implicated as clinical triggers of malignant hyperthermia. Studies have shown that any of these drugs may be able to produce a rapidly progressing MH reaction within a few minutes of induction of anesthesia. The British Journal of Anaesthesia (Halsall & Hopkins, 2003)have identified the several drugs as triggers in malignant hyperthermia and drugs which are labeled as safe drugs. These safe drugs have been evaluated in the laboratory and safely used in patients with known MH susceptibility. These are listed in the table below.
Succinylcholine is also implicated in the occurrence of malignant hyperthermia, with the emerging feature of profound and prolonged rigidity of the jaw muscles in response to the drug. A trend towards poorer survival rates was noted by Britt and Kalow (as cited in Hopkins, 2011), in those who had received the drug. The role of succinylcholine in MH triggering was confirmed and consolidated by Ellis and colleagues(as cited in Hopkins, 2011), who found that in vitro contractures in some subjects from MH families happen when exposure to succinylcholine and halothane were done on their muscle specimens and not on halothane alone. Likewise, no muscle contracture was observed in those applied with succinylcholine alone.
There is little doubt that its combination with a potent inhalation anesthetic can produce a more marked clinical MH response. An example would be the tenfold increase in serum creatine kinase after an MH reaction with combined succinylcholine and an inhalation agent, as when the only trigger is an inhalation agent. Likewise, Pollock and colleagues(as cited in Hopkins, 2011), also identified a significantly enhanced onset in succinylcholine use.
Inhaled anesthetics are volatile liquid compounds which are aerosolized in specialized vaporizer delivery systems. They can be used for induction of anesthesia, as sevoflurane, or for maintenance of anesthesia. The most commonly used inhaled anesthetics include desflurane, sevoflurane and isoflurane. Nitrous oxide gas is continuously used as an important adjuvant to these volatile agents. Pharmacologic properties of these inhaled anesthetics are shown in the succeeding table. From the absorption or uptake from the alveoli, inhaled anesthetic drugs go into the blood stream and are distributed to the brain. Achievement of the desired and adequate depth of anesthesia is dependent on solubility, anesthetic concentration in the inspired air, pulmonary ventilation, pulmonary blood flow, and arteriovenous concentration gradient.
Spontaneous and evoked activity of neurons in many regions of the brain can be depressed by inhaled anesthetics. It primarily acts by activating the GABAa receptor-chloride channel, a major mediator of inhibitory synaptic transmission. Aside from their action on GABAa chloride channels, inhaled anesthetics decrease the duration of opening of nicotinic receptor-activated cation-channels. This action would decrease the excitatory effects of acetylcholine at cholinergic synapses.
Other drugs implicated as triggers of MH
Several studies have been conducted on several other drugs which may trigger MH, this include serotonergic drugs and phosphodiesterase type III inhibitors. Some other drugs have published reports in the use of tetracaine, statins, ondansetron and methylene blue as MH associated (Hopkins, 2011).
Protective Drugs against MH Triggering
I.V. Induction Agents
A study involving MH susceptible pigs showed that thiopental reproducibly delays onset of MH induced by sevoflurane/halothane alone, or halothane in combination with succinylcholine. The mechanism is unknown but the effect is dose-dependent.
Non-depolarizing Neuromuscular Blocking Agents
Previous studies have suggested the protective effect of tubocurarine on MH pigs from the excessive rigidity response to succinylcholine. Studies conducted in the recent years have showed the preventive effect of tubocurarine in 50% of susceptible pigs in exhibiting complete neuromuscular block.
Confirmation of Diagnosis
The mainstay in the confirmation of MH diagnosis is in vitro contracture testing (IVCT) done at specialist centers. A muscle biopsy from the patient is done and subsequent pharmacological testing of fresh muscle strips occurs. Tissue is usually excised from the vastus muscle under regional anesthesia. This involves the measurement of the tension generated in response to separate exposure to halothane and caffeine. In comparison to normal individuals, MH susceptible patients exhibit increased muscle tension at lower halothane and caffeine concentrations(Halsall & Hopkins, 2003).
This is the gold standard for MHS diagnosis(Kim, 2012). There are two protocols standardized for this, the first one mentioned being the European version (IVCT) by the European Malignant Hyperthermia Group, and the North American version known as the Caffeine-Halothane Contracture Test (CHCT) by the North American Malignant Group. Generally, the two protocols are similar and only vary in some areas. For instance, NAMHG protocol allow any muscle site use, whereas EMHG protocol specified use of vastus lateralis. A confirmed case of MH should then be followed by investigation of other family members. Aside from this test, DNA diagnosis has also been recently introduced. However, it is limited by the complexities of the genetics of MH and cannot be used in isolation (IVCT is still needed to be done).
Management of Malignant Hyperthermia
According to the British Journal of Anesthesia(Glahn, et al., 2010), treatment is started as soon as an MH crisis is suspected. As the clinical presentation of MH varies, the treatment should also be modified accordingly.
Immediately after suspicion, all trigger agents should be stopped. The patient must then be hyperventilated using a minute volume 2-3 times normal, with 100% O2 at high flow. Emergency should be declared and help acquired as needed. The vaporized should be disconnected.The patient should then be shifted to non-trigger anesthesia (TIVA) and the surgeon should be informed and requested to terminate or postpone the surgery, or anesthesia can be maintained with intravenous drugs while the surgery is concluded as rapidly as possible(Halsall & Hopkins, 2003).
It is a hydantoin derivative related to phenytoin. It interferes with the excitation-contraction coupling in muscle fibers. Dantrolene interferes with the release of activator calcium through the SR by binding to RYR1 and blocking the opening of the channel. Smooth muscle and cardiac muscle are minimally depressed since the release of calcium from their SR involves RYR2.Only about 1/3 is absorbed of the drug and its half-life is approximately 8 hours. Its major adverse effects include generalized weakness, sedation, and occasionally hepatitis(Katzung, Master, & Trevor, 2009)
Dantrolene should be prepared and administered consequently. It is a spasmolytic drug that works to reduce excessive muscle tone or spasm in acute muscle injury. It has no significant central effects and is used primarily in the treatment of malignant hyperthermia.It is the only drug effective in limiting the accumulation of calcium ions within the muscle cells(Halsall & Hopkins, 2003). It does this by acting on the interface between the t-tubular system and the sarcoplasmic reticulum. Dantrolene 2 mg kg-1 i.v. (ampoules of 20 mg are mixed with 60 ml sterile water) should be given. The drug should be obtained from other sources - nearby pharmacy and hospitals - because as much as 36-50 ampules may be needed for an adult patient. Infusions should be repeated and continued until the cardiac and respiratory systems stabilize. The maximum dose is 10 mgkg-1 and may need to be exceeded at times(Glahn, et al., 2010). Acidosis and hyperkalemia should also be anticipated and treatment done with bicarbonate and insulin with dextrose. Regular blood gas and electrolyte measurement should guide the treatment. Treatment of the other symptoms is shown in the figure below.
Understanding Malignant Hyperthermia
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