In this scenario, there is a 35 year old female patient who develops malignant hyperthermia during surgery. Malignant hyperthermia is an uncommon pharmacogeneric disorder that leads to the hypermetabolic reactions of the skeletal muscle. [Ben Abraham, et al, 1998, Britt, 1985, Hopkins 2008]. Age, type of anesthetic, environmental temperature, mitigating drugs administered simultaneously and degree of stress play an important role in triggering malignant hyperthermia. [Ording, 1985]. Primarily, potent inhalation anesthetic agents and depolarizing muscle relaxants such as succinylcholine are the major triggering factor amongst all the triggering factors. Malignant hyperthermia can happen at any time during surgery especially after the induction of the anesthetic and in the early postoperative period. Besides that, there is a tendency of the recurrent of malignant hyperthermia as well.
Even though hypermetabolic reaction of skeletal muscle will cause hyperthermia and rhabdomyolysis but fever is not the earliest symptom of malignant hyperthermia. The earliest signs and symptoms of malignant hyperthermia are increase in the end-expired carbon dioxide concentration (EtCO2), tachycardia and muscle rigidity (especially when succinylcholine is given). [Britt, 1985]. Furthermore, the late sign of malignant hyperthermia is elevation of the body temperature. [Ali et al, 2003; Britt,1985].The other signs and symptoms are unstable blood pressure, tachypnea, hyperkalemia and arrhythmia.
According to Hogan, 1998 the estimated incidence of malignant hyperthermia during anesthesia in North America and Europe is 1:15000 anesthetics for children and adolescents and 1:50000- 1:150000 anesthetics for adults. [Hogan, 1998].All ethnic groups are affected with malignant hyperthermia and males are more prone to be affected compared to female. [Britt, 1976; Hopkins, 2008]. The mortality was around 80% thirty years ago and has been reduced to less than 10% with the introduction of the muscle relaxant dantrolene sodium, widespread education and clinical and research investigation. [Ali, 2003; MacLennan, 1990]
Malignant hyperthermia is an inherited disorder where the calcium channel that mediates the excitation contraction coupling in skeletal muscle is mutated. As a result, the calcium channel is very sensitive to the anesthetic agents [Hopkins, 2008]. This will lead to the uncontrolled release of cytoplasmic calcium from the sarcroplasmic reticulum upon the induction of anesthetic agents [Hopkins, 2008; Rosenberg et al. 2004]. As a matter of fact, there is a continued interaction between actin and myosin with sustained muscle contraction [Hopkins, 2008; Rosenberg et al. 2004]. The manifestation of the signs and symptoms of malignant hyperthermia can be explained by the increased release of the calcium. At first, this mechanism is compensated by the resequestion of calcium, which has lead to the breakdown of the adenosine trisphosphate (ATP) [Hopkins, 2008; Rosenberg et al. 2004]. This will cause the stimulation of the metabolism and results in increased oxygen consumption, heat and carbon dioxide production. The breakdown of the ATP causes the release of the potassium into the extracellular fluid results in hyperkalemia and this will lead to the development of cardiac arrhythmias. Besides that, the continuous contraction of the skeletal muscle due to the breakdown of the ATP will lead to the further production of heat. As a result, there will be a further increase of oxygen consumption, carbon dioxide and lactic acid production, which, will lead to metabolic acidosis [Britt, 1985; Hopkins, 2008; Rosenberg et al. 2004]. In addition, the increase of the production of heat will also increase the contractility of the skeletal muscle hence further worsening the rhabdomyolysis process. If malignant hyperthermia is untreated, it might lead to vital organ dysfunction, acute renal failure, disseminated intravascular coagulation, congestive heart failure and even death.
In this scenario, since the patient developed malignant hyperthermia during surgery, thereby the management of malignant hyperthermia can be divided into emergency treatment and postoperative treatment. When there is an acute development of malignant hyperthermia during surgery, all triggering agents have to be discontinued and the patient has to be hyperventilated with 100% oxygen to lower the end tidal CO2 immediately. This is followed by administration of 2.5mg/kg dantrolene sodium intravenously every 5 minute until the signs and symptoms of malignant hyperthermia are under controlled. [Morgan et al. 2006]. The dose of dantrolene can be titrated up to 10mg/kg. [Gronert et al., 1976; Harrison, 1988]. The monitoring of blood gases, all serum electrolytes, muscle enzyme such as cretine kinase, clotting profile, blood and urine for myoglobin, blood glucose, lactate and urea nitrogen must be carried out frequently during the surgery. Sodium bicarbonate should be given to correct the metabolic acidosis to the normal level. In addition, patient has to be closed monitored and anti-arrhythmic except calcium channel blocker can be given for arrhythmias. Cooling measures have to be initiated if there is the present of hyperthermia. Ice packs to groin, axilla, and neck, cooling blanket, and nasogastric lavage with iced solution can be used to cooling down the patient. The cooling measures have to be stop if the body temperature is at 38.5oC. In order to treat myoglobinaemia and thus acute prevent renal failure urine output and urine pH should be greater than 3ml/kg/h and pH7 respectively. [Hopkins, 2008]. This diuresis can be achieved by hydrating the patient with crystalloid solutions together with mannitol(0.3g/kg) and furosemide (0.5-1.0mg/kg). [Hopkins, 2008; Mary, 1998]. Hyperkalaemia which is life threatening can be treated with glucose, insulin, intravenous calcium and intravenous potassium chloride. [Britt, 1979; Hopkins, 2008].
Once the surgery is finished, the patient has to be moved to intensive care unit or recovery room until malignant hyperthermia is under controlled and the patient should be monitored closely. Since it is possible for the recrudescence of malignant hyperthermia, dantrolene should be continued giving to patient for at least 48 hours. [Flewellen, 1983; Rosenberg, 2004]. Several laboratory tests such as blood gases, electrolytes, coagulation profile, muscle enzyme, blood and urine for myoglobin should be assessed more frequently. [Hopkin, 2008].
At first, besides dantrolene, procainamide/ procaine was recommended to treat malignant hyperthermia. The use of procainamide/ procaine was due to the successful studies carried out by Harrison, 1971, Denborough, 1972 and Noble, 1973. The study carried out by Harrison, 1971 showed a successful treatment of malignant hyperthermia with large dose of intravenous procaine in 2 out of 5 Landrace pigs. However, the study from Gronert, 1976 showed that the recommendation dose of procaine/ procainamide was ineffective in preventing malignant hyperthermia of the 20 susceptible pigs. Study compared the effectiveness of dantrolene and procainamide conducted by Nelson, 1979 showed that procainamide did not block the contracture response to halothane and it is ineffective for therapeutic and as prophylaxis of malignant hyperthermia. Procainamide or procaine was not been used after all.
Harrison, 1975 demonstrated that dantrolene can relax muscle rigor in pigs with malignant hyperthermia and ceased the excessive heat and acid production. The study showed 100% survival rate in the last seven of eight experiments. Besides that, based on Britt, 1984 that 79 patients who received dantrolene therapy showed a significant 16.56% reduction in mortally (p<0.05). In addition, there was a significant reduction (p<0.01) in the cooling rate in dantrolene group in the study conducted by Channa et al., 1990. According to the study of the rationale for dantrolene versus procainamide for the treatment of malignant hyperthermia carried out by Nelson, 1979 illustrated that 0.8mg/kg dantrolene in vivo reversed the contracture response of malignant hyperthermia muscle strip that induced by halothane and they concluded that dantrolene is effective in preventing malignant hyperthermia during general anesthesia.
Dantrolene is now the only known therapeutic agent used to treat malignant hyperthermia. Dantrolene is a diphenylhydantoin derivative that is highly lipid soluble but poorly water soluble. [PMJ & GG Harrison]. Dantrolene can be administered by oral route or intravenous route. Roughly, 70% of dantrolene is absorbed with the peak plasma concentration reached in 6 hours following the ingestion of dantrolene by mouth. From the experiment performed by Harrison 1975, oral dantrolene was effective in treating procaine malignant hyperthermia. Nevertheless, there is a great variation in the plasma concentration for the oral dantrolene especially in children. Dantrolene is formulated as lyophilized orange powder, which comprises of dantrolene sodium, mannitol and sodium chloride. These contents are dissolved in water to yield a solution with the pH of 9.5 for intravenous injection. Moreover, the additional of the mannitol is to improve the solubility since dantrolene is poorly water soluble and mannitol also acts as diuresis, which prevent the deleterious effects of myoglobinaemia. The biological elimination half life of dantrolene is 12 hours. As a result, after 12 hours the plasma concentration of dantrolene will be 4.2µg/ml with the administration of 2.4mg/kg body weight of dantrolene intravenously. [Allen et al, 1988; Muehlschlegel & Sims, 2009]. Dantrolene is mainly metabolized in the liver through oxidation and reduction reaction. Oxidation and reduction of the dantrolene result in the production 5-hydroxydantrolene and aminodantrolene respectively. Aminodantrolene will then undergo acetylation leads to the formation of reduced acetylated derivative of dantrolene. The metabolites of the dantrolene are excreted in urine and bile with 79% of 5-hydroxydantrolene, 17% reduced acetylated derivative of dantrolene and 4% of the dose is excreted unchanged in the urine. [Dykes, 1975; Lietman et al, 1974]. Moreover, it has been stated that the metabolites of dantrolene especially 5-hydroxydantrolene has some muscle relaxant activity. [Ellis& Wessels, 1978; Ali et al, 2003].
According to Malignant Hyperthermia Association (MHAUS) the recommended dosage of dantrolene is approximately 2-3mg/kg. [Schulte-Sasse]. It had been stated by Flewellen& Nelson 1980 that, 95% of the skeletal muscle of swine was depressed with the administration of 3.5mg/kg dantrolene intravenously. In addition, clinical study showed that administration of 2.4mg/kg of dantrole intravenously was able to depress 75% of the skeletal muscle in human. [Flewellen et al., 1983]. The dose was proved to be effective in the treatment of malignant hyperthermia.[ Hall et al, 1980; Kolb et al, 1982]. Thus, for acute malignant hyperthermia crisis, 2.4mg/kg of intravenous dantrolene is effective in life-saving of treating malignant hyperthermia. [Harrison 1988; Allen et al. 1988; Flewellen et al., 1983]. The single dose of oral dantrolene that is currently given to patient is 1-2mg/kg four times a day.[ Pandit et al, 1979; Fitzgibbons, 1981]. However, it was found that this recommended dose of oral dantrolene was not effective in preventing malignant hyperthermia in human. [Fitzgibbons, 1981; Flewellen et al, 1983]. Administration of oral dantrolene has been recommended before the operation and after the malignant hyperthermia crisis to prevent the recrudescence. Besides administration oral dantrolene, dantrolene can also be given intravenously as a prophylaxis therapy after the crisis. [Flewellen et al, 1983]. The prophylactic continuous intravenous dose of dantrolene is approximately 2.4mg/kg. [Flewellen et al, 1983].
Dantrolene is a muscle relaxant, which, acts on skeletal muscle cell to inhibit the release of calcium from sarcoplasmic reticulum. This will reduce the contractility of the skeletal muscle cell. According to Ellis,1973, the relaxant action of dantrolene acted directly and specifically on skeletal muscle but did not act on cardiac and smooth muscle. Besides that, dantrolene did not have any action on central nervous system. [Harrison,1988 & Ellis, 1972]. Harrison and Chapman 1982, stated that the reduction in the amount and rate of calcium release by dantrolene is effective in preventing and reversing the pathophysiology of malignant hyperthermia in patient. In the experiment carried out by Harrison, 1975 has demonstrated that administration of dantrolene will cause a relaxation of the muscle rigor, cessation of the production of heat and acid.
Based on the study carried out by Nelson, 1996 dantrolene is clinically effective in the treatment of malignant hyperthermia and showed a remarkable reduction in death and syndrome associated with malignant hyperthermia. When the syndrome of malignant hyperthermia was first noticed by the world during 60s, the rate of mortality was about 80%. The increasing awareness of syndrome with resultant in earlier diagnosis and treatment markedly reduced the mortality to 28% during 70s. With the introduction of the dantrolene, the rate of mortality reduced to 7%. [Harrison, 1988]. In addition, the experiment done by Harrison, 1988 showed that 100% survival rate was achieved with the administration of dantrolene.
Long term administration of dantrolene orally is associated with some side effects such as hepatotoxicity and vomiting, which sometimes may be accompanied by diarrhea. [ Faling et al, 1980; Wilkinson et al, 1979]. However, the occurrence of hepatotoxicity is rare and several studies have been failed to prove whether hepatotoxicity is due to ingestion of dantrolene orally alone. [Flewellen et al, 1983; Dykes 1975; Durham et al, 1984]. As the reconstitution solution that is formulated for intravenous injection is highly alkaline, if extravasation occur it may irritate the vein which will lead to phlebitis and tissue necrosis. Therefore, dantrolene is recommended that to be injected into the large vein via a central venous catherter.[Ward et al, 1986; Muehlschlegel& Sims, 2009]. Besides that, the mannitol that added to the dantrolene powder will cause osmotic diuresis with the loss of fluids and electrolytes. This will increase the risk of the patient who has poor renal function. [Bastron,1983]. In addition, in the experiment that carried out by Flewellen and Nelson, chronic administered of dantrolene intravenously will result in difficulty in walking especially down stair. Muscle weakness lasting up to 48hours in 12 malignant hyperthermia subjects and associated with difficulty in walking, especially down stairs. [Flewellen& Nelson,1983]. In the clinical studies that performed by Flewellen and Nelson and Oikkonen and his colleagues, patients were experienced fatigue and difficulty in swallowing accompanied to the long term administration of continuous intravenous dantrolene.[ Flewellen& Nelson, 1983; Oikkonen et al, 1987]. The other common side effects of administered of dantrolene are dizziness, light-headedness, drowsiness, weakness, malaise and nausea. [Ward et al, 1986; Dkyes, 1975].
There is an adverse interaction of dantrolene when co-administration with verapamil. Co-administration of dantrolene and verapamil will cause hyperkalaemia and depression of the cardiac contractility. [Rubin& Zablocki,1987; Saltzman et al, 1984]. The studies carried out by Lynch and colleagues and Saltzman and colleagues stated that administered dantrolene and verapamil concomitantly will cause remarkable hyperkaelemia and cardiac depression in dogs and swine. [ Saltzman et al, 1984; Lynch et al, 1986]. However, not all the calcium channel blockers will cause hyperkaleamia and the depression of cardiac contractility. Neither nifedipine nor amlodipine has significant of hyperkalaemia and depression of cardiac contractility when given together with dantrolene. [Freysz, 1996; Saltzman et al, 1984].
Besides having adverse effects and adverse interaction, another disadvantage of dantrolene is its cost. Dantrolene is an expensive drug, for intravenous dantrolene, it costs £15.08 per 20mg vial. As it is a huge amount of dantrolene are needed for immediate use, this has became an issue for some hospitals when purchase the dantrolene as dantrolene is very expensive especially intravenous dantrolene and dantrolene has a limited shelf life of 18 months to 2 years. [Allen et al, 1988; Hall, 1980].
In conclusion, malignant hyperthermia is uncommon life-threatening inherited disorder of the muscle cells. A sudden hypermetabolic reaction of the skeletal muscle when exposed to potent volatile anaesthetics and depolarizing muscle relaxants such as succinylcholine will endanger the patient by causing hyperthermia and massive rhabdomyolysis. Studies showed that appropriate dose intravenous dose of dantrolene is effective in treating patient during acute malignant hyperthermia crisis. Thus, 2.4mg/kg of dantrolene should be given intravenously during acute malignant hyperthermia crisis and continue giving 2.4mg/kg dantrolene after the crisis for 48 hours to avoid recrudescence of malignant hyperthermia. Besides, hypermetabolic reaction and the mortality rate of malignant hyperthermia can be reduced by taking precautions and increasing the awareness of patient who is malignant hyperthermia susceptible. With appropriate counseling, pre-operative screening and intraoperative monitoring the vital signs and symptoms of malignant hyperthermia can prevent the potential lethal complications arise.
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