Clinical symptoms of MH vary greatly, range from masseter spasm, tachycardia, hypercarbia to fulminant MH crisis with severe rhabdomyolysis, cola-color urine, ventricular fibrillation, excessive bleeding and acute renal and circulatory failure. Larach and colleagues analyzed 255 cases of MH reported to the MHAUS from 1987 to 2006 and found the first appeared clinical symptoms were hypercarbia (38.0%), sinus tachycardia (31.0%), or masseter spasm (20.8%). In this study, the first clinical symptom was hypercarbia followed by sinus tachycardia, rapidly increasing temperature and elevated temperature. The order and percentage of appearance of the clinical symptoms during 255 MH events are listed in Table 1. Similar to the above study, Nelson's study also showed sinus tachycardia, hypercarbia, and rapid temperature increase were the most common signs of MH crisis seen in 73.1%, 68.6%, and 48.5%, respectively. Nelson and colleagues also demonstrated that the youngest patients (0–2 years old) were more likely to develop muscle rigidity and severe metabolic acidosis and the older children present with higher body temperature and higher potassium level.
Clinical symptom Median of appearance number Range of appearance number Percentage of patients (%) Masseter spasm 1.00 1.00–4.00 26.7 Hypercarbia 2.00 1.00–8.00 92.2 Sinus tachycardia 2.00 1.00–7.00 72.9 Generalized muscle rigidity 2.00 1.00–6.00 40.8 Tachypnea 2.00 1.00–6.00 27.1 Cyanosis 2.00 1.00–7.00 9.4 Skin mottling 2.00 1.00–7.00 6.3 Rapidly increasing temperature 3.00 1.00–7.00 64.7 Elevated temperature 3.00 1.00–8.00 52.2 Sweating 4.00 1.00–8.00 17.6 Ventricular tachycardia 4.00 1.00–7.00 3.5 Cola-colored urine 5.00 2.00–9.00 13.7 Ventricular fibrillation 5.50 1.00–8.00 2.4 Excessive bleeding 6.00 4.00–8.00 2.7 Clinical symptoms were listed in order of appearance. Appearance number was the numerical order in which a clinical symptom appeared such as the first clinical symptom that appeared during MH event would be marked 1. If the median of appearance number was same, the order of appearance depended on the percentage of MH patients.
Table 1. Order and percentage of appearance of the clinical symptoms during 255 malignant hyperthermia (MH) events
MH can occur at any time during anesthesia. The interval between induction of anesthesia and the first symptom ranged from 0 minutes (MH occurred immediately on induction) to 168 minutes. MH can also occur in the postoperative period[28,50– 52]. In one study, postoperative MH occurred in 1.9% reported to the MHAUS, the latency period between the anesthesia finish time and the onset of MH ranged from 0 to 40 minutes. An increasing number of cases has been reported that MH may occur one hour after the end of anesthesia[28,50,53], MH even occurred 10 hours after anesthesia. Importantly, MH diagnosed postoperatively almost always exhibited signs of hypermetabolism alongside hyperthermia. Isolated temperature elevations are unlikely to be MH.
The current MH presentations are often more insidious. It is believed that this was most likely due to the lower triggering potency of modern volatile anesthetics, the alleviative effects of several intravenous drugs (such as non-depolarizing muscular relaxants, alpha 2 adrenergic receptor agonists, beta adrenergic blockade), techniques (neuro-axial anesthesia), the routine monitoring of end-tidal CO2 (ETCO2) and early withdrawal of triggering agents. It is very important for anesthesiologists to know these changes in clinical presentation of MH since the early clinical diagnosis and fast appropriate management are critical for MH patient survival. Data clearly showed delays between diagnosis and initiation of dantrolene therapy increased the risk of complications.
Like most other diagnoses, the diagnosis of MH is based on clinical symptoms and laboratory testing. The main clinical presentations of MH are unexplained increased ETCO2 concentration, tachycardia, muscular rigidity, combined metabolic and respiratory acidosis, hyperthermia, cardiac arrhythmia and renal failure. An increasing ETCO2 concentration may be an early warning sign of an impending MH, and unexplained tachycardia, muscular rigidity, acidosis and hyperkalemia are further key signs of a fulminant MH. Initial clinical features can be the elevated ETCO2 followed by the body temperature rapidly exceeding 38.8 °C. However, the elevated temperature often occurs at a later time[48,51]. In some cases, there is no significant increase in body temperature[48,56]. Therefore, the diagnosis should not be delayed and early diagnosis and prompt treatment are quite crucial. Larach and colleagues developed an internationally clinical grading scale to assess the qualitative likelihood of a MH event using the Delphi method and an international panel of eleven experts on MH. This MH clinical grading scale (Table 2) can be used to qualitatively estimate the likelihood of a MH event and MHS. MH is likely to occur when the score goes in excess of 20, while MH may almost be clinically diagnosed when the score goes in excess of 50. Successful treatment of the MH crisis requires early recognition and rapid intervention[58–59].
Process Indicator Score Ⅰ. Rigidity ·Generalized muscular rigidity (in absence of shivering due to hypothermia, or
during or immediately following emergence from inhalational anesthesia)
15 ·Masseter spasm shortly following succinylcholine administration 15 Ⅱ. Muscle breakdown ·Elevated creatine kinase >20 000 IU after anesthetic that included succinylcholine 15 ·Elevated creatine kinase >10 000 IU after anesthetic without succinylcholine 15 ·Cola colored urine in perioperative period 10 ·Myoglobin in urine >60 μg/L 5 ·Myoglobin in serum >170 μg/L 5 ·Blood/plasma/serum K+ >6 mEq/L (in absence of renal failure) 3 Ⅲ. Respiratory acidosis ·PETCO2 >55 mmHg with appropriately controlled ventilation 15 ·Arterial PaCO2 >60 mmHg with appropriately controlled ventilation 15 ·PETCO2 >60 mmHg with spontaneous ventilation 15 ·Arterial PaCO2 >65 mmHg with spontaneous ventilation 15 ·Inappropriate hypercarbia (in anesthesiologist's judgment) 15 ·Inappropriate tachypnea 10 Ⅳ. Temperature increase ·Inappropriately rapid increase in temperature 15 ·Inappropriately increased temperature >38.8 °C (101.8 °F) in the perioperative period 10 Ⅴ. Cardiac involvement ·Inappropriate sinus tachycardia 3 ·Ventricular tachycardia or ventricular fibrillation 3 Ⅵ: Family history (used for MH susceptible) ·Positive MH family history in relative of first degree# 15 ·Positive MH family history in relative not of first degree# 5 Ⅶ. Other indicators that are not part of a single process ·Arterial base excess more negative than −8 mEq/L 10 ·Arterial pH <7.25 10 ·Rapid reversal of MH signs of metabolic and/or respiratory acidosis with intravenous dantrolene 5 ·Positive MH family history together with another indicator from the patient's own
anesthetic experience other than elevated resting serum creatine kinase#
10 ·Resting elevated serum creatine kinase in patient with a family history of MH# 10 #These indicators should be used only for determining malignant hyperthermia (MH) susceptible.
Table 2. Clinical grading scale for malignant hyperthermia
For about 30 years, the gold standard for diagnosing MHS individuals have been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. Two protocols of this test have been used currently, one is the caffeine/halothane contracture test (CHCT) established by the MHAUS, and the other is in vitro contracture test (IVCT) established by the European Malignant Hyperthermia Group (EMHG)[60– 62]. For IVCT, it includes four laboratory diagnostic groups: MHShc, MHSh, MHSc, and MHN. Patients with positive responses to both halothane and caffeine are classified as MHShc, patients with normal responses to both halothane and caffeine are classified as MHN (MH normal), patients with positive responses only to halothane are classified as MHSh, and patients with positive responses only to caffeine are classified as MHSc. Differences between CHCT and IVCT include halothane and caffeine concentration, the number of muscle fiber bundles, the time of exposure and the thresholds for a positive response[63–64]. A sensitivity of 99.0% and a specificity of 93.6% were reported in IVCT, while a sensitivity of 97% and a specificity of 78% in CHCT[65– 66]. It has been demonstrated that these two protocols can reach similar diagnoses. Although they are regarded as the gold standard for the diagnosis of MHS, CHCT/IVCT are invasive, expensive, restricted to a few specialized centers and need a surgical procedure under anesthesia to take a muscle biopsy specimen.
Genetic testing requiring only a blood sample and it has become an attractive alternative to the invasive muscle biopsy[26–27]. As of June 2017, 430 mutations in the RYR1 and CACNA1S gene associated with MHS were identified. As an alternative to CHCT/IVCT, genetic testing has been more and more widely used in last decade, especially in patients with a family history of MH[33,41,43,67–69]. However, genetic mutations in the RYR1 only account for approximately 50%–86% of individuals affected with MH[29– 37]. Discordance between MH diagnosed by the presence of causative mutations and skeletal muscle contracture tests has been reported. CHCT/IVCT is still required to confirm or exclude MHS if genetic testing is negative. So, CHCT/IVCT still cannot be replaced. In 2000, molecular diagnosis for MH was introduced in Europe. There were 15 mutations in the RYR1 was recommended by the EMHG for molecular genetic testing, while 17 mutations in the RYR1 gene were recommended by the MHAUS[71– 73] at that time. Currently, 50 genetic mutations, 48 in RYR1 and 2 in CACNA1S, are accepted. The diagnostic pathway for MHS from the EMHG are showed in Fig. 2.
The prognosis of a MH crisis depends on how soon MH is suspected and how fast treatment is initiated. The treatment includes two steps, the immediate treatment is to interrupt the MH episode, while the symptomatic treatment is to prevent the subsequent complications. According to the guideline from the MHAUS and the EMHG, the specific treatments of MH are listed in Table 3. After immediate treatment, appropriate monitoring should be used. Except continuing the routine anesthetic monitoring, core temperature should be measured at once. An arterial line should be considered to facilitate the amount of arterial blood gas measurements, and a urinary catheter should be placed to assess urine color. Repeated arterial blood gas analysis and monitoring of serum electrolyte, CK, myoglobin, and lactate levels are very important for determining the success of therapy. Renal and hepatic function, coagulation, and signs of compartment syndrome should be closely monitored. When stable, the patient should be transferred to the ICU to be monitored for a minimum of 24 hours.
Immediate treatment Discontinue all trigger agents;
Stop surgery. If surgery must be continued, maintain anesthesia with intravenous (IV) non-trigger anesthetics;
Hyperventilate (use a minute volume 2–3 times normal) with 100% oxygen at flows of 10 L/minute;
Call for help;
Give IV dantrolene 2.5 mg/kg rapidly. Repeat as frequently as needed until the patient responds with a decrease in ETCO2, muscle rigidity, and/or heart rate;
Remove the vaporizer and replace the soda lime.
Symptomatic treatment Treat hyperthermia
(temperature >39 °C
or less if rapidly rising)
2 000 mL of cold crystalloid solutions (4 °C) IV infusion;
Body surface cooling with ice packs and 75% medical alcohol wiped on body surface;
Other cooling procedures available;
Stop cooling when the temperature has decreased to <38 °C.
Treat hyperkalemia (K+ >5.9 or less with ECG changes) Calcium chloride 10 mg/kg or calcium gluconate 30 mg/kg;
Sodium bicarbonate: 1–2 mEq/kg IV;
For pediatric patients: 0.1 units of regular insulin/kg IV and 0.5 g/kg dextrose;
For adult patients: 10 units of regular insulin IV and 50 mL 50% glucose.
For refractory hyperkalemia, dialysis, or ECMO if patient is in cardiac arrest may be required.
Treat acidosis Sodium bicarbonate: 1–2 mEq/kg IV; Treat arrhythmias Amiodarone: 3 mg/kg IV (300 mg for an adult);
β-blockers if tachycardia persists;
Avoid calcium channel blockers which may cause hyperkalemia or cardiac arrest while using dontrolene;
Treat acidosis and hyperkalemia if present (see above).
Maintain urinary output Furosemide 0.5–1 mg/kg and/or mannitol 1 g/kg IV to maintain urine output >
Crystalloids solutions IV;
If creatine kinase or K+ rise, assume myoglobinuria and give bicarbonate infusion of
1 mEq/(kg∙hour) to alkalinize urine.
Table 3. Malignant hyperthermia treatments according to the guideline
Some cases may only need treatment with one dose of dantrolene which is a postsynaptic muscle relaxant that lessens ECC in muscle cells. It achieves this by inhibiting Ca2+ release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. It is the primary drug used for the treatment and prevention of malignant hyperthermia. However, redosing should occur with any sign of recrudescence (increased rigidity, acidosis, temperature elevation, hypercarbia). Subsequent doses should be 1 mg/kg every six hours, although fulminant cases may require continuous infusions to maintain stability. Since 80% of recrudescence events occurred within 16 hours of the initial MH treatment, it seems reasonable to suggest that if a patient receiving dantrolene is metabolically stable for 24 hours after initial therapy, dantrolene could be stopped.
Telephone hotlines for MH counselling and management guidelines have been established in many countries. A smart phone application (MHApp) issued by EMHG in cooperation with MHAUS can also provide direction to MH management. However, the best treatment is to prevent a MH crisis from happening. Recently, Litman and colleagues have presented a guideline to determine what types of patients should be considered MHS and should not receive anesthetic triggering agents.
The current status of malignant hyperthermia
- Received Date: 2018-09-17
- Accepted Date: 2019-03-11
- Rev Recd Date: 2019-03-05
- Available Online: 2019-05-30
- Publish Date: 2020-03-01
Abstract: Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 (RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.
|Citation:||Lukun Yang, Timothy Tautz, Shulin Zhang, Alla Fomina, Hong Liu. The current status of malignant hyperthermia[J]. The Journal of Biomedical Research, 2020, 34(2): 75-85. doi: 10.7555/JBR.33.20180089|