1562 SECTION XIV Pediatric Critical Care Anesthesia Principles in the Pediatric Intensive Care Unit There are cases in which a patient was treated for MH with dantrolene, appeared to recover, and then[.]
1562 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit treated However, in the setting of recent exposure to volatile anesthetic agents or succinylcholine—especially in a patient with a family history of problems after general anesthesia or muscular diseases associated with MH—the presumptive diagnosis of MH must be made In the PICU, the most likely cause of fever is a bacterial infection,33 but elevated temperature can also be the result of trauma, viral infection, lymphoma, leukemia, drug withdrawal and allergy, and other causes.32 Inadequate fluid replacement predisposes to increased core temperature in children.34 Excessive environmental heat with inadequate opportunity for evaporative heat loss can result in temperature elevation Postoperative fever is also common and usually resolves spontaneously In some cases, increased core temperature can be associated with tachycardia, increased expired CO2, and metabolic acidosis, which are consistent with the expected increase in metabolic demand produced by fever This can be so extreme as to mimic MH, but if O2 consumption has not increased severalfold, MH is unlikely When hyperthermia occurs in a child with history of exposure to succinylcholine or volatile anesthetic agents, MH must be considered in the differential diagnosis However, in a retrospective cohort study conducted to analyze the causes of hyperthermia in the PICU over a 9-year period, Schleelein et al noted that the incidence of clinically diagnosed MH was low (0.4%).35 Likewise, the vast majority of episodes of rhabdomyolysis are not attributable to MH The most frequent causes are trauma, overexertion, immobilization, alcoholism, vascular insufficiency, and orthopedic surgery Grand mal seizures, delirium tremens, psychotic agitation, and amphetamine overdose also can lead to rhabdomyolysis in individuals with otherwise normal muscle.36 Some drugs, such as hydroxymethylglutaryl-CoA reductase inhibitors (statins) and colchicine, are directly myotoxic.36 Rhabdomyolysis may also occur in patients with mitochondrial and metabolic myopathies, such as carnitine palmitoyltransferase deficiency and myophosphorylase deficiency or McArdle disease Course of Malignant Hyperthermia The vast majority of human cases of MH follow exposure to a potent inhalational anesthetic agent (sevoflurane, isoflurane, desflurane, or halothane) or the depolarizing neuromuscular blocker succinylcholine The combination of succinylcholine and potent inhalation anesthetic agents produces more episodes of MH than either agent alone.28,29 On very rare occasions, MH may occur during an anesthetic in which no trigger agents were administered or without exposure to any anesthetic.37 An athletic adolescent who had an RYR1 mutation associated with MH died after strenuous exercise.38 While rare in humans, this has been observed repeatedly in MHS animals.39 Signs of MH usually present within 30 minutes after administration of the triggering agent but have also been reported more than hour after admission to the postanesthetic care unit.28 MH can also develop insidiously during a long anesthetic.29,40 When the nonspecific early signs of MH are noted during induction of anesthesia, the potent inhalation anesthetics should be discontinued Early termination of inhalation anesthetic agents may allow spontaneous resolution of the syndrome, which is termed abortive MH Differentiating an abortive episode of MH from an anesthetic complicated by other factors can be difficult, so such patients are considered to be MHS until proven otherwise Core temperature monitoring during anesthesia may improve identification of early MH and decrease the risk of progression to fatal MH events.3 There are cases in which a patient was treated for MH with dantrolene, appeared to recover, and then hours later had another episode of increased metabolic rate and muscular rigidity Recrudescence of MH was seen in 20% of cases reported to the MH Registry41 after initial treatment appeared to be successful Muscular body type, hyperthermia during the MH episode, and a longer time between induction of inhalation anesthesia and the first sign of MH were associated with a greater risk of recrudescence.41 There is no definite or guaranteed time course for these events Close observation of the patient rescued from an MH event for 24 hours will allow for the early recognition of recrudescence, which can progress into fulminant MH and warrants aggressive retreatment with dantrolene and supportive therapy Potential Systemic Complications Significant complications were noted in 35% of 181 MH events reported to the North American MH Registry These included changes in level of consciousness or coma in 9.4%, cardiac dysfunction in 9.4%, pulmonary edema in 8.4%, renal dysfunction in 7.3%, DIC in 7.2%, and hepatic dysfunction in 5.6%.17 The development of DIC was associated with a 50-fold increased likelihood of cardiac arrest and an 89-fold likelihood of death.1 Other reported complications included compartment syndrome, stroke after cardiac arrest, bilateral brachial plexopathy, generalized muscle weakness, significant muscle loss, and prolonged intubation.17 Changes in level of consciousness continue to be seen in over 10% of MH Registry reports, with cerebral edema and coma occurring less frequently These neurologic consequences likely result from thermotoxicity and inadequate O2 supply to the central nervous system during MH events Therefore, supportive care during and after an episode of fulminant MH should include measures to document cerebral function and maximize cerebral perfusion Respiratory failure may occur early in an episode of fulminant MH Desaturation can occur secondary to increased O2 demand; the workload of the respiratory system may be further increased by the occurrence of capillary leak and pulmonary edema Acidemia and electrolyte abnormalities may impair cardiac contractility and promote cardiac dysrhythmias, while increased levels of circulating catecholamines may lead to foci of myocardial fibrosis.42 Rhabdomyolysis will occur when the energy supply of the muscle is exhausted It is characterized by muscle necrosis and the release of intracellular constituents, including CK, myoglobin, and potassium Clinical manifestations include myalgias, swollen extremities, red-to-brown urine due to myoglobinuria, elevated muscle enzymes, and electrolyte imbalances (hyperkalemia, hyperphosphatemia, hypocalcemia) Acute renal failure, compartment syndrome, and life-threatening hyperkalemia may develop.43 Management of an Episode of Malignant Hyperthermia Initial Steps: Discontinue Trigger Agents and Administer Dantrolene When an episode of MH is suspected, additional help should be summoned immediately Multiple life-threatening complications may soon develop—efficient and expert care will be required to prevent significant morbidity and mortality CHAPTER 130 Malignant Hyperthermia 10 (+g/mL) As soon as possible, triggering inhalation anesthetic administration must be stopped High fresh gas flows of 10 L/min or more, or charcoal filters placed into the breathing circuit, are needed to eliminate residual anesthetic gas from the circuit If the patient remains in the operating room, general anesthesia should be maintained with intravenous agents and further surgery should be aborted whenever a safe point is reached The most effective treatment of MH is timely administration of dantrolene MH-associated morbidity increases significantly for every 30-minute delay in intravenous dantrolene administration.17 In most hospitals and surgical centers, dantrolene will be stocked on a dedicated MH cart in perioperative areas in addition to the pharmacy supply This hydantoin with muscle relaxant properties has greatly changed the treatment of and risk of death from MH Before the introduction of dantrolene, Brit and Kalow reported a 36% MH survival rate with symptomatic treatment only.44 Dantrolene decreases both ECCE into muscle cells and SOCE coupled to RYR1, ultimately decreasing the hypermetabolic state of skeletal muscle and resultant complications.10,12 It does not act on the neuromuscular junction or on the passive or active electrical properties of the surface membranes of muscle fibers Dantrolene in the formulations Dantrium and Revonto is supplied in 70-mL vials, containing 20 mg dantrolene sodium and g mannitol It must be diluted with 60 mL of sterile, preservative-free, distilled water to produce a clear yellow solution Dantrolene is also available as Ryanodex, 250 mg of dantrolene with 125 mg mannitol, to which mL of water is added to produce an opaque orange fluid for injection The initial dose of intravenous dantrolene for treatment of MH is 2.5 to mg/kg.45 Repeated dosing may be required to return metabolism and muscle tone to normal If clinical improvement is not seen with cumulative doses greater than 10 mg/kg, alternative diagnoses should be considered Dantrolene may irritate veins and, if it extravasates, it will not be effective in treating MH Therefore, largebore venous access should be used, with central access being preferable As soon as dantrolene is ordered to treat fulminant MH, replacements should be obtained by the pharmacy In children, the intravenous infusion of dantrolene, 2.4 mg/kg IV over 10 to 12 minutes, produces stable blood levels of about 3.5 mg/mL for hours, after which a slow decline in plasma concentration occurs (Fig 130.1).46 It appears that the half-life of dantrolene in the plasma of children is somewhat shorter than in adults: to 10 hours compared with 12 hours, respectively.47 This is consistent with the recommendation to repeat dantrolene (1 mg/kg) every to hours for at least 24 hours as prophylaxis against recurrence of MH in a child The goals of treatment with dantrolene are normalization of heart rate, respiratory rate, and muscle tone, as well as correction of hypercarbia, hyperthermia, electrolyte disturbances, and metabolic acidosis Urinary output should increase and mental status should improve Continuous infusion of dantrolene has not been shown to be superior to intermittent dosing and is not certain to prevent recurrence The major side effect of dantrolene is muscle weakness, noted in approximately 25% of patients.47,48 It is likely that when the plasma concentration of dantrolene is sufficient to inhibit an episode of MH, the patient will experience weakness and possibly disequilibrium The ability to swallow could be compromised The effects of dantrolene on strength may persist for more than 12 hours The MH episode itself may result in chronic muscle pain and weakness in many survivors.49 Phlebitis is a common side effect of dantrolene administration, noted in approximately 1563 10 15 20 Time (h) • Fig 130.1 Whole blood concentration of dantrolene vs time in a cohort of children (Modified from Lerman J, McLeod ME, Strong HA Anesthesiology 70:625,1989.) 10% of patients.48 If dantrolene must be administered to a patient who is also receiving calcium channel antagonists, invasive hemodynamic monitoring is necessary, and serum potassium should be closely monitored If no recurrence is noted in the first 24 to 48 hours following treatment of MH, the patient is metabolically stable, and weakness is marked, dantrolene administration may be discontinued and weaning from supportive therapy begun Dantrolene may be useful in the treatment of fever and muscle spasticity not associated with MH; thus, a therapeutic response to dantrolene is not diagnostic for MH Further Management: Expert Consultation and Symptomatic Treatment While discontinuation of trigger agents and early dantrolene therapy are critical initial steps, comprehensive critical care is needed to limit the multiorgan system effects of MH (Box 130.3) Since most clinicians will treat few cases of MH in their careers, consultation with MH experts, the use of clinical checklists and cognitive aids, and simulation of MH management can improve management The 24/7 MH Hotline is available at 800-644-9737 to lend advice about treating acute MH This service is supported by MHAUS (www.mhaus.org) and staffed by volunteer anesthesiologists Additionally, many perioperative environments contain the MH Operating Room Poster produced by MHAUS, and the Pedi Crisis 2.0 mobile app produced by the Society for Pediatric Anesthesia contains a section on MH Blood gas analysis should be performed regularly during the management of MH O2 desaturation, hypercarbia, and lactic acidemia in mixed venous blood are the results of skeletal muscle hypermetabolism Elevated partial pressure of arterial carbon dioxide (Paco2) is apparent in mixed venous blood before it is abnormal in arterial blood during an episode of MH.6 Because respiratory and cardiovascular compromise result from fulminant MH and because the major side effect of dantrolene is muscular weakness, endotracheal intubation and controlled ventilation may be useful Calculation of O2 consumption and CO2 production is 1564 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit • BOX 130.3 Management of an Acute Malignant Hyperthermia Episode in the Intensive Care Unit Administer high-flow oxygen via a nonrebreathing mask and consider endotracheal intubation For ventilated patients, administer increased Fio2 as guided by Spo2, and increase minute ventilation to control Paco2 Administer dantrolene (2.5 mg/kg intravenously) over 10 and repeat as needed until acidosis and muscle rigidity have resolved Continue dantrolene (1 mg/kg) every to h Initiate cooling with ice packs in the axillae and groin, decrease room temperature, use hypothermia blankets, and administer cold intravenous saline solution (10 mL/kg over 10 min, repeated as needed) if temperature is greater than 39°C Stop active cooling when core temperature falls below 38.8°C to prevent inadvertent hypothermia Correct metabolic acidosis with sodium bicarbonate (1–2 mEq/kg initially) and give subsequent doses based on base excess and body weight Administer calcium chloride (10 mg/kg) or calcium gluconate (30 mg/kg or 30–100 mg/kg) to protect from cardiotoxicity associated with hyperkalemia Give regular insulin (0.1 U/kg) and glucose (0.3–1 g/kg) to correct hyperkalemia Administer lidocaine (1 mg/kg) to treat ventricular arrhythmias Consider amiodarone (5 mg/kg IV) for refractory, stable ventricular tachycardia Do not delay defibrillation or cardiopulmonary resuscitation if indicated by cardiovascular instability Maintain urine output of mL/kg/h with aggressive cold fluid administration, furosemide (0.5–1.0 mg/kg), and additional mannitol (0.25–0.30 g/kg) if needed 10 Consider quantitative end-tidal CO2 monitoring 11 Monitor core temperature (pulmonary artery, esophageal temperature probe, rectal probe) 12 Place arterial catheter for invasive blood pressure monitoring and frequent blood sampling Consider central venous catheter and/or pulmonary artery catheter if indicated by cardiovascular instability 13 Repeat venous blood gas and electrolytes analysis until they normalize Repeat CK at least every hours while the patient is in the ICU and then daily until CK returns to normal Assess glucose, clotting function, hepatic and renal functions, and treat symptomatically Repeat lactic acid measurement after each dantrolene administration 14 Consider hemodialysis if indicated 15 Consider intensive care monitoring for at least 24–48 h after MH episode or after recrudescence of MH 16 Refer the patient for muscle contracture testing and consider exam of RYR1, CACNA1S, and STAC3 Pursue a pathologic diagnosis for other occult myopathies CK, Creatine kinase; CO2, carbon dioxide; Fio2, fraction of inspired oxygen; ICU, intensive care unit; IV, intravenous; MH, malignant hyperthermia; Paco2, partial pressure of arterial carbon dioxide; Spo2, peripheral capillary oxygen saturation simplified by mechanical ventilation; these values serve to monitor the adequacy of treatment of an episode of fulminant MH Minute ventilation should be increased initially to control Paco2 but can be normalized when repeated assessment of blood gases indicates resolution of acidosis Sodium bicarbonate should be administered to treat metabolic acidosis, as low muscle pH may prevent successful treatment of MH If core body temperature is elevated, active measures should be taken to cool the patient The most effective means of cooling are cold intravenous fluid and the topical application of ice packs Ice packs may be placed on the groin and axillae Wet cloths and a fan can be used to promote surface evaporation Active cooling should be stopped when core temperature falls below 38.8°C to prevent inadvertent hypothermia Cardiac dysrhythmias may occur but usually abate when the episode is adequately treated with dantrolene Lidocaine (1 mg/ kg) is recommended for treatment of arrhythmias in MH Amiodarone (5 mg/kg) can be administered for refractory ventricular tachycardia.50 Hyperkalemia may require aggressive treatment, especially if arrhythmias have occurred or myoglobinuria has compromised renal function Administration of calcium gluconate or calcium chloride, and all the other usual treatments to reverse the effects of hyperkalemia, are appropriate during the treatment of MH Volume status and urine output must be closely monitored.51 Large intravascular volume losses may occur secondary to evaporation, tissue edema, and mannitol-induced diuresis (included in dantrolene formulations) Hypovolemia should be avoided because even mild hypovolemia impairs dissipation of heat.34 Cardiovascular support, in the form of isotonic fluid administration as well as vasopressor and inotropic drugs, should be administered as indicated Urine output of mL/kg per hour should be maintained with aggressive fluid administration, furosemide (0.5–1.0 mg/kg), and additional mannitol (0.25–0.30 g/kg) if needed This forced diuresis serves to limit myoglobinuric renal injury Conventional hemodialysis does not remove myoglobin effectively, due to the size of this protein.52 The use of antioxidants and free radical scavengers may be justified in the treatment or prevention of myoglobinuric acute renal injury,53 but more studies are needed In the setting of aggressive fluid administration and tissue injury and edema from MH, vigilance must be maintained for signs of developing compartment syndrome, as this would require emergent surgical fasciotomy Survivors of MH reactions should continue to be managed in an ICU setting for at least 24 to 48 hours following acute treatment This allows for continued dantrolene administration, as above, to prevent recrudescence This also ensures close monitoring and treatment of potential late complications such as liver injury, renal failure, pulmonary edema, cerebral edema, and DIC Urine and Blood Tests in Malignant Hyperthermia Myoglobin is released from damaged muscle and excreted in the urine Myoglobinuria occurs when the renal threshold of 0.5 to 1.5 mg/dL is exceeded and is suggested by persistent red to reddish-brown urine At myoglobin levels of 100 mg/dL, urine tests positive for heme by dipstick The dipstick test has a sensitivity of 80% for detection of rhabdomyolysis.43 Renal injury is frequent when urine myoglobin is more than g/mL Because the half-life of myoglobin in the plasma is approximately 12 hours, less than the half-life of CK,54 persistence of myoglobinuria for more than several days suggests that muscle cell integrity continues to be impaired Patients with chronic myopathies may have moderately raised concentration of plasma myoglobin but not usually overt myoglobinuria.54 CK increases in the plasma more slowly than myoglobin does There is no defined threshold value of serum CK above which the risk of acute kidney injury is increased Usually, the risk is low when the CK level is less than 15,000 to 20,000 U/L.55 With coexisting conditions such as sepsis, dehydration, and acidosis, acute kidney injury may occur with CK values as low as 5000 U/L After an MH episode, CK should be measured at least daily until stable CHAPTER 130 Malignant Hyperthermia 1565 Testing for Malignant Hyperthermia Susceptibility Disorders Associated With Malignant Hyperthermia Muscle Contracture Testing Muscular Diseases and Malignant Hyperthermia The gold standard for evaluating MH susceptibility is muscle contracture testing This is a standardized bioassay performed only in specialized centers Freshly biopsied quadriceps muscle fibers are separately exposed to halothane and caffeine, and muscle tension is measured The protocols and standards for the caffeine-halothane contracture test (CHCT) in North America56 and the comparable test (IVCT) in Europe57 have been described in detail See www.mhaus.org and www.emhg.org for current locations of the MH Diagnostic Testing Centers At least to months should pass between an episode of suspected MH and muscle biopsy for CHCT.58 A video of the CHCT and the surgical biopsy required for this test can be seen at www mhaus.org CHCT has a sensitivity of 97% and a specificity of 78%.59 It was designed to decrease the rate of false negatives Therefore, it may produce false-positive results and should be interpreted in the context of the prior probability of the individual being susceptible to MH.60 A negative in vitro contracture test is currently the only method to rule out MH susceptibility.61 There are a few relatively rare muscular diseases that are closely linked with MH susceptibility These include central core disease, multiminicore and nemaline rod myopathies,66 and King-Denborough syndrome.67 Central core disease (CCD) is a congenital myopathy characterized by motor developmental delay and signs of mild proximal weakness, most pronounced in the hip and girdle musculature Patients with muscular dystrophy (Duchenne or Becker) can develop hyperkalemic cardiac arrest and exacerbation of rhabdomyolysis after administration of succinylcholine or potent inhalation anesthetic agents, but this is due to the fragility of dystrophic muscle rather than MH During initial treatment, such cases can be difficult to differentiate clinically from MH Indeed, calcium is not handled normally in dystrophic muscle, and RYR1 channels are abnormal.68 Myotonias are a class of inherited skeletal muscle diseases characterized by impaired relaxation after sudden voluntary muscle contraction There are defects in the chloride, sodium, and calcium channels in the different types of myotonia Succinylcholine, anticholinesterase drugs, and other perioperative stressors may precipitate myotonic contractures However, the risk of MH is not greater than that of the general population, with the possible exception of hypokalemic periodic paralysis.69 Neither nondepolarizing neuromuscular blocking agents nor dantrolene will counteract myotonic rigidity Patients with mitochondrial disorders may develop acidosis, fever, and rhabdomyolysis While nearly all inhalational and intravenous anesthetics depress mitochondrial function, there is no clear relationship between MH and mitochondrial myopathy Less Invasive Tests of Malignant Hyperthermia Susceptibility Genetic testing for MH susceptibility is an attractive proposition, as it is far less invasive, less costly, and is becoming more widely available However, as reviewed in detail by Stowell20 and by Riazi et al.,61 such DNA-based testing faces challenges and limitations due to the phenotypic and genetic heterogeneity of MH While the list of MH-causative mutations in the RYR1 and CACNA1S genes continues to expand (see www.emhg.org), up to 50% of studied MHS individuals not carry known pathogenic genetic variants Therefore, the absence of a known MHassociated genetic variant does not rule out MH susceptibility Additionally, many genetic variants are currently of unknown MH clinical significance If such a variant is identified, the patient should be regarded as MHS until contracture testing is performed Genetic testing can be helpful in families with a known MHcausative mutation In such families, carriers of the known mutation can be diagnosed as MHS without invasive contracture testing However, because more than one MH-associated genetic variant may be present in the same family, MH susceptibility cannot be ruled out based on absence of the known familial mutation.62 Genetic testing has also been useful postmortem when the clinical circumstances were consistent with MH.3 Given the complexity of DNA-based testing for MH susceptibility, professional genetic counseling and consultation with a neurologist specialized in neuromuscular disorders are appropriate when genetic testing is considered Current genetic laboratories and resources for genetic counseling can be found at www mhaus.org CK levels at rest are of no predictive value in the general population 63,64 In some populations, more than 25% of patients with elevated CK levels were not MHS on CHCT testing.65 However, if a relative of an MHS patient with chronic CK elevation has elevated CK, that individual is likely to be MHS also.64 Heat Illness and Malignant Hyperthermia Susceptibility Exertional heat illness (EHI), exertional rhabdomyolysis (ER), and MH are all hypermetabolic states and can have similar manifestations EHI is caused by excessive heat production with insufficient heat dissipation It can progress to exertional heat stroke (EHS), which includes extreme hyperthermia (core body temperature higher than 40°C [104°F]) associated with central nervous abnormalities (delirium, coma, seizure) EHS can progress to multiorgan failure70 with rhabdomyolysis The CHCT can confirm the diagnosis of MH susceptibility, but it cannot be used to diagnose the potential for EHI or ER Because there is a subset of patients who present with heat stroke and are also susceptible to MH, Grogan and Hopkins71 suggested that EHI patients undergo testing for MH susceptibility While the majority of ER and EHS cases not have a subclinical myopathy such as MH susceptibility,71,72 a case series exists of six African American men with unexplained ER who were subsequently diagnosed as MHS by CHCT.73 One of these patients developed a clinical MH episode during fasciotomy-related surgery following an episode of ER Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS), a potentially fatal response to the antidopaminergic properties of high-potency antipsychotic medications, can closely resemble MH Clinical features 1566 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit include changes in mental status and extrapyramidal function, autonomic lability, hyperthermia, muscular rigidity, and myoglobinuria History is typically the best differentiating factor between MH and NMS MH occurs within minutes to hours of exposure to volatile anesthetics or succinylcholine, while NMS develops insidiously over days after administration of various antipsychotic and antiemetic medications of the phenothiazine and butyrophenone classes.74 The treatment of NMS starts with discontinuation of neuroleptic agents as well as institution of supportive treatment to control hyperthermia, sustain vital functions, and prevent renal failure Medications such as amantadine, bromocriptine, and levodopa have been used in treatment of NMS Dantrolene is also reported to be effective in many hyperthermic patients with NMS.75,76 The potential for susceptibility to both MH and NMS in the same patient is unproven But five of seven NMS patients who underwent muscle contracture testing had significantly abnormal results.77 Therefore, when electroconvulsive therapy (ECT) is used to treat NMS, it may be reasonable to avoid succinylcholine and substitute a nondepolarizing muscle relaxant However, one patient who had experienced NMS is documented to have received succinylcholine repeatedly for ECT without complications.78 See www.mhaus.org/nmsis for information on NMS and similar disorders Malignant Hyperthermia Association and Registry The Malignant Hyperthermia Association of the United States (MHAUS, www.mhaus.org) is a valuable resource for families affected by MH and their physicians This organization offers information, expert consultation, and referral MHAUS also maintains a 24-hour professionally staffed telephone line to assist physicians and patients in dealing with MH (800-644-9737) All cases of suspected MH and similar heat-related disorders should be reported to the North American Malignant Hyperthermia Registry (888-274-7899, https://anest.ufl.edu/namhr/) to support the continued epidemiologic study of MH Key References Butala B, Brandom BW Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility Can J Anesth 2017;64:396-401 Carpenter D, Robinson RL, Quinnell RJ, et al Genetic variation in RYR1 and malignant hyperthermia phenotypes Br J Anaesth 2009; 103(4):538-548 Larach MG, Brandom BW, Allen GC, et al Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States Anesthesiology 2008;108(4):603-611 Riazi S, Kraeva N, Hopkins PM Malignant hyperthermia in the postgenomics era: new perspectives on an old concept Anesthesiology 2018; 128(1):168-180 Riazi S, Larach MG, Hu C, et al Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands Anesth Analg 2014;118:381-387 Schleelein LE, Litman RS Hyperthermia in the pediatric intensive care unitis it malignant hyperthermia? Pediatr Anesth 2009;19(11):1113-1118 Stowell KM DNA testing for malignant hyperthermia: the reality and the dream Anesth Analg 2014;118:397-406 The full reference list for this chapter is available at ExpertConsult.com ... (0.25–0.30 g/kg) if needed This forced diuresis serves to limit myoglobinuric renal injury Conventional hemodialysis does not remove myoglobin effectively, due to the size of this protein.52 The use... syndrome, as this would require emergent surgical fasciotomy Survivors of MH reactions should continue to be managed in an ICU setting for at least 24 to 48 hours following acute treatment This allows... children is somewhat shorter than in adults: to 10 hours compared with 12 hours, respectively.47 This is consistent with the recommendation to repeat dantrolene (1 mg/kg) every to hours for at