e1 References 1 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 H[.]
e1 References 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 Monnier N, Krivosic-Horber R, Payen JF, et al Presence of two different genetic traits in malignant hyperthermia families: Implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility Anesthesiology 2002;97:1067-1774 Larach MG, Brandom BW, Allen GC, et al Malignant hyperthermia deaths related to inadequate temperature monitoring, 20072012: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States Anesth Analg 2014;119:1359-1366 Gommans IM, Vlak MH, de Haan A, et al Calcium regulation and muscle disease J Muscle Res Cell Motil 2002;23(1):59-63 Bouchama A, Knochel JP Heat stroke N Engl J Med 2002;346(25): 1978-1988 Gronert GA Malignant hyperthermia Anesthesiology 1980;53(5): 395-423 Jurkat-Rott K, McCarthy T, Lehmann-Horn F Genetics and pathogenesis of malignant hyperthermia Muscle Nerve 2000;23(1):4-17 Yang T, Riehl J, Esteve E, et al Pharmacologic and functional characteristics of malignant hyperthermia in the R163C RyR1 knock-in mouse Anesthesiology 2006;105(6):1164-1175 Jiang D, Chen W, Xiao, et al Reduced threshold for luminal Ca21 activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia J Biol Chem 2008;283(30):20813-20820 10 Cherednichenko G, Ward CW, Feng W, et al Enhanced excitationcoupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene Mol Pharmacol 2008;73(4):1203-1212 11 Choi RH, Koenig X, Launikonis B Dantrolene requires Mg21 to arrest malignant hyperthermia PNAS 2017;114(18):4811-4815 12 Zhao X, Weisleder N, Han X, et al Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor J Biol Chem 2006;281(44):33477-33486 13 Robinson R, Hopkins P, Carsana A, et al Several interacting genes influence the malignant hyperthermia phenotype Hum Genetics 2003;112(2):217-218 14 Britt BA, Locher WG, Kalow W Hereditary aspects of malignant hyperthermia Can Anaes Soc J 1969;16(2):89-98 15 Girard T, Urwyler A, Censier K, et al Genotype-phenotype comparison of the Swiss malignant hyperthermia population Hum Mutat 2001;18:357-358 doi:10.1002/humu.1203 16 Robinson R, Carpenter D, Shaw M, et al Mutations in RYR1 in malignant hyperthermia and central core disease Hum Mutat 2006; 27(10):977-989 17 Larach MG, Gronert GA, Allen GA, et al Clinical presentation, treatment and complications of malignant hyperthermia in North America from 1987-2006 Anesth Analg 2010;110(2):498-507 18 Brady J, Sun L, Rosenberg H, et al Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005 Anesth Analg 2009;109(4):1162-1166 19 Butala B, Brandom BW Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility Can J Anesth 2017;64:396-401 20 Stowell KM DNA testing for malignant hyperthermia: the reality and the dream Anesth Analg 2014;118:397-406 21 Carpenter D, Ringose C, Leo V, et al The role of CACNA1S in predisposition to malignant hyperthermia BMC Med Genet 2009;10:104 doi:10.1186/1471-2350-10-104 22 Horstick EJ, Linsley JW, Dowling JJ, et al Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy Nat Commun 2013;4:1952 doi:10.1038/ncomms2952 23 Girard T, Treves S, Voronkov E, et al Molecular genetics of MH susceptibility Anesthesiology 2004;100(5):1076-1080 24 Urwyler A, Deufel T, McCarthy T, et al Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia Br J Anaesthesia 2001;86(2):283-287 25 Carpenter D, Robinson RL, Quinnell RJ, et al Genetic variation in RYR1 and malignant hyperthermia phenotypes Br J Anaesth 2009; 103(4):538-548 26 Lopez RJ, Byrne S, Vukcevic M, et al An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities Sci Signal 2016;9(435):ra68 27 Larach MG, Localio AR, Allen GC, et al A clinical grading scale to assess malignant hyperthermia susceptibility Anesthesiology 1994; 80(4):771-779 28 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 29 Visoiu M, Young M, Wieland K, et al Anesthetic drugs and onset of malignant hyperthermia Anesth Analg 2014;118:388-396 30 Newmark JL, Voelkel M, Brandom BW, et al Delayed onset of malignant hyperthermia without creatine kinase elevation in a geriatric, ryanodine receptor type gene compound heterozygous patient Anesthesiology 2007;107(2):350-353 31 Shailesh Kumar MV, Carr RJ, Komanduri V, et al Differential diagnosis of thyroid crisis and malignant hyperthermia in a porcine model Endocr Res 1999;25(1):87-103 32 Herlich A Perioperative temperature elevation: not all hyperthermia is malignant hyperthermia Pediatr Anesth 2013;23:842-850 33 Toltzis P, Rosolowski B, Salvator A Etiology of fever and opportunities for reduction of antibiotic use in a pediatric intensive care unit Infect Control Hosp Epidemiol 2001;22(8):499-504 34 Ezri T, Szmuk P, Weisenberg M, et al The effects of hydration on core temperature in pediatric surgical patients Anesthesiology 2003; 98(4):838-841 35 Schleelein LE, Litman RS Hyperthermia in the pediatric intensive care unit-is it malignant hyperthermia? Pediatr Anesth 2009;19(11): 1113-1118 36 Melli G, Chaudhry V, Cornblath DR, et al Rhabdomyolysis: an evaluation of 475 hospitalized patients Medicine (Baltimore) 2005; 84(6):377-385 37 Brandom BW, Muldoon SM Unexpected MH deaths without exposure to inhalation anesthetics in pediatric patients Pediatr Anesth 2013;23:851-854 38 Tobin JR, Jason DR, Challa VR, et al Malignant hyperthermia and apparent heat stroke JAMA 2001;286(2):168-169 39 Chelu MG, Goonasekera SA, Durham WJ, et al Heat- and anesthesiainduced malignant hyperthermia in an RyR1 knock-in mouse FASEB J 2006;20(2):329-330 40 Karan SM, Crowl F, Muldoon SM Malignant hyperthermia masked by capnographic monitoring Anesth Analg 1994;78(3):590-592 41 Burkman JM, Posner KL, Domino KB Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions Anesthesiology 2007;106(5):901-906 42 Huckell VF, Staniloff HM, Britt BA, et al Electrocardiographic abnormalities associated with malignant hyperthermia susceptibility J Electrocardiol 1982;15(2):137-141 43 Warren JD, Blumbergs PC, Thompson PD Rhabdomyolysis: a review Muscle Nerve 2002;25(3):332-347 44 Britt BA, Kalow W Malignant hyperthermia: a statistical review Can Anaesth Soc J 1970;17(4):293-315 45 Kolb ME, Horne ML, Martz R Dantrolene in human hyperthermia: a multicenter study Anesthesiology 1982;56(4):254-262 46 Lerman J, McLeod ME, Strong HA Pharmacokinetics of intravenous dantrolene in children Anesthesiology 1989;70(4):625-629 47 Flewellen EH, Nelson TE, Jones WP, et al Dantrolene dose response in awake man: implications for management of malignant hyperthermia Anesthesiology 1983;59(4):275-280 e2 48 Brandom BW, Kang A, Sivak EL, et al Update on dantrolene in the treatment of anesthesia induced malignant hyperthermia SOJ Anesthesiol Pain Manage 2015;2:1-6 49 Werneid K, Brandom BW Survey of long-term sequelae in survivors of a malignant hyperthermia reaction Open J Anesthesiol 2016;6:1-7 50 Easley RB, Schleien CL, Shaffner DH Pediatric cardiopulmonary resuscitation In: Motoyama EK, Davis PJ, eds Smith’s Anesthesia for Infants and Children 7th ed Philadelphia, PA: Mosby; 2006: 1110-1154 51 Brandom BW, Larach MG, Chen MA, et al Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States Anesth Analg 2011;112(5):1115-1123 52 Bosch X, Poch E, Grau JM Rhabdomyolysis and acute kidney injury N Engl J Med 2009;361(1):62-72 53 Huerta-Alardin AL, Varon J, Marik PE Bench-to-bedside review: rhabdomyolysis—an overview for clinicians Crit Care 2005;9(2): 158-169 54 Sieb JP, Penn AS Myoglobinuria In: Engel AG, Franzini-Armstrong C, eds Myology 3rd ed New York, NY: McGraw- Hill; 2004:1677-1692 55 de Meijer AR, Fikkers BG, de Keijzer MH, et al Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey Intensive Care Med 2003;29(7):1121-1125 56 Larach MG Standardization of the caffeine halothane muscle contracture test Anesth Analg 1989;69(4):511-515 57 Ording H, Bendixen D Sources of variability in halothane and caffeine contracture tests for susceptibility to malignant hyperthermia Eur J Anaesthesiol 1992;9(5):367-376 58 Larach MG, Landis JR, Bunn JS, et al The North American Malignant Hyperthermia Registry: prediction of malignant hyperthermia susceptibility in low risk subjects Anesthesiology 1992;76(1):16-27 59 Allen GC, Larach MG, Kunselman AR The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry of MHAUS Anesthesiology 1998;88(3):579-588 60 Brandom BW Malignant hyperthermia In: Motoyama EK, Davis PJ, eds Smith’s Anesthesia for Infants and Children 7th ed Philadelphia, PA: Mosby; 2006:1013-1031 61 Riazi S, Kraeva N, Hopkins PM Malignant hyperthermia in the post-genomics era: new perspectives on an old concept Anesthesiology 2018;128(1):168-180 62 Brandom BW, Bina S, Wong CA, et al Ryanodine receptor type gene variants in the malignant hyperthermia-susceptible population of the United States Anesth Analg 2013;116(5):1078-1086 63 Ellis FR, Clarke MC, Modgill M, et al Evaluation of creatine phosphokinase in screening patients for malignant hyperthermia Br Med J 1975;3(5982):511-513 64 Paasuke RT, Brownell AKW Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia JAMA 1986;255(6):769-771 65 Moulds RF, Denborough MA Identification of susceptibility to malignant hyperpyrexia Br Med J 1974;2(5913):245-247 66 Klingler W, Rueffert H, Lehmann-Horn F, et al Core myopathies and risk of malignant hyperthermia Anesth Analg 2009;109(4):11671173 67 Davis PJ, Brandom BW The association of malignant hyperthermia and unusual disease: When you’re hot you’re hot or maybe not Anesth Analg 2009;109(4):1001-1003 68 Kushnir A, Wajsberg B, Marks A Ryanodine receptor dysfunction in human disorders Biochim Biophys Acta 2015;1865(11):1687-1697 69 Parness J, Bandschapp O, Girard T The myotonias and susceptibility to malignant hyperthermia Anesth Analg 2009;109(4):1054-1064 70 Capacchione J, Muldoon S The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia Anest Analg 2009;109(4):1065-1069 71 Grogan H, Hopkins PM Heat stroke: implications for critical care and anesthesia Br J Anaesth 2002;88(5):700-707 72 Fink E, Brandom BW, Torp KD Heatstroke in the super-sized athlete Pediatr Emerg Care 2006;22(7):510-513 73 Sambuughin N, Capacchione J, Blokhin A, et al The ryanodine receptor type gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility Clin Genet 2009;76:564-568 74 Stein MH, Sorscher M, Caroff SN Neuroleptic malignant syndrome induced by metoclopramide in an infant with FreemanSheldon syndrome Anesth Analg 2006;103(3):786-787 75 Henderson A, Longdon P Fulminant metoclopramide induced neuroleptic malignant syndrome rapidly responsive to dantrolene Aust N Z J Med 1991;21(5):742-743 76 Tsutsumi Y, Yamamoto K, Matsuura S, et al The treatment of neuroleptic malignant syndrome using dantrolene sodium Psychiatry Clin Neurosci 1998;52:433-438 77 Caroff SN, Rosenberg H, Fletcher JE, et al Malignant hyperthermia susceptibility in neuroleptic malignant syndrome Anesthesiology 1987;67(1):20-25 78 Geiduschek J, Cohen SA, Khan A, et al Repeated anesthesia for a patient with neuroleptic malignant syndrome Anesthesiology 1988;68(1):134-137 e3 Abstract: Malignant hyperthermia is a rare but potentially lethal autosomal-dominant syndrome with reduced penetrance and variable expression This chapter reviews the presentation, pathophysiology, and treatment of malignant hyperthermia Diagnostic testing and recommendations for further consultations are discussed Key words: malignant hyperthermia, muscle rigidity, rhabdomyolysis, dantrolene, neuroleptic malignant syndrome 131 Neuromuscular Blocking Agents JOSEPH D TOBIAS PEARLS • • Through the blockade of skeletal muscle function, neuromuscular blocking agents (NMBAs) cause cessation of respiratory function, mandating airway control and the institution of mechanical ventilation NMBAs should not be administered if there is any question as to the normalcy of the airway and the ability to successfully accomplish bag-valve-mask ventilation The term NMBA rather than muscle relaxant may be preferable, as the latter may imply some type of sedative or relaxant property that these agents not possess Use of the term NMBAs identifies in their name their mechanism of action, further In the pediatric ICU (PICU) setting, there are clinical circumstances in which prevention of movement is necessary, mandating the use of neuromuscular blocking agents (NMBAs; Box 131.1).1 Although these agents can be used as a single dose to facilitate brief procedures such as endotracheal intubation, prolonged administration may be necessary in specific clinical scenarios With an improved understanding of the techniques for providing sedation and analgesia in the PICU setting and data demonstrating not only their adverse effect profile but also their lack of efficacy in specific clinical scenarios, there has been a decrease in the prolonged administration of NMBAs.2 However, these agents are still used in various clinical scenarios, most commonly as an adjunct in the control of intracranial pressure (ICP), to prevent shivering during hypothermia following cardiac arrest, and during the early care of patients with acute respiratory distress syndrome.3–6 Given their adverse effect profile, including the potential for increased nosocomial infections, longer duration of mechanical ventilation, atelectasis with ventilation-perfusion mismatching, and pressure injuries, NMBAs should be used only when absolutely indicated Daily review of their continued need is suggested Their administration should be guided by healthcare personnel with training in NMBAs’ pharmacologic adverse effect profile Use of the term muscle relaxant should be avoided, as this seems to imply some implicit sedative or relaxing property, which these agents not possess Because these agents provide no amnestic, analgesic, or sedative properties, coadministration of an amnestic agent (benzodiazepine, ketamine, or propofol) is necessary whenever they are used The term NMBA is preferred because it identifies the mechanism of action of these agents as a competitive antagonist for acetylcholine at the neuromuscular junction • emphasizing that they are devoid of sedative or analgesic properties NMBAs can broadly be divided into two separate classes on the basis of their mechanism of action Depolarizing agents such as succinylcholine mimic the action of acetylcholine at the neuromuscular junction and activate or depolarize the muscle, whereas nondepolarizing agents such as vecuronium act as a competitive antagonist to the effects of acetylcholine at the neuromuscular junction, thereby blocking its effects Following the administration of an NMBA and the blockade of skeletal muscle function, including the diaphragm, cessation of ventilation with apnea necessitates airway control with endotracheal intubation and the institution of mechanical ventilation The inability to manage the airway, including the provision of bag-valve-mask ventilation and endotracheal intubation, will result in the potential for hypoxemia and death As such, before these agents are used for endotracheal intubation, the normalcy of the airway and ability to provide bag-valve-mask ventilation and endotracheal intubation should be assessed.7,8 If problems managing the airway or accomplishing endotracheal intubation are anticipated, NMBAs should not be administered Furthermore, when using these medications, one should be familiar with the “cannot intubate/cannot ventilate” algorithm and have ready access to the needed equipment for rescue in this scenario.8 Neuromuscular Junction Normal neuromuscular transmission results from the release of acetylcholine from the presynaptic nerve terminal, its movement across the synaptic cleft, and binding to the postsynaptic nicotinic receptor on the sarcolemma of the skeletal muscle Acetylcholine is synthesized in the cytoplasm of the neuron from acetyl coenzyme A and choline and stored in synaptic vesicles in the axonal terminals of the presynaptic membrane Depolarization of the presynaptic axonal membrane opens calcium channels (P channel) The movement of calcium through the channels in the presynaptic membrane results in the movement of synaptic vesicles to and fusion with the membrane This is followed by the release of acetylcholine into the synaptic cleft After its release from the 1567 1568 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit • BOX 131.1 Potential Applications of Neuromuscular Blockade in the Pediatric Intensive Care Unit Facilitation of procedures or diagnostic studies • Endotracheal intubation • Invasive procedures (central line placement) • Radiologic imaging (magnetic resonance imaging or computed tomography scanning) Immobilization during interhospital or intrahospital transportation Intensive care indications • Facilitating mechanical ventilation (early phases of acute respiratory distress syndrome) • Controlling increased intracranial pressure • Eliminating shivering (during therapeutic hypothermia) • Decreasing peripheral oxygen utilization • Controlling severe agitation unresponsive to adequate sedation • Maintaining immobilization after surgical procedures • Controlling pulmonary vasospasm in patients with pulmonary hypertension • Management of patients with tetanus synaptic vesicles, acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors on the postsynaptic membrane (sarcolemma) This results in depolarization of the sarcolemma, the release of calcium from the sarcoplasmic reticulum, and muscle contraction The P channel can be blocked by cations such as magnesium and lithium but generally not to a clinically significant degree by calcium channel antagonists Given their ability to block the inward movement of calcium and thereby disrupt the release of acetylcholine into the synaptic cleft, magnesium or lithium will potentiate the effect of nondepolarizing NMBAs The excessive administration of either cation can have significant effects on normal neuromuscular function and cause muscle weakness The acetylcholine receptor (nicotinic receptor on the sarcolemma) is a pentameric protein composed of five subunits There are five possible subunits (a, b, g, d, and e), each of which is encoded by a different gene The normal acetylcholine receptor found in adults includes two a subunits combined with one each of the b, d, and e subunits Binding of an acetylcholine molecule to each of the two a subunits is necessary for depolarization of the sarcolemma During various stages of development or in pathologic disease states, the composition of the acetylcholine receptor may change Immature and denervated acetylcholine receptors have a g subunit instead of the e, while a demyelinated neuromuscular junction contains acetylcholine receptors composed of a pentamer of a subunits The importance of these variants is that their response (opening of the ion channel) may be dramatically different from the normal adult variant of the acetylcholine receptor These differences can have devastating consequences following the administration of the depolarizing NMBA succinylcholine The channel may remain open for a prolonged period, resulting in the release of intracellular potassium and systemic hyperkalemia The acetylcholine receptor occupies the entire membrane from the outside of the muscle through the cell membrane to the inside, regulating the transmembrane movement of ions The receptor acts to convert the chemical stimulus (acetylcholine) into an electrical impulse that results in the depolarization of the sarcolemma The depolarization of the sarcolemma results in the release of calcium from the sarcoplasmic reticulum (SR) and muscle contraction Stimulation of the acetylcholine receptor opens ion channels, allowing the movement of small, positively charged cations such as sodium, potassium, and calcium The sodium influx depolarizes the muscle membrane, leading to the release of calcium from the SR and muscle contraction Cessation of muscle contraction is mediated by the metabolism of acetylcholine by the enzyme acetylcholinesterase, which is present in the synaptic cleft Once acetylcholine is metabolized, the sarcolemma can repolarize, resetting the muscle for the next round of depolarization Failure to metabolize acetylcholine that is bound to the receptor results in prolonged depolarization, inability to repolarize the sarcolemma, and cessation of further contraction Neuromuscular Blocking Agents: Depolarizing Agents The two general classes of NMBAs (depolarizing and nondepolarizing agents) differ in their basic mechanism of action Depolarizing agents such as succinylcholine (suxamethonium in Europe and the United Kingdom) mimic the effects of acetylcholine, binding to the acetylcholine receptor at the neuromuscular junction and activating it As succinylcholine is resistant to degradation by acetylcholinesterase, there is sustained occupation of the receptor and failure of repolarization, which results in neuromuscular blockade This action of succinylcholine accounts for the clinical effects observed, including the initial muscle fasciculations followed by flaccid paralysis lasting to 10 minutes, the time necessary for the degradation of succinylcholine by pseudocholinesterase and subsequent repolarization of the sarcolemma The onset of action of succinylcholine is more rapid than any of the nondepolarizing agents with neuromuscular blockade, occurring in 30 to 45 seconds, allowing for rapid control of the airway with endotracheal intubation Additionally, studies comparing succinylcholine to nondepolarizing NMBAs suggest that it produces better conditions for endotracheal intubation.9 After occupancy of the acetylcholine receptor, succinylcholine undergoes rapid redistribution and metabolism by the plasma enzyme pseudocholinesterase (butyrylcholinesterase), which limits its clinical duration to to 10 minutes In rare clinical circumstances, the congenital or acquired deficiency of pseudocholinesterase can prolong the duration of action of succinylcholine Clinical conditions may result in defects in the total amount or concentration of the enzyme (quantitative defect) or efficacy of the enzyme (qualitative defect).10 Decreased enzyme levels (quantitative defects) are usually acquired while qualitative issues are inherited The inherited form of pseudocholinesterase deficiency, resulting in a qualitative defect in the enzyme, is an autosomal-recessive trait with an incidence of 1:2500 to 1:3500 of the general population Only homozygotes have a clinically significant prolongation of the effect of succinylcholine, with neuromuscular blockade lasting up to to hours following a single dose of succinylcholine (1–2 mg/kg) Conditions that lead to a quantitative decrease in pseudocholinesterase levels include severe hepatic disease, thyroid dysfunction (myxedema), pregnancy, protein-calorie malnutrition, and certain malignancies Drugs and medications can also affect pseudocholinesterase levels, including chemotherapeutic agents such as cyclophosphamide and echothiophate ophthalmic drops Deficiency can also result from the recent use of plasmapheresis, as the enzyme is removed with the plasma With either qualitative or quantitative defects of pseudocholinesterase, clinical ... hyperpyrexia Br Med J 1974;2(5913):245-247 66 Klingler W, Rueffert H, Lehmann-Horn F, et al Core myopathies and risk of malignant hyperthermia Anesth Analg 2009;109(4):11671173 67 Davis PJ, Brandom... potentially lethal autosomal-dominant syndrome with reduced penetrance and variable expression This chapter reviews the presentation, pathophysiology, and treatment of malignant hyperthermia... NMBAs’ pharmacologic adverse effect profile Use of the term muscle relaxant should be avoided, as this seems to imply some implicit sedative or relaxing property, which these agents not possess