Malignant Hyperthermia

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Malignant Hyperthermia
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Presentation transcript:

Malignant Hyperthermia Rahul Mistry, Sama Abdulnabi, Xu Tao Li PHM 142 Fall 2018 Instructor: Dr. J. Henderson Date: 20 November 2018

Case Study Don Mahann, 42, underwent surgical repair of his torn anterior cruciate ligament and has arrived in the postanesthesia care. You notice muscle rigidity in his jaw, abnormally quick breathing, and an increased heart rate. His blood pressure is 154/90 and his temperature has jumped to 104 F from 100 F only minutes ago. He has no significant medical history. Looking at his patient records, you notice he received isoflurane for general anesthesia.

What is malignant hyperthermia? Must first understand muscle contraction… Acetylcholine released from presynaptic terminal → Nicotinic Receptors Depolarization in the sarcolemma Conformational change in dihydropyridine voltage-gated receptor Ca2+ channel/ryanodine receptor is RyR1 in the sarcoplasmic reticulum Ca2+ influx into cytosol Initiating the actin-myosin muscle contraction mechanism Malignant - a term for diseases in which abnormal cells divide without control and can invade nearby tissues Hyperthermia - abnormally high body temperature

Triggered by anesthetics and depolarizing muscle relaxants Reuptake of calcium into the sarcoplasmic reticulum via an ATP-dependent calcium pump RyR1 positive feedback and possible cooperativity Triggered by anesthetics and depolarizing muscle relaxants Reference: Schneiderbanger D, Johannsen S, Roewer N, and Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014; 10: 355-362.

Pre-Operative Paralysis Binding to the nicotinic receptors → open for a prolonged period of time Result: permanent refractory period = desired paralysis effect during operations Katzung BG, Masters Sb, Trevor AJ: Basic & Clinical Pharmacology, 11th edition.

Manifestation of Malignant Hyperthermia Lower threshold? Mutant RyR1 : Increased rate of Ca2+ release The rate of Ca2+ uptake remains the same Reference: Schneiderbanger D, Johannsen S, Roewer N, and Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014; 10: 355-362.

Voltage Threshold Sensitivity Theory It was proposed that the threshold for activation of these abnormal RyR1 are lower than the wild type causing Ca2+ spillage→ spasm/rigidity Mutation Arg615Cys in RyR1 found IN PIGS! Jiang D et al. Reduced Threshold for Luminal Ca2+ Activation of RyR1 Underlies a Causal Mechanism of Porcine Malignant Hyperthermia. J. Biol. Chem

Cause of Malignant Hyperthermia For humans, dominant mutation in RyR1 is Gly2434Arg Struk A, Lehmann F, Melzer W. Voltage-Dependent Calcium Release in Human Malignant Hyperthermia Muscle Fibers. Biophys J

Manifestation of Malignant Hyperthermia Mutant DHR Lower threshold? **Arg1086His There can still be a voltage effect: Mutant RyR1 : Increased rate of Ca2+ release OR Abnormal interaction with DHR The rate of Ca2+ uptake remains the same Reference: Schneiderbanger D, Johannsen S, Roewer N, and Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014; 10: 355-362.

Triggers of malignant hyperthermia All volatile (inhalation) anesthetic agents Depolarizing agents Halothane, sevoflurane, desflurane, isoflurane Succinylcholine Skeletal muscle relaxant Poorer survival rates in patients who received both succinylcholine and a volatile anesthetic agent Vigorous exercise and heat Very rare in humans Reference: LiveScience. You Might Be Slightly Conscious Under Anaesthesia. https://www.livescience.com/63068-brain-conscious-anesthesia.html

Clinical signs and symptoms Almost all MH patients don’t show physiological changes without anesthesia Highly variable Early: Tachycardia Tachypnea Masseter spasm Muscular rigidity Combined metabolic-respiratory acidosis Late: Hyperthermia Rhabdomyolysis Acute renal failure Cardiac arrhythmia Hypotension Circulatory failure

Diagnosis Clinical presentation of symptoms Laboratory diagnosis: caffeine-halothane muscle contracture test The gold standard! Small piece of skeletal muscle obtained Muscle exposed to caffeine and then halothane Rate and force of contraction recorded electronically MH-susceptible muscle is more sensitive and contracts with a greater sustained force than normal muscle

Treatment History Numerous anesthesia related deaths due to perioperative hyperthermia 1960: Found MH to be an independent syndrome linked to anesthesia 1975: introduction of dantrolene as a specific ryanodine receptor antagonist Mortality rate due to acute MH dropped from 70-80% to 5%

Initial Treatment As soon as MH is suspected, doctors must act rapidly to treat the symptoms and prevent complications Immediately stop giving trigger medication and stop the surgery Maybe add a point about administering dantrolene to transition to next slide

Dantrolene Acts a specific ryanodine receptor (RyR1) antagonist and inhibits the release of Ca2+ from the SR Relaxes muscles Given intravenously at 2.5 mg/kg repeated every 5 minutes until patient’s cardiac and respiratory systems are stabilized Ca2+ blockers via verapamil should not be used along with dantrolene Hyperkalemia and profound hypotension may occur Reference: Patterson Dental. Dantrium IV, Dantrolene Sodium - Intravenous Injection. https://www.pattersondental.com/Supplies/ItemDetail/070437079

Other Forms of Management Cooling the body by all available routes Intravenous saline at 4 C, topical ice to all exposed areas Lowering body temperature with cooling blankets, fans Administering supplemental oxygen Using medications to control heartbeat and stabilize blood pressure Monitoring in an intensive care unit

Case Study Don Mahann, 42, underwent surgical repair of a torn anterior cruciate ligament and has arrived in the postanesthesia care. You notice muscle rigidity in his jaw, abnormally quick breathing, and an increased heart rate. His blood pressure is 154/90 and his temperature has jumped to 104 F from 100 F only minutes ago. He has no significant medical history. Looking at his patient records, you notice he received isoflurane for general anesthesia.

Summary Malignant hyperthermia is a pharmacogenetic disorder of skeletal muscle Cause of MH in humans: dominant mutation in RyR1 is Gly2434Arg Mutant RyR1 receptor: increased Ca2+ release into the synaptic cleft, reuptake of Ca2+ stays the same Triggers of MH: all volatile anaesthetic agents and succinylcholine Clinical signs are highly variable and not shown without anesthesia Diagnosis: caffeine-halothane muscle contracture test Treatment: stop the anaesthesia and administer dantrolene Cool the body down!

References Endo M., Yagi S., Ishizuka T., Horiuti K., Koga Y., Amaha, K. Changes in the Ca-induced Ca release mechanism in the sarcoplasmic reticulum of the muscle from a patient with malignant hyperthermia. Biomedical Research [Internet]. 1983; 4(1):83-92. Available from: https://www.jstage.jst.go.jp/article/biomedres/4/1/4_83/_article Rosenberg H, Pollack N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet Journal of Rare Diseases [Internet]. 2015;10:93. DOI 10.1186/s13023-015-0310-1 Jiang D et al. Reduced Threshold for Luminal Ca2+ Activation of RyR1Underlies a Causal Mechanism of Porcine Malignant Hyperthermia. J. Biol. Chem [Internet]. 2008 July; 283(30): 20813–20820. doi: 10.1074/jbc.M801944200. Monnier N, Procaccio V, Stieglitz P, Lunardi L. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet [Internet]. 1997 Jun; 60(6): 1316–1325. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1716149/. Flucher BE, Franzini-Armstrong C. Formation of junctions involved in excitation-contraction coupling in skeletal and cardiac muscle. Proc Natl Acad Sci U S A. 1996 Jul 23; 93(15):8101-6. Cheng W, Altafaj X, Ronjat M, Coronado R. Interaction between the dihydropyridine receptor Ca2+ channel β-subunit and ryanodine receptor type 1 strengthens excitation-contraction coupling. Proc Natl Acad Sci U S A [Internet]. 2005 Dec; 102(52): 19225–19230. doi: [10.1073/pnas.0504334102] Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. J Biol Chem. 2007;282:37471–37478. Struk A, Lehmann F, Melzer W. Voltage-Dependent Calcium Release in Human Malignant Hyperthermia Muscle Fibers. Biophys J [Internet]. 1998 Nov; 75: 2402–2410. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9788935 Nursing Management. Malignant hyperthermia: A case study. 2006; 8. Rosenberg H, Pollock N, Schiemann A, Bulger T, and Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015; 10: 93. Schneiderbanger D, Johannsen S, Roewer N, and Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014; 10: 355-362. Hopkins PM. Malignant hyperthermia: pharmacology of triggering. BJA. 2011; 107(1): 48-56. Hommertzheim R, Steinke EE. Malignant hypertherima--the perioperative nurse’s role. AORN J. 2006; 83(3): 601.