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MALIGNANT HYPERTHERMIA Presented by: Christine Nwosu, Husban Ahmad, Taidhg Wickham, Maximus Yaghchi Presented on: November 29, 2016 PHM142 Fall 2016 Instructor: Dr. Jeffrey Henderson What is Malignant Hyperthermia? Malignant Hyperthermia (MH) is a rare life-threating disorder triggered by general anesthesia drugs such as volatile anesthesia and depolarizing muscle relaxants. It leads to a rapid and sustained rise in body temperature due to increase in intracelluar calcium. Occurs in susceptible individuals with autosomal mutations in the ryanodine receptor type 1 gene (RYR1). MH affects 1:5,000-1:100,000 anesthesias all over the world and all ethnic groups. Clinical Signs patientsafetyauthority.org Ryanodine Receptor Type 1 gene (RYR1) RYR1 gene, located on chromosome 19 encodes the ryanodine receptor type 1. Ryanodine receptor type 1 is a calcium channel in skeletal muscle important for excitation-contraction coupling. 50-70% of MH patients have gain of function mutations in the RYR1 gene. R Zalk et al. Nature 000, 1-6 (2014) doi:10.1038/nature13950 Healthy Skeletal Muscle Contraction An electrical impulse is carried by a motor neuron to the muscle motor end plate, thereby depolarizing the sarcolemma The wave of depolarization spreads throughout the fiber, and travels into the T-tubules The change in voltage is detected by the dihydropyridine receptor (DHP) A voltage-dependent, L-type calcium channel The DHP receptors physically interact with Ryanodine (RyR-1) receptors on the sarcoplasmic reticulum which contains Ca++ Activated DHP receptors induce a conformational change in RyR-1 receptors Ca++ is released from the SR and binds to Troponin C Cross-bridges form between actin and myosin, and contraction ensues A Closer Look at RyR-1 RyR-1 is also regulated by its surrounding Ca++ concentration It contains: An A-SITE (high affinity) that can bind Ca++ and activate the channel An I-site (low affinity) that can bind Ca++ and inhibit the channel Mg2+ acts as an inhibitor of the RyR-1 receptor (A-site antagonist, I-site agonist) In MH, the RyR-1 receptor demonstrates a decreased affinity for the Mg2+ ion Deregulation of the receptor induces the release of large quantities of Ca++ from the SR after exposure to an anaesthetic agent Pathophysiology of MH Malignant Hyperthermia (MH) primarily caused by a mutation/defect in the RYR-1 receptor MH effects only seen when susceptible individuals are exposed to triggering agents Volatile anaesthetic gases and depolarizing muscle relaxants are examples Results in a drastic increase in intracellular Ca++ levels and muscle contraction Effects of Elevated Ca++ Levels Anaesthetic agents induce an abnormal release of Ca++ from the SR This results in sustained muscle contraction, which causes an increase in aerobic and anaerobic metabolism (a hyper-metabolic state) Muscle fibers are eventually depleted of adenosine triphosphate (ATP), causing them to become rigid or break-down CO2 and lactic acid levels in the blood are increased, resulting in blood acidosis Hyper-metabolic state prompts an extreme temperature elevation and tachycardia Immediate Risks of MH Potassium ions released from the skeletal muscle result in hyperkalemia, which can have a significant impact on the coordination of heart muscle contraction If untreated the potassium ions will depolarize the cardiomyocyte membranes causing potentially fatal heart rhythms This process begins immediately after onset of MH and can result in fibrillation in as little as a few minutes Irregular heartbeats are the most common cause of death in MH patients Modified from Ho, M. (2015). ECG Changes with Hypo/Hyperkalemia Treatment Dantrolene Hydantoin derivative Inhibits Ca2+ release from the SR by limiting the activation of RyR-1 Amino acid residues of the 1400 base N-terminal region bind dantrolene Dantrolene Study Azumolene: A more soluble analog of dantrolene sodium (N) Used to outcompete [3H]azidodantrolene probe (T) Clinical Procedure Indicators of Malignant Hyperthermia Core Temperature Monitored during and post-operation 1-2 °C increase every 5 minutes Other Symptoms: Muscle Rigidity Tachycardia Increased end-exhale CO2 Clinical Procedure Stop Operation Remove Anesthetic May use Propofol, ketamine, catecholamines, nondepolarizing muscle relaxants, catechol congeners, digitalis, or NO instead Begin External Cooling Administer Dantrolene 2.5 mg/kg every 5 minutes IV up to a 10 mg/kg cumulative Testing for Malignant Hyperthermia Caffeine Halothane Contracture Test A muscle biopsy is completed and the muscle specimen is electrically stimulated in normal conditions and in the presence of halothane and caffeine If abnormal contraction is recorded in the presence of these compounds the result is positive Considered 95% accurate Genetic Testing Genetic testing is currently not sufficient to rule out MH as known MH mutations only account for 50-70% of all MH cases Genetic testing can be used as a preliminary test prior to muscle biopsy as a positive result can be used to accurately diagnose MH Iaizzo P. (2016) The Visible Heart Laboratory, University of Minnesota Prevention + Future Interventions Screening Database (23 and Me) Track carriers before surgery Genetic Counseling Gene editing RYR-1 Summary Malignant Hyperthermia (MH) is a rare life-threating disorder triggered by general anesthesia drugs resulting in rapid increase in body temperature MH is due to a mutation/defect in the gene that codes for RyR-1 on chromosome 19 The receptor demonstrates increased sensitivity towards anaesthetic agents Leads to dysfunction in Ca++ homeostasis and a build-up of calcium in skeletal muscle Sustained muscle contraction drastically increases aerobic and anaerobic metabolism, thereby increasing CO2 production, lactic acid, muscle rigidity and body temperature MH results from a mutation/defect in the gene that codes for RyR-1 on chromosome 19 The receptor demonstrates increased sensitivity towards anaesthetic agents Leads to dysfunction in Ca++ homeostasis and a build-up of calcium in skeletal muscle Sustained muscle contraction drastically increases aerobic and anaerobic metabolism, thereby increasing CO2 production, lactic acid, muscle rigidity and body temperature Rhabdomyolysis (myocyte destruction) results in release of K+ that can cause arrythmias Myoglobin released by destroyed myocytes may cause oxidative damage, which can lead to acute renal failure References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Zalk R, Clarke OB, des Georges A, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR (2015) Structure of a mammalian ryanodine receptor. Nature 517:44–49. Stephens J, Schiemann AH, Roesl C, Miller D, Massey S, Pollock N, Bulger T, Stowell K (2016) Functional analysis of RYR1 variants linked to malignant hyperthermia. Temperature (Austin) 3(2): 328-339. http://www.pie.med.utoronto.ca/mh/index.htm Rosenberg H, Davis M, James D, Pollock N, and Stowell K. (2007) Maliganant Hyperthermia. Orphanet J Rare Disease 2:21. Balog, E., Fruen, B., Shomer, N., & Louis, C. (2001, October). Divergent Effects of the Malignant Hyperthermia-Susceptible Arg6153Cys Mutation on the Ca21 and Mg21 Dependence of the RyR1. Biophysical Journal, 81, 2050-2058. Fill, M., & Copello, J. (2002, January 10). Ryanodine Receptor Calcium Release Channels. Physiological Reviews, 82(4), 893-9. Ording, H. (1989). Pathophysiology of Malignant Hyperthermia. Annales Françaises D'Anesthésie Et De Réanimation, 8(5), 411-416. Dirksen, S., Larach, M., Rosenberg, H., Brandom, B., Parness, J., Lang, R., Gangadharan, M., & Pezalski, T. (2011). Future Directions in Malignant Hyperthermia Research and Patient Care. Anesthesia and Analgesia, 113(5), 1108–1119. Petejova N, Martinek A. (2014) Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a crtical review. Crit Care, 18(3), 224. Stowell K. (2014) DNA testing for malignant hyperthermia: the reality and the dream. Anesthesia and Analgesia, 118, 397–406 Balog, E., Fruen, B., Shomer, N., & Louis, C. (2001, October). Divergent Effects of the Malignant Hyperthermia-Susceptible Arg6153Cys Mutation on the Ca21 and Mg21 Dependence of the RyR1. Biophysical Journal, 81, 2050-2058. Retrieved November 26, 2016, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1301678/pdf/11566777.pd Fill, M., & Copello, J. (2002, January 10). Ryanodine Receptor Calcium Release Channels. Physiological Reviews, 82(4), 893-922. Retrieved November 26, 2016, from http://physrev.physiology.org/content/82/4/893 Ording, H. (1989). Pathophysiology of Malignant Hyperthermia. Annales Françaises D'Anesthésie Et De Réanimation, 8(5), 411-416. Retrieved November 26, 2016, from http://www.sciencedirect.com/science/article/pii/S0750765889800073 Managing An MH Crisis. (2016). MHAUS. Retrieved 29 November 2016, from http://www.mhaus.org/healthcare-professionals/managing-a-crisis Palnitkar, S., Bin, Jimenez, L., Morimoto, H., Williams, P., Paul-Pletzer, K., & Parness, J. (1999). [ 3 H]Azidodantrolene: Synthesis and Use in Identification of a Putative Skeletal Muscle Dantrolene Binding Site in Sarcoplasmic Reticulum ◊. J. Med. Chem., 42(11), 1872-1880. http://dx.doi.org/10.1021/jm9805079 Paul-Pletzer, K., Yamamoto, T., Bhat, M., Ma, J., Ikemoto, N., & Jimenez, L. et al. (2002). Identification of a Dantrolene-binding Sequence on the Skeletal Muscle Ryanodine Receptor. Journal Of Biological Chemistry, 277(38), 34918-34923. http://dx.doi.org/10.1074/jbc.m205487200 Rosenberg, H., Pollock, N., Schiemann, A., Bulger, T., & Stowell, K. (2015). Malignant hyperthermia: a review. Orphanet Journal Of Rare Diseases, 10(1). http://dx.doi.org/10.1186/s13023-015-0310-1