1. PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson Malignant Hyperthermia By: Charlotte Lin, Kathy Nguyen, Keisha Desa, Howard Pan

2. Outline • •Introduction • •Symptoms and Diagnosis • •Treatment and Prevention • •Biochemical Mechanism • •Conclusion

3. Introduction

4. What is MH? - Overview • •Rare, inherited • •Defect in Ryanodine receptor • •Undiagnosed until exposure • to anesthesia • •Hypermetabolic Response

5. What is MH? - Genetics •Autosomal dominant •Close to 100 mutations in the RYR-1 gene identified •Located on chromosome 19q13.1 •Ryanodine protein: N or C terminus •Result: Increased intracellular Calcium

6. Symptoms and Diagnosis

7. Early Symptoms Skeletal Muscle Rigidity

8. Early Symptoms Very Fast Increase in Body Temperature (Hyperthermia)

9. Early Symptoms Tachycardia – increased heart rate

10. Other Early Symptoms • Muscle Spasms • Sweating • Tachypnea – increased breathing rate • Metabolic and Respiratory Acidosis and Cellular Ion Imbalances

11. Late Symptoms Within minutes, the patient can die from cardiac arrest

12. Late Symptoms Within hours, the patient can die from pulmonary edema or coagulopathy:

13. Late Symptoms Within days, the patient can die from neurological damage or obstructive renal failure

14. Summary of Symptoms

15. Clinical Diagnosis • On average, it may take up to 3 anesthesia encounters before a MH episode is triggered • May happen during anesthesia or within the early post-op period (first few hours) • The primary indicative symptoms include: unexplained elevation of end-tidal carbon dioxide (ETCO2) concentration, muscle rigidity, tachycardia, acidosis & hyperthermia • Diagnosis is difficult because of the high degree of clinical variability in the order of the symptoms and the time of onset

16. Clinical Diagnosis • In a 1994 conference, an international panel of 11 MH experts devised the following diagnostic scale:

17. Treatment and Prevention

18. Treatment of Acute MH Crisis • Discontinue triggering agents • Hyperventilation with 100% oxygen to lower end tidal CO2 and eliminate anesthetic from the body • IV admin of dantrolene • initial dose of 2.5mg/kg • repeat every 5 min until all symptoms subside • Cooling measures to reduce fever

19. Management of Complications • Use bicarbonate to treat acidosis • Insulin with glucose to treat hyperkalemia • Beta blockers or lidocaine for arrhythmia and coagulopathy but not calcium channel blockers • Aggressive hydration to treat myoglobinuria

20. Dantrolene • Muscle relaxant • Act on RyR1 and RyR3 direct to inhibit calcium release • Poorly water soluble • Alkaline preparation highly irritating • Drug-drug interaction with calcium channel blockers

21. Prevention • Assess susceptibility • Anesthetic history of patient or family member • Caffeine-halothane contracture test • DNA testing • Preparation of anesthesia machine: • Remove vaporizers • Flush through the machine with 100% oxygen • Use a new breathing circuit

22. Biochemical Mechanisms

23. Biochemical Mechanisms • Most common mutation occurs in the Ryanodine Receptor (RyR) protein • - Other mutations exist • The job of RyR is to release Ca2+ from ER to cytosol • Presence of Ca2+ in cytosol initiate muscle contraction (excitation-contraction coupling) Ryanodine Receptor

24. Biochemical Mechanisms Excitation-contraction coupling: - AP of neuron cause acetylcholine release - Acetylcholine bind to nicotinic receptors - Nicotinic receptors initiate end-plate potential (EPP) - End-plate potential cause RyR to release Ca2+ from endoplasmic reticulum

25. Biochemical Mechanisms • Excitation-contraction coupling: • - Ca2+ causes muscles to contract • - Process is stopped when EPP is stopped and Ca2+ is removed from cytosol • Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) • Ca2+ pumps • Na+-Ca2+ exchanger

26. Biochemical Mechanisms • RyR mutation: • - Leads to very sensitive RyR that release Ca2+ easily • - Frequent release of Ca2+ cause muscles to contract constantly • - High ATP requirement for muscles • Cross-bridge cycling • SERCA • Other Ca2+ pumps

27. Biochemical Mechanisms Problems with high ATP requirement: -Mitochondrial activity pushed to the max • Intense heat production -Mitochondria cannot keep up with oxidative phosphorylation • Instead utilize glycolysis (lactic acid production) • Metabolic acidosis

28. Biochemical Mechanisms • As a result: • - Body temperature increases rapidly • Enzymes won't function properly in body • Organ dysfunction • Muscle breakdown • Heart failure • Kidney failure • - Blood pH drops (metabolic acidosis) • Leads to coma

29. Biochemical Mechanism • A word on general anesthesia induced MH: • - Still an active area of research • - Mechanisms are not yet fully understood

30. Malignant Hyperthermia Summary • MH is a rare, autosomal dominant disorder with a mutation in a part of chromosome 19 coding for the Ryanodine receptor (RyR) gene causing RyR hypersensitivity • Diagnostic symptoms of MH include: skeletal muscle rigidity, hyperthermia and acidosis • Without clinical intervention, the patient will succumb as critical organ systems fail (cardiac arrest, pulmonary edema, neurological damage) • Hypersensitive RyR leads to Ca2+ leakage into cytoplasm from ER causing increased metabolism and continuous muscle contraction. • Hypermetabolic state of cells leads to increased body temperature and metabolic acidosis. • Steps to treatment: • 1. remove triggering agent • 2. hyperventilate • 3. IV administration of dantrolene • 4. cooling measure • 5. bicarbonate, glucose-insulin, hydration

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