1. Hot and Intolerable: Working with MH Brooks Ohlson March 8 th, 2012 University of Washington

2. Case CC: 14 year old boy with abdominal pain HPI: 2 days of constant, achy abdominal pain that started near the umbilicus and is now centered in the RLQ. Complains of fevers, chills, N/V/D, anorexia simultaneously. PMH: Healthy teenage boy PSH: Tonsillectomy at age 5 FH: Mom, “his uncle almost died under anesthesia…” PHYSICAL EXAM VS: T 38.7C, HR 130s, RR 22, BP 142/86 Abd: Tender to palpation in RLQ, Psoas (+), Rebound tenderness Imaging:

4. Outline Overview of Physiology / Pathophysiology Epidemiology and Genetics Symptoms / Diagnosis / Treatment Evaluating for Susceptibility

5. Physiology / Pathophysiology

6. Molecular Mechanics of Skeletal Muscle Activation Miller RD. Miller’s anesthesia. Philadelphia: Churchill Livingstone-Elsevier; 2010. Mg 2+ ATP

7. Molecular Mechanics of Skeletal Muscle Activation Miller RD. Miller’s anesthesia. Philadelphia: Churchill Livingstone-Elsevier; 2010. ATP

8. Epidemiology / Genetics

9. Genetics of MH 50-80% of patients have mutations in RYR1 140+ missense mutations Unclear ethnic distribution Inheritance probably more complicated than autosomal dominant with variable penetrance Miller RD. Miller’s anesthesia. Philadelphia: Churchill Livingstone-Elsevier; 2010.

10. Epidemiology Estimated incidence of 1:5,000 – 100,000 anesthetics given Approximately 3 anesthetics before trigger Males 2:1 Females Mean age of reaction 18.3 years 52.1% of all reactions were < 15 years old Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis. 2007;2:21.

11. Epidemiology Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth. Analg. 1993;77(2):297–304.

12. Diagnosis and Treatment

13. Triggers Inhaled anesthetics: Ether, halothane, enflurane, isoflurane, sevoflurane, desflurane Depolarizing muscle relaxants: Succinylcholine Onset is variable: –Mild hypothermia, Barbiturates, Tranquilizers, Propofol, Nondepolarizing neuromuscular blockers –Fulminant MH can occur even if triggers were tolerated previously Heat, febrile illness, extreme exercise, MDMA(?), statins(?), methylene blue(?), ondansetron(?) are potential triggers What about caffeine? Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011;107(1):48–56.

14. Machine Preparation Kim TW, Nemergut ME. Preparation of Modern Anesthesia Workstations for Malignant Hyperthermia–susceptible Patients. Anesthesiology. 2011;114(1):205–212.

15. Usual Clinical Course 1.Rigidity after induction with thiopental and succinylcholine followed by… 2.Onset of: 1.Sinus tachycardia, ventricular arrhythmias 2.Skeletal muscle rigidity 3.Tachypnea (spontaneous ventilation) 4.Decreased O 2 saturation 5.Increased end-tidal P CO 2 6.Combined acidosis 7.Central Venous desaturation 8.Increase in Temp. > 38.8°C without obvious cause

16. The Differential Miller RD. Miller’s anesthesia. Philadelphia: Churchill Livingstone-Elsevier; 2010.

17. Pathophysiology Skeletal muscle rigidity and membrane disruption –K +, Ca 2+ ion, CK (unreliable), Myoglobin, Na + Increased aerobic, anaerobic metabolism –Heat, CO 2, lactate Sympathetic Hyperactivity –Tachycardia Cell death / ATP exhaustion –Anasarca, DIC, Cardiac failure, Renal failure Lehmann-Horn F, Klingler W, Jurkat-Rott K. Nonanesthetic Malignant Hyperthermia. Anesthesiology. 2011;115(5):915–917.

18. Treatment 1.Discontinue anesthetic gases, hyperventilate the patient with 100% O 2 2.Dantrolene 3.Bicarbonate and frequent pH checks 4.Cooling to T < 39°C 5.Monitor UOP, aggressively diurese 6.Treat electrolyte abnormalities 7.Follow coags

19. Outcomes Prior to Dantrolene, mortality was ~64% Estimated mortality now ~1% Increased odds of mortality in muscular builds In those that experience cardiac arrest, younger patients more likely to survive (12 vs. 22 years old) Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006… Anesthesiology. 2008;108(4):603–611.

20. Evaluation for Susceptibility

21. Screening No sensible option for general population Resting CK levels may be elevated in MH susceptible patients, but this is unreliable Contracture Testing (North American Protocol) Genetic Testing Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia. Anesthesiology. 2002;96(1):232–237.

22. Contracture Testing Obtain 2 g (8-10cm) muscle sample under non-triggering anesthetic Muscle placed in physiologic solution and attached to strain gauge Baseline stretch, stimulated tension measured Muscle then exposed to either halothane or caffeine, stretch measured Baseline Stretch: Electrical stimulation 0.5, 1, 2mM Caffeine 3% Halothane

23. Contracture Testing Standards developed on unequivocal MH episode Sn 97-99% Sp 80-85% High NPV Low prevalence, high false positive  low NPV Caffeine trigger unlikely Flewellen EH, Nelson TE. Is theophylline, aminophylline, or caffeine (methylxanthines) contraindicated in malignant hyperthermia susceptible patients? Anesth. Analg. 1983;62(1):115–118.

24. Genetic Testing 5 potential loci identified, including RYR1 Significant heterogeneity in the disease state Phenotype-genotype discordance “DNA testing should always be used in selected, genetically characterized families” Low sensitivity and highly discordant – cannot rule out disease Highly specific test Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia. Anesthesiology. 2002;96(1):232–237. a. Those who have been tested positive by the contracture test. b. Relatives of those who have been tested positive by the contracture test. c. Relatives of those with a known mutation for MH. d. Those who have been found to have a mutation causative for MH under a research protocol. e. Those who have experienced a clinical episode of MH.

25. Genetic Counseling At least one parent of proband likely affected Siblings potentially 50% chance unless de novo mutation All assumes autosomal dominant inheritance

27. Summary Malignant hyperthermia is a rare, potentially life-threatening condition seen most commonly in children Occurrence of MH is highly variable Early recognition and treatment is vital to survival If susceptibility is in question, screening and proper precautions should be taken to ensure a safe operation / anesthetic

28. Thank You!