1. State of the Art Topics on Malignant Hyperthermia
Sheila Riazi, MSc, MD, FRCPC
University Health Network, Toronto, Canada

2. Member, board of directors of MHAUS
Member, international professional advisory council on MH
Funded by NIH (NIAMS), CIHR, PSI, Ontario Ministry of Health & University of Toronto

3. Outline
What all anesthesiologists need to know about MH (Pathophysiology, Epidemiology, and clinical care with new practice-changing knowledge) Current diagnostic tests for MH and dilemmas of genetic testing Phenotypic variability in MH susceptible patients

4. Pharmacogenetics disorder of skeletal muscle cells
What is MH?
Pharmacogenetics disorder of skeletal muscle cells
Clinical incidence: 1 in 10,000
1 in 400 individuals carries a pathogenic mutation causing MH (Gonsalves et al, Anesthesiology, 2015)
Variable Penetrance
Morbidity >35% & mortality rate: 12-15%
(Larach et al, Anesth & Analg 2010; Rosero et al Anesthesiology, 2009)

5. Why does MH occur?

6. When does MH occur?
Fulminant: onset of full blown syndrome within minutes of induction of GA
Indolent: more often with current volatile
Visoiu et al, Anesth & Analg, 2014
Onset:
Intra-operative: 175 (5-720) min
PACU: 22.5 (5-72) min
Riazi et al, Anesth & Analg, 2014

8. Increase in Intracellular Ca2+
Contracture (rigidity)
Heat
Excess lactate
O2 consumption
CO2 production
Cell breakdown
Hyperthermia (66.7%)
Tachycardia (hypertension) (62.0%)
Tachypnea/ inc MV
Increase ETCO2 (51.9%)
Rigidity: MMR (34.9%) or generalized (25.6%)
Ventricular dysrrhythmia (22.5%)
Skin mottling (17.1%)
Riazi et al, Anesth & Analg, 2014

10. Importance of Temperature Monitoring
The risk of dying from an MH episode has increased approximately 7 fold when compared to a previous cohort. (Larach et al, Anesth & Analg, 2014)
Recommended to use temperature monitoring for cases beyond 30 minutes duration.

11. Treatment of MH crisis =
Supportive (cooling down, hyperventilation and discontinuing the triggers)
Dantrolene ( mg/kg) =
36 Vials
3 Vials

12. Early Dantrolene Use
With 20 minutes delay in dantrolene administration, complication rates increases to 30%, and delay of 50 minutes of longer results in 100% complication rate. (Riazi et al, Anesth & Analg, 2014)

17. Caffeine-Halothane Contracture Test
(CHCT)

18. Normal response Abnormal response Calculated Value 95% CI Sensitivity
97%
84-100%
Specificity
78%
69-85%
Allen GC et al, 1998

19. CHCT Testing Centers in North America
Toronto General Hospital
Malignant Hyperthermia Investigation Unit

Uniformed Services University of the Health Sciences
Bethesda, MD (Military & Civilian)

University of California Davis, CA

University of Minnesota
Minneapolis, MN
Wake Forest Baptist Medical Center, Winston-Salem, NC

20. Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, Obrien PJ, MacLennan DH. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science Jul 26;253(5018):

21. Genetics of MH
Current sensitivity is ~60% (Negative genetic screen cannot be diagnostic).
There are 35 causative mutations listed for MH (
Over 400 variants were identified in three involved genes (RYR1, CACNA1S, STAC3) with unknown functionality.
Exome sequencing has been unsuccessful in identifying any other gene associated with MH.
Our group has started different approach (linkage analysis and exome sequencing, as well genome sequencing).

22. Guideline for genetic testing of at risk patients
Hopkins et al, BJA, 2015

24. Complex Genetics CGS: 73 0.3 1.2 Gly341Arg 0.0 1.7 0.9 3.2 Ø RYR1 0.1
Gen rigidity
CK: 22000
Temp: 39.2
ETCO2:67
HR: 140
Myoglobinuria
pH: 7.12

25. Phenotypic variability of MH patients
Patients with possible MH reaction
Family members of MHS patients.
Others (referred by neurologists):
Idiopathic hyperCKemia/myopathy
>2 episodes of rhabdomyolysis
Between , a total of 136 patients were referred for non-MH reasons and underwent CHCT testing (87/136).
Idiopathic high CK (47/71)
Heat or exercise induced rhabdomyolysis (9/15)
High CK and rhabdomyolysis (2/3)
Other reasons (unexplained myopathy, post infection rhabdomyolysis)

26. Non-reaction MH positive probands
CHCT values were significantly lower compared to the patients with MH reaction.
31% of CHCT+ had at least one RYR1 variant (not polymorphism).
Timmins et al, Anesthesiology 2015
CHCT+
non-reaction
MH history
Caffeine (g contracture), Mean (SD)
0.5 (0.8)
2.2 (2.0)
Halothane (g contracture), Mean (SD)
2.3 (1.7)
4.0 (1.2)

27. Evidence in literature
There is an association between MH and exertional or heat induced rhabdomyolysis:
Various reports show 30-75% positive CHCT or genetics (RYR1 mutations) among the second group.
(Figarella-Branger et al, 1993; Wappler et al, 2001; Dlamini et al, 2013; Fiszer et al, 2015)

28. MH susceptible patients with non anesthetic-induced rhabdomyolysis
Kraeva et al, Can J Anesth, 2017

29. Metabolic dysfunction in anesthetic induced MH positive patients
Thompson et al, Anesth & Analg, 2017, In Press

30. There was a negative correlation between Fatigue Index during the Wingate Test and OXPHOS ATP production rate during the 31P-MRS 30-second exercise bout (r=-0.392, p<0.05).

31. Summary and Conclusion
MH still exists, and its prevalence contradicts the “rare disease” category, but variable penetrance significantly affects the incidence of the observed clinical events.
Morbidity and mortality from MH has been increased in the past decade, partly because of delayed diagnosis and treatment.
We still need to learn more about genetics of MH. With the current genetic knowledge, it is too complex to serve as reliable diagnostic test.

32. MH
EHI
RYR-1 myopathies
Are there predictive factors in MHS that make them more sensitive to heat and exercise, or myopathic?

33. MHAUS Scientific Conference
Save the Date
September 23rd & 24th 2017
MHAUS Scientific Conference
MALIGNANT HYPERTHERMIA:
Risks & Associated Muscle Disorders