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

2. 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.

3. 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

4. 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:

5. 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.

6. 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:

7. 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

8. 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

9. 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:

10. 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.

11. 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

12. 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

13. 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%

14. 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

15. 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.

16. 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

17. 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.

18. 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!

19. 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): Available from:
Rosenberg H, Pollack N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet Journal of Rare Diseases [Internet]. 2015;10:93. DOI /s
Jiang D et al. Reduced Threshold for Luminal Ca2+ Activation of RyR1Underlies a Causal Mechanism of Porcine Malignant Hyperthermia. J. Biol. Chem [Internet] July; 283(30): 20813– doi: /jbc.M
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] Jun; 60(6): 1316–1325. Available from:
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 Jul 23; 93(15):
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] Dec; 102(52): 19225– doi: [ /pnas ]
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] Nov; 75: 2402–2410. Available from:
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:
Hopkins PM. Malignant hyperthermia: pharmacology of triggering. BJA. 2011; 107(1):
Hommertzheim R, Steinke EE. Malignant hypertherima--the perioperative nurse’s role. AORN J. 2006; 83(3): 601.