Transcript Malignant Hyperthermia

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?
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Malignant Hyperthermia (MH) is a rare life-threating
disorder triggered by general anesthesia drugs such
as volatile anesthesia and depolarizing muscle
relaxants.
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It leads to a rapid and sustained rise in body
temperature due to increase in intracelluar calcium.
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Occurs in susceptible individuals with autosomal
mutations in the ryanodine receptor type 1 gene
(RYR1).
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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
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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
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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
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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
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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
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Anaesthetic agents induce an abnormal release of Ca++
from the SR
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This results in sustained muscle contraction, which
causes an increase in aerobic and anaerobic metabolism
(a hyper-metabolic state)
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Muscle fibers are eventually depleted of adenosine
triphosphate (ATP), causing them to become rigid or
break-down
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CO2 and lactic acid levels in the blood are increased,
resulting in blood acidosis
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Hyper-metabolic state prompts an extreme temperature
elevation and tachycardia
Immediate Risks of MH
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Potassium ions released from the skeletal muscle
result in hyperkalemia, which can have a significant
impact on the coordination of heart muscle contraction
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If untreated the potassium ions will depolarize the
cardiomyocyte membranes causing potentially fatal
heart rhythms
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This process begins immediately after onset of MH and
can result in fibrillation in as little as a few minutes
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Irregular heartbeats are the most common cause of
death in MH patients
Modified from Ho, M. (2015). ECG Changes with Hypo/Hyperkalemia
Treatment
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Dantrolene
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Hydantoin derivative
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Inhibits Ca2+ release from the SR by limiting the activation of RyR-1
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Amino acid residues of the 1400 base N-terminal region bind dantrolene
Dantrolene Study
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Azumolene: A more soluble analog of dantrolene sodium (N)
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Used to outcompete [3H]azidodantrolene probe (T)
Clinical Procedure
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Indicators of Malignant Hyperthermia
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Core Temperature
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Monitored during and post-operation
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1-2 °C increase every 5 minutes
Other Symptoms:
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Muscle Rigidity
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Tachycardia
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Increased end-exhale CO2
Clinical Procedure
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Stop Operation
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Remove Anesthetic
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May use Propofol, ketamine, catecholamines, nondepolarizing muscle relaxants,
catechol congeners, digitalis, or NO instead
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Begin External Cooling
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Administer Dantrolene
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2.5 mg/kg every 5 minutes IV up to a 10 mg/kg cumulative
Testing for Malignant Hyperthermia
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Caffeine Halothane Contracture Test
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A muscle biopsy is completed and the muscle specimen is
electrically stimulated in normal conditions and in the
presence of halothane and caffeine
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If abnormal contraction is recorded in the presence of these
compounds the result is positive
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Considered 95% accurate
Genetic Testing
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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
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Screening
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Database (23 and Me)
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Track carriers before surgery
Genetic Counseling
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Gene editing
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RYR-1
Summary
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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
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The receptor demonstrates increased sensitivity towards anaesthetic agents
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Leads to dysfunction in Ca++ homeostasis and a build-up of calcium in skeletal muscle
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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
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Rhabdomyolysis (myocyte destruction) results in release of K+ that can cause arrythmias
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Myoglobin released by destroyed myocytes may cause oxidative damage, which can lead to acute
renal failure
References
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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.
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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
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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.
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Balog, E., Fruen, B., Shomer, N., & Louis, C. (2001, October). Divergent Effects of the Malignant Hyperthermia-Susceptible Arg6153Cys Mutation on the Ca21 and
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