A METABOLIC STORM:
TRAGEDY IN THE
OPERATING ROOM
Maureen
Knabb
Biology
Department
West Chester
University
A TRAGIC EMERGENCY IN THE OR
 Steven Nook, a 20-year-old athletic, af fable, young man had
surgery to repair an injury to his shoulder experienced during
a skiing accident.
 He was a popular sophomore at University of Wisconsin LaCrosse and aspired to be a physical education teacher and
football coach.
 About 3 hours into his surgery, the anesthesiologist
recognized some unusual responses and reported them to
the surgeon.
 “His breathing is 20, heart rate is at 140, pressure is 70/56
and temperature is 106.”
 See the link below to read his story:
http://www.apsf.org/newsletter s/html/2006/summer/malignant.html
2
CLICKER QUESTION #1
Which of Steven’s vital signs is life threatening ?
A.
B.
C.
D.
Increased heart rate
Low blood pressure
Increased respiratory rate
Increased body temperature
3
TURN TO YOUR NEIGHBOR AND DISCUSS…
Three possible mechanisms to explain why Steven had these
changes in his vital signs during the operation.
4
WHAT IS THE PROBLEM?
 The doctors and nurses reacted immediately. “Steven is
having a bad reaction to the anesthetic. His temperature is
very high, which can be dangerous to his organs. Stop the
anesthetic and start the cooling protocol .”
 This condition is called malignant hyperthermia and it can
be fatal.
5
WHAT IS MALIGNANT HYPERTHERMIA
(MH)?
MH is a genetic condition that only becomes obvious when a
patient is exposed to certain anesthetics such as halothane. It
causes:





Muscle rigidity
High temperature
Increase in HR
Increase in blood CO2
Increase in respiratory rate
6
CLICKER QUESTION #2
Which of the following anesthetics does NOT cause MH ?
A.
B.
C.
D.
Halothane
Nitrous oxide
Chloroform
Succinylcholine
Refer to the first two sections of the article Making Anesthesia
Safer: Unraveling the Malignant Hyperthermia Puzzle to answer
the question.
http://opa1.faseb.org/pages/PublicEducators/mh/
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CLICKER QUESTION #3
Based on your reading, the Landrace pig model of MH is
identical to the human model .
A.
B.
True
False
Refer to the section “Serendipitous discovery of an experimental
model” in Making Anesthesia Safer: Unraveling the Malignant
Hyperthermia Puzzle to answer this question.
http://opa1.faseb.org/pages/PublicEducators/mh/
8
HOW DOES MH CAUSE MUSCLE RIGIDIT Y?
Let’s review the steps in excitation/contraction coupling and
focus on:
 How does calcium regulate contraction?
 Which steps require ATP?
9
EXCITATION-CONTRACTION COUPLING
View: http://www.youtube.com/watch?v=CepeYFvqmk4
 A somatic efferent neuron sends action potentials to muscle fibers.
 The neuron releases acetylcholine at the neuromuscular junction.
 Acetylcholine causes depolarization of the muscle cell membrane,
which results in an action potential along the surface of the
muscle.
 The action potential is conducted down the T tubule membrane into
the internal part of the muscle fiber.
 When the action potential meets the membranes of the adjacent
sarcoplasmic reticulum (SR) deep inside the muscle cell, a
permeability change causes calcium release from the SR.
 Calcium binds to troponin, moving tropomyosin away from the
myosin binding site on actin so that actin and myosin bind.
 Cross bridge cycling results in muscle shortening as long as ATP is
available.
10
RELAXATION OF SKELETAL MUSCLE
 Depends on the reuptake of calcium ions via an ATP dependent calcium pump, from the cytosol into the SR.
 Calsequestrin binds and stores calcium in SR.
 With the absence of calcium, troponin and tropomyosin can
resume their blocking role.
 Na is pumped out of the cell in exchange for K via an ATP dependent Na-K pump.
 Calcium can be released again from the SR into the cytosol if
a somatic ef ferent neuron signals the muscle cell with another
action potential.
11
CLICKER QUESTION #4
Which events in muscle contraction require calcium ?
A.
B.
C.
D.
E.
Calcium binds to tropomyosin
Calcium binds to troponin
Calcium binds to myosin
Calcium binds to actin
More than one of the above
12
CLICKER QUESTION #5
Which steps in muscle contraction require ATP?
A.
B.
C.
D.
Cross bridge detachment
Calcium sequestration
Na-K pump
All steps require ATP
13
CLICKER QUESTION #6
Based on your understanding of skeletal muscle contraction,
what do you predict happens in MH when halothane is
administered to susceptible individuals ?
A.
B.
C.
D.
Increase calcium release from SR
Decrease calcium release from SR
Increase calcium uptake into the SR
All of the above
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ROLE OF RYANODINE RECEPTORS (RYRS)
IN CALCIUM RELEASE
 Ryanodine, a plant alkaloid, binds to RyRs
 RyRs function as intracellular calcium release channels
 They trigger Ca ++ release from the SR when an AP travels down
the T-Tubules
15
RYANODINE RECEPTORS (RYRS)
 The channel opens in the presence of Ca ++ and ATP
 There are dif ferent RyR subtypes: RyR1 in skeletal muscle, RyR2
in cardiac muscle
 Anesthetics do not act on RyR2 receptors
Used with the permission of the Muscular Dystrophy Association
16
CLICKER QUESTION #7
Why don’t individuals with MH have any ef fect of anesthetics
on cardiac muscle contraction ?
A.
B.
C.
D.
The genetic mutation only af fects the RYR1 receptor on
skeletal muscle cells.
Anesthetics cannot act on cardiac muscle cells.
Cardiac muscle cells do not possess ryanodine receptors.
Cardiac muscle cells do not use calcium to initiate muscle
contraction.
17
HOW IS ATP GENERATED FOR THE MUSCLE
CONTRACTION?

Creatine phosphate
 First source of energy

Glycolysis
 In absence of oxygen, produces lactic acid

Oxidative phosphorylation
 Produces the majority of ATP
 Generates CO 2
18
HOW DOES RYR1 MUTATION AFFECT ATP
LEVELS AND LEAD TO MH?
 RYR1 mutation leads to sustained calcium release and
skeletal muscle contraction
 ATP depletion results from sustained cross-bridge cycling,
Ca ++ ATPase activity
 Metabolic rate increases to provide ATP
 Increase oxidative phosphorylation
 Increase O 2 consumption and CO 2 release
 Increase glycolysis
 Increase lactate production leads to acidosis
 Increase heat production
19
CLICKER QUESTION #8
What genetic mutation did Steven have that led to MH ?
A.
B.
C.
D.
E.
Genetic mutation
Genetic mutation
Genetic mutation
Genetic mutation
release.
Genetic mutation
sequestration.
in
in
in
in
the protein responsible for Ach release.
the Ach receptor protein.
troponin.
the protein responsible for calcium
in the protein responsible for calcium
20
CLICKER QUESTION #9
Place the following events in order to explain the ef fects of MH:
1) CO 2 and lactic acid levels increase
2) Anesthetic binds to the ryanodine receptor
3) ATP consumption increases
4) Calcium release from SR
A.
B.
C.
D.
1 ,2,3,4
2,3,4,1
2,4,3,1
2,4,1 ,3
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HOW DOES THE ANESTHESIOLOGIST KNOW
THERE IS A PROBLEM?
 Early signs
 Increase exhaled CO 2
 Increase respiratory rate
 Muscle rigidity - especially jaw muscle
 Flushing of skin
 Increase heart rate and arrhythmias
 Electrolyte imbalance due to muscle cell death
Adapted from Table 1 in Stratman, R.C., et al. 2009. Malignant hyperthermia: A pharmacogenetic
disorder. Orthopedics 32(11): 835.
22
HOW DOES THE ANESTHESIOLOGIST KNOW
THERE IS A PROBLEM?
 Late signs
 Increased body temperature
 Acidosis
 Increased destruction of muscle cells
 Renal failure
 Heart failure
 Increased blood clotting
Adapted from Table 1 in Stratman, R.C., et al. 2009. Malignant hyperthermia: A pharmacogenetic disorder.
Orthopedics 32(11): 835.
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CLICKER QUESTION #10
Which initiating early event alerts the anesthesiologist that
the patient is displaying signs of MH ?
A.
B.
C.
D.
E.
Increase in temperature
Kidney failure
Heart failure
Acidosis
Rapid increase in exhaled CO 2 due to increased metabolic
rate
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WHAT DID THE SURGICAL TEAM DO AFTER
STEVEN STARTED SHOWING SIGNS OF MH?
 Discontinued the volatile anesthetic
 Began cooling procedure
 Called the MHAUS (Malignant Hyperthermia Association of
the U.S.) hotline
 Corrected metabolic abnormalities
 Administered Dantrolene sodium
25
HOW DOES DANTROLENE SODIUM WORK?
 Originally discovered as a muscle relaxant
 Blocks calcium release by the RYR receptors
 Prevents the action of the anesthetic on the RYR receptors in
MH-susceptible individuals
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CLICKER QUESTION #11
How does the drug dantrolene prevent the ef fects of MH ?
A.
B.
C.
D.
The drug prevents release of calcium from the
sarcoplasmic reticulum.
The drug prevents the binding of calcium to muscle
proteins.
The drug blocks release of acetycholine at the NM junction.
The drug increases sequestration of calcium into the SR.
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HOW WOULD STEVEN KNOW IF HE HAD THE
GENETIC MUTATION FOR MH?
 Is there a family history?
 The disease is autosomal dominant
 Take a muscle biopsy/Caffeine Halothane Contracture Test
(CHCT)
 The test is very accurate
 There are only 5 centers which conduct the test
 Get a genetic test for RYR1 gene
 Less invasive, more convenient
 The genetic test is expensive ($740-$3,990)
 It is only 50% accurate
For more information about the testing procedure, see
http://www.mhaus.org/testing
28
CLICKER QUESTION #12
Based on your reading, why do the testing centers use caf feine
for the biopsy test?
A.
B.
C.
D.
Caf feine increases the sensitivity of RyRs to calcium,
increasing contraction.
Caf feine decreases the sensitivity of RyRs to calcium,
decreasing contraction.
Caf feine prevents the sequestration of calcium by RyRs,
increasing contraction.
Caf feine increases the sequestration of calcium by RyRs,
decreasing contraction.
29
STEVEN NOOK DIED 2 DAYS AFTER HIS
SURGERY…
His MH symptoms presented after 3 hr of surgery and, despite
the enormous ef forts of the physicians, he was unable to
recover from the tissue damage. He was loved very much by
friends and family. He was also a budding poet. Below is an
excerpt from one of his poems…
In Remembrance, a child does not age
And so they never leave,
They’re in your heart at every stage
Of their life they weave.
“Remembrance” by Steven Nook, December 2004
30
WATCH THIS VIDEO FOR ANOTHER
EXAMPLE OF MH IN THE NEWS.
View: http://www.youtube.com/watch?v=as -VeD1QgIc
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DO SOME ADDITIONAL RESEARCH
 How does a local anesthetic like halothane cause MH?
Describe the mechanism responsible for the clinical ef fects
of anesthetic on individuals that have inherited MH.
 For more information, visit the website for the Malignant
Hyperthermia Association of the United States (MHAUS ) at
http://www.mhaus.org
32