1. A Metabolic Storm: Tragedy in the Operating Room
Maureen Knabb
Biology Department
West Chester University

2. A Tragic Emergency in the OR
Steven Nook, a 20-year-old athletic, affable, 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:

3. Clicker Question #1 Which of Steven’s vital signs is life threatening?
Increased heart rate
Low blood pressure
Increased respiratory rate
Increased body temperature

4. Turn to your neighbor and discuss…
Three possible mechanisms to explain why Steven had these changes in his vital signs during the operation.

5. 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.

6. 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

7. Clicker Question #2
Which of the following anesthetics does NOT cause MH?
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.
Click on this link in full screen mode to obtain a downloadable pdf of the paper

8. Clicker Question #3
Based on your reading, the Landrace pig model of MH is identical to the human model.
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.

9. How does MH cause muscle rigidity?
Let’s review the steps in excitation/contraction coupling and focus on:
How does calcium regulate contraction?
Which steps require ATP?

10. Excitation-contraction coupling View: http://www. youtube. com/watch
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.
Click on the link in full screen mode to view a video on the sequence of events for skeletal muscle contraction

11. 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 efferent neuron signals the muscle cell with another action potential.

12. Clicker Question #4
Which events in muscle contraction require calcium?
Calcium binds to tropomyosin
Calcium binds to troponin
Calcium binds to myosin
Calcium binds to actin
More than one of the above

13. Clicker Question #5 Which steps in muscle contraction require ATP?
Cross bridge detachment
Calcium sequestration
Na-K pump
All steps require ATP

14. 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?
Increase calcium release from SR
Decrease calcium release from SR
Increase calcium uptake into the SR
All of the above

15. 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

16. Ryanodine receptors (RyRs)
The channel opens in the presence of Ca++ and ATP
There are different 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

17. Clicker Question #7
Why don’t individuals with MH have any effect of anesthetics on cardiac muscle contraction?
The genetic mutation only affects 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.

18. 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 CO2

19. 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 O2 consumption and CO2 release
Increase glycolysis
Increase lactate production leads to acidosis
Increase heat production

20. Clicker Question #8
What genetic mutation did Steven have that led to MH?
Genetic mutation in the protein responsible for Ach release.
Genetic mutation in the Ach receptor protein.
Genetic mutation in troponin.
Genetic mutation in the protein responsible for calcium release.
Genetic mutation in the protein responsible for calcium sequestration.

21. Clicker Question #9
Place the following events in order to explain the effects of MH: 1) CO2 and lactic acid levels increase 2) Anesthetic binds to the ryanodine receptor 3) ATP consumption increases 4) Calcium release from SR
1,2,3,4
2,3,4,1
2,4,3,1
2,4,1,3

22. How does the anesthesiologist know there is a problem?
Early signs
Increase exhaled CO2
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 Malignant hyperthermia: A pharmacogenetic disorder. Orthopedics 32(11): 835.

23. 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 Malignant hyperthermia: A pharmacogenetic disorder. Orthopedics 32(11): 835.

24. Clicker Question #10
Which initiating early event alerts the anesthesiologist that the patient is displaying signs of MH?
Increase in temperature
Kidney failure
Heart failure
Acidosis
Rapid increase in exhaled CO2 due to increased metabolic rate

25. 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

26. 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

27. Clicker Question #11
How does the drug dantrolene prevent the effects of MH?
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.

28. 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
Click on the link in full screen mode to get more information about the testing procedure
For more information about the testing procedure, see

29. Clicker Question #12
Based on your reading, why do the testing centers use caffeine for the biopsy test?
Caffeine increases the sensitivity of RyRs to calcium, increasing contraction.
Caffeine decreases the sensitivity of RyRs to calcium, decreasing contraction.
Caffeine prevents the sequestration of calcium by RyRs, increasing contraction.
Caffeine increases the sequestration of calcium by RyRs, decreasing contraction.

30. Steven Nook died 2 days after his surgery…
His MH symptoms presented after 3 hr of surgery and, despite the enormous efforts 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

31. Watch this video for another example of MH in the news.
View:
Click on the link in full screen mode to watch the video

32. Do some additional research
How does a local anesthetic like halothane cause MH? Describe the mechanism responsible for the clinical effects 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
Click on the link in full screen mode to visit the MHAUS website.