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, 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: http://www.apsf.org/newsletters/html/2006/summer/malignant.html

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

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

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.

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

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. http://opa1.faseb.org/pages/PublicEducators/mh/ Click on this link in full screen mode to obtain a downloadable pdf of the paper

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. http://opa1.faseb.org/pages/PublicEducators/mh/

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?

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

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.

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

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

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

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

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

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.

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

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

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.

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

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. 2009. Malignant hyperthermia: A pharmacogenetic disorder. Orthopedics 32(11): 835.

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.

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

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

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

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.

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 http://www.mhaus.org/testing

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.

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

Watch this video for another example of MH in the news. View: http://www.youtube.com/watch?v=as-VeD1QgIc Click on the link in full screen mode to watch the video

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 http://www.mhaus.org Click on the link in full screen mode to visit the MHAUS website.