1. MALIGNANT HYPERTHERMIA When it’s not Cool To be Hot

2. Objectives Define what malignant hyperthermia is and identify the triggering factors of MH Identify the signs and symptoms of MH and identify treatments for MH Explain Dantrolene use, types and side-effects Identify related conditions and special populations

3. Malignant Hyperthermia What is it? A pharmacogenetics disorder Involves the unregulated release of calcium Triggered by exposure to halogenated volatile anesthetic gases and succinylcholine A potentially lethal condition

4. MH Susceptibility Who is susceptible to Malignant Hyperthermia? MH is inherited with an autosomal dominant inheritance trait. This means children and siblings of a patient with MH susceptibility have a 50% chance of inheriting a gene defect for MH and would then be MH susceptible. The gene associated with MH is the ryanodyne receptor form 1 (RYR1) gene located on the sarcoplasmic reticulum (SR). Over 80 genetic defects have been associated with MH. People with the defect may be unaware of the risk until they or a family member are the victim of a life threatening crisis during anesthesia.

5. MH Susceptibility (cont.) A person can have the MH gene and go through several surgeries before an MH episode occurs. This is why pre-admission questioning by nurses and anesthesia personnel is important.

6. MH Incidence What is the incidence of MH? Exact incidence numbers are unknown. Studies estimate MH complicates 1 in 100,000 adult surgeries and 1 in 30,000 surgeries in children. Why the wideness in range? Results vary depending on the concentration of MH families in a geographic area. High incidence areas in the U.S. include Wisconsin, Nebraska, West Virginia and Michigan. About 1 in 2,000 patients harbor a genetic change that could make them susceptible to MH

7. Causes of MH Episodes What causes an MH episode? Susceptible persons have a mutation that results in the presence of abnormal proteins in the muscle cells. When these proteins are exposed to certain anesthetic agents, an abnormal release of calcium occurs in the muscle cells. This results in sustained muscle contraction and an abnormal increase in energy utilization and heat production.

8. Causes of MH Inhaled General Anesthetics Inhaled general anesthetics Desflurane Enflurane Halothane Isoflurane Methoxyflurane Sevoflurane Ether Depolarizing Muscle Relaxants Succinylcholine (seems to accelerate the onset and increase the severity of the episode.)

9. Causes of MH Succinylcholine should not be used with children. This is due to the possible occurrence of rhabdomyolysis in 40% of children who receive IV Succinylcholine.

10. Safe Anesthetic Agent Examples Barbiturates Diazepam Etomidate Ketamine Midazolam Propofol Thiopental Inhaled Non-Volatile Nitrous Oxide Local Anesthetics Lidocaine Ropivicaine Narcotics Codeine Fentanyl Dilaudid Morphine Naloxone Oxycodone Safe Muscle Relaxants Mivacurium Nimbex Zemuron

11. Safe Anesthetic Agent Examples Anxiety Relieving Medications Ativan Librium Midazolam Restoril Valium Paxil

12. What Happens during an MH Crisis An unregulated release of calcium from the sarcoplasmic reticulum into the myoplasm Ryanodyne receptor protein encoded on the RYR1 gene forms the calcium channel Exposure to anesthesia agents stimulates the unregulated release of calcium through the channel

13. MH Signs and Symptoms Tachycardia, nonspecific Increasing EtCO2 Temporarily responsive (early) or unresponsive (late) to increases in minute ventilation Generalized muscle rigidity Trunk or total body Mixed respiratory/metabolic acidosis Rise in temperature can be 1° C to 2° C every 5 min if allowed to continue unchecked Myoglobinuria – cola colored urine

14. Results of MH Episodes The muscles eventually run out of energy due to ATP depletion and die and this leads to large amounts of potassium released into the bloodstream causing hyperkalemia which can cause cardiac arrhythmias. The muscle pigment myoglobin of the dead muscle cells are also released and may be toxic to the kidney. Watch for cola colored urine.

15. Results of MH episode If not treated, this may lead to cardiac arrest, kidney failure, blood coagulation problems, internal hemorrhage, brain injury, liver failure and may be fatal.

16. How Does Dantrolene work? Dantrolene decreases the release of calcium from the muscle. It binds to the sites that cause the calcium release. Dantrolene restores the balance between calcium release and uptake.

17. Dantrolene (cont) Dantrolene does not potentiate the effects of non- polarizing relaxants. It also does not interfere with reversal of muscle relaxants. Care should be used to insure sufficient muscle strength prior to extubation. Dantrolene used with calcium channel blockers may cause life-threatening hyperkalemia and myocardial depression.

18. Treatment of MH Get help! Have someone get the MH cart Start Dantrolene 2.5mg/kg IV until there is a decrease in EtCO2, muscle rigidity and heart rate Treat arrhythmias with other standard antiarrythmic drugs. Avoid Calcium Channel Blockers In the presence of Dantrolene, these may cause hyperkalemia or cardiac arrest.

19. Treatment of MH Monitor core temperature. Treat hyperkalemia with Glucose/insulin – o.1 units regular insulin/kg and 0.5grams/kg dextrose Calcium chloride – 10mg/kg (max dose 2000mg) or calcium gluconate (max dose 3000mg) Bicarbonate – 1-2mEq/kg IV (max dose 50 mEq) Hyperventilation – 100% O2 Furosemide – 0.5-1 mg/kg once (max dose 20 mg)

20. Treatment of MH If core temperature rises rapidly, cool the subject. This can be done by: Nasogastric lavage Gastric, peritoneal or rectal lavage and/or Surface cooling using a hypothermia blanket, refrigerated saline solution and bags of ice. Beware of unintentional hypothermia. Stop cooling when temperature reaches 38°C.

21. Treatment of MH Postoperative rhabdomyolysis (the destruction of skeletal muscle) without intraoperative signs of MH should be treated with hydration, mannitol and bicarbonate. Plasma potassium levels should be measured ASAP. LABS: coagulation profile, electrolytes, ABG, and CK

22. MH Prevention Can MH be prevented? The best way to prevent MH episodes is to identify susceptible patients pre-operatively. Family history should be obtained and any history of a muscle disorder should be forwarded to the anesthesia personnel. Identification (bracelet, card) should be available and used by MH susceptible patients.

23. Identifying susceptible patients All closely related members of a family in which MH has occurred should be considered MH susceptible. Even patients who have never had a problem with anesthesia can not be positive they are not at risk. MH deaths have been known to happen to patients who have had multiple prior uneventful surgeries.

24. Susceptible patients Any family who has had anesthetic deaths or complications should register with the North American MH Registry of MHAUS, Pittsburgh, PA by calling toll free 888-274-7899.

25. Testing for MH The most accurate test for MH is a biopsy of the skeletal muscle of the thigh. This test has been used for the last 30 years. It is called the caffeine halothane contraction test. It is positive in more than 97% of patients with true MH. It is usually only done on patients with a family history of MH or on patients who have had a prior suspicious reaction to anesthesia. There are only 8 medical centers in the U.S. and Canada that do this test. The list of centers can be found at www.mhaus.org.

26. Testing for MH Molecular genetic testing can also be done Will identify the point mutation in the RYR1 Will miss the other 65% of patients Mostly reliable for relatives that have had someone test positive on a molecular genetic test

27. Can MH susceptible patients have surgery? Yes, as long as these rules are followed: 1. Avoid the use of MH-triggering anesthetics 2. Be familiar with the signs and treatment of MH 3. Continuously monitor the patient’s expired CO2 concentration. 4. Continuously monitor the patient’s temperature (also during recovery). Use core temps, skin temps are not reliable in this situation. 5. Have and MH kit or cart within the operating room or in recovery with an adequate supply of Dantrolene (36 vials)

28. Can MH Occur Outside the OR? MH may occur at any time during or emerging from anesthesia, even in PACU. The one-hour period immediately following surgery is a critical time. MH can also occur if trigger anesthetics and succinylcholine are used in ERs, dental surgeries, surgeon’s offices or ICUs.

29. How Can I as a Health Care Professional Get More Info on MH? You can contact the Malignant Hyperthermia Association of America (MHAUS) by calling 800- 98MHAUS or by going to www.mhaus.org.www.mhaus.org For emergencies, call 800-644-9737

30. What to put in your MH cart Dantrolene (Dantrium/Revonto)– 36 - 20 mg vials Ryanodex – 3 - 250 mg vials Sterile water for injection Sodium bicarbonate – 50 ml x 5 Dextrose 50% - 50 ml vials x 2 Calcium chloride (10%) – 10 ml vial x 2 Regular insulin – 100units/ml x 1 (refrigerated) Lidocaine for injection. Amiodarone also acceptable ACLS protocols to be followed when treating MH caused cardiac arrhythmias

31. MH cart Refrigerated cold saline solution – min of 3000 ml for IV cooling (Do not use lidocaine or procainamide if wide QRS might be due to hyperkalemia. May result in assystole)

32. Just Remember… Everyone should know what device (cart, bag) the MH supplies are stored in Everyone should know where the device is Everyone should know how to use the supplies Practice Try to obtain outdated vials of Dantrolene to use MH doesn’t occur often Not the time for long discussions

33. Similar Conditions Neuroleptic malignant syndrome Occurs as a complication when anti psychotic drugs are used Neurological emergency Presents with triad of symptoms Fever, rigidity, cognitive changes Lab work will show elevated serum creatine kinase (CK)

34. Similar conditions Central Core Disease Inherited disorder Some weak at birth, some later in life Found on same gene as MH Patients susceptible to MH and should be treated as such King Denborough Syndrome Multiminicore Disease

35. MH and pregnancy Dantrolene crosses the placenta and side effects will be seen in neonates. Just a risk and should be weighed against the benefits of use. Weakness in neonate may be seen, but studies show low doses can be used with no problems Epidurals are safe Vaginal deliveries are preferred over C-sections. There are other risks other than MH involved with C- sections Few reports of infants triggering with MH, even if they have an MH episode later in life

36. References www.mhaus.org Anesthesiology News. Current Concepts in the Understanding of Malignant Hyperthermia. Available at: www.anesthesiologynews.com. Accessed November 9, 2015www.anesthesiologynews.com