MALIGNANT HYPERTHERMIA Malignant hyperthermia (MH) has the potential to be one of the most devastating anesthesia- related complications.

Malignant hyperthermia (MH) has the potential to be one of the most devastating anesthesia- related complications.Malignant hyperthermia (MH) has the potential to be one of the most devastating anesthesia- related complications.
MH is a genetic hypermetabolic muscle disease that, in its classic form, occurs during anesthesia with inhaled anaesthetics such as halothane, isoflurane, sevoflurane, desflurane, and/or administration of the depolarizing muscle relaxant succinylcholine.
The fulminant MH episode observed clinically involves muscle hypermetabolism as demonstrated by tachycardia and in increasing arterial partial pressure of carbon dioxide (PaCO2). Late signs include rapidly increasing body temperature, by as much as 1°C in 5 minutes, and extreme acidosis

The molecular basis for these signs and symptoms is an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from the sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. Markedly increased adenosine triphosphatase activity results in an uncontrolled hypermetabolic state with greatly increased oxygen consumption and CO2 production, producing severe lactic acidosis and hyperthermia
Although MH was initially associated with a mortality rate of 60%, earlier diagnosis and the use of dantrolene have reduced the mortality to less than 1.4%.
Estimates of the incidence of fulminant MH vary widely from one case per 10,000 to 1:250,000 anesthetics administered.
Males appear to be more susceptible to developing a clinical MH episode than females

1. MALIGNANT HYPERTHERMIA BY DR. HARSH CHAUDHARI MENTROR: DR.NIDHI PATEL [AP]

2. Malignant Hyperthermia Malignant hyperthermia (MH) has the potential to be one of the most devastating anesthesia- related complications. MH is a genetic hypermetabolic muscle disease that, in its classic form, occurs during anesthesia with inhaled anaesthetics such as halothane, isoflurane, sevoflurane, desflurane, and/or administration of the depolarizing muscle relaxant succinylcholine. The fulminant MH episode observed clinically involves muscle hypermetabolism as demonstrated by tachycardia and in increasing arterial partial pressure of carbon dioxide (PaCO2). Late signs include rapidly increasing body temperature, by as much as 1°C in 5 minutes , and extreme acidosis

3. The molecular basis for these signs and symptoms is an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from the sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. Markedly increased adenosine triphosphatase activity results in an uncontrolled hypermetabolic state with greatly increased oxygen consumption and CO2 production, producing severe lactic acidosis and hyperthermia Although MH was initially associated with a mortality rate of 60%, earlier diagnosis and the use of dantrolene have reduced the mortality to less than 1.4%. Estimates of the incidence of fulminant MH vary widely from one case per 10,000 to 1:250,000 anesthetics administered. Males appear to be more susceptible to developing a clinical MH episode than females

4. GENETICS Between 50% and 80% of genotyped patients who have had a clinical MH syndrome and a positive muscle biopsy have had their disease linked to one of more than 230 mutations in the type 1 ryanodine receptor (RyR1; sarcoplasmic reticulum [SR] Ca2+ release channel) gene Situated on chromosome 19 Encodes skeletal muscle isoform of calcium release channel of sarcoplasmic reticulum 3 mutations in CACNA1S which encode the pore containing subunit of the sarcolemmal slow voltage gated L- type Ca2+ channel (also referred to as the dihydropyridine receptor [DHPR ]).

5. PHYSIOLOGY MH is a syndrome caused by dysregulation of excitation contraction coupling (ECC) in skeletal muscle. Normal muscle contraction is initiated by nerve impulses arriving at the neuromuscular junction (i.e., the motor end plate) that trigger the release of acetylcholine (ACh) from the nerve terminal. ACh activates nicotinic cholinergic receptors (nAChR), the nonselective cation channels located at the postsynaptic tic neuromuscular junction, and initiates action potentials. The action potentials propagate rapidly along the sarcolemma (muscle cell membrane) and travel down the transverse tubules A T tubule is flanked on both sides by a terminal cisternae element from the sarcoplasmic reticulum (SR), forming triad junctions. The depolarization of T- tubular membrane is sensed by CaV1.1, the pore subunit of the voltage- gated calcium channel residing within the T tubules. Conformational changes of CaV1.1 mechanically communicate with RyR1, causing it to open and release large amounts of calcium from the SR into the sarcoplasm .

6. The released Ca2+ binds to acces sory protein troponin C which is on the actin thin filament. It then causes a conformational change in tropomyosin, exposing actin’s myosin binding sites, which allows muscle contraction .

7. The contraction ends when the intracellular Ca2+ pumps, SR Ca2+- adenosine triphosphatases [ATPases] (SERCAs), rapidly sequester Ca2+ back into the SR lumen. Muscle relaxation begins when the Ca2+ concentration falls below 10−6 M and ends when the resting sarcoplasmic Ca2+ con centration is restored to 10−7 M. Because both contraction and relaxation are energy- related processes that consume adenosine triphosphate (ATP), knowing the molecular events contributing to ECC and the subsequent relaxation phase is essential to under standing the cause of MH. MH syndrome is associated with a persistent increase in the concentration of sarcoplasmic Ca2+ The increased activity of pumps and exchangers trying to correct the increase in sarcoplasmic Ca2+ associated with triggered MH increases the need for ATP, which in turn produces heat

8. TRIGGERS

9. CLINICAL DESCRIPTION MH may occur at any time during anesthesia and in the early postoperative period The earliest signs are tachycardia, rise in end-expired carbon dioxide concentration despite increased minute ventilation, accompanied by muscle rigidity, especially following succinylcholine administration Hyperthermia, when it occurs, is marked by increase in core temperature at a rate of 1–2°C every five minutes. Severe hyperthermia (core temperature greater than 44°C) may occur, and lead to a marked increase in oxygen consumption, carbon dioxide production, widespread vital organ dysfunction, and disseminated intravascular coagulation (DIC) Other signs include acidosis, tachypnea and hyperkalemia. All inhalation anesthetics except nitrous oxide are triggers for MH

10. Malignant Hyperthermia Larach’s Clinical Grading Scale

11. Intraoperative Diagnosis Usually occurs within minutes of using succinylcholine/volatile agents The principal diagnostic features of MH are unexplained elevation of end-tidal carbon dioxide (ETCO2) Unexplained tachycardia, arrhythmias • Unstable BP Tachypnea, cyanosis, if spontaneous ventilation • Increased temperature, sweating, mottling of skin • Muscle rigidity in the presence of adequate neuromuscular blockade • Combined metabolic and respiratory acidosis • CO2 absorbent becomes warm to touch as the reaction with CO2 is exothermic

12. Investigations Combined metabolic and respiratory acidosis Hyperkalaemia Elevated creatinine kinase (above 20,000 IU/L) Increased myoglobin levels Presence of urinary myoglobin Increased pyruvate, LDH

13. Screening for Malignant Hyperthermia Plasma CK values: (more than 20000 IU/L) Nonspecific test Caffeine Halothane Contracture Test (CHCT): Most sensitive test ,Considered to be the definitive test to rule out MH • It is an in vitro bioassay using the patients skeletal muscle • Skeletal muscle biopsy is (3–4 inch) taken from vastus lateralis muscle • Muscle is divided into strips,These strips are mounted in a muscle bath apparatus, Strips are then stimulated at 0.1–0.2 Hz to check for muscle viability Halothane and caffeine are added to the muscles strips • Patients susceptible to MH show high levels of contractile force (This usually occurs at much lower agonist con centration) • This test has a sensitivity of 97% and specificity 78% • Other variants of this test includes In Vitro Contracture Test (IVCT)

14. Genetic tests: • Tests for most common RYR1 mutations on chromosome 19 Intralymphocytic calcium assay: Increased intracellular Ca2+ response to caffeine indicate MH susceptibility This test is still in experimental stages In vivo microdialysis: • Small quantity of caffeine/halothane is injected through microdialysis catheter into the thigh muscle • Samples of local CO2 and lactate levels taken

15. Differential Diagnosis Anaphylactic reaction Elevated end- tidal CO2 due to laparoscopic operation Environmental heat gain more than loss Equipment malfunction with increased carbon dioxide Pheochromocytoma Thyrotoxicosis Sepsis Rhabdomyolysis Hypoventilation or low fresh gas flow Insufficient anesthesia and/or analgesia Muscular dystrophy Neuroleptic malignant syndrome Contrast dye/drug anaphylaxis Drug abuse/toxic overdose Heat stroke Diabetic coma

16. DIFFERENTIAL DIAGNOSIS A variety of unusual conditions may resemble MH during anesthesia These include sepsis, thyroid storm, pheochromocytoma, and iatrogenic overheating. Hence, a high index of suspicion for these disorders as well as the ability to measure ETCO2 and obtain arterial and venous blood gas analysis is essential in order to differentiate MH from these disorders. Particularly problematic is the unexplained hyperthermia following anesthesia. Since anesthetic gases generally inhibit the febrile response, the first sign of sepsis may be marked hyperthermia on emergence from anesthesia. Response to antipyretics as well the clinical setting is often helpful in differentiating this response from MH. The differential diagnosis of unexplained increased ETCO2 includes hyperthermia secondary to sepsis, or iatrogenic warming, machine valve malfunction, rebreathing, as well as faulty equipment.

17. Outside the operating room, MH-like syndrome may occur following injection of ionic contrast agents into the cerebrospinal fluid, cocaine overdose, and the neuroleptmalignant syndrome(NMS).. NMS is a potentially fatal hyperthermic syndrome that occurs as a result of ingestion of drugs used in the treatment of mental and nervous conditions such as schizophrenia. In many countries, a "hotline" has been established to provide emergency assistance in the management of MH. Many are listed on the web site of the Malignant Hyperthermia Association of the US

18. Management and treatment Acute MH crisis 1. Stop potent inhalation agents and succinylcholine. Hyperventilate with 100% O2in an attempt to meet the requirements of the  body during the crisis period. 2. Increase minute ventilation to lower ETCO2. 3. Get help. The surgeon should close the surgical wound, if possible.  If not, the surgeon  should pack the wound with saline‐soaked surgical towels or laparotomy sponges. Intraoperative Nurse notes, the number of towels/lap sponges used to  pack the wound 4. Prepare and administer dantrolene: - 2.5 mg/kg initial dose; Need to redoes should be individualized based on patient response 1 mg/kg is repeated every 5–10 mins until signs of MH subside ,This is indicated by: ▪ Decrease in ET CO2 ▪ Decrease in muscle rigidity ▪ Decrease in heart rate Up to 10 mg/kg IV may be given, especially in muscular individuals

19. 5. Begin cooling measures: - If hyperthermic, use iced solutions, i.e. Ice Packs to groin, axilla, and neck - Nasogastric lavage with iced solution Peritoneal lavage is probably the safest and most effective of the invasive approaches if the peritoneum is already open. - More aggressive measures as needed . If external cooling is insufficient, infuse 20 mL/kg of refrigerated intravenous (IV) crystalloid. Stop cooling measures at 38.5°C to prevent inadvertent hypothermia.. 6. Treat arrhythmias as needed. Do not use calcium channel blockers. 7. Further therapy is guided by blood gases, electrolytes, CK, temperature, muscle tone, and urinary output. Hyperkalemia should be treated with bicarbonate, glucose, and insulin, typically 10 units of regular insulin and 50 mL of 50% dextrose for adult patients. The most effective way to lower serum potassium is reversal of MH by effective doses of dantrolene. In severe cases, calcium chloride or calcium gluconate may be used. Coagulation profile check values every 6–12 hours (PT-INR Platelet count, Fibrinogen) Once crisis is under control, an MH hotline should be contacted for further guidance. 8. Continue dantrolene at 1 mg/kg every 4–8 hours for 24–48 hours.

20. 9. Ensure urine output of 1 to 2 ml/kg/hour and establish diuresis if urine output is inadequate. Administer bicarbonate to alkalinize urine to protect the kidney from myoglobinuria- induced renal failure. 10. Evaluate need for invasive monitoring and continued mechanical ventilation. 11. Observe patient in Intensive Care Unit for at least 36 hours. 12. Refer patient and family to MH Testing Center for contracture or DNA testing. Discontinuation of the trigger may be adequate therapy for acute MH if the onset is slow or if exposure was brief. Tests for disseminated intravascular coagulation (DIC) should be included, as well as observation of the urine for myoglobinuric renal failure. DIC is most frequent when body temperature exceeds about 41°C.

21. DANTROLENE Dantrolene is the only drug which has been shown to be effective in both preventing and reversing fulminant MH. Dantrolene sodium is a hydantoin derivative that does not block neuromuscular transmission, but causes muscle weakness by direct muscular action. It binds to RYR1 receptor and inhibits calcium ion release –This prevents the sudden surge in myoplasmic calcium concentration Dantrolene suppresses SR Ca2+ release • Loading dose: –IV 2.5 mg/kg is given rapidly through large bore IV cannula Repeat doses : 1 mg/kg is repeated every 5–10 mins Maintenance dose: –IV 1 mg/kg is given Q4–6H for 24 hrs after last observed sign of MH –This is in order to prevent relapse which occurs in 20% patients –Relapse usually occurs around 12–13 hours after the initial reaction –Dantrolene is discontinued when all the following criteria are met: ▪Metabolic stability for more than 24 hour ▪ Absence of muscle rigidity ▪ Core temperature less than 38ºC ▪ No evidence of myoglobinuria ▪ Decreasing creatinine kinase trends

22. the most frequent complications of dantrolene were muscle weak ness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), respiratory failure (3.8%), hyperkalemia (3.3%), and exces sive secretions (8.2%). Given its high pH, it is advisable to administer dantrolene through a large-bore IV line. Tissue necrosis with IV extravasation Use within 6 hours of mixing. It has been demonstrated that dantrolene interferes with EC coupling of intestinal smooth muscle cells, and colon, Caution should be used when ondansetron is to be used in this setting. As a serotonin antagonist, ondansetron may increase serotonin at the 5- HT2A receptor in the presynaptic space. It has been suggested that in MHS individuals, agonism of 5- HT2A receptor may produce a deranged response, precipitating MH.

23. PREVENTIVE MEASURES Preventive measures include a thorough anesthetic history to determine the possibility of the patient or a family member having experienced an MH episode When suspicion of MH exists, family members should not be given trigger anesthetic agents, i.e. potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, isoflurane and succinylcholine, and testing is recommended. Patients with any form of myotonia should not receive succinylcholine. Patients with hypokalemic periodic paralysis, CCD, Duchenne or Becker muscular dystrophy, paramyotonia , or myotonia fluctuans should not receive trigger agents. Young patients (below age 12 approximately) should not receive succinylcholine for elective procedures, in order to avoid the possibility of hyperkalemic response in a patient with undiagnosed muscular dystrophy

24. Management of the MH susceptible for anesthesia Patients who are known to be MH susceptible may be anesthetized with regional anesthesia or local anesthesia without problems If general anesthesia or sedation is required, the potent volatile agents and succinylcholine should be avoided. The anesthesia machine should be prepared by flowing 100% oxygen through the machine at 10 L/min for at least 20 minutes. The ventilator should also be included in purging the machine by cycling the ventilator at the time of the oxygen flow. Charcoal filters attached to both limbs of the anesthesia breathing circuit before and during the procedure are effective for reducing halogenated anesthetics to less than trace amounts. Vaporizers should be disabled, drained or removed if possible change of all disposable components, All intravenous agents and nondepolarizing relaxants are safe to use. Preoperative administration of prophylactic dantrolene is not recommended. Dantrolene should, however, be readily available.

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