Malignant Hyperthermia

Gary Oh

Introduction• Hypermetabolic crisis when an MH-susceptible (MHS) individual is

exposed to a volatile anesthetic (eg, halothane, isoflurane, enflurane, sevoflurane, desflurane) or succinylcholine

Incidence• 1:100,000 administered anesthetics. • Approximately half of patients who develop acute MH have one or

two uneventful exposures to triggering agents.• All ethnic groups.• All parts of the world. • Males > Females (2:1).• Children <19 years (45-52% of reported events).

Pathophysiology• Genetic skeletal muscle receptor abnormality• Excessive Ca accumulation in the presence of certain anesthetic

triggering agents.• Clinical manifestations due to cellular hypermetabolism, leading to

sustained muscular contraction and breakdown (rhabdomyolysis), anaerobic metabolism, acidosis, and their sequelae.

Normal muscle physiology• Depolarization spreads throughout the muscle cell via the transverse

tubule system, which activates dihydropyridine (DHP) receptors located within the t-tubule membrane. • DHP R are coupled to ryanodine receptors (RYR1), which are Ca

channels embedded in the wall of the SR. • Ca release through the DHP R triggers the RYR1 R to release Ca from

the SR into the intracellular space. • Ca combines with troponin to cross-link actin and myosin, resulting in

muscle cell contraction. • Reuptake of Ca by the SR Ca ATPase (SERCA) leads to relaxation.

Malignant hyperthermia• Mutations encoding for abnormal RYR1 or DHP R.• Triggering agents (volatile anesthetics) lead to unregulated passage of

Ca from the SR into the intracellular space causing sustained muscle contraction.• Hyperthermia occurs minutes to hours following the initial onset of

symptoms. (1ºC every few minutes).• Increase in CO2 production, and increased O2 consumption can cause

widespread vital organ dysfunction and disseminated intravascular coagulation (DIC).

Trigger• Volatile anesthetic agent (eg, halothane, isoflurane, sevoflurane,

desflurane) +/- succinylcholine. • MH has been reported following administration of succinylcholine in

the absence of an inhalational agent (eg, to facilitate endotracheal intubation)• MH crisis may develop at first exposure to a triggering agent, however

the average patient has had previous exposures prior to having a documented reaction.

Clinical Signs - Early• Perioperative:• Hypercarbia• Sinus tachycardia• Masseter muscle rigidity (MMR)• Generalized muscle rigidity

• Most common initial sign of an MH crisis is an unexpected rise in end-tidal carbon dioxide (ETCO >60 mmHg ), which is difficult to decrease as minute ventilation is increased. • Masseter muscle rigidity (MMR) (in the presence of succinylcholine

and/or volatile agents).• Generalized muscle rigidity in the presence of neuromuscular

blockade is virtually pathognomonic for MH when other signs are present.

Clinical Signs - Later• Electrocardiogram changes (Hyperkalemia):• Ventricular ectopy/bigeminy• Ventricular tachycardia/fibrillation

• Hyperthermia• Myoglobinuria• Excessive bleeding (DIC)

• Hyperthermia • Widespread misconception that acute MH begins with hyperthermia as the

presenting sign. • Hyperthermia generally a later sign of MH and is typically absent when the

diagnosis is initially suspected.

• Myoglobinuria• Brownish, cola or tea-colored urine indicates the presence of myoglobinuria.

Labs• Excess CO2 and cellular H+ deplete O2 and ATP.• Early Sx: hypercarbia and mixed respiratory/metabolic acidosis. • Shift to anaerobic metabolism worsens acidosis with the production

of lactate. • Once energy stores are depleted, rhabdomyolysis occurs

(hyperkalemia and myoglobinuria).• Elevated creatine kinase and myoglobinuria — Plasma CK and urine

myoglobin levels peak (14 h) after an acute MH episode.

Treatment• Discontinue triggering agents and inform the operating surgeon of the

diagnosis. • Initiate MH protocol - Additional personnel should be mobilized• Dantrolene - Only known antidote which binds to the RYR1 R to inhibit

the release of Ca from the SR; this reverses the negative cascade of effects. ETCO will normalize as the dantrolene takes effect (within minutes). • Optimize O2 and ventilation – 100% oxygen. Increase RR and/or Vt to

maximize ventilation and reduce the ETCO . • Consider ET tube (using only non-depolarizing muscle relaxants)

• Hyperkalemia treatment based upon the presence of abnormal electrocardiogram waveforms (eg, peaked T waves) to prevent the development of life-threatening arrhythmias or cardiac arrest.

• ACLS to treat cardiac arrhythmias. Dysrhythmias usually respond to the treatment of acidosis and hyperkalemia.

• Contraindicated - Use of Ca channel blockers during an acute MH crisis because of the possibility that it can worsen hyperkalemia and hypotension.

• Check labs - electrolytes, blood gasses for acid/base status, CK, serum myoglobin, coagulation parameters, and fibrin split products

• Arterial or venous blood gases should be collected initially and as needed until pH and K levels trend toward normal values.

• Initiate supportive care• Monitor and treat acidosis; consider bicarbonate

• Monitor core temperature continuously.• Bladder catheter (urine color and volume) - Urine output should be kept

above 1 mL/kg/hour until the urine color returns to normal and the CK begins to decrease. • Monitor for myoglobinuria-induced renal failure (ie, hydration, diuretics,

bicarbonate). • Monitor muscle compartments for acute compartment syndrome -

rhabdomyolysis can result in compartment syndrome, especially in patients who have developed DIC. Consider muscle compartment release (ie, four compartment fasciotomy).• Monitor for DIC.

Mortality• Declined significantly and is estimated to be between 1 and 17

percent

References• Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia

due to anesthesia in New York State, 2001-2005. Anesth Analg 2009; 109:1162.• Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine

by dantrolene sodium. Br J Anaesth 1975; 47:62.• Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and

complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 2010; 110:498.• O'Sullivan GH, McIntosh JM, Heffron JJ. Abnormal uptake and release of

Ca2+ ions from human malignant hyperthermia-susceptible sarcoplasmic reticulum. Biochem Pharmacol 2001; 61:1479.