46: Malignant Hyperthermia and Other Motor Diseases

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CHAPTER 46 Malignant Hyperthermia and Other Motor Diseases

James Duke, MD, MBA

1 What is malignant hyperthermia and its underlying defect?

Malignant hyperthermia (MH) is a myopathy characterized by an uncontrolled increase in skeletal muscle metabolism after exposure to a triggering agent. Patients with MH have an uncontrolled release of calcium from the sarcoplasmic reticulum caused by an abnormal ryanodine receptor (RyR1) isoform, a protein crucial for the release of calcium during normal excitation-contraction coupling. RyR1 mutations on chromosome 19 are found in 25% of known MH-susceptible individuals in North America. There are also associations between MH and another protein associated with the calcium channel, the dihydropyridine receptor. The gene for this protein is located on chromosome 7. Other RyR1 mutations are noted in other countries.

2 What are the inheritance pattern and triggering agents for malignant hyperthermia?

MH is inherited as an autosomal-dominant disorder with reduced penetrance and variable expressivity. Succinylcholine and the halogenated inhalational agents may precipitate an episode in a susceptible patient. MH is rare in infants and decreases after 50 years of age.

3 Describe the cellular events, presentation, and metabolic abnormalities associated with malignant hyperthermia

Hypermetabolism of skeletal muscle leads to hydrolysis of adenosine triphosphate, glycolysis, glycogenolysis, uncoupled oxidative phosphorylation, increase in oxygen consumption, and heat production. The earliest symptom is often unexplained tachycardia. The sine qua non of MH is an unexplained rise in end-tidal CO2. Patients may demonstrate peculiar rigidity, even after nondepolarizing relaxants have been administered. If untreated, the patient develops numerous metabolic abnormalities, including metabolic acidosis, respiratory acidosis, hypoxemia, hyperthermia, rhabdomyolysis, hyperkalemia, hypercalcemia, hyperphosphatemia, elevations in creatine kinase, myoglobinuria, acute renal failure, cardiac dysrhythmias, and disseminated intravascular coagulation. Death is common if the problem is unrecognized and untreated. Data from the North American Malignant Hyperthermia Registry (NAMHR) have determined a rate of cardiac arrest of 2.7% and of death 1.4%. Interestingy, although the malady is called MH, temperature increase is a relatively late manifestation.

4 How is malignant hyperthermia treated?

image Call for assistance because aggressive therapy requires more than one person.
image Turn off all triggering agents and hyperventilate the patient with 100% oxygen.
image Change to a non-triggering anesthetic such as propofol infusion.
image Notify the surgeon and operating-room personnel of the situation at hand and expedite conclusion of the procedure, even if it may require that surgery go unfinished.
image Administer dantrolene, 2 mg/kg; repeat every 5 minutes to a total dosage of 10 mg/kg if needed. Dantrolene sodium inhibits calcium release via RyR1 antagonism.
image Monitor blood gases. Administer bicarbonate, 2 to 4 mEq/kg for a pH < 7.1.
image Cool the patient, using interventions such as iced fluids and cooling blankets, but become less aggressive in reducing body temperature at about 38° C.
image Promote urine output (2 ml/kg/hr), principally with aggressive fluid therapy, although mannitol and furosemide may also be required.
image Treat hyperkalemia with calcium chloride, bicarbonate, and insulin.
image Check for hypoglycemia and administer dextrose, particularly if insulin has been administered.
image Treat dysrhythmias with procainamide and calcium chloride, 2 to 5 mg/kg intravenously (calcium chloride is used to treat the hyperkalemia-associated dysrhythmias).

5 How does dantrolene work? How is dantrolene prepared?

Dantrolene impairs calcium-dependent muscle contraction. This rapidly halts the increases in metabolism and secondarily results in a return to normal levels of catecholamines and potassium. The solution is prepared by mixing 20 mg of dantrolene with 3 g of mannitol in 60 ml of sterile water. Since dantrolene is relatively insoluble, preparation is tedious and time consuming, and its preparation should not be the responsibility of the primary anesthesiologist involved in the patient’s management.

6 How is malignant hyperthermia susceptibility assessed in an individual with a positive family history or prior suggestive event?

The diagnosis of MH is immensely difficult. There are clinical grading scales that have been used to help determine how likely a suspected episode is a true MH episode. The gold standard for diagnosis is the caffeine-halothane contracture test (CHCT). The patient’s muscle is exposed to incremental doses of halothane and caffeine, and the muscle is evaluated for the degree of contracture. The test is offered at only five centers in the United States and two in Canada. The test is 85% to 90% specific and 99% to 100% sensitive. It is important that patients who have experienced MH episodes undergo further evaluation because some of these patients will be found to be MH negative.

Genetic testing for the abnormal RyR1 isoform is now available in the United States and other selected countries. The role for genetic testing is expanding. It is much cheaper than muscle biopsy and CHCT and can be performed on children too young to have CHCT (less than 10 years of age or less than 40 kg). Genetic testing is especially valuable in homogeneous populations in whom the genetic defect is constant. However, if genetic testing is negative in a susceptible individual, a CHCT must be performed.

7 What are the indications for muscle biopsy and halothane-caffeine contracture testing?

image Definite indications: Suspicious clinical history for MH, family history of MH, prior episode of masseter muscle rigidity
image Possible indications: Unexplained rhabdomyolysis during or after surgery, sudden cardiac arrest caused by hyperkalemia, exercise-induced hyperkalemia, moderate-to-mild masseter muscle rigidity with evidence of rhabdomyolysis
image Probably not indications: Diagnosis of neuroleptic malignant syndrome or sudden unexplained cardiac arrest during anesthesia or early postoperative period not associated with rhabdomyolysis

8 What is masseter muscle rigidity and what is its relation to malignant hypothermia?

Masseter muscle rigidity (MMR) is defined as jaw muscle tightness with limb muscle flaccidity following a dose of succinylcholine. There is a spectrum of masseter response, from a tight jaw to a rigid jaw to severe spasticity, or trismus, otherwise described as jaws of steel. Of concern, the mouth cannot be opened sufficiently to intubate the patient. If jaws of steel are present, the incidence of MH susceptibility is increased. There is some controversy as to the management of patients experiencing MMR. Most pediatric anesthesiologists agree that, if trismus occurs, the triggering agent should be halted along with the surgical procedure if feasible. The patient should be admitted to the hospital for 24 hours of close observation. Creatine kinase levels should be followed every 6 hours. Creatine kinase levels greater than 20,000 have a 95% predictive value that the patient is MH susceptible.

9 Describe the preparation of an anesthetic machine and anesthetic for a patient with known malignant hypothermia susceptibility

Clean the anesthetic machine; remove vaporizers; and replace CO2 absorbant, bellows, and gas hose. Flush the machine for 20 minutes with 10 L/min of oxygen. Have the MH cart in the operating room. Schedule the patient for the first case of the day and notify the postanesthesia care unit to be prepared with an appropriate number of personnel. A cooling blanket should be placed under the patient. Refrigerated saline should be available. A nontriggering anesthetic technique such as continuous intravenous infusion of propofol should be used. The patient should be monitored for 6 to 8 hours after surgery.

10 Should malignant hypothermia–susceptible patients be pretreated with dantrolene?

Dantrolene pretreatment is no longer indicated, providing that a nontriggering agent and appropriate monitoring are used and an adequate supply of dantrolene is available. Dantrolene pretreatment may cause mild weakness in normal patients and significant weakness in patients with muscle disorders. MH-susceptible patients with an uncomplicated intraoperative course should be monitored for at least 4 hours after surgery.

11 What patients are at risk for redeveloping symptoms of malignant hypothermia after treatment with dantrolene?

Review of data from the NAMHR suggests that about 20% of patients redevelop symptoms, known as recrudescence. It should be mentioned that the accuracy of these data is limited by their retrospective nature. The mean time until symptoms redevelop was 13 hours, with a range of 2.5 to 72 hours. Eighty percent manifested symptoms by 16 hours. Patients at risk were more muscular and thus had greater muscle mass, an MH score of 35 or greater (meaning that MH is very likely to be present), and a temperature increase as much as 38.8° C. There was no strong relationship between use of succinylcholine or a particular volatile anesthetic. Probably the most severely affected are likely to develop recrudescence; these findings suggest that all patients who develop MH require at least 24 hours of posttreatment management in a critical-care setting.

12 What drugs commonly administered intraoperatively are safe to use in malignant hyperthermia–susceptible patients

image Induction agents: barbiturates, propofol, etomidate, ketamine
image Benzodiazepines and opiates
image Amide and ester local anesthetics
image Nitrous oxide
image Nondepolarizing muscle relaxants
image Calcium

13 Compare neuroleptic malignant syndrome with malignant hypothermia

Neuroleptic malignant syndrome (NMS) is characterized by akinesis, muscle rigidity, hyperthermia, tachycardia, cyanosis, autonomic dysfunction, sensorium change, tachypnea, and elevated levels of creatine kinase. It is associated with administration of the psychotropic drugs haloperidol, fluphenazine, perphenazine, and thioridazine, to name a few, and is caused by dopamine receptor blockade in the hypothalamus and basal ganglia. NMS is treated with dantrolene or bromocriptine (a dopamine receptor agonist) and has a mortality rate of 10%. Patients with NMS are not prone to MH.

14 What are the muscular dystrophies and their underlying defect?

The muscular dystrophies (MDs) are genetically determined degenerative muscle diseases and are divided further into muscular and myotonic dystrophies. Painless muscle degeneration and atrophy are common features. MD is associated with mutations of the gene that codes for the protein dystrophin. Dystrophin attaches muscle fibers to an extracellular matrix. Inadequately tethered muscle fibers are injured by shearing forces, degenerate, and are replaced by adipose and connective tissue. Dystrophin also seems to have other roles, including clustering of acetylcholine receptors on the postsynaptic motor membrane and modulation of ionic channels.

15 What are the most common muscular dystrophies and their clinical history?

Duchenne MD (DMD) is the most common. It is an X chromosome–linked recessive disease with signs and symptoms presenting between 2 and 5 years of age. Death often occurs in late adolescence and is typically caused by heart failure or pneumonia. Degeneration of cardiac muscle, as demonstrated by a progressive decrease in R-wave amplitude on electrocardiogram (ECG), is observed to some degree in 70% of DMD patients and may lead to a decrease in contractility and mitral regurgitation secondary to papillary muscle dysfunction. Thus patients with MD may be sensitive to the myocardial depressant effects of inhaled anesthetics. There is weakness of respiratory muscles, and a restrictive pattern is observed on pulmonary function testing. Smooth muscle may also be affected in patients with MD, manifesting as gastrointestinal tract hypomotility, delayed gastric emptying, and impaired swallowing, which may lead to increased risk of aspiration.

Becker MD has similar, although milder, symptoms and a more protracted course.

16 Briefly review of forms of muscular dystrophy

Other forms include the limb-girdle, oropharyngeal, and fascioscapulohumeral muscular dystrophies. Some of these forms are transmitted as autosomal and/or dominant and thus can be identified in both females and males. Bulbar muscles are usually spared; therefore aspiration is less of a risk, although dysrhythmias, conduction abnormalities, occasional sudden death, and cardiomyopathies are noted. One form, Emery-Dreifuss MD, has posterior nuchal muscle contractures as a feature and may render airway management difficult.

17 How do patients with muscular dystrophy respond to muscle relaxants and volatile anesthetics?

Succinylcholine should not be used because of the possibility of severe hyperkalemia and cardiac arrest. Cardiac arrest has been reported in patients with unrecognized MD. Because children with MD may not develop noticeable weakness until they are several years old, many authorities believe succinylcholine should not be used in children except in airway emergencies. Nondepolarizing relaxants are acceptable but may be associated with longer-than-normal recovery times.

There are reports of massive elevations in creatine kinase, severe myoglobinuria, and cardiac arrest after use of volatile anesthetics. Although not all patients with MD are at risk for MH, some are; thus a nontriggering general anesthetic or regional anesthesia is preferred.

18 Are patients with muscular dystrophy at risk for malignant hyperthermia?

After succinylcholine administration children with MH and MD may have similar clinical pictures, including hyperkalemia, elevated creatine kinase, and cardiac arrest, although the mechanism of the diseases is different. There are also reports of children with MD exposed to inhalational agents but not succinylcholine that have demonstrated suggestive signs of MH. However, it is not believed that children with MD are at increased risk for MH.

19 What is myotonic dystrophy?

Myotonic dystrophy is an autosomal-dominant disease that usually presents in the second or third decade and is the most common inherited myopathy in adults. It is characterized by persistent contraction of skeletal muscle after stimulation. The contractions are not relieved by regional anesthetics, nondepolarizing muscle relaxants, or deep anesthesia. It is a multisystem disease; deterioration of skeletal, cardiac, and smooth muscle function is progressive.

20 How does myotonic dystrophy affect the cardiopulmonary system?

Heart failure is rare, but dysrhythmias and atrioventricular block are common. Mitral valve prolapse occurs in 20% of patients. Restrictive lung disease, with mild hypoxia on room air, a weak cough, and inadequate airway protective reflexes, may lead to pneumonia. These patients are also sensitive to medications that depress ventilatory drive.

21 What are the important muscle relaxant considerations in patients with myotonic dystrophy?

Succinylcholine produces exaggerated contraction of skeletal muscles, possibly making mask ventilation and tracheal intubation difficult or impossible. The response to nondepolarizing muscle relaxants is normal; nondepolarizing relaxants will not ablate myotonic contractures.

22 What is myasthenia gravis?

Myasthenia gravis is an autoimmune disease of the neuromuscular junction. Antibodies to the acetylcholine receptor may reduce the absolute number of functional receptors by direct destruction of the receptor, blockade of the receptor, or complement-mediated destruction.

23 Describe the clinical presentation of myasthenia gravis

Myasthenic patients present with generalized fatigue and weakness that worsens with repetitive muscular use and improves with rest. Very commonly extraocular muscles are the first affected, and the patient complains of diplopia or ptosis. Of particular concern are myasthenic patients who develop weakness of their respiratory muscles or the muscles controlling swallowing and the ability to protect the airway from aspiration. Depending on whether extraocular, airway, or respiratory muscles are affected, myasthenia gravis (MG) may be described as ocular, bulbar, or skeletal, respectively.

24 How is myasthenia gravis treated? What can lead to an exacerbation of symptoms?

Cholinesterase inhibitors, corticosteroids, and other immunosuppressants are effective, as is plasmapheresis, although in many thymectomy results in remission. Physiologic stress such as an acute infection, pregnancy, or surgical procedure can lead to exacerbations of MG.

25 What are some of the principal anesthetic concerns in the management of a myasthenic patient for any operative procedure?

Principal concerns include the degree of pulmonary impairment, the magnitude of bulbar involvement with attendant difficulty managing oral secretions (risk of pulmonary aspiration), and adrenal suppression from long-term steroid use. Although uncommon, cardiac disease that is MG related should be considered in the preoperative evaluation. Because symptoms are primarily related to arrhythmias, an ECG should be evaluated. Symptoms of congestive heart failure should be sought as well.

26 Describe the altered responsiveness of myasthenic patients to muscle relaxants

Patients are resistant to succinylcholine. However, the degree of resistance does not appear to be of great clinical significance, and increasing the dose of succinylcholine to 2 mg/kg results in satisfactory intubating conditions.

Myasthenic patients are more sensitive than nonmyasthenic persons to nondepolarizing relaxants. Dosing nondepolarizing relaxants should start at about one tenth the usual recommended doses. Recovery time for these reduced doses varies but may be quite prolonged. Relaxation should be reversed at case conclusion, and the patient carefully evaluated for return of strength.

Often at anesthetic induction no muscle relaxant is necessary to achieve endotracheal intubation. These patients are already weak; if volatile anesthetics are administered, suitable muscle relaxation is achieved. The best course of action for myasthenic patients may be to avoid muscle relaxants altogether.

27 What is Lambert-Eaton myasthenic syndrome? Describe its symptoms, associations, and treatment

This is an immune-mediated disease of the neuromuscular junction that frequently arises in the setting of malignancy, often small-cell carcinoma of the lung. Other associated malignancies include lymphoma, leukemia, prostate, and bladder. Antibodies affect the presynaptic junction and result in decreased acetylcholine release. As opposed to MG, weakness improves with motor activity, although frequently the improvement is transient. Proximal muscles are affected more than distal, and legs more than arms. Cranial nerve involvement is also less frequent when compared to MG. Interestingly, weakness often precedes the cancer diagnosis, although treatment focuses on treatment of the underlying malignancy. Autonomic dysfunction is common and manifests as dry mouth, orthostatic hypotension, and bowel and bladder dysfunction. Corticosteroids, 3,4-diaminopyridine, and other immunosuppressants improve strength.

28 Review the anesthetic concerns for a patient with Lambert-Eaton syndrome

These patients are exquisitely sensitive to both depolarizing and nondepolarizing muscle relaxants, and these medications are best avoided. If given, paralysis can last for days and is not reversible with anticholinesterase medications. Volatile anesthetics are safe and often provide the necessary degree of muscle relaxation to facilitate endotracheal intubation. When applicable, regional techniques are encouraged.

KEY POINTS: Malignant Hyperthermia and Other Motor Diseases image

1. MH is a hypermetabolic disorder that presents in the perioperative period after exposure to inhalational agents or succinylcholine.
2. Early recognition is critical; and treatment is complex and multifaceted, requiring the assistance of other experienced personnel.
3. The sine qua non of MH is an unexplained rise in end-tidal carbon dioxide in a patient with unexplained tachycardia. A temperature rise is a late feature.
4. Patients with a history of MH or who are MH susceptible must receive anesthesia with a nontriggering agent. The anesthesiologist must have a heightened awareness of MH, have prepared the anesthetic machine, and have the MH cart in the room.
5. Succinylcholine must be avoided in children with MD and should be avoided except in airway emergencies in male children.
6. Nondepolarizing muscle relaxants should be used at about one tenth of normal doses (if at all) in patients with myasthenia gravis.
7. Patients with Lambert-Eaton myasthenic syndrome are sensitive to both depolarizing and nondepolarizing muscle relaxants, and these medications are best avoided.
8. Patients with MDs are prone to aspiration and respiratory insufficiency and may have dysrhythmias, conduction blockade, and cardiomyopathy.

Websites image

Myasthenia Gravis Foundation of America

http://www.myasthenia.org

Malignant Hyperthermia Association of the United States

http://www.mhaus.org

SUGGESTED READINGS

1. Bhatt J.R., Pascuzzi R.M. Neuromuscular disorders in clinical practice: case studies. Neurol Clin. 2006;24:233-265.

2. Brambrink A.M., Kirsch J.R. Perioperative care of patients with neuromuscular disease and dysfunction. Anesthesiol Clin. 2007;25:483-509.

3. Brandom B.W. The genetics of malignant hyperthermia. Anesthesiol Clin North Am. 2005;23:615-619.

4. Burkman J.M., Posner K.L., Domino K.B. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology. 2007;106:901-906.

5. Larach M.G., Brandom B.W., Allen G.C., et al. Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006. Anesthesiology. 2008;108:603-611.

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