Abstract
Muscular dystrophies are a genetically and clinically diverse group of hereditary disorders of the structure of skeletal and cardiac muscle. Abnormal striated muscle and myocardial damage with associated cardiomyopathy have profound implications for perioperative management of patients with muscular dystrophies. The author presents a case of a life-threatening complication of general anesthesia in a child with previously undiagnosed Duchenne muscular dystrophy, then reviews the current classification of muscular dystrophies, genetic and molecular pathogenesis, clinical features, long-term complications and prognosis, and implications for the anesthesiologist.
Keywords
muscular dystrophy, anesthesia in muscular dystrophy, cardiomyopathy, malignant hyperthermia-like reaction, respiratory failure in muscular dystrophy
Case Synopsis
An 8-month-old boy undergoes myringotomy tube removal. Previous general anesthesia for tube placement was uneventful. Anesthesia is induced with intravenous thiopental and is maintained with nitrous oxide, halothane, and oxygen via a facemask. After removal of the myringotomy tube, the surgeon decides to perform an adenoidectomy. Airway obstruction at this time necessitates emergency intubation. After succinylcholine 2 mg/kg intravenously, an increase in masseter muscle tone is noted. The electrocardiogram (ECG) monitor shows a wide complex tachycardia progressing to bradycardia. End-tidal carbon dioxide (CO 2 ) of 40 to 50 mm Hg gradually decreases to 25 mm Hg. Arterial saturation decreases from 100% to 80%, then cannot be detected. Halothane is discontinued. Calcium chloride, epinephrine, and sodium bicarbonate are given intravenously. The ECG becomes increasingly dysmorphic, and pulses cannot be palpated. Chest compressions start. Venous blood analysis shows a pH of 7.13, CO 2 tension (P co 2 ) is 73 mm Hg, and serum potassium level is over 10 mmol/L. Calcium, epinephrine, and bicarbonate are repeated. After 13 minutes of cardiopulmonary resuscitation, the ECG shows the return of a narrow complex tachycardia, and systolic blood pressure increases to 100 mm Hg. Twenty minutes after succinylcholine administration, a venous blood sample shows a pH of 7.30, P co 2 of 49 mm Hg, and potassium of 7.1 mmol/L. A urinary catheter reveals red urine. The patient is transported to a pediatric intensive care unit. The creatine kinase (CK) level is 285,760 U/L. The patient is treated with vigorous intravenous hydration. He is discharged home in good condition. DNA studies show a deletion of the dystrophin gene, consistent with a diagnosis of Duchenne muscular dystrophy.
Problem Analysis
Definition
Muscular dystrophies are a clinically and genetically diverse group of hereditary disorders of the structure of striated muscle, characterized by progressive muscle weakness and wasting. The diagnosis of a muscular dystrophy is based on elevated serum CK, myopathic electromyogram features, and muscle biopsy. The morphologic changes common to all forms of muscular dystrophy present a random pattern of normal or hypertrophic muscle fibers, necrotic and necrotizing fibers, and interstitial accumulation of fatty and fibrous tissue. The latter changes result in the characteristic pseudohypertrophy of the calf muscles seen in Duchenne muscular dystrophy.
The previous classification of muscular dystrophies was based on patterns of inheritance and clinical features. A more recently proposed classification takes into account the type, localization, and function of defective proteins involved in the pathogenesis of different muscular dystrophies.
Plasma Membrane–Associated Proteins
Defective plasma membrane–associated proteins or the lack of such proteins causes the most common muscular dystrophies, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), the sarcoglycanopathies, and other forms of limb-girdle muscular dystrophy (LGMD).
Dystrophinopathies
The most common muscular dystrophies are X-linked recessive disorders caused by mutations of the dystrophin gene. Dystrophin is a large sarcolemmal protein essential for maintaining the integrity of the sarcolemma. The severe DMD form results from deficiency of dystrophin. The milder allelic form (BMD) is associated with a reduced amount of the truncated protein. The incidence of DMD is approximately 1 in 3500 live male births. A DMD or BMD phenotype may be expressed by a female patient with the dystrophin gene mutation and an X0 karyotype (Turner syndrome). Affected patients have delayed motor development, and when they start walking, they present with gait abnormalities. By the age of 5 years, muscle weakness is evident and calf pseudohypertrophy develops. Lumbar hyperlordosis and toe-walking result from progressive loss of muscle strength and tendon contractures. By age 12, most patients are confined to a wheelchair. Scoliosis, chest deformity, and diaphragmatic weakness lead to restrictive pulmonary disease by age 16 to 18. Respiratory failure, the most common cause of death, occurs in the third decade of life. Almost all patients have cardiomyopathy, but this rarely causes death. Intellectual impairment is common.
Compared with DMD, BMD has a later onset and a milder clinical course. Symptoms of proximal muscle weakness commonly start between ages 5 and 15, although the onset may be delayed until the third or fourth decade of life. Patients generally ambulate beyond age 15. Calf enlargement occurs early and is prominent. Patients have a short life expectancy, but many live to their thirties or forties. Mental retardation is milder than in DMD. In patients with mild or subclinical BMD, dilated cardiomyopathy may be the presenting feature of the disease. Most BMD patients die of complications of cardiomyopathy.
Sarcoglycanopathies
These disorders are caused by mutations of genes encoding four transmembrane glycoproteins of the sarcoglycan complex. Mutations of any of the four sarcoglycan genes (alpha, beta, gamma, and delta) result in LGMD 2D, 2E, 2C, and 2F. Males and females are similarly affected. Proximal leg muscle weakness generally appears in the second or third decade but may be delayed. Upper limb involvement with scapular winging develops. Diaphragmatic weakness with respiratory insufficiency, cardiomyopathy, congestive heart failure (CHF), and arrhythmias may develop. Intellectual function is normal.
Caveolin Deficiency
This is a rare form of autosomal dominant muscular dystrophy. LGMD 1C is caused by deficient caveolin, a ubiquitous plasma membrane protein.
Extracellular Matrix Proteins
Deficiencies in extracellular matrix proteins result in congenital muscular dystrophies (CMDs), a group of autosomal recessive disorders that become symptomatic at birth or in infancy. They are diagnosed by hypotonia and a dystrophic muscle biopsy. The most severe form is merosin-deficient CMD. The maximal functional ability of a child with CMD is sitting unsupported. Cardiomyopathy may be present.
Proteins With Enzymatic Activity
Mutations in Genes Encoding Glycosyltransferases
These mutations are a recently identified mechanism for CMDs. The gene encoding the fukutin-related protein (FKRP—a glycosyltransferase) is mutated in a severe form of muscular dystrophy, CMD type 1C, as well as a mild form, LGMD 2I. Central nervous system involvement is present in the severe form, with cerebellar cysts, seizures, and developmental delay. Mild cardiomyopathy also may be present.
Protein Kinases
Heterozygosity for a trinucleotide repeat ([CTG]n) expansion mutation in the 3′ untranslated region of a protein kinase gene on chromosome 19 is the cause of myotonic dystrophy, the most common adult form of muscular dystrophy. This has a prevalence of 1 in 8000. Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia, slowly progressive muscle weakness and wasting, frontal baldness, cataracts, and insulin resistance secondary to aberrant insulin receptor expression.
Other Muscle Proteins
Sarcomeric Proteins
Mutations in the titin gene, encoding a giant sarcomeric protein, underlie an autosomal dominant form of congenital dilated cardiomyopathy. Recently mutations of the same gene have been found in patients with isolated tibial muscular dystrophy.
Nuclear Proteins
Defects in two nuclear proteins are responsible for two distinct forms of Emery-Dreifuss muscular dystrophy (EDMD). X-linked EDMD is due to mutations in the gene encoding the nuclear protein emerin. Autosomal dominant EDMD results from mutations in the lamin A/C gene, encoding a protein of the nuclear lamina. Mutations in this gene also lead to a form of dominant proximal LGMD 1B and dilated cardiomyopathy. Skeletal muscle involvement in EDMD is usually mild and slowly progressive. Cardiac involvement is the predominant feature of the disease.
Cardiomyopathy in Muscular Dystrophies
Cardiac involvement is a universal feature of muscular dystrophies. The severity of cardiac involvement may determine the long-term prognosis for persons with any type of muscular dystrophy.
In DMD and BMD, lacking or faulty dystrophin has been demonstrated in both skeletal and cardiac muscle. Heart failure is often the cause of death, alone or in association with respiratory failure. Myocardial damage is initially subclinical but can be recognized through minor ECG and echocardiographic changes. Myocardial involvement progresses to a clinically evident stage of hypertrophy; arrhythmias, characterized by conduction defects (atrioventricular block, bundle branch block) or severe supraventricular or ventricular arrhythmias; and, eventually, dilated cardiomyopathy due to widespread myocardial fibrosis. Heart failure is the most common cause of death in patients with BMD. Female carriers of DMD and BMD have a 10% incidence of age-progressive cardiomyopathy. Patients with severe forms of muscular dystrophy rarely are candidates for heart transplant given the poor long-term prognosis of the disease. The use of destination left ventricle assist device in DMD patients with end-stage dilated cardiomyopathy has recently been described.
Sarcoglycanopathies (LGMD 2C, 2D, 2E, 2F) may have associated dilated cardiomyopathy. This results from disrupted sarcoglycan complexes in both skeletal and cardiac muscle.
LGMD due to mutations in the FKRP gene (LGMD 2I) may be associated with myocardial fibrosis, leading to dilated cardiomyopathy and repolarization abnormalities.
In myotonic dystrophies, cardiac conduction defects are a major cause of sudden death. The incidence of complete atrioventricular block among these patients is higher than in the general population. A prolonged His-ventricular conduction interval puts these patients at risk of paroxysmal atrioventricular block and justifies early pacemaker implantation. In congenital (neonatal) myotonic dystrophy, abnormal myocardial relaxation results in left ventricular diastolic dysfunction.
Severe cardiac involvement is common in EDMD. Both X-linked and autosomal dominant forms involve the risk of bradyarrhythmias (often requiring pacemaker implantation) and atrial fibrillation or flutter. Atrial fibrillation often precedes atrial standstill and may be the cause of embolic stroke at a young age. Prophylactic anticoagulation is recommended in EDMD patients with atrial arrhythmias or standstill. Finally, left ventricular failure is rare but may be severe.
Recognition
Patients with muscular dystrophy usually present for muscle biopsy, tendon contracture release, correction of kyphoscoliosis, or pacemaker implantation. Pediatric or young adult patients with undiagnosed muscular dystrophy may present for procedures unrelated to the disease.
All patients with muscular dystrophy should be suspected of having respiratory and cardiac dysfunction. Pulmonary function tests should be performed in all patients with muscle weakness because of the high incidence of restrictive lung disease secondary to diaphragmatic weakness and scoliosis. In asymptomatic patients with a diagnosis of muscular dystrophy, the specific type of dystrophy and the risk of cardiac involvement determine the need for further cardiac workup.
Intraoperative CHF may present as tachycardia and hypotension unresponsive to intravenous fluids. Physical signs of CHF include jugular vein distention, pulmonary rales, and dyspnea in a spontaneously breathing patient. Severe CHF may result in acute pulmonary edema. Diagnosis may be confirmed by transesophageal echocardiogram or by hemodynamic measurements with a pulmonary artery catheter. Typically, pulmonary artery occlusion pressure is elevated (>18 mm Hg), cardiac index is low (<2.2 L/min/m 2 body surface area), and systemic vascular resistance is high (>1200 dynes/sec/cm −5 ).
In children with undiagnosed DMD, succinylcholine has been reported to induce hyperkalemic cardiac arrest. On the basis of these reports, the Food and Drug Administration recommended against the use of succinylcholine for nonemergent intubation in all children.
Exposure of patients with DMD and BMD to volatile anesthetics, halothane, isoflurane, and sevoflurane may result in hyperthermia, muscle rigidity, massive rhabdomyolysis, and hyperkalemia. Hyperkalemic cardiac arrest has been reported as the first manifestation of occult DMD in young patients undergoing general anesthesia without the use of succinylcholine. This clinical picture mimics malignant hyperthermia (MH) and it has long been believed to be true MH. However, dystrophinopathies (DMD and BMD) and MH are genetically distinct entities: dystrophinopathies result from an X chromosome mutation, whereas MH is caused by a mutation of the gene encoding the ryanodine receptor (RYR), located on chromosome 19.
Risk Assessment
All patients with muscular dystrophy are at risk for cardiomyopathy or conduction disorders. Signs and symptoms of myocardial dysfunction at the time of preoperative evaluation may be overt or masked by confinement to a wheelchair. Therefore all patients with muscular dystrophy should have their cardiac function evaluated preoperatively. ECG abnormalities (sinus tachycardia or bradycardia, short P-R interval, signs of left ventricular hypertrophy, conduction defects) are common. However, the best correlation between severe cardiac involvement and mortality is the degree of left ventricular echocardiographic dysfunction. Guidelines for the assessment of cardiac involvement in patients with DMD and BMD advise that those with DMD have an echocardiogram and ECG at the time of diagnosis, every 2 years up to age 10, and annually thereafter. BMD patients should have an echocardiogram and ECG at the time of diagnosis and then every 5 years. The same recommendations apply to patients with other forms of muscular dystrophy. Additional echocardiograms or ECGs should be obtained before surgery or when clinically indicated.
Patients with EDMD should have an ECG and echocardiogram at the time of diagnosis and annually thereafter. They should also be monitored annually for arrhythmias with a Holter monitor. An implanted pacemaker is justified for symptomatic patients or for asymptomatic patients whose ECG shows sinus node or atrioventricular node dysfunction. In autosomal dominant EDMD, sudden death is a possibility. Therefore an internal cardioverter-defibrillator should be considered whenever antibradycardia pacing is indicated. When atrial fibrillation or atrial standstill is diagnosed, systemic anticoagulation is indicated.
Intracardiac conduction should be evaluated in all adult myotonic dystrophy patients. Patients are selected to undergo cardiac electrophysiologic investigation based on the results of signal-averaged ECGs.
In patients with DMD, a steady decrease in vital capacity (VC) follows progressive muscle weakness and the development of scoliosis. Once VC falls below 20% of predicted values, ventilatory failure is inevitable, and 73% of patients die of respiratory failure. Obstructive sleep apnea (OSA) is common, leading to chronic hypoxemia and right ventricular failure. Preoperative pulmonary function tests and sleep studies are indicated to assess the severity of restrictive pulmonary disease and OSA.
Implications
Patients with muscular dystrophies are at an increased risk of perioperative CHF, arrhythmias, and respiratory failure. If the VC is less than 30% of predicted, the patient will likely require prolonged postoperative ventilatory support. OSA and weak pharyngeal muscles increase the risk for early postoperative airway obstruction and hypoxia. Outpatient general anesthesia is not advised, owing to the risk of delayed respiratory depression. Also, delayed gastric emptying increases the risk of aspiration.
Succinylcholine can cause hyperkalemic cardiac arrest; therefore its use is contraindicated. Nondepolarizing muscle relaxants (NDMRs) may have prolonged effects, and their reversal with neostigmine is unpredictable. Volatile anesthetics may trigger an MH-like reaction (muscle rigidity, rhabdomyolysis, hyperkalemia, and hyperthermia) in patients with Duchenne or Becker dystrophy.
In patients with myotonic dystrophy, hypothermia, shivering, succinylcholine, neostigmine, and direct muscle stimulation may precipitate a myotonic crisis, characterized by prolonged contracture of the skeletal muscles.
For these reasons, regional or local anesthesia, when suitable, is preferred for all patients with muscular dystrophy. Finally, patients with DMD previously treated with glucocorticoid steroids require supplemental perioperative steroids.
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