Symposium on Recent Clinical Advances
Rhabdomyolysis and Myoglobinuria in Childhood James L. Robotham, M.D.,* and James E. Haddow, M.D.t
Rhabdomyolysis with its attendant myoglobinuria is an uncommon but serious problem which may occur even in the early months of life. 52 ,74,loB Symptomatology is nonspecific, but pigmenturia should direct attention toward the correct diagnosis. Prompt diagnosis is important since serum electrolyte abnormalities, cardiac arrhythmias, and renal or respiratory failure may rapidly lead to death. Treatment of acute episodes to this date has been nonspecific, directed at supporting the patient until the attack subsides. The generally favorable prognosis is linked closely to this phase of management. Prevention has centered on avoidance of those situations known to precipitate an attack. Considerable progress had been made toward understanding and defining a number of primary metabolic lesions associated with rhabdomyolysis, but a large number of cases are still classified as "idiopathic" in spite of detailed histologic, enzymatic, and biochemical studies. Every effort should be made to identify a specific cause for each patient diagnosed as having rhabdomyolysis and methods for preventing future attacks investigated. In addition, the family should be studied for other possible cases and genetic counseling made available when appropriate. Rhabdomyolysis results in myoglobin release and myoglobinuria, a term which traditionally has described conditions in which the urine was visibly pigmented. There are also times, however, when myoglobin is present in concentrations too low to be visible. For that reason, the term rhabdomyolysis will be used in the following discussions to imply myoglobinuria whether visible or not. Athletes, both trained and untrained, often excrete measurable but not visible amounts of myoglobin in the urine with no apparent ill effects,B6 and small amounts of myoglobin have been found in the serum of children after standard doses of succinylcholine.1 l2 Cardiac muscle damage may be confirmed by the presence of myoglobin in the urine in adults following myocardial infarction. 73 It has been calculated that at least 1 to 5 per cent ofthe total body muscle mass must be destroyed before visible darkening occurs in the urine. lOB "Research Fellow, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada t Associate Director, Rheumatic Disease Laboratory, Maine Medical Center, Portland, Maine
Pediatric Clinics of North America-Vol. 23, No.2, May 1976
279
280
JAMES
L. ROBOTHAM AND JAMES E. HADDOW
This paper focuses on several aspects of rhabdomyolysis: its exclusion from other causes of pigmenturia, its biochemical and clinical features, and its defined and theoretical etiologies. A conceptual framework for diagnostic and preventive considerations based on an understanding of muscle metabolism is developed. Supportive therapy is mentioned only with regard to those aspects peculiar to rhabdomyolysis.
MYOGLOBINURIA VERSUS OTHER PIGMENTURIAS Gross pigmenturia in an acutely ill patient focuses attention on a limited differential diagnosis which includes hemoglobinuria, porphyria, and myoglobinuria. These may be differentiated in part by history and physical examination followed by rapid preliminary laboratory confirmation. Previous episodes may have occurred with infection, fasting, or exercise. The known association of general anesthetics or heroin with myoglobinuria,99,102,108,131 oxidant drugs with hemoglobinuria, and barbiturates or steroids with porphyria80 are examples where historical information may be of help. Weakness and hypoactive deep tendon reflexes, often associated with tense, edematous, painful muscles, point toward myoglobinuria. Severe abdominal pain, autonomic dysfunction, peripheral neuropathy, or skin lesions should focus attention on porphyria. 80,123,126 Central nervous system dysfunction, a recognized symptom of porphyria, 123,126 may also occur in rhabdomyolysis, 52 particularly in association with heroin. 131 Both hemoglobin and myoglobin will produce positive reactions to benzidine reagents, orthotoluidine* and the commonly used urinary dipsticks for hemet. Urine centrifugation with observation of supernatant color will differentiate pigmenturia from hematuria. Color may vary from pink to red to red-brown in hemoglobinuria. Myoglobinuria produces a color varying from brown to pink, and porphyria shows a burgundy color. Red blood cells are commonly found in small to moderate numbers in the sediment of patients with rhabdomyolysis in addition to red-gold pigmented granular casts 46 and, occasionally, myoglobin crystals. 115 Addition of (NH4)2 S04 to an aliquot of urine to 80 per cent of saturation (76.7 gm added to 100 ml at 25°C. equals 100 per cent saturation) will cause hemoglobin to precipitate but leave myoglobin in solution. The clinical reliability of this test has been questionable. 82 ,108,115 Hemoglobinuria produced by hemolysis will be associated with pink serum because haptoglobin, a serum globulin, complexes with free circulating hemoglobin up to a level of 100 to 150 mg/lOO m!. Only after haptoglobin binding sites have been saturated will free hemoglobin be filtered into the urine, and serum becomes pink above a level of 40 mg/lOO ml of hemoglobin. A similar globulin exists for myoglobin, but the binding is looser and the system is saturated at 20 mg/100 ml allowing myoglobin to be cleared rapidly by glomerular filtration before pink *Hematest-Ames Co., Inc., Division of Miles Laboratories, Elkhart, Indiana. tHemastix-Ames Co., Inc., Division of Miles Laboratories, Elkhart, Indiana.
~
Table 1. Physical and Biochemical Features of the Pigmenturias
tI
MYOGLOBINURIA
HEMOGLOBINURIA
PORPHYRIA
PHYSICAL EXAMINATION
o
a:: ~
t"'
>
Rhabdomyolysis and Myoglobinuria in Childhood James L. Robotham, M.D.,* and James E. Haddow, M.D.t
Rhabdomyolysis with its attendant myoglobinuria is an uncommon but serious problem which may occur even in the early months of life. 52 ,74,loB Symptomatology is nonspecific, but pigmenturia should direct attention toward the correct diagnosis. Prompt diagnosis is important since serum electrolyte abnormalities, cardiac arrhythmias, and renal or respiratory failure may rapidly lead to death. Treatment of acute episodes to this date has been nonspecific, directed at supporting the patient until the attack subsides. The generally favorable prognosis is linked closely to this phase of management. Prevention has centered on avoidance of those situations known to precipitate an attack. Considerable progress had been made toward understanding and defining a number of primary metabolic lesions associated with rhabdomyolysis, but a large number of cases are still classified as "idiopathic" in spite of detailed histologic, enzymatic, and biochemical studies. Every effort should be made to identify a specific cause for each patient diagnosed as having rhabdomyolysis and methods for preventing future attacks investigated. In addition, the family should be studied for other possible cases and genetic counseling made available when appropriate. Rhabdomyolysis results in myoglobin release and myoglobinuria, a term which traditionally has described conditions in which the urine was visibly pigmented. There are also times, however, when myoglobin is present in concentrations too low to be visible. For that reason, the term rhabdomyolysis will be used in the following discussions to imply myoglobinuria whether visible or not. Athletes, both trained and untrained, often excrete measurable but not visible amounts of myoglobin in the urine with no apparent ill effects,B6 and small amounts of myoglobin have been found in the serum of children after standard doses of succinylcholine.1 l2 Cardiac muscle damage may be confirmed by the presence of myoglobin in the urine in adults following myocardial infarction. 73 It has been calculated that at least 1 to 5 per cent ofthe total body muscle mass must be destroyed before visible darkening occurs in the urine. lOB "Research Fellow, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada t Associate Director, Rheumatic Disease Laboratory, Maine Medical Center, Portland, Maine
Pediatric Clinics of North America-Vol. 23, No.2, May 1976
279
280
JAMES
L. ROBOTHAM AND JAMES E. HADDOW
This paper focuses on several aspects of rhabdomyolysis: its exclusion from other causes of pigmenturia, its biochemical and clinical features, and its defined and theoretical etiologies. A conceptual framework for diagnostic and preventive considerations based on an understanding of muscle metabolism is developed. Supportive therapy is mentioned only with regard to those aspects peculiar to rhabdomyolysis.
MYOGLOBINURIA VERSUS OTHER PIGMENTURIAS Gross pigmenturia in an acutely ill patient focuses attention on a limited differential diagnosis which includes hemoglobinuria, porphyria, and myoglobinuria. These may be differentiated in part by history and physical examination followed by rapid preliminary laboratory confirmation. Previous episodes may have occurred with infection, fasting, or exercise. The known association of general anesthetics or heroin with myoglobinuria,99,102,108,131 oxidant drugs with hemoglobinuria, and barbiturates or steroids with porphyria80 are examples where historical information may be of help. Weakness and hypoactive deep tendon reflexes, often associated with tense, edematous, painful muscles, point toward myoglobinuria. Severe abdominal pain, autonomic dysfunction, peripheral neuropathy, or skin lesions should focus attention on porphyria. 80,123,126 Central nervous system dysfunction, a recognized symptom of porphyria, 123,126 may also occur in rhabdomyolysis, 52 particularly in association with heroin. 131 Both hemoglobin and myoglobin will produce positive reactions to benzidine reagents, orthotoluidine* and the commonly used urinary dipsticks for hemet. Urine centrifugation with observation of supernatant color will differentiate pigmenturia from hematuria. Color may vary from pink to red to red-brown in hemoglobinuria. Myoglobinuria produces a color varying from brown to pink, and porphyria shows a burgundy color. Red blood cells are commonly found in small to moderate numbers in the sediment of patients with rhabdomyolysis in addition to red-gold pigmented granular casts 46 and, occasionally, myoglobin crystals. 115 Addition of (NH4)2 S04 to an aliquot of urine to 80 per cent of saturation (76.7 gm added to 100 ml at 25°C. equals 100 per cent saturation) will cause hemoglobin to precipitate but leave myoglobin in solution. The clinical reliability of this test has been questionable. 82 ,108,115 Hemoglobinuria produced by hemolysis will be associated with pink serum because haptoglobin, a serum globulin, complexes with free circulating hemoglobin up to a level of 100 to 150 mg/lOO m!. Only after haptoglobin binding sites have been saturated will free hemoglobin be filtered into the urine, and serum becomes pink above a level of 40 mg/lOO ml of hemoglobin. A similar globulin exists for myoglobin, but the binding is looser and the system is saturated at 20 mg/100 ml allowing myoglobin to be cleared rapidly by glomerular filtration before pink *Hematest-Ames Co., Inc., Division of Miles Laboratories, Elkhart, Indiana. tHemastix-Ames Co., Inc., Division of Miles Laboratories, Elkhart, Indiana.
~
Table 1. Physical and Biochemical Features of the Pigmenturias
tI
MYOGLOBINURIA
HEMOGLOBINURIA
PORPHYRIA
PHYSICAL EXAMINATION
o
a:: ~
t"'
>
