An eight-year-old girl was in good health until two days prior to presentation, when pain and swelling developed in both legs. She was evaluated in a local hospital and then was transferred to the pediatric intensive care unit at our institution because of deteriorating renal function. Soon after she arrived, the pediatric orthopaedic team was consulted to evaluate the bilateral lower-extremity pain. There was no history of rash or drug ingestion prior to presentation and no evidence of intercurrent infections or illnesses.
The patient's brother had a similar clinical problem at the age of two years. He had swelling in the compartments of the upper and lower extremities and myalgias, which led to renal and cardiac failure with a fatal outcome.
The patient had a temperature of 36.8°ree;C, a pulse rate of 140 bpm, a respiratory rate of 21 breaths/min, and a blood pressure of 160/72 mm Hg. The anterior tibial compartments in the legs were tense, with the right side worse than the left, and she had severe pain on passive stretch of the anterior leg muscles. Pulses were palpable in the lower extremity bilaterally. There was no active motor function in either anterior tibial compartment, and there was loss of sensation to light touch and pain on the dorsal surfaces of both feet. The knee and ankle reflexes were absent.
Creatinine kinase was markedly elevated to 295,000 U/L (normal, 91 to 391 U/L). Urinalysis showed brown urine and 85 mg/dL of protein (normal, 27 to 93 mg/dL/24 h). The compartment pressures were elevated to 65 and 37 mm Hg in the right and left anterior compartments, respectively. In the right and left posterior compartments, the pressures measured 34 and 12 mm Hg, respectively. Acute surgical decompression, consisting of fasciotomy of all four compartments in the right leg and fasciotomy of the anterior and lateral compartments in the left, was carried out. Intraoperatively, all muscles in the anterior compartments were found to be pale, noncontractile, and edematous. No gross purulence, liquefaction, or necrosis of the muscles was encountered. Because of the family history and the absence of any identifiable cause for the compartment syndromes, multiple biopsy specimens of the muscles of the anterior, lateral, and posterior compartments were obtained.
Biopsy Results
The muscle fibers ranged from 15 to 45 µm in diameter. The biopsy specimens showed signs of fresh infarction, which was likely the consequence of an acute anterior compartment syndrome that was due to edema. The scattered necrotic and regenerating fibers in the peroneus longus muscle were consistent with rhabdomyolysis of recent onset ( Fig. 1 ). In most biopsy specimens, approximately 50% to 60% of the muscle mass was necrotic. In addition, the muscle fibers contained an increased number of lipid droplets. Nicotinamide-adenine dinucleotide dehydrogenase, succinate dehydrogenase, cytochrome-c oxidase, and adenosinetriphosphatase reactions were absent or attenuated in the necrotic fibers. Phosphofructokinase, lactate dehydrogenase, and aldolase activities were normal in the non-necrotic fibers. The regenerating fibers were found to express vimentin, desmin, isoforms of neural cell adhesion molecules, major histocompatibility complex class-I molecules, and isoforms of fetal myosin.
Five days following the fasciotomy, all wounds were closed and bilateral ankle-foot orthoses were prescribed. The patient was discharged seventeen days after admission. At the time of discharge, renal function and all of the serum enzyme levels had returned to nearly normal. There was a trace of activity in the tibialis anterior muscle on the left side. The remaining muscle groups in the left leg and the entire anterior muscle group in the right leg remained paralyzed. Outpatient physical therapy was prescribed. The patient continued to have improvement following discharge and, four months later, had complete return of function of the anterior compartment muscles bilaterally. The sensory loss over the dorsal surfaces of the feet also resolved.
Rhabdomyolysis results from injury to the membrane of skeletal muscle cells. Membrane disruption causes the release of intracellular substances into the plasma, including myoglobin, lactate dehydrogenase, aldolase, and creatine phosphokinase 7 , which are excreted in the urine and can adversely affect renal function. Acute renal failure, which was seen in our patient, is a major complication of rhabdomyolysis and can develop in up to one-third of these patients 8 . Therefore, it is important to suspect rhabdomyolysis in a patient who has myalgia and myoglobinuria.
There are many causes of rhabdomyolysis ( Table I ). Common orthopaedic conditions that cause rhabdomyolysis include trauma, ischemia in a limb, reperfusion injury in a limb, compartment syndrome, extreme muscular exertion, tourniquet use, and prolonged or poor positioning of patients during surgery. Other causes of rhabdomyolysis include infection 9 , substance abuse 10 , and metabolic disorders 11,12 .
There is no doubt that rhabdomyolysis can develop as a result of compartment syndrome or vice versa. The interesting finding of this study is that the compartment syndrome developed as a consequence of the acute rhabdomyolysis. Familial paroxysmal rhabdomyolysis with myoglobinuria is a rare and life-threatening disease in young children 13,14 . Although the exact cause of rhabdomyolysis in this patient was not identified, the family history suggests a genetic basis. Extensive investigations did not reveal any known type of enzyme deficiency in this patient.
The exact etiology of familial rhabdomyolysis remains unknown. Several genetic defects leading to enzyme deficiencies have been identified and proposed as the cause of myoglobinuria in some patients 15,16 . These genetic defects include inherited glycogen storage disease of muscle, which results from deficiencies of glycolytic enzymes such as phosphorylase, phosphofructokinase, phosphoglycerate mutase, phosphoglycerate kinase, and lactate dehydrogenase. Most patients with an inherited glycogen storage disease become symptomatic during childhood. Pain, weakness, cramps, and myoglobinuria typically follow a period of intense exercise until patients learn to adapt and adjust their exercise pattern. Recurrent myoglobinuria and muscle pain are even more common in patients with a deficiency of carnitine palmitoyltransferase, the enzyme responsible for the transport of free long-chain fatty acids across the mitochondrial membrane. However, muscle necrosis occurs in these patients during prolonged periods of exercise, even at low intensity, when they have not maintained adequate intake of food or when they are subjected to prolonged psychological stress associated with examinations, courtroom trials, etc. The frequency of myoglobinuria in carnitine palmitoyltransferase deficiency sharply contrasts with its infrequency in most storage diseases, such as acid-maltase or carnitine deficiency, and also in some of the mitochondrial myopathies in which tachycardia, tachypnea, and fatigue prevent further exercise. Several other disorders of mitochondrial metabolism have recently been shown to cause muscle necrosis with myoglobinuria 15 . Patients with a deficiency of long-chain acyl-coenzyme A dehydrogenase have presented with episodic hypoglycemic coma, which may also be associated with myopathy, cardiomyopathy, or myoglobinuria in some of them 17 . The degree of muscle necrosis and the resulting myoglobinuria vary for each condition and with each predisposing factor.
We believe that it is imperative that the diagnosis of compartment syndrome be considered in patients with a known or a suspected history of familial rhabdomyolysis. Prompt diagnosis and intervention in these patients may result in complete recovery of the affected muscle groups, as was seen in our patient. On the basis of the clinical examination, which revealed complete paralysis of the affected muscles, and the intraoperative ischemic appearance of the muscle group in the anterior compartment, we did not expect complete recovery of the muscle, but such recovery has been previously reported 5,6,10 . Parker et al. reported on two siblings with familial rhabdomyolysis who also had complete recovery of the affected muscle group following fasciotomy 5 .
We believe that the reasons for the complete recovery of muscle function in this patient are multifactorial. First and foremost is the known excellent regenerative capacity of muscle, especially in children. The ability of muscle to regenerate is related to the extent of tissue necrosis, the preservation of innervation and blood supply to the area, and the degree to which the architecture of the muscle is preserved 17 . Subtotal necrosis with preservation of some muscle architecture may partly explain the favorable outcome in our patient. Extensive muscle regeneration can occur by means of proliferation of the surviving muscle nuclei, extension from the intact portion of the fiber (muscle budding), and rebuilding or regeneration of the intracellular contractile elements. The term satellite cell is used synonymously for myoblast , presumptive myoblast, and myoblast stem cell . It is usually assumed that the resting satellite cell is activated when the muscle fiber is damaged and that it plays a major role in regeneration of the muscle fiber 15 .
The need to preserve intact muscle tissue cannot be overemphasized. As was observed in our patient, even muscles that were seen to be 50% to 60% necrotic histologically showed full recovery. Because necrosis is difficult to determine grossly at the time of surgery, any muscle with questionable viability should be preserved. The most effective regeneration of muscle occurs when there are supporting cells surrounding the surviving muscle cell to serve as guides to preserve the configuration and the direction of the muscle fiber growth.
Other very important factors involved in determining the degree of muscle regeneration are the nature of the initiating disease process and the timing of treatment. Early surgical intervention with a fasciotomy that restored excellent blood supply in our young patient no doubt played a substantial role in allowing optimal muscle regeneration. We therefore believe that a better outcome can be expected following compartment syndrome in young patients who have subtotal rhabdomyolysis. Extensive débridement of muscle compartments should not be undertaken at the initial surgery because of the tremendous ability of the injured muscle fibers to regenerate and because it is difficult to quantify the degree of muscle necrosis upon gross inspection. Purulence and systemic toxicity would be the only indications for débridement of muscle in young patients with acute myonecrosis.
Note: We thank Dr. Andrew G. Engel for interpreting the muscle biopsy specimens.