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Influenza A Induced Rhabdomyolysis Resulting in Extensive Compartment Syndrome

Swaringen, J., C.; Seiler, J., G., III; Bruce, R., W., Jr.

Clinical Orthopaedics and Related Research: June 2000 - Volume 375 - Issue - p 243-249
Section II: Original Articles: Infection

This is a case of influenza A induced rhabdomyolysis resulting in extensive compartment syndrome and acute renal failure in a 10-year-old child. The patient required fasciotomies in all four extremities. Even after fasciotomies were performed, the muscle tissue continued to swell, suggesting a primary myositis. This case emphasizes the importance of considering the diagnosis of compartment syndrome in patients with influenza infection and severe myalgia.

From the Department of Orthopaedic Surgery, Emory University, School of Medicine, Atlanta, GA.

Reprint requests to J.G. Seiler, III, MD, Georgia Hand and Microsurgery, 1938 Peachtree Road NW, Suite 603, Atlanta, GA 30309.

Received: April 7, 1999.

Revised: September 30, 1999; October 8, 1999.

Accepted: October 11, 1999.

Compartment syndrome results from elevated pressure within a closed fascial space.8 The most common causes are fractures, soft tissue injury, arterial injury, prolonged limb compression, and burns.8 Extreme exertion and bleeding disorders have been associated less commonly with compartment syndrome.8

An unusual case of influenza induced rhabdomyolysis that caused compartment syndrome in all four extremities is reported. The purpose of this report is to emphasize consideration of the diagnosis of compartment syndrome in patients with influenza and severe myalgia.

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A 10-year-old girl was seen in the emergency room with severe pain in her legs. The patient was in her usual state of good health until 6 days before admission, when she began having headaches and a fever of 39° C. Four days before admission, she began having bilateral lower extremity pain. Three days before admission, she was unable to walk because of severe pain and was taken to an outside hospital. There, she was given intramuscular antibiotics and ibuprofen. Because of her dark urine and a creatine phosphokinase level of 14,000 U/L, she was referred for evaluation at the authors' tertiary referral center.

When she arrived, she reported severe leg pain. She also reported decreased appetite, one episode of diarrhea, decreased urine output, and decreased ability to sleep. She had no history of a rash or drug ingestion other than the antibiotics and ibuprofen and no antecedent trauma or weakness or excessive exercise. She had no family history of myopathy. Her immunizations were current.

On physical examination, she had a temperature of 35° C, pulse rate of 140 beats per minute, respiratory rate of 26 breaths per minute, and systolic blood pressure of 120 mm Hg. Her extremity examination, reported by the pediatric service, showed edema in both lower extremities from the middle thigh down. Both legs were tender to palpation. Pulses were palpable bilaterally. Deep tendon reflexes of both knees and ankles were absent, and sensation to light touch and pain was intact. Motor examination revealed markedly decreased strength in her lower extremities. Her arms had mild swelling, were mildly tender to palpation, and had normal pulses, deep tendon reflexes, and strength.

Initial laboratory values included a creatine phosphokinase level of 16,220 U/L, lactate dehydrogenase level of 1728 U/L, aspartate aminotransferase level of 566 U/L, and alanine aminotransferase level of 256 U/L. Her leukocyte count was 15,900 per mm3 with 64% segmented neutrophils, 2% band neutrophils, 17% lymphocytes, 12% monocytes, and 4% atypical lymphocytes. Urinalysis showed brown urine with large amounts of blood and 100 mg/dL protein. Microscopic urine analysis showed less than 4 erythrocytes per high power field.

Within 12 hours of admission, the patient became more tachycardic, tachypnic, hypotensive, and anuric, and she was transferred to the intensive care unit.

She required intubation, inotropic cardiac support, and fluid resuscitation. An echocardiogram showed a large pericardial effusion, which was drained. Creatine phosphokinase levels increased to 57,560 U/L. After blood specimens were drawn for culture, she was started empirically on cefotaxime and vancomycin for possible infection. At the recommendation of the rheumatology service, steroids were administered to the patient to decrease the presumed inflammation. Later laboratory analyses revealed thrombocytopenia and coagulopathy. The patient's laboratory values included a platelet count of 38,000 per mm3, prothrombin time of 17.0 seconds, partial thromboplastin time of 46.5 seconds, d-dimers less than 250, and fibrinogen of 186 mg/dL. She required transfusion of platelets, fresh frozen plasma, and packed erythrocytes.

The orthopaedic service was consulted to evaluate her lower extremity swelling; her legs were diffusely swollen and cool. Compartments were firm but not tense. Capillary refill was 3 to 4 seconds bilaterally, and both dorsalis pedis pulses were heard with Doppler examination. Compartment pressures were measured using the Stryker intracompartmental pressure monitor system (Stryker Surgical, Kalamazoo, MI). Compartment pressures of the right thigh were 32 mm Hg in the anterior compartment and 22 mm Hg in the posterior compartment. The superficial posterior and the deep posterior compartments of the right leg had compartment pressures of 20 mm Hg. In the left thigh, anterior and posterior compartments had compartment pressures of 22 mm Hg. Compartment pressures of the left leg were 21 mm Hg in the superficial posterior compartment and 19 mm Hg in the deep posterior compartment. Her diastolic blood pressure at this time was 62 mm Hg. Her upper extremities had some mild forearm edema, but the skin was not tense. Motor and sensory examination was normal. She did not have passive stretch signs.

Three hours later, secondary assessment showed progression of her lower extremity swelling and tense compartments in the legs. Compartment pressures in the right thigh were 45 mm Hg in the anterior compartment and 39 mm Hg in the posterior compartment. Compartment pressures in the left thigh were 38 mm Hg in the anterior compartment and 36 mm Hg in the posterior compartment. The pressures in the compartments of both legs ranged from 40 to 50 mm Hg. Diastolic blood pressure at this time was 70 mm Hg. Because of the significant progression of edema and compartmental swelling on physical examination, the patient was taken to the operating room for bilateral anterior and posterior compartment thigh fasciotomies and four compartment leg fasciotomies.

During the next 2 days, the patient's arm edema progressively increased. Compartment pressures in the right arm were 34 mm Hg in the volar compartment, 48 mm Hg in the dorsal compartment, and less than 20 mm Hg in the antebrachial compartment. Compartment pressures in the left arm were 36 mm Hg in the volar compartment, 35 mm Hg in the dorsal compartment, and less than 20 mm Hg in the antebrachial compartment. Her diastolic blood pressure at this time was 55 mm Hg. Again, because of significant deterioration on clinical examination, the patient was taken to the operating room for bilateral forearm and hand fasciotomies.2 On incision of the compartments of the right upper extremity, portions of the flexor carpi radialis, flexor digitorum superficialis, and flexor pollicis longus were observed to be necrotic (Fig 1) with thin, tan stripes of necrosis without evidence of infection (Fig 2).

Fig 1

Fig 1

Fig 2

Fig 2

Secondary operative evaluation of the lower extremities showed continued muscular swelling. Areas of necrosis were identified in portions of the right flexor digitorum, right posterior tibialis, and right and left soleus muscles. These muscles were debrided to a margin of viable tissue.

Irrigation and debridement along with sterile dressing changes were performed on all fasciotomy wounds every 48 hours. On the ninth day in the hospital, delayed primary closure was done, and split thickness skin grafts were placed to complete skin coverage.

The patient also had acute renal failure develop secondary to rhabdomyolysis. During the first week of her hospital stay, her peak blood urea nitrogen and creatinine values were 76mg/dL and 4.5mg/dL, respectively. She required 1 month of peritoneal dialysis. Her renal status improved during her hospital course, with her blood urea nitrogen and creatinine levels returning to normal by the time of discharge.

Multiple diagnostic tests were performed to determine the cause of the rhabdomyolysis. Muscle biopsy specimens were not diagnostic but showed extensive muscle lysis with interstitial edema (Fig 3). All blood and muscle biopsy cultures were negative, and the initial tracheal aspirate was positive for the influenza A virus. She also had an influenza A antibody titer of 1:256. Rheumatologic studies included a positive antinuclear antibody titer of 1:160 and a negative rheumatoid factor. Based on these studies and her clinical course, it was concluded that the rhabdomyolysis was secondary to an influenza A infection.

Fig 3

Fig 3

Despite intensive occupational therapy, stretching casts, and ankle to foot orthoses, equinovarus contractures of both feet occurred. Three months after her discharge, posteromedial releases were done. One year 6 months after surgery, she is able to ambulate independently. She also has the ability to toe and heel walk with minimal residual weakness. Her upper extremities are functionally normal, with normal flexion, extension, grasp, and release abilities. She also has normal cognitive function for her age.

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This unique case of compartment syndrome secondary to influenza A induced rhabdomyolysis is atypical because of the mechanism of rhabdomyolysis resulting in compartment syndrome, the extent of compartments involved, and the continued swelling of the muscles after fasciotomy.

Rhabdomyolysis results from injury to the cell membrane of skeletal muscle. Membrane disruption results in the release of intracellular substances into the plasma, including myoglobin and creatine phosphokinase.10Figure 4 shows how muscle breakdown ultimately can lead to compartment syndrome and how the presence of compartment syndrome can perpetuate a cycle of additional tissue damage.

Fig 4

Fig 4

There are many potential causes of rhabdomyolysis. Chronic alcohol ingestion, muscle compression, and generalized seizures are among the three most common.3 Other causes include infection, substance intoxication, hereditary enzyme defects, and metabolic disorders.3 Common orthopaedic circumstances causing rhabdomyolysis include trauma, limb ischemia, reperfusion injury, compartment syndrome, extreme muscular exertion, posterior spinal surgery, tourniquet use, and poor positioning of obese patients during surgery.10 Viral infection may cause rhabdomyolysis either by direct cell injury or indirectly by toxin release.11,13 Influenza, human immunodeficiency virus, and enteroviruses have been reported to be associated with rhabdomyolysis.13

The presentation of rhabdomyolysis is varied, and the diagnosis of rhabdomyolysis is important to suspect in a patient with a suggestive clinical history, myalgia, and myoglobinuria. Acute renal failure, which was seen in this case, is a major complication of rhabdomyolysis, affecting as many as 1/3 of patients.3 To detect myoglobin in the urine, its concentration must be at least 100 mg/dL.3,11 The orthotolidine dipstick test used to detect blood on urinalysis detects heme and cannot differentiate myoglobin from hemoglobin.3 However, this test is useful when used in conjunction with the microscopic urine analysis because few erythrocytes should be seen in patients with myoglobinuria. Thus, the positive heme test, in a clinical situation suggesting rhabdomyolysis, is indicative of myoglobin. Myoglobinuria may be diagnosed conclusively using a specific assay or visualizing pigmented granular casts of myoglobin in the urine sediment.3,11 Elevated serum creatine phosphokinase and myoglobin also suggest significant muscle injury. Creatine phosphokinase has a much slower clearance from the plasma than does myoglobin, and thus is detected for a longer duration after muscle damage.3,11 Other abnormal laboratory values in rhabdomyolysis include serum hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia.3,10,11 Aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels also may be elevated.11

Typical musculoskeletal signs and symptoms of rhabdomyolysis include muscle pain, stiffness, and weakness. However, these may be present only 50% of the time.3 Muscle involvement may be diffuse or involve specific muscle groups. The myopathy of rhabdomyolysis usually is self limited, resulting in little residual muscle damage.11

Rarely, compartment syndrome may be a complication of rhabdomyolysis. Typically, it is the rhabdomyolysis associated with trauma and prolonged immobilization that results in compartment syndrome.11 Although influenza is the most common viral cause of rhabdomyolysis, influenza induced rhabdomyolysis infrequently results in compartment syndrome.11,13 The authors could locate only one other case of influenza infection associated rhabdomyolysis leading to compartment syndrome. That report involved influenza B infection leading to bilateral lower extremity compartment syndrome.9 The current authors' study is significant because of much more widespread muscle injury, resulting in the need for fasciotomy in all four extremities, and the involvement of influenza A.

Compartment syndrome leads to muscle and nerve damage by the pathway of increased tissue pressure. As the tissue pressure approaches terminal arteriolar pressure, the nutrients in the circulation cannot reach the capillary bed, and tissue ischemia results. Terminal arteriolar pressure has been shown to be equal to diastolic blood pressure.14 Blood flow in the microcirculation ceases when tissue pressure approaches diastolic blood pressure.1 Initially, the surrounding tissues are able to compensate for the decrease in blood flow by autoregulation of the microcirculation, enhanced venous oxygen extraction, and oxygen tension normally in excess of critical levels.4 However, with increasing or prolonged elevation of tissue pressures, compensatory mechanisms fail.4 In the current report, the increase in tissue pressure was caused by primary muscle destruction and resulting edema.

Another interesting aspect of this study was the continued muscle swelling after the release of the lower extremity compartments. This progressive swelling likely is related to the directly toxic effects of influenza infection on muscle. Whether the virus directly invades the muscle or releases a muscle damaging toxin has not been established.11,13 Histologic examination of muscle associated with influenza infection reveals clusters of necrotic muscle mixed with normal muscle, sometimes associated with a lymphocytic infiltrate, as was seen in this patient.13 Identification of the viral particles within the tissue sometimes is possible, although it was not done in this case.13 Normally in compartment syndrome, once the compartments are released, external pressure is released and blood flow increases, resulting in an end to the injury. Progressive swelling is a unique finding of this case and may be unique to influenza associated rhabdomyolysis. Continued swelling may suggest a primary muscle pathologic process, or myositis, as opposed to other more common causes of compartment syndrome.

There is no exact value of compartment pressure that is accepted universally as an indication for fasciotomy. Normal compartment pressure ranges from 0 to 8 mm Hg.12 Some authors recommend decompression at an absolute compartment pressure in the clinical setting of compartment syndrome. Mabee and Bostwick5 and Matsen et al7 recommended using 45 mm Hg, and Mubarak and Hargens recommended using 30 mm Hg as the critical decompression pressure.8 Other authors suggested there is no absolute tissue pressure defining compartment syndrome. Heppenstall et al4 recommended evaluating the difference between the mean arterial blood pressure and the compartment pressure to define compartment syndrome. They suggested the lowest pressure difference allowing muscle to remain viable is 30 mm Hg in atraumatic muscle and 40 mm Hg in traumatized muscle.4

In the patient reported here, continued deterioration of physical examination and tissue pressure measurement were important diagnostic tools. At the authors' institution, the criteria suggested by Matava et al6 and Whitesides and Heckman15 for compartment decompression is preferred. They recommended decompression when intracompartmental pressures approach 20 mm Hg below diastolic blood pressure. Clinicians should maintain careful observation of these difficult wounds to ensure adequate debridement of necrotic muscle and adequate compartment decompression and should anticipate additional swelling attributable to progressive muscle injury.

Compartment pressures should be measured intraoperatively to ensure adequate decompression. After surgery, limbs should be monitored closely for signs of progressive swelling, as was seen in the patient reported here. Serial debridements and secondary procedures for coverage and reconstruction often are necessary. Range of motion exercises and intensive occupational therapy should be started early to limit the severity of postoperative stiffness and facilitate muscle tendon and nerve excursion.7

Although rare, compartment syndrome must be considered in the evaluation of a patient with influenza and severe myalgia. Standard physical examination methods and diagnostic assessment strategies are useful in diagnosis. The outcome in patients with compartment syndrome caused by influenza infection may be guarded because of numerous factors, including the potential involvement and compromise of multiple organ systems and the severity of the myositis and duration of pressure elevation.

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