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BMJ Case Reports 2017; doi:10.1136/bcr-2016-218942
  • CASE REPORT

Rhabdomyolysis-induced compartment syndrome secondary to atorvastatin and strenuous exercise

  1. Sarah Tucker
  1. Department of Plastic Surgery, John Radcliffe Hospital, Oxford, UK
  1. Correspondence to Dr Louise Dunphy, dunphylmb{at}yahoo.com
  • Accepted 28 February 2017
  • Published 16 March 2017

Summary

A 50-year-old male UK resident with a history of hypertension and hypercholesterolaemia presented to the emergency department with a 48-hour history of sudden onset bilateral thigh swelling and pain unrelieved by regular analgesia. 3 days prior to presentation, he performed a vigorous workout in the gym. His medications included ramipril 5 mg once daily and atorvastatin 20 mg at night time. He was a non-smoker and did not consume alcohol. He reported no known drug allergies. Physical examination confirmed bilateral swollen thighs, with no overlying skin changes, clinically suggestive of compartment syndrome. His creatine kinase was >50 000 IU with normal renal and liver function tests. Further investigation with MRI-identified prominent swelling of the vastus intermedius and medialis muscles, more marked on the left, with extensive diffuse short tau inversion recovery (STIR) signal hyperintensity and isointensity on T1 sequences, suggestive of rhabdomyolysis. He underwent bilateral fasciotomies of his thighs and aggressive intravenous fluid resuscitation with close monitoring of his electrolytes. Intraoperatively his muscle was healthy, with no evidence of haematoma or necrosis. His medication atorvastatin was stopped due to his rhabdomyolysis. 48 hours later, he returned to theatre and review of his fasciotomy wounds was unremarkable. 4 days later, he was discharged uneventfully. His postoperative recovery was complicated by a serous discharge from his left medial thigh wound. Further investigation with an ultrasound confirmed a 4×1×1cm multiloculated collection within the superficial tissue directly underlying the wound. An aspirate was performed and cultures revealed no growth. He remains under review in the department of plastic surgery. This case report discusses the aetiological spectrum, clinical presentation, pathophysiology, differential diagnosis, investigations, management and complications of rhabdomyolysis.

Case presentation

A 50-year-old male UK resident presented to the emergency department with a 48-hour history of increased pain and swelling of his thighs following a vigorous workout in the gym; running on the treadmill for 60 min and the exercise bike for 15 min. Over 24 hours, he reported increased swelling of his thighs and difficulty in weight bearing, mobilising and ascending the stairs. Furthermore, he described deep, constant and poorly localised pain unrelieved by regular paracetamol. A few hours prior to presentation he reported ‘tea-coloured’ urine and an inability to flex his right knee. His medical history included hypertension and hypercholesterolaemia. He was taking ramipril and atorvastatin (started 18 months earlier). Limb neurology and perfusion, including capillary refill and distal pulses were unremarkable. The anterolateral aspects of his thighs were painful on palpation, clinically suggestive of compartment syndrome, with no overlying skin changes or evidence of necrosis. The pain was aggravated by passively stretching the muscle group within the compartment and actively flexing it. The posterior and medial compartments were unremarkable. In addition, he was unable to straight leg raise bilaterally. Cardiovascular, respiratory and abdominal examinations were otherwise unremarkable. He was referred to plastic surgery for further management.

Investigations

His observations were as follows: respiratory rate 14, SpO2 98% on air, heart rate 80 bpm, blood pressure 150/87 mm Hg and temperature 36.8°C. A 12-lead ECG confirmed sinus rhythm. An arterial blood gas analysis revealed the following: pH 7.409, HCO3 24.7 mmol/L, base excess 0.4 mmol/L, glucose 7.9 mmol/L and lactate 1.5 mmol/L. His urine dip was negative. Haematological investigations confirmed a normal white cell count, 8.67×109/L, with unremarkable renal and liver function tests (table 1). However, his creatine kinase (CK) was significantly elevated at 51 128 IU. MRI of his femurs demonstrated prominent swelling of the vastus intermedius and medialis muscles, more marked on the left, with extensive diffuse STIR signal hyperintensity and isointensity on T1 sequences. Appearances were consistent with acute muscle oedema secondary to rhabdomyolysis (figures 1 and 2). Medications that were known to be risk factors for rhabdomyolysis, such as statins, atorvastatin in this case and those deemed nephrotoxic were stopped immediately.

Table 1

Haematological investigations confirmed a normal WCC, renal and liver function tests

Figure 1

MRI of his bilateral femurs. Identified prominent swelling of the vastus intermedius and medialis muscles more marked on the left, with extensive diffuse STIR signal hyperintensity and isointensity on T1 sequences.

Figure 2

MRI of his femur. Appearances were consistent with acute muscle oedema secondary to rhabdomyolysis.

Treatment

Intravenous fluid resuscitation was started and a urinary catheter was inserted. He underwent emergency bilateral thigh fasciotomies. An incision from the greater trochanter to the lateral epicondyle and over his gracilis muscle was performed. The anterior, posterior, medial and lateral compartments were released. The anterior compartment of his right leg was bulging and viable muscle was observed, with no evidence of haematoma or necrosis. The posterior and medial compartments were unremarkable. Copious irrigation with 1 L of 0.9% normal saline was performed. Haemostasis was achieved. The compartments were not closed. Twenty-four hours postfluid resuscitation, his CK was significantly reduced at 33 564 IU and his renal function remained stable (urea 4.1 mmol/L, creatine 91 μmol/L, estimated glomerular filtration rate 76 mL/min). Forty-eight hours postoperative, he returned to the theatre for a review of his bilateral fasciotomy wounds. Intraoperatively, his muscle was healthy, with no obvious sign of infection. Copious saline irrigation was performed. Primary wound closure was achieved.

Outcome and follow-up

Four days postadmission, his CK was 6484 IU and he was discharged uneventfully. Ten days later, he presented to the emergency department with discharge from his left thigh medial incision. He was systemically well. Clinical examination confirmed a serous discharge from the centre of his left thigh medial incision and the wound was dressed with Aquacell Ag. He was reviewed 1 week later in the plastic surgery clinic and an ultrasound scan of his left thigh confirmed a 4×1×1 cm multiloculated collection within the superficial tissue directly underlying the wound. Three millilitres of 1% lidocaine was infiltrated into his skin and under ultrasound guidance, a 21-gauge needle was advanced into the largest pocket of fluid, aspirating 1 mL of clear straw fluid. Occasional mononuclear cells on Gram stain were demonstrated. The cultures showed no significant growth. Further review confirmed a healed wound.

Discussion

Historically, rhabdomyolysis can be traced back to biblical times, with the ‘Book of Numbers’ describing a condition with similar characteristics when the Jews suffered ‘plague’ during their exodus from Egypt, after abundant consumption of hemlock herbs that quails consume during spring migration.1 It also commonly occurs after natural disasters such as earthquakes and war.2 Rhabdomyolysis was first reported in Germany in 1881 but it was not until 1944 that the role of myoglobin was first described.3 Rhabdomyolysis can be defined as a severe form of myopathy involving muscle breakdown, with myoglobin released in to the circulation, leading to acute renal failure, electrolyte imbalance and disseminated intravascular coagulation.4 To the authors’ knowledge, the global incidence of rhabdomyolysis remains unknown as there are no prospective studies and many mild cases probably go unreported.

The aetiological spectrum of rhabdomyolysis is extensive but the most common form of aetiology is muscle trauma and compression resulting in crush injuries. Malignant hyperthermia which can occur with anaesthetic agents such as succinylcholine or halothane have been implicated.

Furthermore, infections such as herpes simplex, HIV, legionella, sepsis and endocrinopathies such as hypothyroidism, hyperaldosteronism and ketoacidosis have been described. Chronic autoimmune conditions such as polymyositis and dermatomyositis, as well as solid organ transplant recipients can also result in rhabdomyolysis. Carnitine palmitoyl transferase II deficiency, a genetically determined metabolic myopathy, is the commonest metabolic cause. It can also occur with glycolytic enzyme deficiencies, muscle phosphorylase deficiency (McArdle's disease), fatty acid oxidation disorders and with many of the mitochondrial cytopathies. Hyperosmotic conditions and other electrolyte imbalances including hypernatraemia, hypocalcaemia, hyponatraemia, hypokalaemia and hypophosphataemia can increase the risk.5 Antipsychotics resulting in neuroleptic malignant syndrome, antidepressants, sedative hypnotics, antihistamines, diuretics and drugs of addiction such as cocaine, amphetamines, heroin and methadone may also induce it. Acute alcohol-induced rhabdomyolysis can also occur. As in our reported case, individuals who participate in strenuous exercise are at a high risk, as according to Schiff et al,6 even in healthy individuals, myoglobinaemia, myoglobinuria and a mild increase in CK may be observed. With the advent of high-intensity resistance training and programmes such as CrossFit becoming more popular in gymnasiums, exertional rhabdomyolysis has been reported in long distance runners, bodybuilders and military recruits. Electrolyte imbalance, especially hypokalaemia, known to limit vasodilation in the muscle microvasculature may also result in the aforementioned. In addition, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown, for example, muscular dystrophy. 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors such as statins can increase liver transaminase and result in myopathy and rhabdomyolysis.7 Rhabdomyolysis resulting from prolonged simvastatin use can result in renal failure, may be precipitated by physical exertion and result in compartment syndrome.8 ,9 Sixteen years ago, in 2001, cerivastatin was withdrawn because its incidence of myotoxicity was 10 times greater.10 A recent article in ‘The Lancet’ in September 2016, discussing the evidence retrieved from randomised controlled trials yielding information on the efficacy and safety of statin therapy, states that typically, treatment of 10 000 patients with a standard statin regimen, such as atorvastatin 40 mg daily, as in our reported case, would be expected to cause about five cases of myopathy.11 The Clinical Advisory on Statins defined statin-induced rhabdomyolysis as muscle symptoms with marked CK elevation is typically >10 times the upper limit of normal, with brown urine and myoglobinuria.12 The underlying mechanisms for statin-related myopathy are not well understood; however, the risk appears to be dose related. Statins have been postulated to interfere with ATP production by reducing levels of coenzyme Q, a component of the electron transport chain. Rhabdomyolysis may develop acutely, within 2–3 weeks after initiating therapy, or months or years later, as in our case, after a precipitating event such as infection, strenuous exercise or a drug interaction.13

The main clinical presentation includes muscle weakness and ‘tea-coloured’ urine as described in our case. Muscle tenderness, swelling, stiffness and cramping, accompanied by weakness and loss of function in the involved muscle groups have been described. The postural muscles of the thighs, calves and lower back are most frequently involved. Individuals may also present with non-specific systemic features, and arrhythmias or cardiac arrest stemming from electrolyte imbalance may also occur. An arterial blood gas analysis should be performed to evaluate the acid–base balance, typically demonstrating metabolic acidosis with an elevated anion gap, reflecting the increase in organic acid levels in the serum due to muscle necrosis. An ECG is a useful adjunct to determine cardiac arrhythmias secondary to an electrolyte imbalance. A complete blood count, liver function tests, renal function tests and clotting studies should be performed. An elevated plasma CK level, mainly the CK-MM subtype, is the most sensitive laboratory finding pertaining to muscle injury with normal levels estimated at 38–174 IU in men; whereas hyperkalaemia, acute renal failure and compartment syndrome represent the major life-threatening complications.14 CK rises in rhabdomyolysis within 12 hours of the onset of muscle injury, peaks in 1–3 days and declines 3–5 days after the cessation of muscle injury. The half-life of CK is 1.5 days and so it remains elevated longer than serum myoglobin level, which has a short half-life of 2–3 hours and is rapidly cleared by renal excretion and metabolism to bilirubin.15 Toxicological screening should be performed if drugs are suspected. A urine dipstick is a quick way to screen for myoglobinuria occurring when urinary myoglobin exceeds 250 μg/L (normal is <5 ng/mL). Urinalysis will reveal the presence of protein, brown casts and uric acid crystals. MRI is very effective in localising rhabdomyolysis, especially when fasciotomy is considered as a treatment option and it has a higher sensitivity than either CT or ultrasound.16 The spectrum of complications is broad, including hypovolaemia and haemodynamic shock. As well as this, tubular obstruction in the presence of hypovolaemia and the nephrotoxic effects of myoglobin contribute to acute kidney injury. Hyperuricaemia may occur as uric acid is released from purines derived from damaged muscle cells and is prominent in acute kidney injury. Compartment syndrome can develop, with the ischaemic and oedematous muscle further raising the intracompartmental pressure potentiating a vicious cycle of continuing ischaemia.17 Immediate surgical consultation is required to perform a fasciotomy. Failure to relieve the pressure can result in necrosis of the tissue in that compartment resulting in Volkmann's contracture in the affected limb. As well as occurring after tibial or forearm fractures, prolonged limb compression and eschars from burns, compartment syndrome can also occur following surgery in the Lloyd-Davies lithotomy position. Severe electrolyte disturbance, such as hyperkalaemia occurring secondary to massive muscle breakdown, can precipitate cardiac arrhythmias and even sudden cardiac arrest. Proteases released from injured muscle cause hepatic dysfunction in ∼25% of patients.18 In addition, disseminated intravascular coagulation can occur resulting in haemorrhagic complications. Lactic acidosis from ischaemia and uraemia are known to occur. Rhabdomyolysis-induced common peroneal nerve palsy has also been described.19 Early aggressive fluid resuscitation to promote vigorous diuresis with close monitoring of renal function is imperative. Unfortunately, no guidelines for the management of rhabdomyolysis are available, with paucity of randomised controlled trials to date.

Management is currently based on observations from retrospective studies and case series, with many experts advocating the addition of mannitol and bicarbonate after the initial resuscitation with saline, especially in crush injury to prevent acute kidney injury.20 Unfortunately, despite optimal medical management, renal replacement therapy, daily haemodialysis or continuous haemofiltration may be required to correct electrolyte and acid–base abnormalities. Hypercalcaemia can occur in up to one-third of patients in the recovery phase of acute renal failure. Rhabdomyolysis, a potentially life-threatening condition, remains a major clinical challenge, often presenting with non-specific symptoms, multiple aetiologies and systemic complications. As already mentioned, there is a paucity of randomised controlled trials with management based on observational studies and case series. However, aggressive hydration remains the cornerstone of treatment, preventing hypovolaemia. This case demonstrates the importance of prompt recognition of a developing acute compartment syndrome and of performing an urgent fasciotomy.

Learning points

  • Rhabdomyolysis is a severe form of myopathy involving muscle breakdown, with myoglobin released into the circulation, leading to acute renal failure, electrolyte imbalances and disseminated intravascular coagulation. An elevated plasma creatine kinase (CK) level, mainly the CK-MM subtype, is the most sensitive laboratory finding pertaining to muscle injury.

  • The aetiological spectrum is extensive, but the most common cause is muscle trauma and compression resulting in crush injuries. Other causes include infection, drugs, toxins and metabolic factors. Rhabdomyolysis resulting from prolonged statin use may be precipitated by strenuous physical exertion and result in compartment syndrome requiring a fasciotomy.

  • Compartment syndrome can develop, with the ischaemic and oedematous muscle raising the intracompartmental pressure potentiating a vicious cycle of continuing ischaemia. Decompression of muscle compartments with fasciotomy is required. Severe electrolyte disturbance, such as hyperkalaemia occurring secondary to massive muscle breakdown, can precipitate cardiac arrhythmias and even sudden cardiac arrest.

  • Early aggressive fluid resuscitation to promote vigorous diuresis and prevent hypovolaemia is imperative, urine alkalinisation to protect the kidneys from myoglobin, mannitol to increase perfusion to the kidneys and decrease muscle oedema.

Footnotes

  • Contributors All authors contributed to the writing of this manuscript. LD wrote case report and discussion. RM performed the literature search. ST edited paper and final approval of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

References

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