Review article
The syndrome of rhabdomyolysis: Complications and treatment

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Abstract

Rhabdomyolysis is a syndrome of skeletal muscle cell damage that leads to the release of toxic intracellular material into the systemic circulation. The pathogenesis of rhabdomyolysis is based on an increase in free ionized calcium in the cytoplasm. Its main complications include (a) acute renal failure, which is triggered by renal vasoconstriction and ischemia, (b) myoglobin cast formation in the distal convoluted tubules, and (c) direct renal toxic effect of myoglobin on the epithelial cells of proximal convoluted tubules. Other major complications include electrolyte disorders, such as hyperkalemia, which may cause cardiac arrhythmias, metabolic acidosis, hyperphosphatemia, early hypocalcemia, and late hypercalcemia. Compartmental syndrome and disseminated intravascular coagulopathy may also emerge. The management of myoglobinuric acute renal failure includes aggressive fluid administration to restore the hypovolemia and urine alkalization. The concomitant electrolyte and metabolic disorders should also be treated appropriately; hemodialysis should be considered when life-threatening hyperkalemia and metabolic acidosis exist. In the case of compartmental syndrome, it is important to monitor the intra-compartmental pressure and to perform fasciotomy, if required. When diagnosed early and if the appropriate treatment is initiated promptly, the complications of rhabdomyolysis are preventable and the syndrome has a good prognosis.

Introduction

Rhabdomyolysis refers to the traumatic, ischemic, pharmaceutical, toxic, metabolic, or infectious skeletal muscle cell damage that influences the integrity of plasma membrane (sarcolemma) and leads to the release of toxic intracellular material into the systemic circulation [1], [2], [3], [4]. The causes of rhabdomyolysis are divided into hereditary and acquired ones. The hereditary causes are mainly related to a lack or insufficiency of enzymes that participate in the catabolism of different energy macromolecules (e.g., carbohydrates, lipids) [1]; the most frequent cause in this category is McArdle's disease [5]. The acquired causes are classified as traumatic and non-traumatic. The traumatic ones, such as crush syndrome, accidents, natural disasters, or intense exercise, cause direct muscle injury and rupture of the sarcolemma [6], [7], [8]. The non-traumatic causes are the most common ones during peacetime and include alcohol abuse, medicines (e.g., statins, amphetamines, anti-psychotics, diuretics), seizures, and coma [9], [10], [11], [12], [13], [14], [15].

Despite the great diversity in the etiology of rhabdomyolysis, the final pathogenetic pathway is common and includes an increase in free ionized calcium in the cytoplasm (sarcoplasm) [3], [4], [6]. The increased cytoplasmic calcium initiates a complex network of intracellular processes, such as the activation of phospholipase A2, prolonged contraction of muscle cells, mitochondrial dysfunction, and production of reactive oxygen species, which eventually promote muscle cell damage and the release of various substances (e.g., myoglobin, creatine phosphokinase, potassium, organic acids, and other enzymes and electrolytes) into the systemic circulation, thereby leading to the clinical manifestation of rhabdomyolysis [16], [17], [18], [19], [20]. Typically, rhabdomyolysis presents with muscle pain, weakness, and reddish-brown urine due to myoglobinuria [21]. Nevertheless, more than half of the patients do not report muscular symptoms. In more severe cases of rhabdomyolysis, general symptoms, such as malaise, fever, tachycardia, nausea, and vomiting, may also occur [22]. The severity of rhabdomyolysis varies from an asymptomatic increase in creatine phosphokinase to heavy complications, such as acute renal failure (ARF), cardiac arrhythmias, compartmental syndrome, and disseminated intravascular coagulopathy [21], [23].

In this review, we summarize the existing literature regarding the major complications of rhabdomyolysis, as well as their treatment. An enhanced understanding and awareness of these complications is necessary to enable the clinician to recognize and treat them promptly and successfully.

Section snippets

Acute renal failure

Baywaters and Beall [24] first described rhabdomyolysis-induced ARF in 1941 after they followed the progress of four victims who had developed ARF during the London bombardment in 1940. Although the authors attributed the ARF to rhabdomyolysis as a result of compression, they did not reveal the actual pathogenetic mechanism underlying this observation. A few decades later, it was found that the nephrotoxic effect of myoglobin, which is released by the disrupted muscle cells, is responsible for

Management of rhabdomyolysis

The major therapeutic interventions in rhabdomyolysis are conservative and include treatment of the underlying cause, prevention of ARF, early correction of potentially lethal electrolyte disorders (e.g., severe hyperkalemia), treatment of metabolic acidosis, and management of other coexisting complications (Table 1). Upon failure of conservative treatment and onset of ARF, patients should undergo hemodialysis.

Prognosis of rhabdomyolysis

Acute renal failure and hyperkalemia are the major complications that worsen the prognosis of rhabdomyolysis and require special attention. However, in most cases, ARF is completely reversible [55], [75]. Due to the fact that rhabdomyolysis is a rather rare syndrome and that few studies with large series of patients exist, it is difficult to reveal the true prognosis of the syndrome and its complications. Patients with severe injury who develop rhabdomyolysis-induced ARF have a mortality of

Conclusions

Rhabdomyolysis is a rather rare syndrome with serious potential complications. Although the prognosis of the syndrome is generally good, complications such as ARF and hyperkalemia are accompanied by high mortality. With regard to treatment, it is crucial that there is prompt and aggressive fluid replacement in combination with urine alkalization and close clinical follow-up of the patient. As rhabdomyolysis is the cause of ARF in a considerable percentage of cases, physicians should be well

Learning points

  • Rhabdomyolysis is a syndrome of skeletal muscle cell damage that leads to the release of toxic intracellular material into the systemic circulation.

  • The main complications of rhabdomyolysis include acute renal failure, electrolyte disorders such as hyperkalemia, hyperphosphatemia, early hypocalcemia, and late hypercalcemia, metabolic acidosis, compartmental syndrome, and disseminated intravascular coagulopathy.

  • The management of myoglobinuric acute renal failure includes aggressive fluid

References (75)

  • R. Zager et al.

    Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack

    Kidney Int

    (1998)
  • B. Halliwell et al.

    Role of free radicals and catalytic metal ions in human disease: an overview

    Meth Enzymol

    (1990)
  • R.A. Zager

    Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria

    Kidney Int

    (1996)
  • K.P. Moore et al.

    A causative role for redox cycling and its inhibition by alkalinisation in the pathogenesis and treatment of rhabdomyolysis induced renal failure

    J Biol Chem

    (1998)
  • S. Holt et al.

    Increased lipid peroxidation in patients with rhabdomyolysis

    Lancet

    (1999)
  • A. Perron et al.

    Orthopedic pitfalls in the ED: acute compartment syndrome

    Am J Emerg Med

    (2001)
  • N. Gill et al.

    Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management

    Chest

    (2005)
  • R.A. Zager et al.

    Iron, heme oxygenase and glutathione: effects on myoglobinuric proximal tubular injury

    Kidney Int

    (1995)
  • J.R. Lopez et al.

    Myoplasmic Ca2+ concentration during exertional rhabdomyolysis

    Lancet

    (1995)
  • R. Vanholder et al.

    Rhabdomyolysis

    J Am Soc Nephrol

    (2000)
  • J.P. Knochel

    Mechanisms of rhabdomyolysis

    Curr Opin Rheumatol

    (1993)
  • S. Dimaur et al.

    Myophosphorylase deficiency (glycogenosis type V; McArdle disease)

    Curr Mol Med

    (2002)
  • J. Warren et al.

    Rhabdomyolysis: a review

    Muscle Nerve

    (2002)
  • O.S. Better

    Post-traumatic acute renal failure: pathogenesis and prophylaxis

    Nephrol Dial Transplant

    (1992)
  • E.B. Larbi

    Drug-induced rhabdomyolysis

    Ann Saud Med

    (1998)
  • G. Melli et al.

    Rhabdomyolysis: an evaluation of 475 hospitalized patients

    Medicine

    (2005)
  • J.D. Warren et al.

    Rhabdomyolysis: a review

    Muscle Nerve

    (2002)
  • B.D. Prendergast et al.

    Drug-induced rhabdomyolysis — mechanisms and management

    Postgrad Med J

    (1993)
  • P.D. Thompson et al.

    Statin-associated myopathy

    JAMA.

    (2003)
  • I.M. Gommans et al.

    Calcium regulation and muscle disease

    J Muscle Res Cell Motil

    (2002)
  • N. Gordon

    Glycogenosis type V or McArdle's disease

    Dev Med Child Neurol

    (2003)
  • D. Gonzalez

    Crush syndrome

    Crit Care Med

    (2005)
  • P.A. Gabow et al.

    The spectrum of rhabdomyolysis

    Medicine (Baltimore)

    (1982)
  • A. Koffler et al.

    Acute renal failure due to non-traumatic rhabdomyolysis

    Ann Int Med

    (1976)
  • R. Beetham

    Biochemical investigation of suspected rhabdomyolysis

    Ann Clin Biochem

    (2000)
  • E.G.L. Bywaters et al.

    Crush injuries with impairment of renal function

    BMJ

    (1941)
  • G. Woodrow et al.

    The clinical and biochemical features of acute renal failure due to rhabdomyolysis

    Ren Fail

    (1995)
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