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The syndrome of rhabdomyolysis: Complications and treatment

Published:April 28, 2008DOI:https://doi.org/10.1016/j.ejim.2007.06.037

      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.

      Keywords

      1. 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 [
      • Poels P.J.
      • Gabreels F.J.
      Rhabdomyolysis: a review of the literature.
      ,
      • Vanholder R.
      • Sever M.S.
      • Erek E.
      • Lameire N.
      Rhabdomyolysis.
      ,
      • Knochel J.P.
      Mechanisms of rhabdomyolysis.
      ,
      • Giannoglou G.D.
      • Chatzizisis Y.S.
      • Misirli G.
      The syndrome of rhabdomyolysis: pathophysiology and diagnosis.
      ]. 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) [
      • Poels P.J.
      • Gabreels F.J.
      Rhabdomyolysis: a review of the literature.
      ]; the most frequent cause in this category is McArdle's disease [
      • Dimaur S.
      • Andreu A.L.
      • Bruno C.
      • Hadjigeorgiou G.M.
      Myophosphorylase deficiency (glycogenosis type V; McArdle disease).
      ]. 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 [
      • Warren J.
      • Blumbergs P.
      • Thompson P.
      Rhabdomyolysis: a review.
      ,
      • Better O.S.
      Post-traumatic acute renal failure: pathogenesis and prophylaxis.
      ,
      • Better O.S.
      • Rubinstein I.
      • Reis D.N.
      Muscle crush compartment syndrome: fulminant local edema with threatening systemic effects.
      ]. 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 [
      • Larbi E.B.
      Drug-induced rhabdomyolysis.
      ,
      • Allison R.C.
      • Bedsole D.L.
      The other medical causes of rhabdomyolysis.
      ,
      • Melli G.
      • Chaudhry V.
      • Cornblath D.R.
      Rhabdomyolysis: an evaluation of 475 hospitalized patients.
      ,
      • Warren J.D.
      • Blumbergs P.C.
      • Thompson P.D.
      Rhabdomyolysis: a review.
      ,
      • Prendergast B.D.
      • George C.F.
      Drug-induced rhabdomyolysis — mechanisms and management.
      ,
      • Zager R.A.
      Rhabdomyolysis and myohemoglobinuric acute renal failure.
      ,
      • Thompson P.D.
      • Clarkson P.
      • Karas R.H.
      Statin-associated myopathy.
      ].
      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) [
      • Knochel J.P.
      Mechanisms of rhabdomyolysis.
      ,
      • Giannoglou G.D.
      • Chatzizisis Y.S.
      • Misirli G.
      The syndrome of rhabdomyolysis: pathophysiology and diagnosis.
      ,
      • Warren J.
      • Blumbergs P.
      • Thompson P.
      Rhabdomyolysis: a review.
      ]. 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 [
      • Knochel J.P.
      Neuromuscular manifestations of electrolyte disorders.
      ,
      • Nohl H.
      • Gille L.
      • Staniek K.
      Intracellular generation of reactive oxygen species by mitochondria.
      ,
      • Gommans I.M.
      • Vlak M.H.
      • de Haan A.
      • van Engelen B.G.
      Calcium regulation and muscle disease.
      ,
      • Gordon N.
      Glycogenosis type V or McArdle's disease.
      ,
      • Gonzalez D.
      Crush syndrome.
      ]. Typically, rhabdomyolysis presents with muscle pain, weakness, and reddish-brown urine due to myoglobinuria [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ]. 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 [
      • Koffler A.
      • Friedler R.
      • Massry S.
      Acute renal failure due to non-traumatic rhabdomyolysis.
      ]. 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 [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ,
      • Beetham R.
      Biochemical investigation of suspected rhabdomyolysis.
      ].
      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.

      2. Complications of rhabdomyolysis

      2.1 Acute renal failure

      Baywaters and Beall [
      • Bywaters E.G.L.
      • Beall D.
      Crush injuries with impairment of renal function.
      ] 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 the renal damage [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ]. It is estimated that roughly 10–40% of cases of rhabdomyolysis leads to ARF, while 5–15% of ARF cases is attributed to rhabdomyolysis [
      • Larbi E.B.
      Drug-induced rhabdomyolysis.
      ,
      • Chander V.
      • Chopra K.
      Molsidomine, a nitric oxide donor and l-arginine protects against rhabdomyolysis-induced myoglobinuric acute renal failure.
      ,
      • Woodrow G.
      • Brownjohn A.M.
      • Turney J.H.
      The clinical and biochemical features of acute renal failure due to rhabdomyolysis.
      ].
      Myoglobin plays a dominant role in the pathogenesis of rhabdomyolysis-induced ARF. The basic mechanisms involved in the pathophysiology of myoglobinuric ARF are presented in Fig. 1 and include [
      • Heyman S.N.
      • Rosen S.
      • Fuchs S.
      • Epstein F.H.
      • Brezis M.
      Myoglobinuric acute renal failure in rat: a role for medullary hypoperfusion, hypoxia and tubular obstruction.
      ,
      • Thadhani R.
      • Pascual M.
      • Bonventre J.V.
      Acute renal failure.
      ,
      • Zager R.A.
      • Gamelin L.M.
      Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.
      ]: (a) renal constriction and ischemia, (b) myoglobin cast formation in the distal convoluted tubules, and (c) direct cytotoxic action of myoglobin on the epithelial cells of the proximal convoluted tubules. The coexisting hypovolemia and acidic pH of urine, due to the metabolic acidosis, are regulating factors that intensify the nephrotoxic action of myoglobin [
      • Zager R.A.
      • Gamelin L.M.
      Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.
      ,
      • Sandhu J.S.
      • Sood A.
      • Midha V.
      • Singh A.D.
      • Jain D.
      • Sandhu P.
      Non-traumatic rhabdomyolysis with acute renal failure.
      ,
      • Sułowicz W.
      • Walatek B.
      • Sydor A.
      • Ochmański W.
      • Miłkowski A.
      • Szymczakiewicz-Multanowska A.
      • et al.
      Acute renal failure in patients with rhabdomyolysis.
      ].
      Figure thumbnail gr1
      Fig. 1Renal ischemia, formation of myoglobin casts at the distal convoluted tubules, and the cytotoxic effect of iron (Fe) on the epithelial cells of the proximal convoluted tubules are the principal pathogenetic mechanisms of myoglobinuric acute renal failure (ARF). Coexisting hypovolemia and acidic urine pH further intensify these processes. Acute renal failure is induced by the combination of a decreased oxygen supply at the tubular cells, tubular obstruction, and acute tubular necrosis (ATN). NO, nitric oxide.

      2.1.1 Renal vasoconstriction and ischemia

      The necrosis of muscular tissue creates a “third space” in which a large amount of intravascular fluid accumulates and causes hypovolemia [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. The hypovolemia activates the sympathetic nervous system and the rennin–angiotensin–aldosterone system, increases the production of vasoconstricting molecules (e.g., endothelin I, vasopressin), and inhibits the production of vasodilatory prostaglandins [
      • Prendergast B.D.
      • George C.F.
      Drug-induced rhabdomyolysis — mechanisms and management.
      ,
      • Gonzalez D.
      Crush syndrome.
      ,
      • Lameire N.
      • Vanholder R.
      New perspectives for prevention/treatment of acute renal failure.
      ,
      • Lameire N.
      • De Vriese A.
      • Vanholder R.
      Prevention and nondialytic treatment of acute renal 0failure.
      ,
      • Sheridan A.M.
      • Bonventre J.V.
      Cell biology and molecular mechanisms of injury in ischemic acute renal failure.
      ]. Muscle damage provokes the release of endotoxins and cytokines into the systemic circulation, which also promote vasoconstriction [
      • Badr K.F.
      • Kelley V.E.
      • Rennke H.G.
      • Brenner B.M.
      Role for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure.
      ,
      • Devarajan P.
      Cellular and molecular derangements in acute tubular necrosis.
      ,
      • Zager R.A.
      • Prior R.B.
      Gentamycin and gram negative bacteremia: a synergism for the development of experimental nephrotoxic acute renal failure.
      ], whereas the myoglobin that is released by the dead muscle cells degrades nitric oxide (NO), which is the most potent endogenous vasodilatory factor [
      • Furchgott R.F.
      • Jothianandan D.
      Endothelial-dependent and -independent vasodilation involving cGMP: relaxation induced by nitric oxide, carbon oxide and light.
      ,
      • Neto L.M.
      • Nascimento O.R.
      • Tabak M.
      • Caracelli I.
      The mechanism of reaction of nitrosyl with met and oxymyoglobin: an ESR study.
      ,
      • Sharma V.S.
      • Traylor T.G.
      • Gardiner R.
      • Mizukami H.
      Reaction of nitric oxide with heme proteins and model compounds of hemoglobin.
      ]. Ultimately, the abovementioned processes lead to renal vasoconstriction, renal ischemia and, subsequently, decreased ATP production due to decreased oxygen supply in the renal tubular cells.

      2.1.2 Myoglobin cast formation

      The presence of myoglobin casts inside the distal convoluted tubules constitutes a common finding in myoglobinuric ARF. Depletion of ATP causes epithelial cell necrosis, accumulation of dead cells in the tubular lumen, and subsequent precipitation of myoglobin and creation of casts [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ,
      • Molitoris B.A.
      • Sandoval R.
      • Sutton T.A.
      Endothelial injury and dysfunction in ischemic acute renal failure.
      ,
      • Slater M.S.
      • Mullins R.J.
      Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
      ]. The formation of these casts is dependent on the concentration of filtered myoglobin in the preurine. The larger the extent of muscular damage, the higher the concentration of myoglobin in the serum and, consequently, the amount of myoglobin that is filtered at the renal glomeruli [
      • Akimau P.
      • Yoshiya K.
      • Hosotsubo H.
      • Takakuwa T.
      • Tanaka H.
      • Sugimoto H.
      New experimental model of crush injury of the hindlimbs in rats.
      ]. An increased concentration of myoglobin in the preurine, in combination with an acidic pH, enhances the accumulation of myoglobin inside the distal convoluted tubules, resulting in myoglobin cast formation [
      • Gonzalez D.
      Crush syndrome.
      ,
      • Slater M.S.
      • Mullins R.J.
      Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
      ]. Obstruction of distal convoluted tubules by myoglobin casts reduces blood flow and glomerular filtration rate, thereby promoting the accumulation and aggregation of necrotic epithelial cells and proteins and the creation of casts [
      • Thadhani R.
      • Pascual M.
      • Bonventre J.V.
      Acute renal failure.
      ].

      2.1.3 Direct cytotoxic effect of myoglobin

      Besides the formation of casts, myoglobin exerts a direct cytotoxic effect through enhancement of local oxidative stress in the tubular cells of the proximal convoluted tubules [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ,
      • Zager R.
      • Burkhart K.
      Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack.
      ]. Once the concentration of myoglobin that is filtered at the glomerulus exceeds the normal level, the tubular cells of the proximal convoluted tubules increase their reabsorbing capacity in order to limit the excretion of myoglobin into the urine and to protect the kidney from its nephrotoxic effect. The increased reabsorption of myoglobin through endocytosis and its subsequent intracellular degradation to proteins, heme and iron, which mainly occurs at a urine pH below 5.6 [
      • Zager R.
      • Burkhart K.
      Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack.
      ], leads to free iron overloading of tubular cells. Free iron is an oxidative metal that either facilitates the production of free oxygen radicals (Fe2++H2O2Fe3++OH+OH) or acts as a free radical by itself [
      • Braun S.R.
      • Weiss F.R.
      • Keller A.I.
      • Ciccone J.R.
      • Preuss H.G.
      Evaluation of the renal toxicity of heme proteins and their derivatives: a role in the genesis of acute tubular necrosis.
      ,
      • Paller M.S.
      Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.
      ,
      • Nath K.A.
      • Norby S.M.
      Reactive oxygen species and acute renal failure.
      ,
      • Halliwell B.
      • Gutteridge J.M.
      Role of free radicals and catalytic metal ions in human disease: an overview.
      ]. The oxidative stress generated in the cytoplasm of tubular cells promotes the peroxidation of lipids, proteins, and DNA, leading to acute tubular necrosis (ATN) [
      • Zager R.
      • Burkhart K.
      Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack.
      ,
      • Zager R.A.
      Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria.
      ,
      • Moore K.P.
      • Holt S.G.
      • Patel R.P.
      • Svistunenko D.A.
      • Zackert W.
      • Goodier D.
      • et al.
      A causative role for redox cycling and its inhibition by alkalinisation in the pathogenesis and treatment of rhabdomyolysis induced renal failure.
      ]. Heme itself can also enhance cellular oxidative stress [
      • Holt S.
      • Reeder B.
      • Wilson M.
      • Harvey S.
      • Morrow J.D.
      • Roberts 2nd, L.J.
      • et al.
      Increased lipid peroxidation in patients with rhabdomyolysis.
      ,
      • Reeder B.
      • Wilson M.
      Desferrioxamine inhibits production of cytotoxic heme to protein cross-linked myoglobin: a mechanism to protect against oxidative stress without iron chelation.
      ]. ATP reduction further facilitates the toxic effect of myoglobin on the epithelial cells of the proximal convoluted tubules as it causes morphologic and functional changes in the cells, which alter membrane permeability, allowing heme to enter into the cell [
      • Thadhani R.
      • Pascual M.
      • Bonventre J.V.
      Acute renal failure.
      ,
      • Devarajan P.
      Cellular and molecular derangements in acute tubular necrosis.
      ]. On the other hand, the distal tubule obstruction caused by the myoglobin casts increases the intra-tubular concentration of nephrotoxic myoglobin and its reabsorption by the tubular cells of the proximal convoluted tubules and intensifies ATN.

      2.1.4 Other mechanisms

      In the setting of acidic pH in blood and urine, hyperuricemia provokes the deposition of uric acid crystals in the lumen of distal convoluted tubules, intensifying tubular obstruction [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ,
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. Also, the release of tissue thromboplastin from the dead muscle cells triggers the cascade of disseminated intravascular coagulopathy and results in the formation of multiple microthrombi within the renal parenchyma and onset of renal ischemia [
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      • Acute Dialysis Quality Initiative
      Acute renal failure — definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      ].

      2.2 Electrolyte disorders and metabolic acidosis

      Hyperkalemia, which is defined as a potassium level greater than 5.0 mEq/L (normal range: 3.5–5.0 mEq/L), causes serious cardiac arrhythmias that may lead to cardiac arrest [
      • Huerta-Alardín A.L.
      • Varon J.
      • Marik P.E.
      Bench-to-bedside review: rhabdomyolysis — an overview for clinicians.
      ,
      • Criddle L.M.
      Rhabdomyolysis: pathophysiology, recognition, and management.
      ]. Ninety-eight percent of potassium is in the intracellular space, whereas 60–70% of the total cellular mass of the human body consists of skeletal muscle cells; consequently, even an acute necrosis of only 100 g of muscular mass could increase serum potassium by 1.0 mEq/L [
      • Giannoglou G.D.
      • Chatzizisis Y.S.
      • Misirli G.
      The syndrome of rhabdomyolysis: pathophysiology and diagnosis.
      ]. Hyperkalemia is further aggravated by metabolic acidosis induced by the release of various organic acids (e.g., lactic acid, uric acid) from the disrupted muscle cells [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ,
      • Allen D.G.
      Skeletal muscle function: role of ionic changes in fatigue, damage and disease.
      ,
      • Singh D.
      • Chander V.
      • Chopra K.
      Rhabdomyolysis.
      ]. The hypocalcemia that occurs in the initial stages of rhabdomyolysis further enhances the cardiotoxic effect of potassium [
      • Gonzalez D.
      Crush syndrome.
      ]. Therefore, the cardiotoxic potential of hyperkalemia should always be considered in the setting of coexisting metabolic acidosis and decreased calcium levels [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ]. Hyperkalemia lower than 6.0 mEq/L is usually asymptomatic, whereas levels of potassium above 6.0 mEq/L require urgent treatment. Electrocardiographic follow-up is mandatory for the diagnosis of hyperkalemia: acute, peaked T waves, decreased QT interval and, in more severe hyperkalemia, low P waves, extension of QRS interval, and ventricular arrhythmias, are the most frequent electrocardiographic findings.
      Furthermore, during the destruction of muscle cells, the release of inorganic phosphorus into the plasma causes hyperphosphatemia [
      • Koffler A.
      • Friedler R.
      • Massry S.
      Acute renal failure due to non-traumatic rhabdomyolysis.
      ,
      • Singh D.
      • Chander V.
      • Chopra K.
      Rhabdomyolysis.
      ] and subsequent hypocalcemia through deposition of calcium phosphate onto the destroyed muscle cells and other tissues [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. Inhibition of kidney 1a-hydroxylase, which results in downregulation of the production of the active form of vitamin D [1,25(OH)2D3], can further promote hypocalcemia [
      • Zager R.A.
      Rhabdomyolysis and myohemoglobinuric acute renal failure.
      ]. However, in the course of rhabdomyolysis, the calcium that is entrapped in the cytoplasm of muscle cells is released back into the plasma after their destruction, resulting in late hypercalcemia [
      • Meneghini L.F.
      • Oster J.R.
      • Camacho J.R.
      • Gkonos P.J.
      • Roos B.A.
      Hypercalcemia in association with acute renal failure and rhabdomyolysis. Case report and literature review.
      ,
      • Llach F.
      • Felsenfeld A.J.
      • Haussler M.R.
      The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol.
      ].

      2.3 Compartmental syndrome

      Compartmental syndrome is not a rare finding in rhabdomyolysis [
      • Vanholder R.
      • Sever M.S.
      • Erek E.
      • Lameire N.
      Rhabdomyolysis.
      ,
      • Larbi E.B.
      Drug-induced rhabdomyolysis.
      ]. Most skeletal muscles are enfolded in confined, inflexible compartments created by bones, fascia, and other structures. Compartmental syndrome develops more often in the compartments of the extremities, such as the anterior compartment (containing the biceps-brachialis muscle) and the posterior compartment (containing the triceps muscle) of the upper arm, the volar compartment (wrist and finger flexors) and dorsal compartment (wrist and finger extensors) of the forearm, the three gluteal compartments, the anterior and posterior compartments of the thigh, and the four compartments of the lower leg [
      • Perron A.
      • Brady W.
      • Keats T.
      Orthopedic pitfalls in the ED: acute compartment syndrome.
      ,
      • Edwards S.
      Acute compartment syndrome.
      ]. The impairment of muscle cells during rhabdomyolysis and the massive influx of calcium and sodium promote the accumulation of large amounts of extracellular fluid into the cells, resulting in the formation of local edema and an increase in intramuscular pressure [
      • Better O.S.
      • Rubinstein I.
      • Reis D.N.
      Muscle crush compartment syndrome: fulminant local edema with threatening systemic effects.
      ,
      • Edwards S.
      Acute compartment syndrome.
      ]. The increased intramuscular pressure impedes blood perfusion of the region as well as the venous return of the blood, thereby intensifying the local edema [
      • Better O.S.
      • Rubinstein I.
      • Reis D.N.
      Muscle crush compartment syndrome: fulminant local edema with threatening systemic effects.
      ]. Furthermore, the local ischemia increases the permeability of the capillaries, thus worsening the edema and establishing a self-perpetuating vicious cycle [
      • Slater M.S.
      • Mullins R.J.
      Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
      ]. The clinical symptoms of compartmental syndrome include local pallor and pain, weakening or complete absence of pulse, and sensory and motor disturbances in the case of severe ischemia [
      • Better O.S.
      • Rubinstein I.
      • Reis D.N.
      Muscle crush compartment syndrome: fulminant local edema with threatening systemic effects.
      ,
      • Gonzalez D.
      Crush syndrome.
      ].

      2.4 Disseminated intravascular coagulopathy

      The release of various prothrombotic substances (mainly thromboplastin) from the destroyed muscle cells activates the coagulation cascade and triggers the syndrome of disseminated intravascular coagulopathy, which is usually asymptomatic [
      • Huerta-Alardín A.L.
      • Varon J.
      • Marik P.E.
      Bench-to-bedside review: rhabdomyolysis — an overview for clinicians.
      ,
      • Criddle L.M.
      Rhabdomyolysis: pathophysiology, recognition, and management.
      ,
      • Bonventre J.
      • Shah S.
      • Walker P.
      • Humphrey S.M.
      Rhabdomyolysis induced acute renal failure.
      ]. Seldom does the insult of respiratory muscles, especially in severe forms of rhabdomyolysis, lead to ARF [
      • Gonzalez D.
      Crush syndrome.
      ,
      • Sion M.L.
      • Hatzitolios A.
      • Toulis A.
      • Kounanis A.
      • Prokopidis D.
      Rhabdomyolysis and acute renal failure associated with Salmonella enteritidis bacteremia.
      ].

      3. 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.
      Table 1Management of myoglobinuric acute renal failure and other complications of rhabdomyolysis
      1. General preventive measures
      2. Prevention of acute renal failure
       a. Fluid replacement
       b. Alkaline diuresis
      3. Correction of electrolyte disorders (e.g., hyperkalemia) and metabolic acidosis
      4. Hemodialysis
      5. Treatment of other complications

      3.1 General measures

      Patients should be encouraged to report to their care provider every inexplicable muscle pain, sensitivity, or weakness, especially if it is accompanied by fever or fatigue. On the other hand, the care provider must be aware that early recognition of the symptoms of rhabdomyolysis constitutes the cornerstone in the diagnosis of the syndrome.

      3.2 Prevention of ARF

      3.2.1 Fluid replacement

      According to experimental and clinical data, early (i.e., before the formation of casts, increased endocytosis of myoglobin from the epithelial cells, and onset of ATN) intravascular volume expansion by intravenous administration of NaCl 0.9% is crucial for the prevention of myoglobinuric ARF as it increases renal blood flow and, consequently, glomerular filtration and urination [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. The pace of fluid replacement is dependent on the severity of myoglobinuria; the treatment objective is to achieve at least 300 ml/h urine excretion [
      • Sion M.L.
      • Hatzitolios A.
      • Toulis A.
      • Kounanis A.
      • Prokopidis D.
      Rhabdomyolysis and acute renal failure associated with Salmonella enteritidis bacteremia.
      ]. Early recognition of the onset of ATN is essential as it may prevent excessive administration of crystalloid and other fluids that can lead to non-cardiac pulmonary edema [
      • Esson M.L.
      • Schrier R.W.
      Diagnosis and treatment of acute tubular necrosis.
      ].

      3.2.2 Urine alkalization

      Alkalization of urine is achieved through intravenous administration of sodium bicarbonate (NaHCO3) and appears to be particularly effective in the prevention of ARF [
      • Warren J.
      • Blumbergs P.
      • Thompson P.
      Rhabdomyolysis: a review.
      ,
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. The alkaline pH of urine increases the solubility of myoglobin and uric acid and limits the formation of myoglobin casts and uric acid crystals, respectively, while it impedes the degradation of myoglobin into heme and free iron and the accompanying nephrotoxic effect [
      • Prendergast B.D.
      • George C.F.
      Drug-induced rhabdomyolysis — mechanisms and management.
      ,
      • Nath K.A.
      • Norby S.M.
      Reactive oxygen species and acute renal failure.
      ]. In addition, NaHCO3 corrects the metabolic acidosis and, subsequently, hyperkalemia. The treatment objective of urine alkalization is to reach a urine pH above 6.5 and a serum pH between 7.40 and 7.45 [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ].

      3.2.3 Diuresis

      After hypovolemia is corrected and satisfactory hourly excretion of urine is achieved, the patient should be subjected to forced diuresis, which is achieved through intravenous administration of mannitol and/or one of Henle's loop diuretics, such as furosemide or bumetanide [
      • Thadhani R.
      • Pascual M.
      • Bonventre J.V.
      Acute renal failure.
      ,
      • Lameire N.
      • De Vriese A.
      • Vanholder R.
      Prevention and nondialytic treatment of acute renal 0failure.
      ]. Mannitol is an osmolar diuretic that acts through the following mechanisms [
      • Better O.S.
      Post-traumatic acute renal failure: pathogenesis and prophylaxis.
      ,
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      • Acute Dialysis Quality Initiative
      Acute renal failure — definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      ]: (a) provokes vasodilation on the renal parenchyma, improving renal perfusion and glomerular filtering; (b) acts on the proximal convoluted tubules and contributes to the excretion of myoglobin, heme, and iron, minimizing the probability of myoglobin cast formation and its direct cytotoxic effect on epithelial cells; and (c) exerts antioxidative action, thereby decreasing the oxidative stress in the tubular cells. Nevertheless, recent studies have shown that administration of NaCl 0.9% in combination with mannitol is not more effective in the prevention of ARF than the administration of NaCl 0.9% alone. Hence, there is strong skepticism regarding the need for mannitol administration in rhabdomyolysis [
      • Zager R.A.
      Combined mannitol and deferoxamine therapy for myoglobinuric renal injury and oxidant tubular stress: mechanistic and therapeutic implications.
      ,
      • Brown C.V.
      • Rhee P.
      • Chan L.
      • Evans K.
      • Demetriades D.
      • Velmahos G.C.
      Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?.
      ]. However, it is considered beneficial when there is suspicion of compartmental syndrome [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ].
      Furosemide, which causes more intense diuresis, thereby preventing the accumulation of myoglobin in distal convoluted tubules, has also been used in myoglobinuric ARF. However, it has the disadvantage of producing low pH urine [
      • Beetham R.
      Biochemical investigation of suspected rhabdomyolysis.
      ]. Furthermore, studies have not shown any advantage of the administration of Henle's loop diuretics in patients with ARF, and their contribution to the treatment of ARF remains uncertain [
      • Lameire N.
      • De Vriese A.
      • Vanholder R.
      Prevention and nondialytic treatment of acute renal 0failure.
      ].

      3.2.4 Prevention of nephrotoxicity

      Avoidance of exposure to nephrotoxic substances, such as non-steroidal anti-inflammatory drugs, nephrotoxic antibiotics, and radiocontrast media, is essential for the recovery of patients presenting with rhabdomyolysis [
      • Gill N.
      • Nally Jr, J.V.
      • Fatica R.A.
      Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.
      ]. Studies have shown that the administration of antioxidant substances, such as desferrioxamine, a chelating agent that binds nephrotoxic free iron, glutathione, and vitamin E, may protect the renal epithelium from the toxic effect of myoglobin [
      • Zager R.
      • Burkhart K.
      Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack.
      ,
      • Zager R.A.
      Combined mannitol and deferoxamine therapy for myoglobinuric renal injury and oxidant tubular stress: mechanistic and therapeutic implications.
      ,
      • Zager R.A.
      • Burkhart K.M.
      • Conrad D.S.
      • Gmur D.J.
      Iron, heme oxygenase and glutathione: effects on myoglobinuric proximal tubular injury.
      ]. Allopurinol may also act beneficially, as it restricts the production of uric acid crystals [
      • Beetham R.
      Biochemical investigation of suspected rhabdomyolysis.
      ]. Dantrolene, which blocks calcium channels in the sarcoplasmic reticulum, has also been proposed for the treatment of rhabdomyolysis [
      • Lopez J.R.
      • Rojas B.
      • Gonzales M.A.
      • Terzic A.
      Myoplasmic Ca2+ concentration during exertional rhabdomyolysis.
      ].

      3.3 Treatment of electrolyte disorders and metabolic acidosis

      3.3.1 Hyperkalemia

      When the level of potassium exceeds 6.0 mEq/L, urgent treatment is needed. Intravenous administration of glucose and insulin solution (12–14 IU of insulin in 1000 ml dextrose 5%) or NaHCO3 (50–100 nmol daily) can restore the normal levels of intracellular potassium [
      • Knochel J.P.
      Pigment nephropathy.
      ]. Since both approaches have a temporary effect, especially when ARF is well established, they should be accompanied by more effective therapeutic strategies, such as per os or per anus administration of sorbitol solution, which contains the cation-exchange resin disodium polysterene sulphonate that binds the excess potassium in the intestines [
      • Beetham R.
      Biochemical investigation of suspected rhabdomyolysis.
      ,
      • Russell T.A.
      Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis and collaborative management.
      ]. Great caution is needed with medications that have negative inotropic, antihypertensive, or hyperkalemic properties, such as angiotensin-converting enzyme inhibitors, calcium channel blockers, and β-blockers [
      • Better O.S.
      Post-traumatic acute renal failure: pathogenesis and prophylaxis.
      ]. The administration of calcium chloride or calcium gluconate should be avoided unless it is absolutely necessary, e.g., in the case of lethal cardiac arrhythmias [
      • Russell T.A.
      Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis and collaborative management.
      ]. Finally, hemodialysis, which constitutes the ultimate solution, is recommended only when life-threatening hyperkalemia emerges [
      • Larbi E.B.
      Drug-induced rhabdomyolysis.
      ,
      • Russell T.A.
      Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis and collaborative management.
      ].

      3.3.2 Metabolic acidosis

      It is not recommended to treat metabolic acidosis unless the concentration of serum bicarbonate is lower than 15 nmol/L or the blood pH is lower than 7.2 [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ,
      • Brady H.R.
      • Brenner B.M.
      Acute renal failure.
      ]. In such a case, the correction of acidosis is achieved through intravenous administration of NaHCO3, and, upon failure of conservative treatment, with hemodialysis. Following NaHCO3 administration, the patient should be watched for the emergence of possible complications, such as hypervolemia, metabolic alkalosis, hypokalemia, or hypocalcemia.

      3.3.3 Hypocalcemia

      Normally, hypocalcemia is automatically corrected and no intervention is required [
      • Harriston S.
      A review of rhabdomyolysis.
      ]. The administration of calcium chloride or calcium gluconate would intensify the accumulation of calcium in the muscular tissue and consequently reinforce the mechanism of rhabdomyolysis [
      • Holt S.G.
      • Moore K.P.
      Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
      ]. However, calcium should be administered in cases of severe hyperkalemia (potassium>6.0 mEq/L) associated with potentially lethal cardiac arrhythmias or intense muscular convulsions [
      • Knochel J.P.
      Pigment nephropathy.
      ,
      • Gozal Y.
      Calcium administration in rhabdomyolysis may be detrimental.
      ].

      3.3.4 Hyperphosphatemia

      Correction of hyperphosphatemia is achieved by per os administration of agents that bind phosphorus, such as calcium carbonate or calcium hydroxide [
      • Knochel J.P.
      Pigment nephropathy.
      ]. Along with hyperphosphatemia, hypocalcemia is also regulated [
      • Harriston S.
      A review of rhabdomyolysis.
      ].

      3.4 Hemodialysis

      The indications for hemodialysis include severe and resistant hyperkalemia, an abrupt increase in potassium levels, persistent metabolic acidosis, and ongoing ARF despite conservative treatment [
      • Vanholder R.
      • Sever M.S.
      • Erek E.
      • Lameire N.
      Rhabdomyolysis.
      ,
      • Gill N.
      • Nally Jr, J.V.
      • Fatica R.A.
      Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.
      ,
      • Russell T.A.
      Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis and collaborative management.
      ].

      3.5 Management of compartmental syndrome

      The intra-compartmental pressure should be monitored either invasively, with the use of a special catheter, or non-invasively, with Doppler ultrasound, in order to avoid potential infections [
      • Perron A.
      • Brady W.
      • Keats T.
      Orthopedic pitfalls in the ED: acute compartment syndrome.
      ]. When the intra-compartmental pressure exceeds 40 mm Hg, direct surgical decompression with fasciotomy should be performed in order to avoid necrosis of the region and subsequent amputation [
      • Vanholder R.
      • Sever M.S.
      • Erek E.
      • Lameire N.
      Rhabdomyolysis.
      ,
      • Slater M.S.
      • Mullins R.J.
      Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
      ]. Intravenous administration of mannitol also reduces the intra-compartmental pressure [
      • Gabow P.A.
      • Kaehny W.D.
      • Kelleher S.P.
      The spectrum of rhabdomyolysis.
      ].

      3.6 Management of disseminated intravascular coagulopathy

      The treatment of disseminated intravascular coagulopathy is mainly supportive and the overall treatment for rhabdomyolysis is the essential treatment for disseminated intravascular coagulopathy. Nevertheless, in cases of severe hemorrhagic predisposition, the administration of fresh frozen plasma is required [
      • Prendergast B.D.
      • George C.F.
      Drug-induced rhabdomyolysis — mechanisms and management.
      ].

      4. 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 [
      • Huerta-Alardín A.L.
      • Varon J.
      • Marik P.E.
      Bench-to-bedside review: rhabdomyolysis — an overview for clinicians.
      ,
      • Gozal Y.
      Calcium administration in rhabdomyolysis may be detrimental.
      ]. 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 approximately 20%, and this percentage increases in patients with multiple organ failure syndrome [
      • Huerta-Alardín A.L.
      • Varon J.
      • Marik P.E.
      Bench-to-bedside review: rhabdomyolysis — an overview for clinicians.
      ]. According to some clinical series, the mortality rate in patients who develop ARF ranges from 7% to 80% [
      • Slater M.S.
      • Mullins R.J.
      Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
      ]. Dialysis is required in about 85% of patients with oliguric ARF and in 30% of patients with non-oliguric ARF, whereas the mortality rate in patients with ARF who require dialysis is between 50% and 80% [
      • Esson M.L.
      • Schrier R.W.
      Diagnosis and treatment of acute tubular necrosis.
      ,
      • Gill N.
      • Nally Jr, J.V.
      • Fatica R.A.
      Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.
      ].

      5. 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 informed and prepared to recognize the signs of the syndrome in order to provide immediate and proper treatment.

      6. 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 administration to restore the hypovolemia and urine alkalization.
      • The concomitant electrolyte and metabolic disorders should also be treated appropriately, whereas hemodialysis should be considered only when life-threatening hyperkalemia and metabolic acidosis emerge.
      • In the case of compartmental syndrome, it is important to monitor the intra-compartmental pressure and to perform fasciotomy, if required.
      • When there is an early diagnosis and prompt initiation of the appropriate treatment, the complications of rhabdomyolysis are preventable and the syndrome has a good prognosis.

      References

        • Poels P.J.
        • Gabreels F.J.
        Rhabdomyolysis: a review of the literature.
        Clin Neurol Neurosurg. 1993; 95: 175-192
        • Vanholder R.
        • Sever M.S.
        • Erek E.
        • Lameire N.
        Rhabdomyolysis.
        J Am Soc Nephrol. 2000; 11: 1553-1556
        • Knochel J.P.
        Mechanisms of rhabdomyolysis.
        Curr Opin Rheumatol. 1993; 5: 725-731
        • Giannoglou G.D.
        • Chatzizisis Y.S.
        • Misirli G.
        The syndrome of rhabdomyolysis: pathophysiology and diagnosis.
        Eur J Int Med. 2007; 18: 90-100
        • Dimaur S.
        • Andreu A.L.
        • Bruno C.
        • Hadjigeorgiou G.M.
        Myophosphorylase deficiency (glycogenosis type V; McArdle disease).
        Curr Mol Med. 2002; 2: 189-196
        • Warren J.
        • Blumbergs P.
        • Thompson P.
        Rhabdomyolysis: a review.
        Muscle Nerve. 2002; 25: 332-347
        • Better O.S.
        Post-traumatic acute renal failure: pathogenesis and prophylaxis.
        Nephrol Dial Transplant. 1992; 7: 260-264
        • Better O.S.
        • Rubinstein I.
        • Reis D.N.
        Muscle crush compartment syndrome: fulminant local edema with threatening systemic effects.
        Kidney Int. 2003; 63: 1155-1157
        • Larbi E.B.
        Drug-induced rhabdomyolysis.
        Ann Saud Med. 1998; 18: 525-530
        • Allison R.C.
        • Bedsole D.L.
        The other medical causes of rhabdomyolysis.
        Am J Med Sci. 2003; 326: 79-88
        • Melli G.
        • Chaudhry V.
        • Cornblath D.R.
        Rhabdomyolysis: an evaluation of 475 hospitalized patients.
        Medicine. 2005; 84: 377-385
        • Warren J.D.
        • Blumbergs P.C.
        • Thompson P.D.
        Rhabdomyolysis: a review.
        Muscle Nerve. 2002; 25: 332-347
        • Prendergast B.D.
        • George C.F.
        Drug-induced rhabdomyolysis — mechanisms and management.
        Postgrad Med J. 1993; 69: 333-336
        • Zager R.A.
        Rhabdomyolysis and myohemoglobinuric acute renal failure.
        Kidney Int. 1996; 49: 314-326
        • Thompson P.D.
        • Clarkson P.
        • Karas R.H.
        Statin-associated myopathy.
        JAMA. 2003; 289: 1681-1690
        • Knochel J.P.
        Neuromuscular manifestations of electrolyte disorders.
        Am J Med. 1982; 72: 521-535
        • Nohl H.
        • Gille L.
        • Staniek K.
        Intracellular generation of reactive oxygen species by mitochondria.
        Biochem Pharmacol. 2005; 69: 719-723
        • Gommans I.M.
        • Vlak M.H.
        • de Haan A.
        • van Engelen B.G.
        Calcium regulation and muscle disease.
        J Muscle Res Cell Motil. 2002; 23: 59-63
        • Gordon N.
        Glycogenosis type V or McArdle's disease.
        Dev Med Child Neurol. 2003; 45: 640-644
        • Gonzalez D.
        Crush syndrome.
        Crit Care Med. 2005; 33 (Supplement): S34-S41
        • Gabow P.A.
        • Kaehny W.D.
        • Kelleher S.P.
        The spectrum of rhabdomyolysis.
        Medicine (Baltimore). 1982; 61: 141-153
        • Koffler A.
        • Friedler R.
        • Massry S.
        Acute renal failure due to non-traumatic rhabdomyolysis.
        Ann Int Med. 1976; 85: 23-27
        • Beetham R.
        Biochemical investigation of suspected rhabdomyolysis.
        Ann Clin Biochem. 2000; 37: 581-587
        • Bywaters E.G.L.
        • Beall D.
        Crush injuries with impairment of renal function.
        BMJ. 1941; 1: 427-432
        • Chander V.
        • Chopra K.
        Molsidomine, a nitric oxide donor and l-arginine protects against rhabdomyolysis-induced myoglobinuric acute renal failure.
        Biochim. Biophys. Acta. 2005; 1723: 208-214
        • Woodrow G.
        • Brownjohn A.M.
        • Turney J.H.
        The clinical and biochemical features of acute renal failure due to rhabdomyolysis.
        Ren Fail. 1995; 17: 467-474
        • Heyman S.N.
        • Rosen S.
        • Fuchs S.
        • Epstein F.H.
        • Brezis M.
        Myoglobinuric acute renal failure in rat: a role for medullary hypoperfusion, hypoxia and tubular obstruction.
        J Am Soc Nephrol. 1996; 7: 1066-1074
        • Thadhani R.
        • Pascual M.
        • Bonventre J.V.
        Acute renal failure.
        N Engl J Med. 1996; 334: 1448-1460
        • Zager R.A.
        • Gamelin L.M.
        Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.
        Am J Physiol. 1989; 256: F446-F455
        • Sandhu J.S.
        • Sood A.
        • Midha V.
        • Singh A.D.
        • Jain D.
        • Sandhu P.
        Non-traumatic rhabdomyolysis with acute renal failure.
        Ren Fail. 2000; 22: 81-86
        • Sułowicz W.
        • Walatek B.
        • Sydor A.
        • Ochmański W.
        • Miłkowski A.
        • Szymczakiewicz-Multanowska A.
        • et al.
        Acute renal failure in patients with rhabdomyolysis.
        Med Sci Monit. 2002; 8: CR24-CR27
        • Holt S.G.
        • Moore K.P.
        Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.
        Intens Care Med. 2001; 27: 803-811
        • Lameire N.
        • Vanholder R.
        New perspectives for prevention/treatment of acute renal failure.
        Curr Opin Anaesth. 2000; 13: 105-112
        • Lameire N.
        • De Vriese A.
        • Vanholder R.
        Prevention and nondialytic treatment of acute renal 0failure.
        Curr Opin Crit Care. 2003; 9: 481-490
        • Sheridan A.M.
        • Bonventre J.V.
        Cell biology and molecular mechanisms of injury in ischemic acute renal failure.
        Curr Opin Nephrol Hypertens. 2000; 9: 427-434
        • Badr K.F.
        • Kelley V.E.
        • Rennke H.G.
        • Brenner B.M.
        Role for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure.
        Kidney Int. 1986; 43: 1397-1401
        • Devarajan P.
        Cellular and molecular derangements in acute tubular necrosis.
        Curr Opin Pediatr. 2005; 17: 193-199
        • Zager R.A.
        • Prior R.B.
        Gentamycin and gram negative bacteremia: a synergism for the development of experimental nephrotoxic acute renal failure.
        J Clin Invest. 1986; 78: 196-204
        • Furchgott R.F.
        • Jothianandan D.
        Endothelial-dependent and -independent vasodilation involving cGMP: relaxation induced by nitric oxide, carbon oxide and light.
        Blood Vessels. 1991; 28: 52-61
        • Neto L.M.
        • Nascimento O.R.
        • Tabak M.
        • Caracelli I.
        The mechanism of reaction of nitrosyl with met and oxymyoglobin: an ESR study.
        Biochem Biophys Acta. 1988; 956: 189-196
        • Sharma V.S.
        • Traylor T.G.
        • Gardiner R.
        • Mizukami H.
        Reaction of nitric oxide with heme proteins and model compounds of hemoglobin.
        Biochemistry. 1987; 26: 3837-3843
        • Molitoris B.A.
        • Sandoval R.
        • Sutton T.A.
        Endothelial injury and dysfunction in ischemic acute renal failure.
        Crit Care Med. 2002; 30 (Supplement): S235-S240
        • Slater M.S.
        • Mullins R.J.
        Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
        J Am Coll Surg. 1998; 186: 693-716
        • Akimau P.
        • Yoshiya K.
        • Hosotsubo H.
        • Takakuwa T.
        • Tanaka H.
        • Sugimoto H.
        New experimental model of crush injury of the hindlimbs in rats.
        J Trauma. 2005; 58: 51-58
        • Zager R.
        • Burkhart K.
        Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack.
        Kidney Int. 1998; 53: 1661-1672
        • Braun S.R.
        • Weiss F.R.
        • Keller A.I.
        • Ciccone J.R.
        • Preuss H.G.
        Evaluation of the renal toxicity of heme proteins and their derivatives: a role in the genesis of acute tubular necrosis.
        J Exp Med. 1970; 131: 443-460
        • Paller M.S.
        Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.
        Am J Physiol. 1988; 255: F539-F544
        • Nath K.A.
        • Norby S.M.
        Reactive oxygen species and acute renal failure.
        Am J Med. 2000; 109: 655-678
        • Halliwell B.
        • Gutteridge J.M.
        Role of free radicals and catalytic metal ions in human disease: an overview.
        Meth Enzymol. 1990; 186: 1-85
        • Zager R.A.
        Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria.
        Kidney Int. 1996; 49: 741-751
        • Moore K.P.
        • Holt S.G.
        • Patel R.P.
        • Svistunenko D.A.
        • Zackert W.
        • Goodier D.
        • 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; 273: 31731-31737
        • Holt S.
        • Reeder B.
        • Wilson M.
        • Harvey S.
        • Morrow J.D.
        • Roberts 2nd, L.J.
        • et al.
        Increased lipid peroxidation in patients with rhabdomyolysis.
        Lancet. 1999; 353: 1241
        • Reeder B.
        • Wilson M.
        Desferrioxamine inhibits production of cytotoxic heme to protein cross-linked myoglobin: a mechanism to protect against oxidative stress without iron chelation.
        Chem Res Toxicol. 2005; 18: 1004-1011
        • Bellomo R.
        • Ronco C.
        • Kellum J.A.
        • Mehta R.L.
        • Palevsky P.
        • Acute Dialysis Quality Initiative
        Acute renal failure — definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
        Crit Care. 2004; 8: R204-R212
        • Huerta-Alardín A.L.
        • Varon J.
        • Marik P.E.
        Bench-to-bedside review: rhabdomyolysis — an overview for clinicians.
        Crit Care. 2005; 9: 158-169
        • Criddle L.M.
        Rhabdomyolysis: pathophysiology, recognition, and management.
        Crit Care Nurse. 2003; 23: 14-30
        • Allen D.G.
        Skeletal muscle function: role of ionic changes in fatigue, damage and disease.
        Clin Exp Pharmacol Physiol. 2004; 31: 485-493
        • Singh D.
        • Chander V.
        • Chopra K.
        Rhabdomyolysis.
        Methods Find Exp Clin Pharmacol. 2005; 27: 39-48
        • Meneghini L.F.
        • Oster J.R.
        • Camacho J.R.
        • Gkonos P.J.
        • Roos B.A.
        Hypercalcemia in association with acute renal failure and rhabdomyolysis. Case report and literature review.
        Miner Electrolyte Metab. 1993; 19: 1-16
        • Llach F.
        • Felsenfeld A.J.
        • Haussler M.R.
        The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol.
        N Engl J Med. 1981; 305: 117-123
        • Perron A.
        • Brady W.
        • Keats T.
        Orthopedic pitfalls in the ED: acute compartment syndrome.
        Am J Emerg Med. 2001; 19: 413-416
        • Edwards S.
        Acute compartment syndrome.
        Emerg Nurse. 2004; 12: 32-38
        • Bonventre J.
        • Shah S.
        • Walker P.
        • Humphrey S.M.
        Rhabdomyolysis induced acute renal failure.
        in: Jacobson H Striker G Klahr S The principles and practice of nephrology. (2nd Ed). Mosby, St. Louis1995: 569-573
        • Sion M.L.
        • Hatzitolios A.
        • Toulis A.
        • Kounanis A.
        • Prokopidis D.
        Rhabdomyolysis and acute renal failure associated with Salmonella enteritidis bacteremia.
        Nephrol Dial Transplant. 1998; 13: 532
        • Esson M.L.
        • Schrier R.W.
        Diagnosis and treatment of acute tubular necrosis.
        Ann Intern Med. 2002; 137: 744-752
        • Zager R.A.
        Combined mannitol and deferoxamine therapy for myoglobinuric renal injury and oxidant tubular stress: mechanistic and therapeutic implications.
        J Clin Invest. 1992; 90: 711-719
        • Brown C.V.
        • Rhee P.
        • Chan L.
        • Evans K.
        • Demetriades D.
        • Velmahos G.C.
        Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?.
        Trauma. 2004; 56: 1191-1196
        • Gill N.
        • Nally Jr, J.V.
        • Fatica R.A.
        Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.
        Chest. 2005; 128: 2847-2863
        • Zager R.A.
        • Burkhart K.M.
        • Conrad D.S.
        • Gmur D.J.
        Iron, heme oxygenase and glutathione: effects on myoglobinuric proximal tubular injury.
        Kidney Int. 1995; 48: 1624-1634
        • Lopez J.R.
        • Rojas B.
        • Gonzales M.A.
        • Terzic A.
        Myoplasmic Ca2+ concentration during exertional rhabdomyolysis.
        Lancet. 1995; 345: 424-425
        • Knochel J.P.
        Pigment nephropathy.
        in: Greenberg A Primer on kidney diseases. (2nd Ed). Academic Press, Boston1998: 273-276
        • Russell T.A.
        Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis and collaborative management.
        Nephrol Nurs J. 2000; 27: 567-575
        • Brady H.R.
        • Brenner B.M.
        Acute renal failure.
        in: Fauci AS Braunwalld E Isselbacher KJ Wilson JD Martin JB Kasper DL Hauser SL Longo DL Harrison's principles of internal medicine. (14th Ed). McGraw-Hill, 1998: 1505-1513
        • Harriston S.
        A review of rhabdomyolysis.
        Dimens Crit Care Nurs. 2004; 23: 155-161
        • Gozal Y.
        Calcium administration in rhabdomyolysis may be detrimental.
        Anesth Analg. 1996; 82: 185-186