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Rhabdomyolysis
Complications of poisoning
Rhabdomyolysis Allister Vale
Abstract Figure 1 Wrist drop resulting from peripheral nerve damage.
Non-traumatic rhabdomyolysis may be caused by a direct insult to the cell membrane, affecting its ability to maintain ion gradients, or be secondary to local muscle compression as a result of coma or seizures. Acute renal failure and peripheral nerve damage are the two most common and important complications observed, though hyperkalaemia leading to a dysrhythmia is the main cause of death.
Secondly, renal vasoconstriction occurs due to activation of the sympathetic nervous system and the renin–angiotensin system in response to reduced effective circulating blood volume, scavenging of the vasodilator nitric oxide (NO) by myoglobin and release of isoprostanes (particularly 15-F2t and 15-E2t which are potent vasoconstrictors), formed as a result of free radical damage to phospholipid membranes.
Keywords creatine kinase; myoglobin; myoglobinuria; renal failure
Definition Rhabdomyolysis is a condition in which there is dissolution of striated muscle fibres, with leakage of muscle cell contents (enzymes, myoglobin, potassium and phosphate). In patients who are poisoned, non-traumatic rhabdomyolysis may be caused by a direct insult to the cell membrane, affecting its ability to maintain ion gradients or be secondary to local muscle compression as a result of coma or seizures. Two clinically important complications are observed: acute renal failure (which may be non-oliguric) and peripheral nerve damage (secondary to compartment syndrome), resulting predominantly in wrist (Figure 1) or foot drop (Figure 2). Rhabdomyolysis accounts for 5–9% of all cases of acute renal failure1,2 and 5–30% of patients with rhabdomyolysis develop acute renal failure.3,4 Pathogenesis of rhabdomyolysis-induced renal failure Three main mechanisms are involved.5 First, tubular necrosis occurs by free-radical mediated lipid peroxidation. This involves redox cycling between two oxidation states of myoglobin haem: Fe3+ (ferric) and ferryl (Fe4+).6 The formation of ferryl myoglobin requires the presence of lipid hydroperoxides (LOOH). Once formed, the ferryl species reacts with lipids and lipid hydroperoxides (LOOH) to form lipid alkyl (LOO.) and lipid peroxyl (L.) radicals that progressively damage renal tubular membranes. Thus, ferryl myoglobin can initiate lipid peroxidation.
Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS is Director of the National Poisons Information Service (Birmingham Unit) and the West Midlands Poisons Unit at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
Figure 2 Foot drop resulting from peripheral nerve damage.
554
© 2007 Published by Elsevier Ltd.
Complications of poisoning
Thirdly, tubular obstruction occurs due to the formation of tubular casts formed by binding of free myoglobin to TammHorsfall protein (uromodulin), a renal glycoprotein,7 and as a result of urate crystal deposition.
renal failure. The administration of sodium bicarbonate (8.4% 225 mL) should produce urine alkalinization further boluses of sodium bicarbonate will be required to maintain the urine pH greater than 7.5. ◆
Diagnosis The key to making the diagnosis is to detect an increased creatine kinase activity in the plasma or myoglobin in the urine. The creatine kinase activity must be at least 5 times normal (CK-MB fraction <5%) 2–12 hours after the precipitating cause, but is often several thousand units per litre; the creatine kinase activity may continue to rise for more than 24 hours. This is associated with a transient increase in serum myoglobin and visible (tea or coca-cola coloured urine) myoglobinuria (myoglobinuria >250 mg/L in the presence of normal renal function). The absence of myoglobinuria does not exclude the diagnosis. A positive urine dipstick for haem but no red cells on microscopic examination of urine also supports the diagnosis. In addition, hyperkalaemia (which may precipitate fatal dysrhythmias), hypocalcaemia (due to calcium binding by damaged muscle proteins and phosphates), hyperuricaemia (>750 μmol/L), hyperphosphataemia (>2.5 mmol/L), and an increase in aminotransferase, lactic dehydrogenase and aldolase activities may be present.
References 1 Grossman RA, Hamilton RW, Morse BM, et al. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med 1974; 291: 807–11. 2 Thomas MA, Ibels LS. Rhabdomyolysis and acute renal failure. Aust N Z J Med 1985; 15: 623–28. 3 Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982; 61: 141–52. 4 Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med 1988; 148: 1553–57. 5 Holt SG, Moore KP. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med 2001; 27: 803–11. 6 Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol 2000; 8: 72–76. 7 Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest 1989; 60: 619–29. 8 Moore KP, Holt SG, Patel RP, et al. A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure. J Biol Chem 1998; 273: 31731–37. 9 Eneas JF, Schoenfeld PY, Humphreys MH. The effect of infusion of mannitol-sodium bicarbonate on the clinical course of myoglobinuria. Arch Intern Med 1979; 139: 801–5. 10 Homsi E, Leme Barreiro MFF, Orlando JMC, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19: 283–88. 11 Brown CVR, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma Injury Infect Crit Care 2004; 56: 1191–96.
Management of rhabdomyolysis-induced renal failure Experimentally, urine alkalinization has been shown to suppress the rate of conversion of ferryl (Fe4+) myoglobin to ferric (Fe3+) myoglobin particularly at a urine pH >7.0. Thus, alkalinization inhibits the cyclical formation of lipid peroxide radicals and limits lipid peroxidation,8 so reducing tubular damage. Isoprostane release is also reduced by alkalinization, thereby lessening vasoconstriction. In addition, binding of myoglobin to Tamm-Horsfall protein is reduced under alkaline conditions, so that tubular casts are not formed.7 However, limited experimental and clinical data9–11 suggest that early volume replacement is more important than urine alkalization in preventing rhabdomyoloysis-induced
MEDICINE 35:10
555
© 2007 Published by Elsevier Ltd.
Rhabdomyolysis Allister Vale
Abstract Figure 1 Wrist drop resulting from peripheral nerve damage.
Non-traumatic rhabdomyolysis may be caused by a direct insult to the cell membrane, affecting its ability to maintain ion gradients, or be secondary to local muscle compression as a result of coma or seizures. Acute renal failure and peripheral nerve damage are the two most common and important complications observed, though hyperkalaemia leading to a dysrhythmia is the main cause of death.
Secondly, renal vasoconstriction occurs due to activation of the sympathetic nervous system and the renin–angiotensin system in response to reduced effective circulating blood volume, scavenging of the vasodilator nitric oxide (NO) by myoglobin and release of isoprostanes (particularly 15-F2t and 15-E2t which are potent vasoconstrictors), formed as a result of free radical damage to phospholipid membranes.
Keywords creatine kinase; myoglobin; myoglobinuria; renal failure
Definition Rhabdomyolysis is a condition in which there is dissolution of striated muscle fibres, with leakage of muscle cell contents (enzymes, myoglobin, potassium and phosphate). In patients who are poisoned, non-traumatic rhabdomyolysis may be caused by a direct insult to the cell membrane, affecting its ability to maintain ion gradients or be secondary to local muscle compression as a result of coma or seizures. Two clinically important complications are observed: acute renal failure (which may be non-oliguric) and peripheral nerve damage (secondary to compartment syndrome), resulting predominantly in wrist (Figure 1) or foot drop (Figure 2). Rhabdomyolysis accounts for 5–9% of all cases of acute renal failure1,2 and 5–30% of patients with rhabdomyolysis develop acute renal failure.3,4 Pathogenesis of rhabdomyolysis-induced renal failure Three main mechanisms are involved.5 First, tubular necrosis occurs by free-radical mediated lipid peroxidation. This involves redox cycling between two oxidation states of myoglobin haem: Fe3+ (ferric) and ferryl (Fe4+).6 The formation of ferryl myoglobin requires the presence of lipid hydroperoxides (LOOH). Once formed, the ferryl species reacts with lipids and lipid hydroperoxides (LOOH) to form lipid alkyl (LOO.) and lipid peroxyl (L.) radicals that progressively damage renal tubular membranes. Thus, ferryl myoglobin can initiate lipid peroxidation.
Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS is Director of the National Poisons Information Service (Birmingham Unit) and the West Midlands Poisons Unit at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
Figure 2 Foot drop resulting from peripheral nerve damage.
554
© 2007 Published by Elsevier Ltd.
Complications of poisoning
Thirdly, tubular obstruction occurs due to the formation of tubular casts formed by binding of free myoglobin to TammHorsfall protein (uromodulin), a renal glycoprotein,7 and as a result of urate crystal deposition.
renal failure. The administration of sodium bicarbonate (8.4% 225 mL) should produce urine alkalinization further boluses of sodium bicarbonate will be required to maintain the urine pH greater than 7.5. ◆
Diagnosis The key to making the diagnosis is to detect an increased creatine kinase activity in the plasma or myoglobin in the urine. The creatine kinase activity must be at least 5 times normal (CK-MB fraction <5%) 2–12 hours after the precipitating cause, but is often several thousand units per litre; the creatine kinase activity may continue to rise for more than 24 hours. This is associated with a transient increase in serum myoglobin and visible (tea or coca-cola coloured urine) myoglobinuria (myoglobinuria >250 mg/L in the presence of normal renal function). The absence of myoglobinuria does not exclude the diagnosis. A positive urine dipstick for haem but no red cells on microscopic examination of urine also supports the diagnosis. In addition, hyperkalaemia (which may precipitate fatal dysrhythmias), hypocalcaemia (due to calcium binding by damaged muscle proteins and phosphates), hyperuricaemia (>750 μmol/L), hyperphosphataemia (>2.5 mmol/L), and an increase in aminotransferase, lactic dehydrogenase and aldolase activities may be present.
References 1 Grossman RA, Hamilton RW, Morse BM, et al. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med 1974; 291: 807–11. 2 Thomas MA, Ibels LS. Rhabdomyolysis and acute renal failure. Aust N Z J Med 1985; 15: 623–28. 3 Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982; 61: 141–52. 4 Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med 1988; 148: 1553–57. 5 Holt SG, Moore KP. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med 2001; 27: 803–11. 6 Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol 2000; 8: 72–76. 7 Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest 1989; 60: 619–29. 8 Moore KP, Holt SG, Patel RP, et al. A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure. J Biol Chem 1998; 273: 31731–37. 9 Eneas JF, Schoenfeld PY, Humphreys MH. The effect of infusion of mannitol-sodium bicarbonate on the clinical course of myoglobinuria. Arch Intern Med 1979; 139: 801–5. 10 Homsi E, Leme Barreiro MFF, Orlando JMC, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19: 283–88. 11 Brown CVR, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma Injury Infect Crit Care 2004; 56: 1191–96.
Management of rhabdomyolysis-induced renal failure Experimentally, urine alkalinization has been shown to suppress the rate of conversion of ferryl (Fe4+) myoglobin to ferric (Fe3+) myoglobin particularly at a urine pH >7.0. Thus, alkalinization inhibits the cyclical formation of lipid peroxide radicals and limits lipid peroxidation,8 so reducing tubular damage. Isoprostane release is also reduced by alkalinization, thereby lessening vasoconstriction. In addition, binding of myoglobin to Tamm-Horsfall protein is reduced under alkaline conditions, so that tubular casts are not formed.7 However, limited experimental and clinical data9–11 suggest that early volume replacement is more important than urine alkalization in preventing rhabdomyoloysis-induced
MEDICINE 35:10
555
© 2007 Published by Elsevier Ltd.