|How to cite this article:|
Malik GH. Rhabdomyolysis and Myoglobin-induced Acute Renal Failure. Saudi J Kidney Dis Transpl 1998;9:273-84
| Introduction|| |
In 1812, Larrey, the great military surgeon of the Napoleonic Army first described muscle necrosis in comatose subjects. He reported on skin and muscle necrosis in comatose soldiers Ipeisoned by carbon monoxide  . Traumatic .muscle destruction was described by the German Von Colmers in the casualties of the, 199l Messina earthquake  . Acute renal failure (ARF) associated with traumatic rhabdomyolysis in war injuries was reported by Frankenthal in 1916  . Minawi in 1923 described further cases of muscle crush injury and renal failure and raised the possibility that the muscle damage somehow contributed to the renal failure  . In 1941, Bywaters and Beall described in detail the pathophysiological mechanisms of ARF due to rhabdomyolysis following crush injuries in victims of bombing raids in World War II  .
| Physiologic Anatomy of Skeletal Muscle|| |
Approximately 600 skeletal muscles of the human body form 40 to 45 percent of its weight. Each muscle is composed of numerous muscle fibers ranging from 10 to 80 micrometers in diameter. In most muscles, the fibers extend the entire length of the muscle, each being innervated by only one nerve ending located near the middle of the fiber ,, . The cell membrane of the muscle fiber is the Sarcolemma, which is a true cell membrane. Surrounding individual muscle fibers is connective tissue called the endomysium, which contains small blood vessels and nerves. Groups of muscle fibers are bound together by denser layers of collagenous and elastic fibers (Perimysium) and finally the connective tissue binds the fascicles into definite muscle. At the ends of the elongated muscles, the connective tissue forms tendons, which are inserted into the bone ,, .
Each muscle fiber contains hundreds to thousands of myofibrils containing myosin and act in filaments, which are large polymerized protein molecules responsible for muscle contraction. The myofibrils are suspended inside the muscle fiber in a matrix called Sarcoplasm which is composed of the usual intracellular constituents: potassium, magnesium, phosphate, protein and enzymes. The presence of a large number of mitochondria is indicative of a great need for a large amount of adenosine triphosphate (ATP) formed by mitochondria and needed for muscle contraction. ATP provides the energy for the active transport of calcium into the Sarcoplasm, and both contraction and relaxation of muscle require ATP. All muscle fibers are metabolically similar and are of two types. Slow-fibers: are characterized by .oxidative metabolism with abundant numbers of mitochondria and a high myoglobin content (red fibers). Fast-fibers: are predominantly glycolytic with relatively few mitochondria and scanty myoglobin content (white fibers).
The slow fibers are thus utilized for prolonged sustained contractions and the fast fibers are used in sudden forceful contractions. 95% of glycogen as a source of energy is stored in skeletal muscle ,, .
| Etiopathogenesis of Rhabdomyolysis|| |
Rhabdomyolysis is defined as injury to skeletal muscle cells of such severity that their contents are released into the circulation. Myoglobinuria is a consequence of rhabdomyolysis. The causes of rhabdomyolysis are given in [Table - 1]. ARF occurs in about 30% of patients with rhabdomyolysis  .
| A. Traumatic Rhabdomyolysis|| |
| The Crush Syndrome|| |
The crush injuries leading to myoglobinuria and ARF were extensively studied in the victims of World War II. The patients studied had been buried beneath falling debris. They all died of uremia and postmortem examination showed extensive skeletal muscle necrosis and specific pigment nephropathy ,,, . Further reports described the victims of bombing of Beirut barracks in 1983  and those of the Armenian earthquake in 1988 where 600 patients developed myoglobinuric ARF  . Crush injury of the muscle leads to a series of consequences. The intracellular concentration of water, sodium, chloride and calcium is increased partly by the external pressure or tension on the muscle and partly by the impairment of activity of a sodium potassium adenosine triphosphatase in the damaged muscle. When the muscles are released from the crushing object; the impeded circulation restarts leading to further loss of water and electrolytes into the damaged muscle. Also, it is during this time that myoglobin gains access to the circulation ,,,, .
| Physical Torture|| |
ARF due to rhabdomyolysis and myoglobinuria following physical torture involving beating of skeletal muscles akin to crush injuries was first reported by our group from Kashmir (India) in 1993 , . Emphasis has been put on considering the possibility of ARF rather than concentrating on surface injuries in a physically tortured person. Further reports of ARF due to physical torture also came from Israel wherein the condition has been described as pseudo-crush syndrome  and from Pakistan  . In these studies, the muscles were physically crushed during interrogation by the Police forces by blunt trauma using sticks, buts of guns, iron rods, leather belts and electric shocks leading to rhabdomyolysis. Myoglobinuria and "forced dehydration" during torture were considered as pathogenetic mechanisms of ARF in these studies , .
| Prolonged Muscle Activity|| |
Myoglobinuric ARF may follow any event involving violent and unaccustomed muscular activity ,, . The condition is characterized by pain, swelling and tenderness due to skeletal muscle necrosis associated with the passage of dark colored urine and renal failure  . Status epilepticus  , Status asthmaticus  , prolonged labor during pregnancy  and high voltage electric shock  have all resulted in ARF due to rhabdomyolysis. ARF, usually non-oliguric type, as a result of rhabdomyolysis and myoglobinuria has been described in tetanus  .
| B. Non-traumatic Rhabdomyolysis|| |
| Arterial Embolization|| |
ARF due to myoglobinemia and myoglobinuria following arterial emboli occluding major blood vessels to the lower limbs has been reported , .
Rhabdomyolysis and ARF in patients undergoing cardiopulmonary bypass surgery have been described  . Release of myoglobin into the systemic circulation follow the restoration of blood flow to an ischemic muscle. Cases of ARF due to myoglobinuria have also been described in sickle cell disease , .
| Metabolic Disorders|| |
Hypokalemia as a cause of rhabdomyolysis has been described in a number of reports ,,,,,,. It has been suggested that arteriolar dilatation in the skeletal muscle occurs due to the release of potassium from the contracting muscle into the interstitial fluid. This leads to increase in blood flow to the muscle during exercise  . Knochel and Schlein demonstrated that electrically stimulated muscular exercise in potassium depleted dogs results in myonecrosis  . The authors suggested that potassium deficiency prevents the increase in muscle blood flow that would normally occur during exercise, thus resulting in rhabdomyolysis. So a combination of potassium depletion and exercise is detrimental to skeletal muscle metabolism. Hypophosphatemia may lead to cellular injury due to severe depletion of ATP content of the muscle  . A decrease in intracellular inorganic phosphorus concentration may interfere with the regeneration of ATP from ADP. Serum inorganic phosphorus levels of about 0.48 mmol/L (1.5 mg/dl) has been suggested as a crucial minimum  .
| Muscle Diseases|| |
Various hereditary muscle disorders associated with rhabdomyolysis and ARF include glycogen storage diseases marked by lack of phosphorylase (McArdle's disease), phosphofructokinase (Tarui's disease) or the muscle lipid metabolic disorder due to absence of carnitine palmityl transferase. Abnormalities in glycogen or lipid metabolism result in a block of anaerobic glycosis that predisposes to the loss of integrity of the sarcolemmal membrane and the liberation of myoglobin following exercise ,,, . Rhabdomyolysis and ARF have also been reported in association with other muscle diseases like polymyositis  , dermatomyositis  and tropical pyomyositis  . Muscle diseases can lead to acute episodes of muscle necrosis when there is further stress by exercise or an inter-current infection  .
| Toxins and Drugs|| |
Alcohol is a common cause of rhabdomyolysis ,,, which is due to multiple factors. Stupor or coma due to alcohol or any other drug can cause myonecrosis if the muscles are compressed by the body's own weight for long periods , . Alcoholic myopathy, sometimes with ARF, may occur due to altered cell membrane permeability ,,,, .
Alcohol abuse also causes phosphate depletion, which causes rhabdomyolysis. Myoglobinuria is found in 50 percent of these patients, half of them develop ARF and mortality may reach up to 50 percent due to hyperkalemia. Hypokalemia and hypomagnesemia, both common in alcoholics, may potentiate alcoholic myopathy , .
Heroin addicts may develop myoglobinuria and ARF as a result of multiple factors like muscle damage resulting from coma, direct toxic effects of heroin or one of its contaminants or as a result of tetanus secondary to the use of contaminated needles used for intravenous drug use ,, .
Cocaine has been reported as a cause of myoglobinuria induced ARF and the mechanisms of rhabdomyolysis suggested are abnormal postures and vasoconstriction by cocaine, causing ischemia of muscles and renal vasoconstriction leading to tubular injury , .
Phenylcyclidine, a hallucinogenic agent may produce rhabdomyolysis by inducing tremors, posturing and seizures , . Pentamidine  , Paraphenylenediamine  , Terbutaline overdose  high dose haloperidol  , Doxepine and nitrazem  , Lovastatin  have been reported as causes of rhabdomyolysis and acute renal failure.
| Infections and Envenomation|| |
Some of the viral infections reported as causes of myoglobinuria and ARF are influenza, echovirus 9 and Varicella zoster infection ,,, . Direct invasion of muscle fibers has been postulated as one of the mechanisms of myoglobinuria  .
Some of the bacterial infections reported as causes of rhabdomyolysis and ARF are Legionnaire's disease, Salmonella More Details and Brucella More Details ,, .
Myonecrosis, myoglobinuria and ARF are induced by envenomation by snakebites  and honeybee stings  .
| Prolonged Coma|| |
Prolonged coma induced by alcohol, narcotics and other sedatives has been reported to cause rhabdomyolysis due to pressureinduced myonecrosis in a prolonged immobilized state , . Due to prolonged pressure there is an interference with the local blood supply causing loss of integrity of the sarcolemmal membrane and release of myoglobin.
| Heat Stroke and Malignant Hypothermia|| |
Rhabdomyolysis and acute renal failure has been reported in exertion as well as classical heat stroke ,, . Heat stress leads to rhabdomyolysis by interfering with glycolysis. Hypokalemia, which occurs in heat stroke, also plays an important role in causing rhabdomyolysis since potassium is necessary for maintaining muscle cell membrane potential  . Potassium deficiency also interferes with glycogen synthesis  .
| Carbon Monoxide Poisoning|| |
Carbon monoxide poisoning by causing hypoxia because of formation of monoxyhemoglobin leads to rhabdomyolysis  .
Hypothyroidism causes elevated creatine phosphokinase and, sometimes, frank rhabdomyolysis  .
| Pathophysiology of Myoglobin-induced ARF|| |
Myoglobin, a heme pigment with a molecular weight of approximately 17800 is present in the sarcoplasm of striated skeletal and cardiac muscle. It is released into the blood stream by any process that causes destruction of skeletal muscle. Due to its relatively small size, myoglobin is readily filterable and is excreted in urine at a serum concentration of less than 15 mg per decimeter which requires damage to about 200 gm of muscle .
A large number of Marine recruits have been shown to develop myoglobinemia and other evidences of exertion rhabdomyolysis without significant clinical symptoms  . Moreover, myoglobinuria is common, following exercise in patients with hereditary or progressive muscle disease but ARF is unusual  . These studies indicate that myoglobinuria alone may not be sufficient to induce ARF. Bywaters and Beall, however, suggested that myoglobin and other muscle constituents impair renal function  . In their experimental studies it was recognized that hypovolemia and aciduria are two critical factors which predispose to myoglobinuric ARF , . Infusion of saline and bicarbonate solutions early during rhabdomyolysis has prevented development of ARF, favoring this postulation  .
It has been postulated that at the nephronal level three basic mechanisms underlie heme protein toxicity: renal vasoconstriction, intrarenal cast formation and direct hemeprotein induced nephrotoxicity  . Renal hypoperfusion and vasoconstriction occur due to different mechanisms. Fluid thirdspacing leading to hypovolemia is an important factor for causing hypoperfusion. As much as 18 liters of fluid may extravagate into damaged limbs  . Myoglobin is a potent inhibitor of the vasodilator nitric oxide and may trigger intrarenal vasoconstriction and ischemia in patients with borderline renal hypoperfusion  . Besides, severe muscular injury can, for unknown reasons, activate the endotoxincytokine cascade, thus eliciting renal vasoconstriction  .
Once the myoglobin molecule is filtered by the glomerulus it enters the proximal tubular cells and is taken up by lysomes at acid pH. The heme pigment then splits into its globulin and ferrihemate components. Ferrihemate is transported out of the tubular cell at the expense of ATP. The tubular cell, thus is injured due to renal ischemia, hypoxia and a critical reduction of ATP stores  .
Distal nephron pigment casts thought to cause tubular obstruction have been noted in different studies. The heme protein cast formation is determined by the heme protein concentration in. the distal tubule and the urinary pH, aciduria being an important determinant of pigment induced ARF ,, .
In addition to the vasomotor, nephrotoxic and obstructive agents noted above as pathogenic in myoglobin induced ARF, other factors released into circulation by rhabdomyolysis appear to be operative in humans  . Hyperphosphatemia can markedly potentiate ischemic and nephrotoxic renal damage  . Hyperuricemia contributes to intratubular obstruction and also increases heme protein associated ischemic tubular damage  . The formation of thrombi in the glomerular capillary tufts due to disseminated intravascular coagulation can be triggered in rhabdomyolysis  . These factors may independently or together cause impairment of renal function particularly during hemodynamic shock.
| Clinical Features and Diagnosis of Myoglobinuric ARF|| |
The ARF following rhabdomyolysis takes the usual course but has distinctive clinical features. The diagnosis in the first instance lies on a good index of clinical suspicion. Localized rhabdomyolysis is clinically obvious by swollen, painful and tender muscles  . As a result of muscle damage, many substances are released into the circulation and the biochemical findings in acute rhabdomyolysis are as follows  .
- Elevation of serum creatine phosphokinase (CK) aldolase and lactic dehydrogenase.
- Heme pigment (myoglobin) in urine
- High creatinine: blood urea nitrogen
- (BUN) ratio
- Disseminated intravascular coagulation
The CK-MM isoform is present in the skeletal muscle and its raised serum level is the most sensitive test to confirm the diagnosis of rhabdomyolysis. The serum levels depend upon the severity of rhabdomyolysis and may range from thousands to 1,000,000 IU/L or even higher. Without ongoing muscle necrosis the CK levels peak at 12-36 hours. Measurement of other muscle enzymes such as aldolase, lactic dehydrogenase or transaminases provides no additional useful information in clinical practice  .
Myoglobin is lightly bound to a2- globulin and is quickly cleared from plasma by excretion in urine. From the clinical point of view, dark urine and pink serum are indicative of hemolysis whereas dark urine and clear serum suggest rhabdomyolysis  . In marathon runners Schiff et al showed that although 89% gave no history of pigmenturia, myoglobin was present in the blood of 25 out of 44 runners  . Specific radio-immunoassays are used to distinguish myoglobin and hemoglobin in urine. A simple laboratory test may be used to, distinguish the two pigments  . To 5ml of urine, 2.8 grams of Ammonium sulfate is added and the mixture is allowed to stand for 5 minutes and then filtered. Hemoglobinuria is indicated by a colored precipitate whereas colored supernatant indicates the presence of myoglobin. The test can be very useful in situations where both hemoglobinuria and myoglobinuria are simultaneously present as in cases of physical torture  .
The presence of pigmented granular casts in urine sediment is characteristic of rhabdomyolysis  . All ten cases in our study of ARF following physical torture showed the presence of pigment casts .
ARF due to rhabdomyolysis is associated with severe hypocalcemia in the oliguric phase and hypercalcemia in the recovery phase. Hypocalcemia occurs even without ARF due to calcium deposition in the injured muscle, and mobilization of this calcium in the diuretic phase causes hypercalcemia  Once ARF is established, hypocalcemia is a consequence of hyperphosphatemia and partly due to reduced 1,25 dihydroxycholecalciferol (l,25-DHCC) levels. Hypercalcemia in the recovery phase is associated with raised levels of 1, 25DHCC, which plays contributory role in its etiology  .
A transient elevation of ratio of serum creatinine to BUN, which usually is 1:10 is commonly seen in acute rhabdomyolysis. The large quantity of creatine phosphate released from damaged muscle is spontaneously dehydrated to creatinine leading to the rise in this ratio. Hyperuricemia is caused by release of purenes from damaged muscle. These purenes are converted to uric acid in liver. Hypoalbuminemia results from the leakage of plasma components due to capillary damage  .
Disseminated intravascular coagulation is a usual occurrence, noted usually on the 3rd to the 5th day. Lactic acidosis is a common feature in rhabdomyolysis due to muscle glycogen metabolism, and results from hypoxemia, volume depletion and decreased intestinal blood flow  .
| Prevention and Treatment of ARF Associated with Rhabdomyolysis|| |
From studies on rhabdomyolysis Better and Stein concluded that hyperkalemia, hyperphosphatemia, hypocalcemia and metabolic acidosis appear before azotemia  . They suggested that early aggressive volume replacement and forced alkalinediuresis therapy may protect the kidney against ARF. Isotonic saline solution should be infused at a rate of 1.5 liters per hour as soon as a trapped person's limb has been freed. This is followed by a forced alkaline diuresis using hypotonic sodium chloride, to which 40 mmol of sodium bicarbonate and 10 grams of 20% mannitol are added to each liter. A young adult may need up to 12 liters per day. This regimen will protect against the nephrotoxicity of myoglobin and urate and also control hyperkalemia and acidosis. Calcium infusion should be avoided as treatment of Ihyperkalemia unless there is danger of hyperkalemic cardiac arrhythmias  . Moreover, its administration will correct hypocalcemia temporarily and most infused calcium will get deposited in the traumatized muscles, thus aggravating rhabdomyolysis and causing metastatic calcification  . This will also increase the problem of hypercalcemia during the diuretic phase of recovery. Delaying volume expansion to six hours or more resulted in ARF in all the seven cases of traumatic rhabdomyolysis studied by Reis and Michaelson  . In contrast none of the seven cases with almost similar injuries in another study developed ARF when intravenous saline therapy was started immediately at the site of catastrophe  .
Dialysis may be needed for severe metabolic disturbances like hyperkalemia in the oliguric phase and hypercalcemia in the diuretic phase  . Nine out of our 10 cases of ARF following physical torture needed dialysis and recovered in 14-30 (mean 18) days  .
Development of compartment syndromes may lead to persistent rhabdomyolysis and delay the recovery from ARF.
Fasciotomy may be needed to reduce tissue damage and also avoid unnecessary amputations.
However, Better and Stein have urged conservative management because of the risk of infections in open wounds, which may become uncontrollable  . They suggested measurement of intra-compartmental pressure by manometry. If the pressure is very high, surgical exploration should be undertaken. Rainford and Stevens, however, recommend surgical exploration in all doubtful cases  .
Myoglobin, because of its size, is poorly removed by either hemofiltration or peritoneal dialysis  . However, even in the presence of severe ARF, circulating myoglobin levels fall probably because of hepatic and splenic uptake  . There are no data indicating a role for removal of heme proteins by extracorporeal methods like plasmapheresis  .
| Prognosis|| |
The prognosis for recovery of renal function is excellent. The mortality from the crush syndrome' is 60-70% usually due to sepsis and adult respiratory distress syndrome (54), In our study of 10 cases of ARF following physical torture all recovered  whereas 5 out of 34 (15%) in another study died, predominantly (4 out of 5) due to sepsis  ,
| Acknowledgment|| |
I greatly appreciate the secretarial assistance of Sita J. Benedicto in the preparation of this manuscript and Alice Haddadin for literature search.
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Ghulam Hassan Malik
Department of Internal Medicine, Security Forces Hospital, P.O. Box 3643, Riyadh 11481
[Table - 1]