The expression rhabdomyolysis alludes to disintegration of striated muscle, which develops the release of muscular cell constituents into the extracellular fluid and into the blood. One of the more important components released is myoglobin, an 18 800 D oxygen carrier. It is similar to hemoglobin, but contains only one heme group. Normally, myoglobin is loosely bound to plasma globulins and only a small quantity reach the urine. When massive quantities of myoglobin are released, the binding capacity of the plasma protein is surpassed. Myoglobin is then purified by the glomeruli and arrives at the tubules, where it may cause impediment and renal dysfunction.
The level of rhabdomyolysis that can manifest ranges from a subclinical growth of creatine kinase (CK) to a medical emergency consisting of interstitial and muscle cell edema, contraction of intravascular volume, and acute renal failure.
One of the main causes of rhabdomyolysis is the crush syndrome: myolysis is connected to traumatic compression of muscle followed by reperfusion, as is commonly seen in accidents. Muscular trauma, however, does not always cause rhabdomyolysis and not all rhabdomyolysis cause acute renal failure. Alternative agents in rhabdomyolysis may comprehend dehydration, sepsis, and drug abuse. But a lot of cases of rhabdomyolysis are non traumatic; they are most frequently the consequence of seizures, alcohol consume, or compression as a result of coma.
Trauma and compression:
- traffic or working crashes
- long-term state in the same position
Occlusion or hypoperfusion of a part of the muscular tissue:
- vessel clamping
Forced used of muscles:
- psychiatric agitation
- delirium tremens
- amphetamine overdose
- status asthmaticus
- high-voltage electrical injury lightning
- high temperatures
- neuroleptic malignant syndrome
- malignant hyperthermia
- metabolic myopathies
- mitochondrial respiratory chain enzyme deficiencies
- carnitine palmitoyl transferase deficiency
- myoadenylate deaminase deficiency
- phosphofructokinase deficiency
Drugs and toxins:
- regular and illegal drugs
- snake and insect venoms
- local infection with muscular invasion (pyomyositis)
- metastatic infection (sepsis)
- systemic effects
- toxic shock syndrome
- plasmodium falciparum
- herpes virus
- hyperosmotic conditions
- diabetic coma, related to electrolyte disturbances
Pathophysiology of Myolysis:
Changes in Cellular Metabolism:
Stretching or strain work of muscle cells increases sarcoplasmic influx of sodium, chloride, and water, which results in cell swelling and autodestruction. Calcium enters the cell, in exchange for intracellular sodium. Large quantities of free calcium ions trigger persistent contraction, resulting in energy depletion and cell death. In addition, calcium activates phospholipase A2, as well as various vasoactive molecules and proteases. Furthermore, it leads to the production of free oxygen radicals. Damaged muscle is invaded by activated neutrophils that amplify the damage by releasing proteases and free radicals. The result is an inflammatory, self-sustaining myolytic reaction, rather than pure necrosis.
During ischemic trauma (for example infarctions), most of the injury is not inflicted in the period of ischemia, but when the blood flow into the damaged tissue is replaced (reperfusion-injury). Leukocytes get the damaged tissue only after reperfusion has started, and production of free radicals starts only when there is a large disponibility of oxygen. A similar mechanism is at work in both traumatic and nontraumatic muscular damage.
In the case of traumatic rhabdomyolysis, the muscles are initially compressed and ischemic, and muscle dysfunction starts to develop only when the patient is evacuated, when perfusion of the damaged muscles is restored.
Most skeletal muscles are contained within rigid compartments formed by fasciae, bones, and other rigid structures. If the energy-dependent transcellular pump systems fail in the injured tissue, the muscle cells bulge. As a result, intracompartmental pressure rises and may occasionally reach excessive values. High intracompartmental pressure provokes additional damage and necrosis. Because such compartments are not communicating, the only way to decrease the pressure is to decompress the fascial system surgically by fasciotomy. Not all researchers are enthusiastic about fasciotomy, because the procedure may create a source of infection. On the other hand, prolonged pressure may provoke irreversible paralytic damage to the peripheral nerves. It is generally accepted that compartment pressures >30 mmHg produce clinically significant muscle ischemia. In hypotensive patients, even lower compartment pressures will cause perfusion problems.
Metabolic Derangements during the course of Rhabdomyolysis:
Release of constituents of necrotic muscle results in changed plasma concentrations of some inorganic and organic components, responsible for toxicity and kind of clinical complications. The accumulation of these compounds is intensified by the contemporaneous progression of renal insufficiency.
Necrosis of the muscular cells, with inflammation, results in the accumulation of a big quantity of fluid in the affected part. Unless large amounts of volume are administered, shock, hypernatremia, and deterioration of renal function will supervene. If muscles recover faster than the kidneys, fluid is released into the circulation at a later stage. Delayed renal elimination may then result in expansion of the extracellular and plasma volume.
First of all, dehydration causes hyperalbuminemia, whereas later malnutrition, inflammation, capillary crack, and fluid overcharge cause hypoalbuminemia. Changes in serum albumin may result in the misinterpretation of total plasma calcium concentrations.
Release of organic acids from dying muscle cells lead to high anion gap acidosis. Especially, hypoxic muscles release lactic acid into the blood flow; its elimination by the liver is incomplete if the patient is hypovolemic. Acidosis will have a deleterious effect on numerous metabolic functions and will increase the hyperkalemia. The inferior urinary pH and intratubular acidity will intensify intratubular precipitation of myoglobin and uric acid.
In the early stages of rhabdomyolysis, calcium cumulates in the muscles. Sometimes extensive calcification of necrotic muscles is seen and in the presence of hyperkalemia, severe hypocalcemia may lead to cardiac arrhythmia, muscular contraction, or convultions
Phosphorus is released from damaged muscle and accumulates in patients with renal insufficiency. Hyperphosphatemia causes tissutal deposition of calcium-phosphate complexes in tissues and inhibition of 1 α-hydroxylase, the enzyme that products the active vitamin D analogue calcitriol. All these factors together contribute to the early hypocalcemia.
In patients with a big collapse of muscles, large quantities of potassium are released into the blood. Elimination by the kidneys fails if patients have an acute renal failure. Hyperkalemia in patients with rhabdomyolysis is very dangerous, requiring immediate treatment. In nontraumatic rhabdomyolysis, hyperkalemia is not so present at the time of admission.
Nucleosides are released from disintegrating cell nuclei into the blood and metabolized in the liver to purines such as xanthine, hypoxanthine, and uric acid, among which the last may contribute to tubular obstruction.
The precursor of creatinine, creatine, is one of the main constituents of muscle, where it is an important energy delivery. It is largely released from obstructed muscle cells and transformed into creatinine.
Myolysis 1999 Rhabdomyolysis 1999
Pathophysiology of acute kidney injury
The pathophysiology of myoglobinuric Acute kidney injury has been studied extensively in the animal model of glycerol-induced ARF. The main pathophysiologic mechanisms are renal vasoconstriction, intraluminal cast formation, and direct heme-protein-induced cytotoxicity. Myoglobin is easily filtered through the glomerular basement membrane. Water is progressively reabsorbed in the tubules, and the concentration of myoglobin rises proportionally, until it precipitates and causes obstructive cast formation. Dehydration and renal vasoconstriction, which decrease tubular flow and enhance water reabsorption, favor this process. The high rates of generation and urinary excretion of uric acid further contribute to tubular obstruction by uric acid casts. Another factor favoring precipitation of myoglobin and uric acid is a low pH of tubular urine, which is common because of underlying acidosis. The degradation of intratubular myoglobin results in the release of free iron, which catalyzes free radical production and further enhances ischemic damage. Even without invoking release of free iron, the heme center of myoglobin will initiate lipid peroxidation and renal injury. Alkaline conditions prevent this effect by stabilizing the reactive ferryl myoglobin complex.
Rhabdomyolysis and Renal Failure 1993
Prevention and Treatment
The primary therapeutic goal is to prevent the factors that cause renal insufficiency: volume depletion, tubular obstruction, aciduria, and free radical release. The ideal fluid regimen for patients with rhabdomyolysis consists of half isotonic saline (0.45%, or 77 mmol/L sodium), to which 75 mmol/L sodium bicarbonate is added. This combination may be complemented by 10 ml/h of mannitol 15%, if sufficient urinary flow is still present. Once apparent renal failure has developed, the only reliable therapeutic modality is extracorporeal blood purification.
Hypovolemia may result from sequestration of H2O by muscles and must be prevented by the aggressive administration of intravenous fluids. To obtain volume equilibrium, the amount of fluid required is as high as 10 L or more per day. In cases in which muscles are compressed as a result of trauma, it is important to start administration of fluid before the victim is extricated from under the rubble. Potassium- or lactate-containing solutions should be avoided.
Large numbers of patients all developing rhabdomyolysis at the same time are observed after disasters, as earthquakes. Starting in 1988, several earthquake disasters caused great numbers of patients with dialysis-dependent acute renal failure.
The number of patients is influenced largely by local circumstances, such as the global mortality, the severity of the shock, the size of the disaster area, the quality of the buildings, the time needed for extrication, the triage and identification procedures, and the availability of local rescue teams and medical facilities.