Rhabdomyolysis

Mentioning rhabdomyolysis, they usually mean a syndrome that occurs as a result of the destruction of striated muscles. This process, in turn, causes the release of decomposition products of muscle cells and the appearance in the circulatory system of a free oxygen-binding protein - myoglobin. "Rhabdomyolysis" literally means that in the body the cellular structures of muscles are massively destroyed. [1]

Myoglobin is a specific protein substance of skeletal and cardiac muscles. In the normal state of muscle tissue, this protein is absent in the blood. When pathology enters the bloodstream, myoglobin begins to exert a toxic effect, and its large molecules “clog” the renal tubules, which causes their necrosis. Competition with erythrocyte hemoglobin for a connection with pulmonary oxygen and failure to transport oxygen to tissues lead to a deterioration in the processes of tissue respiration and the development of hypoxia. [2]

Epidemiology

Rhabdomyolysis syndrome is diagnosed when an elevated plasma creatine kinase level is detected to an index exceeding 10,000 units / liter (normal - 20-200 units / liter). It should be borne in mind that intense physical activity can lead to a moderate increase in the level to 5,000 units / liter, which is associated with muscle necrosis due to unusual overload.

The intensity of the damaging process increases during the first days after training or another damaging factor. The peak occurs approximately in the period from 24 to 72 hours, then there is a gradual improvement - within a few days (up to one week).

Persons of any age and gender are susceptible to the disease, however untrained athletes with insufficient basic physical fitness belong to a special risk group.

Causes of the rhabdomyolysis

Although rhabdomyolysis is most often caused by direct trauma, the condition can also be the result of medication,  [3] exposure to toxins, infections,  [4] muscle ischemia,  [5] electrolyte and metabolic disorders, genetic disorders, physical activity  [6],  [7] or prolonged bed rest and temperature conditions, such as antipsychotic-associated malignant syndrome (NMS) and malignant hyperthermia (MH). [8]

There is no one reason for the development of the disease: most often there are many and they are diverse. For example, one of the reasons is metabolic myopathy. We are talking about a whole series of hereditary pathologies that are united by a common symptom - myoglobinuria. Among other common features, one can name the lack of energy transport to the muscles, which is provoked by a disorder of glucose metabolism, as well as fat, glycogen, nucleoside metabolism. As a result, there is a tissue deficiency of ATP and, as a result, the decomposition of muscle cell structures.

Excessive physical overload may be another cause. Rhabdomyolysis during exercise can develop if overload is combined with fever and lack of moisture in the body.

Other common causes are:  [9],  [10], [11]

• severe muscle injuries, ATP (crash syndrome); 
• embolic syndrome, thrombosis;
• squeezing of blood vessels;
• shock conditions;
• prolonged attack of epilepsy (status epilepticus);
• pillar;
• defeat by high voltage electric shock, lightning strike;
• overheating against a background of elevated body temperature; [12]
• general blood poisoning;
• malignant neurolepsy;
• malignant hyperthermic syndrome;
• alcohol and surrogate intoxications, poisoning by plant poisons, snakes, insects.
• infections. Legionella bacteria have been associated with bacterial rhabdomyolysis. [13] Viral infections are also involved in the development of rhabdomyolysis, often influenza viruses A and B  [14],  [15] cases of rhabdomyolysis due to other viruses such as HIV, have also been described  [16] coxsackie virus,  [17] Epstein-Barr virus,  [18] cytomegalovirus,  [19] herpes simplex virus,  [20] varicella zoster virus,  [21] and West Nile virus. [22]

Medicinal rhabdomyolysis occurs with the use of amphetamines, statins, antipsychotics and some other medicines. Myopathy and rhabdomyolysis when taking statins are especially common. For example, simvastatin can lead to severe muscle pain, muscle weakness, a pronounced increase in the content of creatine kinase.

Rhabdomyolysis occurs both in isolation and in combination with acute renal failure, but death is rare. The risk of the disease increases against the background of high activity of statins in the blood serum. In this situation, the risk factors are:

• age over 65 years;
• gender affiliation;
• decreased thyroid function;
• renal failure.

The development of rhabdomyolysis is also associated with a dosage of statins. For example, with a daily dosage of less than 40 mg, the incidence of the disease is significantly lower than when taking more than 80 mg of drugs. [23]

Risk factors

Risk factors that increase the likelihood of developing muscular rhabdomyolysis are:

• lack of water in the body, dehydration;
• muscle oxygen deficiency;
• training in conditions of elevated air temperature or high body temperature;
• playing sports during acute respiratory viral infections, against the background of alcohol intoxication, as well as during treatment with certain drugs - for example, analgesics.

Rhabdomyolysis is especially common in athletes practicing cyclic sports. This is long-distance running, triathlon, marathon races.

Pathogenesis

Regardless of the original cause, the subsequent steps leading to rhabdomyolysis include either direct damage to myocytes or a disruption in the supply of energy to muscle cells.

During normal muscle physiology, resting ion channels (including Na + / K + pumps and Na + / Ca 2+ channels) located on the plasma membrane (sarcolemma) maintain low intracellular concentrations of Na + and Ca 2+ and high K concentrations + within the muscle fiber. Muscle depolarization leads to an influx of Ca 2+ from reserves stored in the sarcoplasmic reticulum into the cytoplasm (sarcoplasm), causing muscle cells to contract due to a reduction in the actin-myosin complex. All these processes depend on the availability of sufficient energy in the form of adenosine triphosphate (ATP). Therefore, any damage that damages the ion channels as a result of direct damage to myocytes or reduces the availability of ATP for energy will disrupt the proper balance of intracellular electrolyte concentrations.

When muscle damage or ATP depletion occurs, the result is an excessive intracellular influx of Na + and Ca 2+. An increase in intracellular Na + draws water into the cell and violates the integrity of the intracellular space. The prolonged presence of high intracellular Ca 2+ levels leads to a sustained reduction in myofibrillation, which further depletes ATP. In addition, an increase in the level of Ca 2+ activates Ca 2+ -dependent proteases and phospholipases, contributing to the lysis of the cell membrane and further damage to the ion channels. The end result of these changes in the environment of muscle cells is an inflammatory, myolytic cascade that causes necrosis of muscle fibers and releases muscle contents into the extracellular space and bloodstream. [24], [25]

The main points of the development mechanisms of rhabdomyolysis are considered as follows:

• Myocytic metabolism is disturbed, concerning the structures of striated muscles. Excessive overload of myocytes leads to an increase in the inflow to the sarcoplasm of water and sodium, which leads to edema and cellular destruction. Calcium enters the cell instead of sodium. The high content of free calcium provokes cellular contraction, as a result - energy deficiency and cell destruction. At the same time, enzymatic activity is activated, active forms of oxygen are produced, which further exacerbates the pattern of damage to muscle structures.
• Reperfusion injury is growing: all toxic substances enter the bloodstream en masse, and severe intoxication develops.
• In the enclosed space of the muscle bed, pressure increases greatly, which exacerbates the damage and leads to necrosis of the muscle fibers. The peripheral nerves are irreversibly damaged, and the compartment syndrome develops.

As a consequence of these processes, there is a blockage of the renal tubules by myoglobin, acute renal failure develops. The death of muscle tissue and the further activation of the inflammatory process cause accumulation of fluid in the affected structures. If assistance is not provided, the patient develops hypovolemia, hyponatremia. Severe hyperkalemia can be fatal as a result of cardiac arrest.

Symptoms of the rhabdomyolysis

Rhabdomyolysis ranges from asymptomatic disease with an increase in creatine kinase levels to a life-threatening condition associated with an extreme increase in HC, electrolyte imbalance, acute renal failure (OD), and disseminated intravascular coagulation. [26]

Clinically, rhabdomyolysis is manifested by a triad of symptoms: myalgia, weakness, and myoglobinuria, manifested in tea-colored urine. However, this description of symptoms can be misleading, since the triad is observed only in <10% of patients, and> 50% of patients do not complain of muscle pain or weakness, and the initial symptom is discolored urine.

Specialists subdivide the symptoms of rhabdomyolysis into mild and severe manifestations. They say about a serious form of the disease if muscle destruction occurs against the background of insufficient renal function. With a mild course, acute renal failure does not develop.

The first signs of a violation are as follows:

• muscle weakness appears;
• urinary fluid becomes darker than usual, which indicates an impaired renal function impairment and is considered one of the main signs of rhabdomyolysis;
• skeletal muscles swell, become painful. [27]

Against the background of insufficient renal function, the patient's well-being suddenly worsens. The clinical picture is supplemented by the following symptoms:

• limbs swell;
• the amount of liquid withdrawn sharply decreases, up to anuria;
• muscle tissue swells, squeezing adjacent internal organs, which as a result is manifested by shortness of breath, hypotension, the development of a shock state;
• palpitations become more frequent, when the condition worsens, the pulse becomes threadlike.

If you do not provide the necessary medical care, the water-electrolyte balance is disturbed, the patient falls into a coma.

At an early stage of rhabdomyolysis, dehydration can cause hyperalbuminemia, and later hypoalbuminemia occurs, which is caused by the inflammatory process, nutritional deficiency, hypercatabolism, increased capillary permeability and fluid overload. This can lead to a false interpretation of the plasma content of total calcium.

Attempts to correlate an increase in creatine kinase levels with the severity of muscle damage and / or renal failure have had mixed results, although significant muscle damage is likely at creatine kinase levels> 5000 IU / L. [28]

Complications and consequences

It is important to understand that medical intervention in the early stages of rhabdomyolysis can inhibit pathology and prevent a lot of possible adverse complications. Therefore, even at the slightest suspicion of the disease, care should be taken in advance about diagnosing, passing laboratory tests of blood and urinary fluid. [29]

If assistance is not provided, rhabdomyolysis can be complicated by the following conditions:

• damage to most tissues in the body, as well as vital organs, which are subjected to excessive pressure from the edematous muscles;
• the development of acute renal failure;
• the development of disseminated intravascular coagulation (DIC) syndrome associated with coagulation disorders;
• in severe rhabdomyolysis - death.

Studies have shown that the percentage of children with rhabdomyolysis who develop acute renal failure may be even higher, up to 42% -50%. [30], [31]

Diagnostics of the rhabdomyolysis

All patients with suspected rhabdomyolysis undergo all necessary general clinical, biochemical studies, an electrocardiogram, ultrasound of the abdominal cavity and retroperitoneal space. Some patients are additionally prescribed echocardiography, computed tomography, Doppler scanning of the renal vessels. Depending on the anamnestic data obtained by the clinical and laboratory information, on the state of renal hemodynamics, the scale of diagnostic prescriptions can be changed and supplemented.

Laboratory tests, which are carried out primarily:

• a study of the level of creatine kinase in blood plasma;
• study of the level of electrolytes in blood plasma;
• urinalysis to assess the functional ability of the kidneys;
• detailed version of the blood test.

Instrumental diagnostics, among other things, may include a biopsy of muscle tissue - this is an invasive research procedure involving the removal of a small area of tissue for further histological examination.

The diagnosis of rhabdomyolysis is considered confirmed when such diagnostic signs are detected:

• increased content of creatine phosphokinase;
• the presence of myoglobin in the bloodstream;
• increased content of potassium and phosphorus, a decrease in the presence of calcium ions;
• development of renal failure due to elevated levels of creatinine and urea;
• detection of myoglobin in the urinary fluid.

Differential diagnosis

The differential diagnosis of rhabdomyolysis is to exclude any hereditary types of this disease. Determination of glycogen content eliminates McArdle disease, and an assessment of the level of omoylcarnitine and palmitoylcarnitine helps to differentiate rhabdomyolysis from deficiency of carnitine palmitoyl transferase.

Treatment of the rhabdomyolysis

Treatment measures for rhabdomyolysis should be undertaken as an emergency, as soon as possible - that is, immediately after an appropriate diagnosis has been made. Therapy is carried out under stationary conditions, since the only way to establish control over the quality of the water-electrolyte balance in the patient’s body. First of all, rehydration procedures are carried out: in case of severe rhabdomyolysis, infusion of isotonic sodium chloride solution is performed. 

Azotemia is prevented primarily by aggressive hydration at a rate of 1.5 l / h.  [32] Another option is 500 ml / h of physiological saline, alternating every hour with 500 ml / h of 5% glucose solution with 50 mmol of sodium bicarbonate for every next 2-3 l solution. Urine productivity of 200 ml / h, urine pH> 6.5 and plasma pH <7.5 should be achieved. 2 It is noteworthy that alkalinization of urine with sodium bicarbonate or sodium acetate has not been proven, as well as the use of mannitol to stimulate diuresis. 

An important link is the maintenance of water-electrolyte balance. To correct diuresis, therapy is supplemented with the introduction of diuretics - for example, Mannitol or Furosemide. In critical cases, hemodialysis is connected. With an increase in muscle pressure above 30 mm. Hg. Art. There is a need for surgical intervention - surgical excision of tissues, or fasciotomy. This operation helps to quickly stop the growing compression of organs.

Allopurinol is used to inhibit the production of uric acid and to block damage to cells by free radicals. Among other purine-based drugs in rhabdomyolysis, Pentoxifylline is actively used, which can enhance capillary circulation, reduce the adhesive properties of neutrophils and inhibit the production of cytokines.

One of the important goals of treatment is the correction of hyperkalemia, because high levels of potassium in the bloodstream can pose a threat to the patient's life. They resort to the appropriate appointments even when they reach values greater than 6.0 mmol / liter. Sustained and rapid hyperkalemia is a direct indication for hemodialysis.

Prevention

The development of rhabdomyolysis can be prevented by obligatory “warming up” of the muscles before a sports session: preliminary special exercises prepare muscle tissues for loads, strengthen their protection.

During training, you should replenish the body with fluid to avoid dehydration. A special need for the use of water is present during intensive power and aerobic loads.

It is necessary to load the body gradually. The first classes should take place without weighting, with the development of the correct exercise technique. You should not immediately strive for power records, arrange competitions with more trained rivals.

Between approaches, it is necessary to take periods of pause so that the frequency of cardiac activity can return to calmer indicators. Training should be stopped if dizziness begins, or nausea or other unpleasant symptoms appear.

Forecast

There is no unambiguous prognosis of rhabdomyolysis: it depends on the severity of the disease, on the timeliness of medical care.

The initial stage of the pathology is well adjusted medically. Exacerbations are possible only with repeated damage to muscle tissue.

The severe course of the disease has a less optimistic prognosis: in a similar situation, rhabdomyolysis can be cured using an integrated approach that includes conservative therapy and surgical intervention. The addition of acute renal failure is significantly worsening the quality of the prognosis: with this diagnosis, two out of ten patients die.