Rhabdomyolysis

When rhabdomyolysis is mentioned, it is usually a syndrome that occurs as a result of the destruction of striated muscles. This process, in turn, causes the release of muscle cell breakdown products and the appearance of free oxygen-binding protein, myoglobin, in the circulatory system. “Rhabdomyolysis” literally means that the body is experiencing massive destruction of muscle cell structures. [ 1 ]

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

Epidemiology

Rhabdomyolysis syndrome is diagnosed when elevated plasma creatine kinase levels are detected, exceeding 10,000 units/liter (normal range: 20-200 units/liter). It should be noted that intense physical activity can cause a moderate increase in levels 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 24 hours after training or another damaging factor. The peak occurs approximately in the period from 24 to 72 hours, then a gradual improvement occurs - over several days (up to one week).

People of any age and gender are susceptible to the disease, but untrained athletes with insufficient basic physical fitness are at particular risk.

Causes rhabdomyolysis

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

There is no single cause for the development of the disease: most often there are many and they are diverse. For example, one of the causes is metabolic myopathy. We are talking about a number of hereditary pathologies that are united by a common feature - 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 consequence, the decomposition of muscle cellular structures.

Another reason may be excessive physical overload. Rhabdomyolysis during training can develop if the overload is combined with elevated temperature and lack of moisture in the body.

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

• severe muscle injuries, Crush Syndrome;
• embolic syndrome, thrombosis;
• compression of blood vessels;
• shock states;
• prolonged epileptic seizure (status epilepticus);
• tetanus;
• high-voltage electric shock, lightning strike;
• overheating due to elevated body temperature; [ 12 ]
• general blood poisoning;
• malignant neurolepsy;
• malignant hyperthermic syndrome;
• alcohol and surrogate intoxication, poisoning with plant, snake and insect venom.
• infections. Legionella bacteria have been associated with bacterial rhabdomyolysis.[ 13 ] Viral infections have also been implicated in the development of rhabdomyolysis, most commonly influenza A and B viruses.[ 14 ],[ 15 ] Cases of rhabdomyolysis due to other viruses have also been described, such as HIV,[ 16 ] coxsackievirus,[ 17 ] Epstein-Barr virus,[ 18 ] cytomegalovirus,[ 19 ] herpes simplex virus,[ 20 ] varicella-zoster virus,[ 21 ] and West Nile virus.[ 22 ]

Drug-induced rhabdomyolysis occurs with amphetamines, statins, neuroleptics, and some other medications. Myopathy and rhabdomyolysis are especially common with statins. For example, Simvastatin can cause severe muscle pain, muscle weakness, and a marked increase in creatine kinase levels.

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;
• belonging to the female gender;
• hypothyroidism;
• renal failure.

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

Risk factors

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

• lack of water in the body, dehydration;
• oxygen deficiency in muscles;
• training in conditions of high 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 medications - for example, analgesics.

Rhabdomyolysis is especially common in athletes who practice cyclic sports, such as long-distance running, triathlon, and marathon running.

Pathogenesis

Regardless of the initial cause, the subsequent steps leading to rhabdomyolysis involve either direct damage to myocytes or disruption of the energy supply to muscle cells.

During normal resting muscle physiology, ion channels (including Na+/K+ pumps and Na+/Ca2+ channels) located on the plasma membrane (sarcolemma) maintain low intracellular Na+ and Ca2+ concentrations and high K+ concentrations within the muscle fiber. Muscle depolarization results in an influx of Ca2+ from reserves stored in the sarcoplasmic reticulum into the cytoplasm (sarcoplasm), causing muscle cells to contract via contraction of the actin-myosin complex. All of these processes are dependent on the availability of adequate energy in the form of adenosine triphosphate (ATP). Therefore, any insult that damages the ion channels, either through direct injury to myocytes or by reducing 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 Ca2+. The increase in intracellular Na+ draws water into the cell and disrupts the integrity of the intracellular space. The prolonged presence of high intracellular Ca2+ levels results in sustained myofibrillation contraction, which further depletes ATP. In addition, the increased Ca2+ levels activate Ca2+-dependent proteases and phospholipases, promoting cell membrane lysis and further damage to ion channels. The end result of these changes in the muscle cell environment is an inflammatory, myolytic cascade that causes muscle fiber necrosis and releases muscle contents into the extracellular space and bloodstream.[ 24 ]

The main points of the mechanisms of rhabdomyolysis development are considered to be the following:

• Myocyte metabolism is disrupted, concerning the structures of striated muscles. Excessive overload of myocytes leads to an increase in the influx of water and sodium to the sarcoplasm, which leads to edema and cellular destruction. Calcium enters the cell instead of sodium. High levels of free calcium provoke 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 aggravates the picture of damage to muscle structures.
• Reperfusion damage increases: all toxic substances enter the bloodstream en masse, and a severe form of intoxication develops.
• In the closed space of the muscle bed, the pressure increases greatly, which aggravates the damage and leads to the death of muscle fibers. Peripheral nerves are irreversibly damaged, and compartment syndrome develops.

As a consequence of the above processes, the renal tubules are blocked by myoglobin, and acute renal failure develops. Muscle tissue necrosis and further activation of the inflammatory process cause fluid accumulation in the affected structures. If no assistance is provided, the patient develops hypovolemia and hyponatremia. A severe form of hyperkalemia can lead to death due to cardiac arrest.

Symptoms rhabdomyolysis

Rhabdomyolysis ranges from an asymptomatic illness with elevated creatine kinase levels to a life-threatening condition associated with extreme elevations in creatine kinase levels, electrolyte imbalances, acute renal failure (ARF), and disseminated intravascular coagulation.[ 25 ]

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

Experts divide the symptoms of rhabdomyolysis into mild and severe degrees of manifestation. A severe form of the disease is said to occur if muscle destruction occurs against the background of renal insufficiency. In mild cases, acute renal failure does not develop.

The first signs of a violation look like this:

• weakness in the muscles appears;
• the urine becomes darker than usual, which indicates impending renal dysfunction and is considered one of the main signs of rhabdomyolysis;
• skeletal muscles swell and become painful. [ 26 ]

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

• limbs swell;
• the amount of fluid excreted is sharply reduced, leading to anuria;
• muscle tissue swells, compressing nearby internal organs, which results in shortness of breath, hypotension, and the development of a state of shock;
• the heartbeat quickens, and as the condition worsens, the pulse becomes threadlike.

If the necessary medical care is not provided, the water-electrolyte balance is disturbed and the patient falls into a coma.

In the early stages 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 total calcium content.

Attempts to correlate elevated creatine kinase levels with the severity of muscle injury and/or renal failure have had mixed results, although creatine kinase levels >5000 IU/L are likely to indicate significant muscle injury.[ 27 ]

Complications and consequences

It is important to understand that medical intervention in the early stages of rhabdomyolysis can slow down the pathology and prevent a lot of possible adverse complications. Therefore, even at the slightest suspicion of the disease, you should take care of diagnostics in advance, take laboratory tests of blood and urine. [ 28 ]

If no assistance is provided, rhabdomyolysis may be complicated by the following conditions:

• damage to most tissues in the body, as well as vital organs that are subject to excessive pressure from swollen muscles;
• development of acute renal failure;
• development of disseminated intravascular coagulation (DIC) syndrome associated with a coagulation disorder;
• In severe cases of rhabdomyolysis, the outcome is fatal.

Studies have shown that the percentage of children with rhabdomyolysis who develop ARF may be even higher, up to 42%-50%.[ 29 ],[ 30 ]

Diagnostics rhabdomyolysis

All patients with suspected rhabdomyolysis undergo all necessary general clinical and biochemical studies, 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, the obtained clinical and laboratory information, and the state of renal hemodynamics, the scope of diagnostic appointments may change and be supplemented.

Laboratory tests that are carried out first:

• study of the level of creatine kinase in blood plasma;
• study of the level of electrolytes in blood plasma;
• urine analysis to assess the functional capacity of the kidneys;
• Extended version of blood test.

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

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

• elevated creatine phosphokinase levels;
• the presence of myoglobin in the bloodstream;
• increased content of potassium and phosphorus, decreased presence of calcium ions;
• development of renal failure against the background of increased levels of creatinine and urea;
• detection of myoglobin in urine fluid.

Differential diagnosis

Differential diagnosis of rhabdomyolysis involves excluding any hereditary types of the disease. Determination of glycogen levels helps to exclude McArdle's disease, and assessment of omoylcarnitine and palmitoylcarnitine levels helps to differentiate rhabdomyolysis from carnitine palmitoyltransferase deficiency.

Treatment rhabdomyolysis

Treatment for rhabdomyolysis should be undertaken urgently, as soon as possible - that is, immediately after the diagnosis is made. Therapy is carried out in hospital conditions, since this is 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 severe cases of rhabdomyolysis, an infusion of isotonic sodium chloride solution is performed.

Azotemia is prevented primarily by aggressive hydration at a rate of 1.5 L/h.[ 31 ] Another option is 500 mL/h of normal saline, alternating every hour with 500 mL/h of 5% glucose solution with 50 mmol sodium bicarbonate for every subsequent 2-3 L of solution. A urine output of 200 mL/h, urine pH > 6.5, and plasma pH < 7.5 should be achieved. 2 Notably, alkalinization of urine with sodium bicarbonate or sodium acetate has not been proven, nor has the use of mannitol to stimulate diuresis.

An important link is maintaining water-electrolyte balance. To correct diuresis, therapy is supplemented by the introduction of diuretics - for example, Mannitol or Furosemide. In critical cases, hemodialysis is connected. If muscle pressure increases above 30 mm Hg, there is a need for surgical intervention - surgical excision of tissue, or fasciotomy. This operation helps to quickly stop the increasing compression of organs.

Allopurinol is used to inhibit the production of uric acid and to block cell damage by free radicals. Among other purine-based drugs, Pentoxifylline is actively used for rhabdomyolysis; it can enhance capillary blood 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. The corresponding prescriptions are resorted to when values exceed 6.0 mmol/liter. Persistent and rapid hyperkalemia is a direct indication for hemodialysis.

Prevention

The development of rhabdomyolysis can be prevented by mandatory “warming up” of the muscles before a sports activity: preliminary special exercises prepare muscle tissue for stress and strengthen their protection.

During training, you should replenish your body with liquid to avoid dehydration. There is a special need for water consumption during intense strength and aerobic exercise.

The body should be loaded gradually. The first training sessions should be held without adding weight, with practicing the correct exercise technique. You should not immediately strive for strength records, or arrange competitions with more prepared opponents.

It is necessary to take periods of pause between approaches so that the heart rate can return to calmer values. The training should be stopped if dizziness begins, or nausea or other unpleasant symptoms appear.

Forecast

There is no clear prognosis for rhabdomyolysis: it depends on the severity of the disease and the timeliness of medical care.

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

Severe course of the disease has a less optimistic prognosis: in such a situation, rhabdomyolysis can be cured using a comprehensive approach, including conservative therapy and surgical intervention. The addition of acute renal failure significantly worsens the quality of the prognosis: with such a diagnosis, two out of ten patients die.