What is rhabdomyolysis

Rhabdomyolysis is a serious condition caused by the breakdown of muscle tissue that leads to the release of muscle fiber contents into the blood. This can lead to several forms of systemic insult, with the most important being acute kidney injury, electrolyte imbalance, and disseminated intravascular coagulation (DIC) ¹. Rarely, rhabdomyolysis can cause death. However, when treated early, the chances of a recovery are high.

When muscle tissue gets seriously injured, it breaks down and dies, releasing its contents, including a protein called myoglobin, into the bloodstream.

The kidneys filter out myoglobin, but since too much myoglobin is harmful to kidney cells, rhabdomyolysis can lead to kidney failure.

Rhabdomyolysis occurs in adults and children; however, adults make up a majority of the cases ¹. All age groups and both sexes can develop rhabdomyolysis. Because different definitions for rhabdomyolysis have been used, the exact incidence is difficult to determine. Despite this, African Americans, males, obese patients, patients younger than ten years of age, and patients older than 60 years old all have a higher incidence of rhabdomyolysis ¹.

Several causes and conditions, such as trauma and drug use, can lead to the development of rhabdomyolysis. Rhabdomyolysis is most commonly caused by an infection in children, accounting for approximately one-third of cases. In adults rhabdomyolysis is most commonly multifactorial, often involving trauma and drugs.

Problems that may lead to rhabdomyolysis include:

• Trauma or crush injuries
• Use of drugs such as cocaine, amphetamines, statins, heroin, or PCP
• Genetic muscle diseases
• Extremes of body temperature
• Ischemia or death of muscle tissue
• Low phosphate levels
• Seizures or muscle tremors
• Severe exertion, such as marathon running or calisthenics
• Lengthy surgical procedures
• Severe dehydration

Acute renal failure plays a major role in mortality from rhabdomyolysis. Acute renal failure develops in 10% to 40% of patients with rhabdomyolysis. Rhabdomyolysis causes 7% to 10% of all acute renal failure. Mortality for intensive care until (ICU) patients with rhabdomyolysis without acute renal failure is 22%. This mortality jumps to 59% when these patients develop acute renal failure ².

It is important to understand how to identify and treat rhabdomyolysis because, in most cases, the systemic complications can be prevented or reversed ³.

What causes rhabdomyolysis

Trauma, extreme physical activity, immobility, prolonged muscle compression, illicit drug use, medications, toxins, infection, potassium imbalance, hypothyroid states, hyperthyroid states, hypothermia, and hyperthermia can cause rhabdomyolysis ¹. Inherited diseases that affect muscle structure and muscle energy metabolisms, such as glycogen storage diseases, fatty acid disease, mitochondrial disease and muscle dystrophy, also can cause rhabdomyolysis ¹.

Trauma (traumatic rhabdomyolysis) is a very common cause of rhabdomyolysis, especially in adults. Crush injuries are a specific type of trauma that is highly associated with rhabdomyolysis. In addition to excessive intentional muscle activity (exertional rhabdomyolysis), such as marathon running, it is also important to recognize that unintentional muscle activity such as seizures and psychomotor agitation in the setting of psychosis and/or stimulant use can lead to rhabdomyolysis.

Several drugs, medications, and toxins can lead to rhabdomyolysis by causing immobility, muscle compression and/or direct muscle toxicity. Alcohol, cocaine, amphetamines and heroin are the most common recreational drugs associated with rhabdomyolysis. Statin drugs being the most common prescription drug associated with rhabdomyolysis. Several toxic causes exist, some examples are snake venom, bee venom, and carbon monoxide.

Viruses, such as influenza and HIV, are the most common infectious cause of rhabdomyolysis. In fact, the viral infection is the most common cause of rhabdomyolysis in children, with influenza being the most common specific virus. The most common bacterial infection causing rhabdomyolysis has classically been Legionella. However, rhabdomyolysis from organisms in the Enterobacteriaceae family, especially Escherichia coli, is increasing in frequency.[3][4][5]

Rhabdomyolysis is caused by direct or indirect injury to muscle tissue, such as:

• trauma or crush injuries, for example, from a car accident (traumatic rhabdomyolysis)
• taking illegal drugs such as cocaine, amphetamines or heroin
• extreme muscle exertion, for example, running marathons (exertional rhabdomyolysis)
• a side effect of some medicines, such as statins (although the risk is very low)
• prolonged muscle pressure, for example when someone is lying unconscious on a hard surface
• very high body temperature (hyperthermia) or heat stroke.

Rhabdomyolysis pathophysiology

Muscle damage is central to the pathophysiology of rhabdomyolysis. All of the causes of rhabdomyolysis cause muscle damage, most commonly by causing energy depletion and/or by causing direct destruction of the myocyte cell membrane. Both energy depletion and direct muscle cell membrane injury lead to increased intracellular ionized calcium levels which activate destructive enzymes, such as phospholipase and protease. These enzymes cause myolysis and cell death. When the muscle damage is occurring, the myocytes sequester fluid which can lead to hypovolemia and compartment syndrome. When myolysis occurs, the intracellular components, such as potassium, myoglobin, creatine kinase, phosphate and various organic acids leak into the bloodstream. This leads to the complications of hyperkalemia and hyperphosphatemia. The myoglobin is nephrotoxic, and its accumulation is thought to be the primary cause of renal injury in rhabdomyolysis. Hypovolemia and metabolic acidosis in rhabdomyolysis also play a major role in renal injury. In rhabdomyolysis, hypocalcemia is observed initially followed by hypercalcemia. This is because calcium first moves into the myocyte during injury then it leaks out into extracellular spaces after cell lysis. Disseminated intravascular coagulation (DIC) is thought to be due to thromboplastin released during muscle injury ⁴.

Rhabdomyolysis prevention

Rhabdomyolysis can be avoided by:

• Drinking plenty of fluids after strenuous exercise.
• Removing extra clothes and immersing the body in cold water in case of heat stroke.

Rhabdomyolysis signs and symptoms

The most common signs and symptoms of rhabdomyolysis include ¹:

• Severe muscle aching throughout the entire body, especially in the shoulders, thighs or lower back
• Muscle weakness
• Dark or cola-colored urine

Common rhabdomyolysis symptoms include:

• muscle pain or tenderness (myalgia), especially in the shoulders, thighs or lower back
• muscle weakness or stiffness, or trouble moving arms or legs
• confusion, dehydration or fever
• lack of consciousness
• dark red or brown urine
• reduced or no urine output.

Rhabdomyolysis possible complications

If not treated early, rhabdomyolysis can lead to complications, such as:

• Very high potassium levels in the blood (hyperkalemia); this can lead to an irregular heartbeat or cardiac arrest
• Kidney failure or problems with the liver
  • Acute tubular necrosis
  • Acute renal failure
• Harmful electrolyte imbalances in the blood
• Compartment syndrome; this occurs when too much pressure builds up in the injured group of muscles (compartment). The extreme pressure hinders blood flow to and from the affected tissues and can cause further muscle damage and death.
• Shock (low blood pressure)

Rhabdomyolysis diagnosis

The classic triad of rhabdomyolysis is a weakness, myalgia, and tea-colored urine ¹. However, less than 10% of patients have the classic triad. One study showed only 3.6% of patients had tea-colored urine. In children, muscle pain, fever, and viral prodromes are common symptoms. Arrhythmias from electrolyte imbalance, compartment syndrome, and disseminated intravascular coagulation (DIC) can also be seen. Patients also often have other signs and symptoms specific to the condition that is causing the rhabdomyolysis. Since this occurs in less than 10% of patients, the clinician should suspect rhabdomyolysis in anybody who has risk factors, for example, trauma, immobility, or increased activity.

Rhabdomyolysis is often diagnosed in hospital. Physical examination, blood tests and urine tests are all needed. Other tests may be needed too.

The following tests may be done:

• Creatine kinase (CK) level
• Serum calcium
• Serum myoglobin
• Serum potassium
• Urinalysis
• Urine myoglobin test
• Creatine kinase (CK)isoenzymes
• Serum creatinine
• Urine creatinine

Rhabdomyolysis is best diagnosed by the serum creatine kinase (CK) level ¹. This marker is the most specific marker for rhabdomyolysis. Although no unified definition exists, most experts agree that a creatine kinase (CK) level five times the normal limit constitutes rhabdomyolysis. Serum creatine kinase (CK) rises two to 12 hours after muscle injury, peaking anywhere from one to five days after injury. Creatine kinase (CK) then returns to baseline six to ten days after muscle injury. Creatine kinase is useful because it has a long half-life, which has been reported to be 42 hours.

Urine myoglobin is helpful only if positive ¹. Negative urinary myoglobin does not rule out rhabdomyolysis ¹. False negative urinary myoglobin rate in one study was 26%. Serum myoglobin is not helpful because of its short half-life. A clue to diagnosis is the finding of blood on the urine dip with the absence of red blood cells on urinalysis microscopy. This is because the urine dip mistakes the myoglobin for hemoglobin.

Increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can aid in the diagnosis of rhabdomyolysis ¹. These enzymes are found in the muscle as well as the liver. AST (aspartate aminotransferase) has a much higher muscle concentration than ALT (alanine aminotransferase). One study found aspartate aminotransferase (AST) elevation in 93% of rhabdomyolysis cases and alanine aminotransferase (ALT) elevation in 75% of cases. One study found that rhabdomyolysis patients with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) had a higher mortality.

The best predictors for developing acute kidney injury appear to be high initial serum creatine, low serum bicarbonate, low serum calcium, and increased serum phosphate. Hypoalbuminemia and increased BUN (Blood Urea Nitrogen) has also been associated with the development of acute kidney injury.

The ability to predict mortality and acute kidney injury with initial serum creatine kinase (CK) levels and serum myoglobin levels are unclear and inconsistent ⁵.

In most cases of rhabdomyolysis, the histology will reveal necrotic or fragmented muscle fibers. A muscle biopsy is not usually done for routine cases of rhabdomyolysis but only in patients with an inherited disorder where muscle breakdown is a concern.

Rhabdomyolysis treatment

Rhabdomyolysis is usually treated in hospital, with intravenous fluids to help you produce enough urine and prevent kidney failure.

There are no defined guidelines for treating rhabdomyolysis ¹. Very few well-designed studies have been conducted to investigate the management of rhabdomyolysis. However, most experts agree that fluid therapy and addressing the cause of the rhabdomyolysis should be the cornerstone of treatment. Some suggest giving fluids early and aggressively with the goal of preventing acute kidney injury. Specific fluid types and rates are not well defined. Sodium bicarbonate, mannitol, and furosemide have been suggested as treatments for rhabdomyolysis ¹. It is important to note that using sodium bicarbonate, to increase myoglobin excretion, and diuretics, to increase urine output, is unproven ¹. However, some experts recommend these agents in the setting of metabolic acidosis and decreased urine output.

Hyperkalemia should be treated in standard fashion. Hypocalcemia should not be treated unless it is causing severe cardiac arrhythmias. Hyperphosphatemia should not be corrected initially because it may promote increased calcium deposition in injured muscles ⁶.

Rarely, dialysis is needed if kidney function is poor. If you have compartment syndrome, you may need immediate surgery to avoid further muscle death or nerve damage.

Rhabdomyolysis recovery

Early diagnosis and treatment of rhabdomyolysis and its causes increases your chances of a full recovery. The outcome of patients with rhabdomyolysis depends on the cause, patient age, and other comorbidities. Ongoing muscle breakdown without an identifiable cause has a mortality rate of 4% ¹. With better treatment, the mortality rates have decreased over the recent years, but rhabdomyolysis still carries a significant morbidity. Rapid intervention with aggressive hydration is the key in order to prevent the renal injury and renal failure. Even after recovery, many patients take months to recover the muscle mass, and some even have residual pain for a few years ⁷, ⁸.

Rhabdomyolysis can have significant morbidity on the patient, and the key is education on causes of muscle breakdown and how to prevent them. College and high school students need to be educated about the heat-related injuries and the importance of hydration. Patients with rhabdomyolysis may also need to enter a rehabilitation or a physical therapy program to regain muscle mass and recover joint function. Finally, patients should be warned about the risk of rhabdomyolysis associated with recreational drugs, alcohol or prescription medications ⁹.

Rehabilitation care

Dietary supplementation may be required in people with phosphorylase deficiency. Addition of fructose or glucose may help reduce the fatigue and pain. Patients with a deficiency of carnitine palmityl transferase deficiency may benefit from low fat and high carbohydrate diets. During the recovery phase, strenuous physical activity should be avoided to prevent further muscle breakdown. Finally, athletes should refrain from exercising in extreme heat and remain well hydrated.

Rhabdomyolysis prognosis

The outcome of rhabdomyolysis depends on the amount of kidney damage. Acute kidney failure occurs in many people. Getting treated soon after rhabdomyolysis will reduce the risk of permanent kidney damage.

People with milder cases may return to their normal activities within a few weeks to a month. However, some people continue to have problems with fatigue and muscle pain.

References

1. Stanley M, Adigun R. Rhabdomyolysis. [Updated 2018 Dec 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448168
2. Brinley A, Chakravarthy B, Kiester D, Hoonpongsimanont W, McCoy CE, Lotfipour S. Compartment Syndrome with Rhabdomyolysis in a Marathon Runner. Clin Pract Cases Emerg Med. 2018 Aug;2(3):197-199
3. Kynes JM, Blakely M, Furman K, Burnette WB, Modes KB. Multidisciplinary Perioperative Care for Children with Neuromuscular Disorders. Children (Basel). 2018;5(9):126. Published 2018 Sep 12. doi:10.3390/children5090126 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162674/
4. Rastogi V, Singh D, Kaur B, Arora P, Gadikota JP. Rhabdomyolysis: A Rare Adverse Effect of Levetiracetam. Cureus. 2018 May 29;10(5):e2705
5. Kim JH, Kim YJ, Koh SH, Kim BS, Choi SY, Cho SE, Song JH, Kim CH, Lee KH, Cho SG. Rhabdomyolysis revisited: Detailed analysis of magnetic resonance imaging findings and their correlation with peripheral neuropathy. Medicine (Baltimore). 2018 Aug;97(33):e11848
6. Servonnet A, Dubost C, Martin G, Lefrère B, Fontan E, Ceppa F, Delacour H. Myoglobin: still a useful biomarker in 2017? Ann. Biol. Clin. (Paris). 2018 Apr 01;76(2):137-141.
7. Divine JG, Clark JF, Colosimo AJ, Detherage JP, Donaworth MA, Hasselfeld KA, Himmler A, Rauch JT, Mangine RE. American Football Players in Preseason Training at Risk of Acute Kidney Injury Without Signs of Rhabdomyolysis. Clin J Sport Med. 2018 Aug 16
8. Caughey GE, Gabb GM, Ronson S, Ward M, Beukelman T, Hill CL, Limaye V. Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population. JAMA Intern Med. 2018 Sep 01;178(9):1224-1229.
9. Poussel M, Guerci P, Kaminsky P, Heymonet M, Roux-Buisson N, Faure J, Fronzaroli E, Chenuel B. Exertional Heat Stroke and Susceptibility to Malignant Hyperthermia in an Athlete: Evidence for a Link? J Athl Train. 2015 Nov;50(11):1212-4.