“RAPID BREAKDOWN OF SKELETAL MUSCLE” PHM142 Fall 2017 Instructor: Dr. Jeffrey Henderson RHABDOMYOLYSIS “RAPID BREAKDOWN OF SKELETAL MUSCLE” MADELINE POWERS, KATHERINE HOUSTON, KRISTEN GIFFEN AND VICTORIA BUGAJ

WHAT IS RHABDOMYOLYSIS? Condition that causes the breakdown of skeletal muscle fibres Causes release of myoglobin, intracellular proteins and electrolytes into circulation The earliest reports were in 1910 in German literature as Meyer Betz Disease The common symptoms presented are a classic triad of muscle pain, muscle weakness and brown urine

HOW COMMON IS RHABDOMYOLYSIS? The incidence rate of rhabdomyolysis in the United States is as many as 26 000 cases per year Men have a slightly higher incidence Most cases of the disease are reversible Severe cases of rhabdomyolysis may be associated with complications including kidney damage Due to direct injury to the kidney or plugging of the filtering tubes by circulating muscle proteins Can lead to hospitalization and dialysis

WHAT CAUSES RHABDOMYOLYSIS? Traumatic Crush injury Long lasting muscle compression Electrical shock injury Lighting strike Third degree burn Venom from a snake or insect bite Non-Traumatic Use of alcohol or illegal drugs Extreme muscle strain due to exercise (crossfit, soul cycle) Very high body temperatures Metabolic disorders Muscle diseases Viral infections and bacterial infections A previous history of rhabdomyolysis also increases the risk of having rhabdomyolysis again Long-lasting muscle compression such as that caused by prolonged immobilization after a fall or lying unconscious on a hard surface during illness Electrical shock injury, lightning strike, or third-degree burn The use of alcohol or illegal drugs such as heroin, cocaine or amphetamines untrained athlete; this can happen in elite athletes, too, and it can be more dangerous if there is more muscle mass to break down. The use of medications such as antipsychotics or statins, especially when given in high doses A very high body temperature (hyperthermia) or heat stroke Seizures or delirium tremens A metabolic disorder such as diabetic ketoacidosis Diseases of the muscles (myopathy) such as congenital muscle enzyme deficiency or Duchenne's muscular dystrophy Viral infections such as the flu, HIV, or herpes simplex virus Bacterial infections leading to toxins in tissues or the bloodstream (sepsis)

BIOCHEMICAL MECHANISM Na+ Surviving cells experience influx in calcium and depletion of ATP Destruction of muscle cells Imagine we have an individual who is developing rhabdomyolysis. If we zoom into their muscle, the first thing we see is the rapid influx of fluid from plasma and a particular ion, which is sodium (Na+). This results in cellular swelling which has two fates; the first one is the immediate destruction of these cells spilling their contents. These molecular components will be discussed further in the next slides. The second fate is that surviving cells will start experiencing an increase in the intracellular calcium due to the previous influx of sodium. Once the calcium accumulates, it begins to pool outside the sarcolemma and leads to continuous muscle contraction, depleting the cell of ATP. This persistent contraction eventually causes the destruction of the cell.

BIOCHEMICAL MECHANISM Free phosphate will bind to calcium, lowering blood calcium levels. More K+ which may cause hyperkalaemia DAMPs recruits neutrophils and causes inflammation High [myoglobin] in blood can cause kidney failure CPK is a diagnostic marker clinicians will use Creatine phosphokinase (CPK) Release of K+, phosphate Damage associated molecular patterns (DAMPs) Myoglobin I’ve high lighted some key molecules that end up outside of the cell that end up attributing to the pathogenesis of the disease. CPK, myoglobin, danger associated molecular patterns, or DAMPs, free phosphate and potassium. So the first one, CPK, is not normally found outside of the cell in high concentrations, therefore it is an excellent diagnostic marker for the disease. Next, when muscle cells burst they will release a bunch of myoglobin into the blood stream and this becomes an issue for the kidney. The kidney can’t handle such high concentrations of myoglobin in the blood as seen in rhabdomyolysis and if it is not supported, you can get kidney failure. Next, molecules such as DNA, ATP and etc. are all molecules that should not be seen outside of the cell. If they are – this prompts an immune response, and we will get infiltration of neutrophils and other immune cells to the damaged tissue, propogating more damage through ROS. Lastly, two important molecules which I’ve paired together are phosphate and potassium. If you recall, phosphate carries a negative charge and what we will see is a bunch calcium binding, lowering our blood calcium levels. Meanwhile, the influx of potassium can cause hyperkalaemia and this can be very dangerous to the heart.

BIOCHEMICAL SUMMARY Increase in intracellular Na+ Increase in intracellular Ca2+ Depletion of ATP Overall destruction of cells and overwhelming release of contents CPK Diagnostic marker Myoglobin Kidney damage DAMPs Inflammation Phosphate and K+ ⇣ Blood [Ca2+] ⇡ Blood [K+] http://www.pnas.org/content/107/6/2699.figures-only

SYMPTOMS Classic Triad: muscle pain, weakness, reddish-brown urine -only occurs in about 50% of patients Muscle Pain Weakness Reddish-Brown Urine What would cause this colour? Extreme cases ie. Hyperkalaemia Paralysis, severe weakness Myoglobin: Heme-containing protein As previously mentioned rhabdo presents itself as a classic triad of symptoms including muscle pain (as a result of inflammation), weakness, and reddish-brown urine. However, only about 50% of patients get these symptoms. Who can guess what would causes this urine colour? As we know from class, myoglobin is a heme containing protein, and the iron center in the heme is a result of the coloration. In extreme cases such as hyper or hypokalaemia, symptoms such as paralysis and severe weakness can arise.

DIAGNOSIS Urine dipstick False positive for blood Negative for RBCs Creatine Phosphokinase (CPK) Protein released when muscles are damaged Diagnosis when levels are 5 times greater than the normal range High levels of : Potassium Results in hyperkalemia Electrolytes Uric acid To diagnose rhabdo, a urine dipstick will show positive for blood but negative for RBC. The reason for the false positive is because it cannot distinguish between the myoglobin and hemoglobin. Levels of CPK are increased as well because it is released when the muscles are damaged. Medical professionals will only make a diagnosis of rhabdo when the levels are 5 times greater than the normal range. High potassium levels are also present which causes hyperkalemia and ultimately muscle cell necrosis. Finally, high levels of uric acid and electrolytes are also present.

COMPLICATIONS Late Complications: Early Complications: Acute renal failure Disseminated intravascular coagulation Early Complications: Hyperkalemia Hypocalcemia Cardiac arrhythmia Cardiac arrest Hepatic inflammation Early or Late Complication: Compartment Syndrome There are multiple complications that can arise in a patient with rhabdomyolysis and these can be classified as ‘early’ or ‘late’ complications. Early complications include hyperkalemia and hypocalcemia - both of which arise from the large amounts calcium and phosphate in the blood and can further lead to cardiac arrhythmia or cardiac arrest. Hepatic dysfunction is another early complication that occurs in 25% of patients with rhabdo due to the proteases released from injured muscle. http://www.aafp.org/afp/2002/0301/p907.html In terms of late complications - Acute kidney injury or AKI, as mentioned earlier, is one of the most serious complications and occurs in 15% of patients. https://www.ncbi.nlm.nih.gov/pubmed/18711286 The main pathophysiological mechanisms of renal injury are renal vasoconstriction from myoglobin precipitation, the toxic effect of free iron tubules, and hypovolemia (a decrease in blood volume). The other late complication is Disseminated intravascular coagulation (DIC) and is characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body Finally, compartment syndrome may be an early or a late complication resulting directly from muscle injury and is due to pressure build up in the injured muscles to dangerous levels. Basically it decreases blood flow which prevents nutrients and oxygen from reaching the nerves and muscles. This syndrome can be either acute or chronic.

TREATMENTS First component is managing the source of the muscle injury IV fluid therapy (main and most important treatment) Bicarbonate/mannitol Continuous Renal Replacement Therapy Treatment First component of treatment is managing the source of muscle injury This can involve removing a harmful drug, controlling patient’s body temp, or treating an infection IV fluid therapy Main and most important course of treatment This increases renal blood flow and causes secretion of the nephrotoxic compounds in the patient’s system IV fluid therapy should ideally be initiated within 6 h of muscle injury, targeting a urine output of 300 mL/h Facilitates excretion of uric acid Bicarbonate for prevention of AKI (acute kidney injury) Based on concept that an acidic environment promotes myoglobin toxicity Therefore, a more basic environment will help regulate this Mannitol The use of mannitol remains controversial Continuous renal replacement therapy (CRRT) Clears myoglobin from the bloodstream, thereby potentially decreasing the amount of renal damage This treatment is typically used only if initial attempts to to prevent AKI are ineffective and it has become life-threatening

SUMMARY SLIDE Condition that causes the breakdown of skeletal muscle fibres causing release of myoglobin, intracellular proteins and electrolytes into circulation Two fates: the immediate destruction of these cells spilling their contents or the surviving cells will experiencing an increase in intracellular calcium Calcium accumulates and begins to pool outside the sarcolemma and leads to continuous muscle contraction, depleting the cell of ATP The most common symptoms include muscle pain, weakness, and reddish-brown urine Diagnosis includes a false positive urine test for blood but negative for RBCs and increased CPK levels Early complications include hyperkalemia and hypocalcemia which can lead to cardiac arrhythmia or cardiac arrest. Late complications include acute renal failure and disseminated intravascular coagulation First component of treatment is managing the source of muscle injury but the most important course of treatment is IV fluid therapy Non-traumatic rhabdomyolysis may cause 7% of all cases of acute renal failure.

REFERENCES Bagley, W. Yang, H. Shah, K. (2007). Rhabdomyolysis. Intern Emerg Med, 2:210-218 Chavez et al. (2016). Beyond muscle destruction: A systematic review of rhabdomyolysis for clinical practice. Critical Care, 20:135-146 Sauret, J. Marinides, G. Wang, G. (2002). Rhabdomyolysis. Am Fam Physician, 65(5):907-913 Lima et al. Saudi (2008). Acute kidney injury due to rhabdomyolysis. J Kidney Dis Transpl, 19(5):721-729

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