بنام خدا

1. بنام خدا

2. Rhabdomyolysis and Acute Kidney Injury Dr Fazel.FCCM

3. Although acute renal failure owing to crush injury after war wounds and motor vehicle accidents was described early in the 20thcentury(1941)Bywaters and Beall highlighted the syndrome in detail after the Battle of London. .during World War II

4. “Crush syndrome” first recorded in bombing of London during WWII: 5 people who were crushed presented in shock with swollen extremities, dark urine. • Later died from renal failure. • 5-35% of patients with rhabdomyolysis develop ARF • mortality is 3-50%

5. In December 1988, an earthquake with a magnitude of 6.9 on the Richter scale killed more than 25,000 people in Armenia. In the aftermath, the occurrence of nearly 600 cases of acute renal failure created a second catastrophe, subsequently called a “renal disaster.” At least 225 victims required .dialysis

6. Rhabdomyolysis — literally, the dissolution of striped (skeletal) muscle — is characterized by the leakage of muscle-cell contents, including electrolytes, myoglobin, and other sarcoplasmic proteins (e.g., creatinekinase, aldolase, lactate dehydrogenase,alanineaminotransferase, and aspartateaminotransferase) into the circulation

7. The characteristic triad of complaints in :rhabdomyolysis is muscle pain Weakness dark urine

8. Massive necrosis, which is :manifested as limbweakness, myalgia,swelling, and, commonly, gross pigmenturia without hematuria, is the common denominator of both traumatic and nontraumaticrhabdomyolysis.

9. Additional symptoms that are more common in severely affected patients :include malaise, fever, tachycardia, nausea and vomiting, and abdominal pain . Altered mental status may occur from the underlying etiology (eg, toxins, drugs, trauma, or electrolyte abnormalities).

10. First,Direct injury to skeletal muscle tissue ,when the mechanism of injury resulted in transfer of a great deal ofenergy . Second, rhabdomyolysiscan occur secondary to compression of tissues for a prolonged periodafter the injury. Lastly, rhabdomyolysis can result from compartment syndrome due to a fracture. All three mechanismsofrhabdomyolysis can be .exacerbated by hemorrhagic shock

11. Acute kidney injury is a potential complication of severe rhabdomyolysis, regardless ofwhetherthe rhabdomyolysis is the result of trauma or some other cause, and the prognosis is substantially worse if renal failure develops and it may be life-threatening

12. Acute kidney injury as a complication of rhabdomyolysis is quite common, representing about 7 to 10% of all cases of acute kidney injury in the .United States

13. The true incidence of acute kidney injury in rhabdomyolysis is difficult to establish owing to varying definitions and clinical scenarios. The reported incidence :ranges from 13% to approximately 50%

14. Among patients in the intensive care unit, the mortality has been reported to be 59% when acute kidney injury is present and 22% when it is not .present

15. Long-term survival among patients with rhabdomyolysis and acute kidney injury is reported to be close to 80%, and the majority of patients with rhabdomyolysis-induced acute kidney injury recover renal function.

17. Pathogenesis of Myoglobin-Induced Acute Kidney Injury

18. Myocyte Injury Tolerable-no permanent histological changes Muscle necrosis Hours of ischemia 0 2 4 6 Irreversible anatomic and functional changes

19. The mechanisms involved in the pathogenesis of rhabdomyolysis: 1-direct sarcolemmicinjury (e.g., trauma) 2-depletion of ATP within the myocyte, leading to an unregulated increase in intracellular calcium.

20. Ultimately, the myofibrillar network .breaks down In rhabdomyolysiscaused by trauma, additional injury results from ischemia reperfusion andinflammationby neutrophils.that infiltrate damaged muscle

21. Rhabdomyolysis Myoglobinemia Endotoxin cascade 3,rd spacing NO scavenging Myoglobinuria Volume depletion Acidemia Proxmial tubule Fe loading Aciduria Renal hypoperfusion/ Ischemia Cast formation Luminal stasis Synergistic tubular damage ARF ATN

22. Although the exact mechanisms by which rhabdomyolysis impairs the GFR are unclear, experimental evidence suggests that intrarenalvasoconstriction, direct and ischemic tubule injury, and tubular .obstructionall play a role

23. Myoglobin seems to have no marked nephrotoxic effect in the tubules unless the urine is acidic. cellular release of myoglobin leads to uncontrolled leakage of reactive oxygen species, and free radicals .cause cellular injury

24. Renal vasoconstriction is a characteristic feature of rhabdomyolysis-induced acute kidney injury and is the result of various combinations of several mechanisms.

25. First:intravascular volume depletion due to fluid sequestration within damaged muscle promotes homeostatic activation of the renin–angiotensin system, vasopressin, and the sympathetic nervous system. Second: there are additional vascular mediators in the reduction of renal blood flow, including endothelin-1, thromboxane A2, tumor necrosis factor α; and F2-isoprostanes. a deficit in the vasodilator nitric oxide, which can be attributed to the scavenging effect of myoglobin in the renal microcirculation, has also been shown to be a mediator in the reduction in renal blood flow

26. Renal Manifestations of Rhabdomyolysis

27. pigmented granular casts reddish-brown urinsupernatant and markedly raised serum creatinekinase

28. CPK had been used traditionally to diagnose and trend compartment syndrome. However, it should not be used for early detection but can be used for monitoring after compartment .decompression

29. There is nodefined threshold value of serum creatinekinase above which the risk of acute kidney injury is markedly increased. A very weak correlation between the peak creatinekinase value and the incidence of acute kidney injury or peak serum creatinine has been reported. The risk of acute kidney injury in rhabdomyolysisis usually low when creatinekinase levels at admission are less than 15,000 to 20,000 U per liter.

30. Although acute kidney injury may be associated with creatinekinase values as low as 5000 U per liter, this usually occurs when coexisting conditions such as sepsis, dehydration, and acidosis are present

31. Acute kidney injury associated with rhabdomyolysis often leads to a more rapid increase in plasma creatinine than do other forms of acute kidney injury. Similarly, a low ratio of blood urea nitrogen to creatinine is often seen in patients with rhabdomyolysis. Rhabdomyolysis-induced acute kidney injury frequently causes oliguria and occasionally causes anuria.

32. electrolyte levels should be measured as soon as rhabdomyolysis is diagnosed. hyperkalemia (which can be rapidly increasing), hyperphosphatemia, hyperuricemia,hypocalcemiahigh anion-gap metabolic acidosis, and hypermagnesemia mainly when renal .failure is present

33. the general goals for preventive therapy are: 1-Correction of volume depletion, if present 2-Prevention of intratubular cast formation

34. Treatment and Prevention the main step in managing the condition remains the early, aggressive repletion of fluids; patients often require about 10 liters of fluid per day, with the amount administered depending on the severity of the rhabdomyolysis.

35. the composition of the fluid used for repletion remains .controversial

36. sodium bicarbonate, which results in an alkaline urine First, it is known that precipitation of the Tamm–Horsfall protein–myoglobin complex is increased in acidic urine. Second, alkalinizationinhibits reduction–oxidation (redox) cycling of myoglobin and lipid peroxidationin rhabdomyolysis, thus ameliorating tubule injury. Third, it has been shown that metmyoglobin induces vasoconstriction only in an acidic medium in the .isolated perfused kidney

37. If sodium bicarbonate is used urine pH and serum bicarbonate, calcium, and potassium levels should be monitored, and if the urine pH does not rise after 4 to 6 hours of treatment or if symptomatic hypocalcemia develops, alkalinization should be discontinued and hydration continued with normal saline.

38. The use of diuretics remains controversial Mannitol may have several benefits: as an osmotic diuretic, it increases urinary flow and the flushing of nephrotoxic agents through the renal tubules; as an osmotic agent, it creates a gradient that extracts fluid that has accumulated in injured muscles and thus improves hypovolemia; .finally, it is a free-radical scavenger

39. During the time mannitol is being administered, plasma osmolalityand the osmolal gap (i.e., the difference between the measured and calculated serum osmolality) should be monitored frequently and therapy discontinued if adequate diuresis is not achieved or if the osmolal gap rises above 55mOsm per kilogram.

40. When acute kidney injury is severe enough to produce refractory hyperkalemia, acidosis, or volume overload, renal-replacement therapy is indicated, principally with intermittent hemodialysis, which can correct electrolyte abnormalities rapidly and efficiently

41. plasmapheresis has been shown to have no effect on outcomes or on the myoglobin.burden of the kidneys

43. Early fluid resuscitation (within the first six hours, preferably before the victim is extricated) is essential. The preferred fluid is isotonic saline, given at a rate of 1 liter per hour (10 to 15 ml per kilogram of body weight per hour), while the victim is under the rubble, followed by hypotonic saline soon after rescue. Adding 50 mEq of sodium bicarbonate to each second or third liter of hypotonic saline (usually a total of 200 to 300 mEq the first day) will maintain urinary pH above 6.5 and prevent intratubular deposition of myoglobin and uric acid. If urinary flow exceeds 20 ml per hour, 50 ml of 20 percent mannitol (1 to 2 g per kilogram per day [total, 120 g], given at a rate of 5 g per hour) may be added to each liter of infusate.

44. Once a patient with the crush syndrome has been hospitalized, urinary output should ideally exceed 300 ml per hour. Such a goal may require the intravenous infusion of up to 12 liters of fluid per day (4 to 6 liters of which will contain bicarbonate). The volume administered is generally much greater than the urinary output; the difference between intake and output is due to the accumulation of fluid in the damaged muscles, which may exceed 4 liters. This protocol should be continued until clinical or biochemical evidence of myoglobinuria disappears (usually by day 3).

45. This approach was tested in the 1999 earthquake in the Marmara region, Turkey, in which 639 victims had acute renal failure; in the 2003 earthquake in Bam, Iran; and in the 2005 earthquake in Kashmir, Pakistan

46. empirical administration of potassium-containing solutions in the field should be strictly avoided.Serum potassium levels should be measured at least three or four times daily, especially in the first days after a patient is admitted and in patients with severe trauma, who are at higher risk for hyperkalemia. Hypocalcemia should be treated only if it is symptomatic, because early intramuscular accumulation of calcium is followed by hypercalcemia at later stages.

47. Administration of iron-chelating agents such as desferrioxamine (standard dosage for rhabdomyolysis not established) and alkalinizationof urine using sodium bicarbonate as 50% of the resuscitationfluid (150 mEq dissolved in 1 L of 5% dextrose solution) or a carbonicanhydraseinhibitor such as Acetazolamide is recommended by some .expert

48. In our institution, we aim to maintain a urine output greater than 1 to 2 mL/kg/h using IV fluids, and we follow serial serum and urine myoglobin levels. We have had good success in avoiding acute renal failure without the use of urine alkalinizationOr iron chelating agents.

49. how long dialysis will be needed? the average is 13 to 18 days. Twice- and even thrice-daily dialysis may be needed. Dialysis can be discontinued only after kidney function has recovered, as suggested by a normalization of urinary volume in a patient with improving serum biochemical values in the absence of fluid overload.

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