بنام خدا

Rhabdomyolysis and

Acute Kidney Injury

Dr Fazel.FCCM

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

•“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%

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

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., creatine kinase, aldolase, lactate dehydrogenase,alanineaminotransferase, and aspartate aminotransferase )

into the circulation

The characteristic triad of complaints in :rhabdomyolysis ismuscle painWeakness

dark urine

Massive necrosis, which is :manifested as

limb weakness, myalgia, swelling, and, commonly, gross pigmenturia without hematuria, is the common denominator of both traumatic and nontraumatic rhabdomyolysis.

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.)

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 mechanismsof rhabdomyolysis can be .exacerbated by hemorrhagic shock

Acute kidney injury is a potential complication of severe rhabdomyolysis, regardless ofwhether the 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

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

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%

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

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.

Pathogenesis of Myoglobin-Induced Acute Kidney Injury

Myocyte Injury

Hours of ischemia

0 2 4 6

Tolerable-no permanent histological

changes

Irreversible anatomic and

functional changes

Muscle necrosis

The mechanisms involved in the pathogenesis of rhabdomyolysis:

1-direct sarcolemmic injury (e.g., trauma)

2-depletion of ATP within the myocyte, leading to an

unregulated increase in intracellular calcium.

Ultimately, the myofibrillar network .breaks downIn rhabdomyolysis caused by trauma, additional injury results from ischemia reperfusion andinflammation by neutrophils .that infiltrate damaged muscle

Rhabdomyolysis

Endotoxincascade

Renal hypoperfusion/Ischemia

3,rd spacing

Volume depletion

Acidemia

Aciduria

Myoglobinemia

NO scavenging Myoglobinuria

Proxmial tubuleFe loading

Cast formation

Luminal stasis

Synergistic tubular damage

ATNARF

Although the exact mechanisms by which rhabdomyolysis impairs the GFR are unclear, experimental evidence suggests that

intrarenal vasoconstriction, direct and ischemic tubule injury, and tubular .obstruction all play a role

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

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

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

Renal Manifestations of

Rhabdomyolysis

pigmented granular casts reddish-brown urinsupernatant

and markedly raised serum creatine kinase

CPK had been used traditionally to diagnose and trendcompartment syndrome. However, it should not be used for earlydetection but can be used for monitoring after compartment

.decompression

There is no defined threshold value of serum creatine kinase above which the risk of acute kidney injury is markedly increased. A very weak correlation between the peak creatine kinase value and the incidence of acute kidney injury or peak serum creatinine has been reported. The risk of acute kidney injury in rhabdomyolysis is usually low when creatine kinase levels at admission are less than 15,000 to 20,000 U per liter.

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

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.

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

the general goals for preventive therapy are:

1-Correction of volume depletion, if present

2-Prevention of intratubular cast formation

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.

the composition of the fluid used for repletion remains .controversial

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, alkalinization inhibits reduction–oxidation (redox) cycling of myoglobin and lipid peroxidation in rhabdomyolysis, thus ameliorating tubule injury.

Third, it has been shown that metmyoglobin induces vasoconstriction only in an acidic medium in the .isolated perfused kidney

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.

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

During the time mannitol is being administered, plasma osmolality and 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 55 mOsm per kilogram.

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

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

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.

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).

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

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 .

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 carbonicanhydrase inhibitor such asAcetazolamide is recommended by some .expert

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 alkalinization Or iron chelating agents.

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.

Thanks for joining us today!