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be closely monitored. (See 'Urine output goal' below.) The rate of fluid administration is decreased after the first 24 hours but is still maintained at a rate that is greater than the urine output, as long as there is no evidence of fluid overload. Generally, a total of 200 to 300 mEq of bicarbonate is given on the first day as long as the patient is not alkalemic. The exact rate and regimen is altered based upon ongoing clinical assessment and laboratory values. (See 'Urine output goal' below.) Potential risks associated with alkalinization of the plasma include promoting calcium phosphate deposition and inducing or worsening the manifestations of hypocalcemia by both a direct membrane effect and a reduction in ionized calcium levels . Manifestations of severe ionized hypocalcemia include tetany, seizures, and arrhythmias. To minimize the risk of these complications, the arterial pH should not exceed 7.5. (See "Clinical manifestations of hypocalcemia".) Alkalinization can also reduce the plasma potassium concentration secondary to intracellular shift.
This is often a beneficial effect, since the combination of tissue breakdown and renal failure often leads to hyperkalemia. (See "Causes of hypokalemia", section on 'Increased entry into cells'.) Because of the potential risks with bicarbonate therapy, we recommend close monitoring of serum bicarbonate, calcium, and potassium, and the urine pH. The urine pH can be measured by immersion of a simple urine dipstick, but this is only reliable on freshly voided urine, unless urine is collected under paraffin (which is difficult to obtain in chaotic disaster conditions). The goal urine pH is greater than 6.5. We recommend discontinuing the bicarbonate-containing solution (but continuing to replete volume with isotonic saline) if the arterial pH exceeds 7.5, the serum bicarbonate exceeds 31 mEq/L, or the patient develops symptomatic hypocalcemia. Calcium supplementation should be given only for symptomatic hypocalcemia or severe hyperkalemia, since early deposition of calcium in muscle is followed by hypercalcemia later in the injury process. (See "Treatment of hypocalcemia".) Use of mannitol — If urinary flow is adequate (defined as 20 mL/hour), adding 50 mL of 20 percent mannitol (1 to 2 g/kg per day [total, 120 g], given at a rate of 5 g per hour) to each liter of fluid is suggested. Mannitol is contraindicated in patients with oligoanuria.
Mannitol should be discontinued if the desired diuresis of approximately 200 to 300 mL/hour cannot be achieved, since there is a risk of hyperosmolality, volume overload, and hyperkalemia with continued mannitol administration under these conditions. (See "Complications of mannitol therapy".) The mechanism by which mannitol protects against heme pigment-induced ATN is not completely clear. Experimental studies have suggested that mannitol may be protective by causing a diuresis, which minimizes intratubular heme pigment deposition and cast formation . It has also been proposed that mannitol may act as a free radical scavenger, thereby minimizing cell injury . In addition to these beneficial effects on the kidney, mannitol may extract sequestered water from the injured muscles, thus preventing compartmental syndrome .
However, at least some studies have shown no amelioration of proximal tubular necrosis with mannitol, and mannitol may cause hyperosmolality and other complications . The available retrospective series, most of which are uncontrolled, report conflicting results regarding the effectiveness of mannitol plus bicarbonate in preventing heme pigment-induced AKI [18,19,26,27].
As an example, 154 of 382 patients with serum CK concentration 5000 U/L were treated with mannitol plus bicarbonate . There was no statistically significant difference in the incidence of AKI (defined as creatinine 2.0 mg/dL [177 micromol/L]; 22 versus 18 percent), dialysis (7 versus 6 percent), or death (15 versus 18 percent) in patients who were or were not treated with mannitol plus bicarbonate. However, there was a trend toward improved outcomes in patients with extremely
high CK levels (30,000 U/L) treated with mannitol and bicarbonate. This is relevant, given that such high levels are not unusual in victims of earthquakes [19,22].
The interpretation of these findings is hampered by the lack of reporting of other elements of treatment, such as adequacy of volume resuscitation, presence of other factors contributing to AKI (eg, drugs, sepsis, hypotension), timing of interventions, and relatively low rate of severe AKI (eg, requiring dialysis).
Unless the patient is carefully monitored and losses replaced when appropriate, mannitol can lead to both volume depletion and, since free water is lost with mannitol, hypernatremia. Mannitol administered in very high doses, or to patients with reduced renal excretion due to renal insufficiency, can also raise plasma osmolality sufficiently to cause symptoms of hyperosmolality and volume expansion. The increase in plasma osmolality can also cause passive movement of potassium out of cells and raise the plasma potassium concentration. AKI may occur if patients are treated with more than 200 g of mannitol per day. (See "Complications of mannitol therapy".) Prevention of hyperkalemia — Although sporadic patients with rhabdomyolysis or the crush syndrome may develop hypokalemia, the large majority are hyperkalemic, which is life-threatening [6,13,28,29]. Hyperkalemia may occur even in the absence of AKI, since a large amount of potassium may be released from injured muscle. Since potassium measurements at first triage are seldom available in disaster conditions, transport of victims with a potential crush syndrome to safer areas for more intensive treatment should be started, if possible, after the administration of a preventive oral dose of the potassium binding resin, sodium polystyrene sulfonate, in combination with 33 percent sorbitol, at a 1:3 ratio .
Although efficacy of sodium polystyrene sulfonate has been questioned, and although sorbitol has sporadically been associated with ulcers of the intestinal wall , we suggest their use in disaster crush victims, since the risk of fatal hyperkalemia is extremely high. (See "Treatment and prevention of hyperkalemia", section on Cationic exchange resin for further discussion of this topic.) Since a calcium load is to be avoided, sodium polystyrene sulfonate should be preferred to calcium polystyrene sulfonate. (Calcium polystyrene sulfonate is not available in the United States, although it is available elsewhere.) Many of the isotonic solutions for fluid repletion contain potassium (eg, Ringer's lactate). Because of the risk for life-threatening hyperkalemia, empiric administration of such preparations is absolutely contraindicated in patients at risk for the crush syndrome.
We recommend monitoring plasma potassium several times daily until stabilized. Hyperkalemia should be appropriately treated. (See "Treatment and prevention of hyperkalemia".) If serum potassium concentration cannot be measured due to field conditions, electrocardiography (ECG) can offer useful information, although a normal ECG may be present in spite of overt hyperkalemia. (See "Treatment and prevention of hyperkalemia".) Urine output goal — Once the patient can be closely monitored (such as hospital or triage setting), the administration of intravenous fluid should be adjusted to maintain the urinary output at approximately 200 to 300 mL/hour. This is done to help ensure adequate renal perfusion and to wash out any obstructing casts. Patients must be followed closely to ensure that fluid overload, as defined by signs of pulmonary congestion, does not occur. As previously mentioned, limb swelling alone may not represent volume overload.
If the urine output goal is achieved, this fluid regimen should be administered until the disappearance of myoglobinuria (either clinically or biochemically). This usually requires several days.
However, if the desired diuresis is not established, we recommend placement of a central venous pressure (CVP) catheter in addition to close monitoring of input and all losses (urinary volume plus other losses together) of the previous day. Forced diuresis should be abandoned if CVP measurements exceed acceptable thresholds (15 cm H2O).
Therapy should be based on CVP measurements, biochemical analysis, close monitoring of fluid intake and output, and body weight. A stable weight may suggest that the appropriate amount of fluid is being administered to the patient. However, if the patient is anuric and catabolic, a stable body weight may be deceptive. In those cases, we administer 500 to 1000 mL of fluid in excess of all losses of the previous day.
After serum CK levels begin to return to normal, the volume of administered fluids should be gradually tapered under close clinical and laboratory monitoring. A parallel decrease in urinary output together with normal clinical and biochemical findings indicates that tubular function has been restored.
Dialysis should be initiated in the setting of persistent oligoanuria or other indications. (See 'Treatment of established AKI' below.) Total volume administered — The total amount of volume administered depends upon the clinical scenario. A positive fluid balance is always necessary in crush syndrome casualties, since extreme amounts of fluids can diffuse into the damaged muscles. Mannitol-alkaline solution can be administered at quantities of up to 12 L/day to an adult weighing 75 kg and with appropriate urine response. Eight liters of urinary output can be expected following an infusion of 12 L of this solution. Therefore, it is reasonable to administer 4 to 4.5 L more fluid than all of the total losses of the previous 24-hour period . Analysis of the Bingol earthquake demonstrated that dialysis was avoided in many patients with crush syndrome by administering more than 20 L of fluid per day to each patient . The relatively low number of victims injured in this particular disaster allowed for more careful monitoring of each victim, which allowed the vigorous volume repletion.
Fluid administration should be individualized and may need to be less aggressive in chaotic disaster circumstances when it is impossible to monitor patients appropriately to avoid volume overload.
Under these circumstances, more modest volume repletion is recommended. Although the exact optimal limit is unknown, we suggest administering up to a maximum of 6 L of fluid per day under prolonged conditions in which close monitoring may not be possible. More cautious volume repletion is also warranted in victims who are prone to cardiac failure, such as the elderly, and in those who are anuric .
Calcium — Calcium supplementation should be given only for symptomatic hypocalcemia or severe hyperkalemia, because early deposition of calcium in muscle is followed by hypercalcemia later in the injury process. (See "Treatment of hypocalcemia".) Loop diuretics — Loop diuretics have no impact on outcome in AKI [32,33]. (See "Possible prevention and therapy of postischemic acute tubular necrosis".) In the context of rhabdomyolysis, loop diuretics may worsen the already existing trend for hypocalcemia, since they induce calciuria and may increase the risk of cast formation [8,22]. Despite these concerns, however, judicious use of loop diuretics may be justified in elderly patients, especially if volume overloaded.
TREATMENT OF ESTABLISHED AKI — Other than maintenance of fluid and electrolyte balance and tissue perfusion, there is no specific therapy once the patient has developed AKI. Dialysis is initiated for the usual indications, including volume overload, hyperkalemia, severe acidemia, and uremia. Frequent (twice or even three times daily) hemodialysis may be indicated in patients with crush syndrome, given the high risk of fatal hyperkalemia. A detailed discussion of the indications for dialysis is presented elsewhere. (See "Renal replacement therapy (dialysis) in acute kidney
injury (acute renal failure): Indications, timing, and dialysis dose".) Intermittent hemodialysis is suggested over other renal replacement modalities in the setting of crush syndrome. Compared with other modalities, intermittent hemodialysis is most efficient at removing potassium, which is one of the major causes of death . (See "Acute hemodialysis prescription".)
The other renal replacement modalities have the following additional limitations:
Peritoneal dialysis (PD) might be difficult to perform in case of abdominal and/or thoracic trauma, or in patients who cannot lie down due to hypervolemia-related heart failure and/or respiratory failure. PD may also not adequately treat the metabolic and electrolyte derangements caused by rhabdomyolysis (eg, hyperkalemia and other abnormalities), especially in the heavily traumatized patients. Furthermore, PD may create logistic problems in mass disasters, due to the necessity to deliver large loads of bags containing sterile dialysis fluid to the disaster area. (See "Use of peritoneal dialysis for the treatment of acute kidney injury (acute renal failure)".) Continuous dialysis strategies are limited by the need for large amounts of sterile replacement fluid that may be difficult to obtain in disaster conditions. In addition, only one patient can be treated per machine when continuous modalities are used. Finally, continuous anticoagulation by heparin may enhance a bleeding tendency in heavily traumatized patients. Regional citrate anticoagulation avoids the problems associated with anticoagulation but is difficult to monitor in chaotic disaster circumstances. (See "Continuous renal replacement therapies: Overview" and "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure): Indications, timing, and dialysis dose".)
SUMMARY AND RECOMMENDATIONS
High circulating levels in the plasma of myoglobin secondary to rhabdomyolysis can directly cause acute tubular necrosis (ATN), resulting in acute kidney injury (AKI). Rhabdomyolysisassociated AKI due to crush injury is a major source of morbidity in natural or man-made disasters.
(See 'Introduction' above.) Among entrapped subjects prone to develop the crush syndrome, we suggest the following