Crush-related acute kidney injury

INTRODUCTION — Natural or manmade disaster victims often suffer from crush-related injury [1,2]. Such injuries can cause extensive muscle damage and rhabdomyolysis, which can lead to myoglobin-associated acute kidney injury (AKI) [3-6]. (See "Definition and staging criteria of acute kidney injury in adults".)

The epidemiology, clinical features, diagnosis, prevention, and treatment of crush-related AKI due to traumatic rhabdomyolysis will be discussed in this topic. General management of crush injury is discussed at length elsewhere. (See "Severe crush injury in adults".)

AKI due to nontraumatic rhabdomyolysis and hemolysis and general overviews of rhabdomyolysis, hemolysis, and drug-induced myopathies are discussed in detail separately:

●(See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

●(See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

●(See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

●(See "Diagnosis of hemolytic anemia in adults".)

●(See "Drug-induced myopathies".)

DEFINITIONS AND EPIDEMIOLOGY — Systemic manifestations that are induced by crush injury are often referred to as crush syndrome. According to some estimates, the incidence of crush syndrome ranges between 2 and 5 percent of all injured victims of catastrophic earthquakes [7-10] and 30 to 50 percent of patients with traumatic rhabdomyolysis. Children are at a lower risk of suffering from crush-related injury [9,11,12] and, if injured, have a lower risk of mortality [9]. All disaster victims, irrespective of whether they are mildly or severely injured, should be considered at increased risk of crush syndrome. (See "Severe crush injury in adults", section on 'Crush syndrome'.)

The incidence of crush-injury-related AKI and the frequency with which dialysis is required in these cases have varied widely in different studies. The following reports have analyzed these aspects as part of crush injury following catastrophic earthquakes.

In a report from Bam, Iran, dialysis was required in 6.5 percent of 1975 patients admitted to the hospital [11]. The majority of victims were rescued in less than four hours. The short time under the rubble might thus explain, at least in part, the lower rate of requiring dialysis in Bam compared with other reports, although this is not entirely certain.

Much higher rates of dialysis requirement were noted in two other catastrophic earthquakes: 54 percent in the Kobe earthquake and 75 percent in the Marmara earthquake [10,13]. In the Kobe earthquake, the need for hemodialysis correlated directly with increased serum creatine kinase (CK) levels as dialysis was required in 84 and 39 percent of patients with a CK level greater or less than 75,000 units/L, respectively [10].

Although not many other natural disasters cause traumatic rhabdomyolysis, a number of manmade disasters may do so (such as terrorist attacks, mining accidents, wars, and torture) [14-16].

CLINICAL MANIFESTATIONS — Kidney manifestations of crush-related injuries are discussed here. Other systemic manifestations of crush-related injury are discussed at length elsewhere. (See "Severe crush injury in adults", section on 'Clinical manifestations' and "Severe lower extremity injury in the adult patient", section on 'Lower extremity evaluation'.)

Acute kidney injury — AKI can range from mild to severe and dialysis-requiring. The severity of AKI depends upon the extent of injury to muscle, the degree of volume depletion, the presence or absence of underlying comorbid conditions, and the development of complications (eg, sepsis) [17-19].

Crush-related AKI can result from prerenal, intrarenal, or postrenal etiologies:

●Prerenal AKI can result from severe hypovolemia, which is common among victims of crush-related injuries for several reasons. Patients lose access to water while remaining trapped for hours or days but continue to have ongoing losses that ultimately result in negative fluid balance. Patients with vascular injury may lose intravascular volume and develop hypovolemic shock. Additionally, upon rescue, decompression at the sites of muscle injury can result in reperfusion-related third spacing of fluid leading to intravascular hypovolemia and prerenal AKI.

●Intrarenal AKI in the setting of crush-related injury is typically due to rhabdomyolysis. The characteristic manifestation of rhabdomyolysis-related acute tubular necrosis (ATN) is dark red, brown, or black urine. However, urine may not be discolored among some patients with rhabdomyolysis-related ATN if their urine is diluted from aggressive fluid resuscitation [20]. Microscopic evaluation of the urinary sediment often reveals pigmented granular casts. AKI resulting from heme pigment-induced ATN is usually characterized by an initial oliguric period, followed by polyuria, which usually starts within one to three weeks after the primary event. Some cases may present with a nonoliguric course. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

Other causes of intrarenal AKI in patients with crush-related injury include ischemic or toxic injury from prolonged shock, sepsis, use of nephrotoxic agents, cardiac failure, arrhythmias, or transfusion reactions.

●Postrenal AKI may develop due to traumatic injury or obstruction of urinary outflow tract, mostly in patients suffering from pelvic trauma.

Biochemical abnormalities — The biochemical abnormalities that characterize rhabdomyolysis-associated AKI include hyperkalemia that may be life threatening, hyperphosphatemia, hypocalcemia (which is occasionally followed by hypercalcemia during the recovery stage), a high creatine kinase (CK), and a low fractional excretion of sodium. These are discussed elsewhere. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

High serum levels of myoglobin are very rarely detected because of the short half-life of myoglobin and its quick clearance from the plasma.

DIAGNOSIS — Patients with rhabdomyolysis-induced acute tubular necrosis (ATN) typically present with a red to brown color of the urine without presence of erythrocytes at microscopic examination, pigmented granular casts in the urinary sediment, varying severity of kidney dysfunction, and a marked elevation in the plasma creatine kinase (CK) level. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

DIFFERENTIAL DIAGNOSIS — The intermittent excretion of red to brown urine can be seen in a variety of clinical settings, including heme pigment-induced acute tubular necrosis (ATN). The approach to this issue is discussed separately.

AKI can also be caused by other conditions or abnormalities commonly observed in patients with traumatic rhabdomyolysis. These include drug-induced AKI (such as aminoglycosides and nonsteroidal antiinflammatory drugs), sepsis, severe hypotension due to marked hypovolemia, and others. This is also discussed elsewhere. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

PREVENTION — The general goals for preventive therapy in all cases of heme pigment-induced AKI are to both enhance kidney perfusion (thereby minimizing ischemic injury) and increase the urine flow rate to wash out obstructing casts. Volume resuscitation should be initiated before the crush is relieved or as soon as possible thereafter, before heme pigment and other intracellular elements have been released into the circulation and before third spacing at the site of muscle injury worsens hypovolemia [4,21-23]. In the case of disaster, preventive measures should be applied to crush victims already at the disaster field, in the field hospitals, during transportation to the hospitals, and after admission to regular hospitals.

The most important preventive measure at the disaster field is the correction of volume depletion. During volume resuscitation, the timing and rate of fluid administration, volume of fluids, and also types of fluid are important elements to consider.

The approach to prevention of AKI also may vary based upon the location of the patient and ability to closely monitor the victim or not.

Before and during extrication — Aggressive fluid repletion should be started before the extrication of entrapped subjects who are prone to develop crush syndrome, if possible (algorithm 1). Third spacing at the site of muscle injury worsens hypovolemia. Thus, patients with rhabdomyolysis may require massive amounts of fluid (up to 20 liters) to trigger and maintain a vigorous diuresis [21].

Children similarly require early and aggressive fluid resuscitation. Intravenous fluids at the rate of 15 to 20 mL/kg/h should be started when the victim is still under the rubble. If extrication takes longer than two hours, then the rate of fluid administration should be reduced to 10 mL/kg/h or lower [24]. If fluids cannot be given before extrication, then volume resuscitation should begin as soon as possible after extrication.

Evidence — The rationale of early and generous volume resuscitation is based upon the observations that early adequate fluid resuscitation is very important to help prevent AKI in patients with rhabdomyolysis due to crush injury.

Practically all of the published experience with volume resuscitation in patients with heme pigment-induced acute tubular necrosis (ATN) has come from retrospective reports of rhabdomyolysis in subjects with crush injury [4-6,21,23,25]. The following studies serve as examples of the importance of early fluid repletion in this setting [21,23]:

●Seven patients with crush syndrome who were trapped under rubble (all with creatine kinase [CK] concentrations >30,000 units/L) were treated with alkaline diuresis immediately after extrication; none developed kidney failure [23]. One patient who did not receive prophylactic volume repletion developed AKI and required hemodialysis [26].

●Sixteen earthquake victims trapped for a mean of 10 hours (12 had CK concentrations >20,000 units/L) were treated initially with isotonic saline at 1 L/hour, then with an alkaline-mannitol solution [21]. The four patients who required dialysis were treated approximately nine hours after extrication and received significantly less fluids compared with 12 patients who did not require dialysis and who were treated four hours after extrication with more massive quantities of fluid.

●In other reports of earthquake-related crush injury, AKI occurred in over 50 percent of patients for whom therapy was instituted much later [25,27].

However, in the aftermath of the Marmara earthquake, more extensive fluid administration was unexpectedly associated with a more frequent need for dialysis. This seemingly contradictory finding may be explained by the fact that many victims had already established AKI when they were admitted to hospitals [9]. In such cases, delayed fluid resuscitation might result in hypervolemia and a subsequent higher need for dialysis. Therefore, this finding does not indicate that disaster victims should receive less fluid in order to avoid dialysis, but underscores that, once AKI is established, the risk of volume overload is substantial. (See 'Treatment of established acute kidney injury' below.)

The optimal type and rate of fluid repletion are unclear. No studies have directly compared the efficacy and safety of different types and rates of fluid administration in this setting.

Prior to and during extrication, we agree with the Renal Disaster Relief Task Force (RDRTF) of the International Society of Nephrology (ISN) that isotonic saline, rather than isotonic bicarbonate, be administered because saline solutions are more readily available in massive disasters and have a well-described efficacy for volume replacement [28]. If available, isotonic saline plus 5 percent dextrose may be used since it provides the advantage of supplying calories and attenuating hyperkalemia.

Isotonic saline should initially be given at a rate of 1 L/hour (10 to 15 mL/kg of body weight per hour) while the victim is still under the rubble (algorithm 1). After 2 liters are given, the rate of administration should be decreased to 500 mL/hour to avoid volume overload. However, this volume should be individualized. Factors to consider are age (fluid administration should be performed more carefully in older adults); body mass index (more fluids are needed for the victims with larger body volume); trauma pattern (more fluid is needed in patients with more serious trauma); and amount of presumed fluid losses (more fluids are needed in hot climates and in victims who produce urine or have ongoing blood losses).

There is a potential role for isotonic bicarbonate therapy after extrication (see 'Use of bicarbonate' below), but this application is hampered in the aftermath of mass disasters for practical reasons (eg, availability).

More than 70 percent of total body potassium is contained in muscle, and therefore, patients with crush injuries frequently have severe hyperkalemia and a rapidly rising serum potassium. Thus, the use of potassium-containing solutions (such as Lactated Ringer) should generally be avoided, if possible. If there is no alternative, a balanced electrolyte solution containing no more than 5 mmol/L of potassium may be used; in such situations, the potassium should be closely monitored and therapy should be switched to a solution without potassium (eg, isotonic saline) as soon as possible.

After extrication — Extricated victims should be evacuated as quickly as possible from the site of structural collapse. Vital signs should be checked and a primary survey performed to define the extent and type of medical and surgical interventions needed. Victims with a low potential for survival should be triaged to determine who should receive priority for treatment. Afterwards, an initial systematic assessment of the injured patient should be performed to identify any life-threatening injuries and to prioritize urgent therapeutic needs. Hydration status of victims should be evaluated to determine the volume of fluids required. If no intravenous fluid was given prior to extraction, intravenous isotonic saline at a rate of 1 L/hour for adults should be initiated as soon as possible after rescue. The victim should be evaluated regularly, and urinary output should be monitored at least six hours while administering 3 to 6 L of fluid (algorithm 1) [28].

Use of bicarbonate — After urine output has been documented and overt alkalosis has been excluded, we agree with the RDRTF that an alkaline solution that is approximately isotonic may be used where feasible (such as in small-scale disasters) in an attempt to achieve a forced alkaline diuresis [28]. However, the use of complex solutions such as bicarbonate-containing solutions may be limited by logistic circumstances in mass disasters. The preparation of such solutions is time consuming and carries the risk of contamination and error in preparation.

The rationale for this approach is that raising the urine pH above 6.5 may prevent heme-protein precipitation with Tamm-Horsfall protein, intratubular pigment cast formation, and uric acid precipitation; correct metabolic acidosis; and reduce hyperkalemia [3,5,29]. Alkalinization may also decrease the release of free iron from myoglobin and the formation of F2-isoprostanes, which may enhance renal vasoconstriction. Administration of isotonic bicarbonate instead of NaCl may also prevent chloride accumulation and subsequent hyperchloremic acidosis. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

Despite these potential benefits, there is no clear clinical evidence that an alkaline diuresis is more effective than a saline diuresis in preventing AKI as no direct comparative trial has been performed. The best data in support of an alkaline diuresis are derived from uncontrolled case series. In a study cited above, for example, kidney failure did not develop in seven patients with crush syndrome who were trapped under rubble and were treated with alkaline diuresis immediately after extrication [23]. By comparison, one patient who did not receive prophylactic volume developed AKI and required hemodialysis [26].

The optimal regimen and rate of administration of bicarbonate are unknown. We generally administer one of the following two fluid regimens after extrication:

●One liter of isotonic saline alternating with 1 liter of half-isotonic saline plus 50 mEq of sodium bicarbonate.

●Isotonic saline for the first two liters, followed by 1 liter of half-isotonic saline plus 50 mEq of sodium bicarbonate. This sequence is then repeated, as indicated.

The choice between these two regimens depends in part upon the general clinical and biochemical condition of the patient and the blood pH. As an example, if measured laboratory values reflect only a mild acidosis, more liters of isotonic saline and fewer liters of bicarbonate-containing solution are given.

The rate of fluid administration with either regimen is based upon the ability to attain urinary output goals and assessment of volume status. In general, we administer the intravenous solution at 500 mL/hour for the first 24 hours, as long as there is no evidence of fluid overload and the patient can 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 are 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 [5]. 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 kidney failure often leads to hyperkalemia. (See "Causes of hypokalemia in adults", 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). The target urine pH is >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 30 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 recovery process. (See "Treatment of hypocalcemia".)

Use of mannitol — The use of mannitol to prevent AKI in the setting of crush injury is controversial; mannitol may or may not have benefit in patients with rhabdomyolysis and has the potential to cause harm. In our clinical experience, mannitol may represent a useful adjunct to intravenous crystalloid in nonoliguric patients with traumatic rhabdomyolysis, provided close monitoring is possible.

Mannitol is contraindicated in patients with oligoanuria.

If urinary flow is adequate (defined as >20 mL/hour), 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) may be added to each liter of fluid, providing an increase in urine output is demonstrated following a test dose of mannitol. Among members of the RDRTF-European Renal Best Practice (ERBP) crush recommendation work group, there was no consensus regarding mannitol administration, although most experts suggested assessing the response to a test dose first if mannitol were used [28]. A reasonable test dose is 60 mL of a 20 percent solution of mannitol administered intravenously over three to five minutes [28]. If there is no significant increase in the urine output by at least 30 to 50 mL/hour above baseline levels, mannitol should not be continued.

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".)

Unless the patient is carefully monitored and losses are 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 kidney function impairment 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".)

The mechanism by which mannitol may protect 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 [30]. It has also been proposed that mannitol may act as a free radical scavenger, thereby minimizing cell injury [6]. In addition to these beneficial effects on the kidney, mannitol may extract sequestered water from the injured muscles, thus preventing compartmental syndrome [31].

However, at least some studies have shown no amelioration of proximal tubular necrosis with mannitol, and mannitol may cause hyperosmolality and other complications [30]. 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 [21,23,32,33]. As an example, 154 of 382 patients with serum CK concentration >5000 units/L were treated with mannitol plus bicarbonate [33]. There was no statistically significant difference in the incidence of AKI (defined as creatinine >2 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 units/L) treated with mannitol and bicarbonate. This is relevant given that such high levels are not unusual in victims of earthquakes [23,27].

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).

Prevention of hyperkalemia — Although sporadic patients with rhabdomyolysis or the crush syndrome may develop hypokalemia, the large majority are hyperkalemic, which is life threatening [34-37]. 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 a gastrointestinal cation exchanger, such as sodium zirconium cyclosilicate (SZC) or patiromer.

SZC is generally preferred over patiromer because of its more rapid onset of action. Although sodium polystyrene sulfonate (SPS) has been associated with ulcers of the intestinal wall [38], we use SPS in disaster crush victims when SZC and patiromer are unavailable (or unaffordable in resource-limited settings) since the risk of fatal hyperkalemia is extremely high [22]. (See "Treatment and prevention of hyperkalemia in adults", section on 'Sodium polystyrene sulfonate (SPS) in rare settings'.)

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. In many victims, fluid administration is initiated in the field or during transportation; but, contrary to all recommendations, these solutions may contain potassium [39]. Therefore, on admission to hospitals, all fluid infusions should be checked, and potassium-containing solutions should be stopped immediately.

Hyperkalemia should be appropriately treated. (See "Treatment and prevention of hyperkalemia in adults".)

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. In the 2010 Haiti earthquake, point-of-care devices (eg, iSTAT) were invaluable in disaster-field conditions, providing direct electrolyte and creatinine measurements [40]. Such devices and an ECG can be used for the early detection of hyperkalemia to identify patients who may need urgent dialysis. (See "Treatment and prevention of hyperkalemia in adults", section on 'Determining the urgency of therapy' and "Treatment and prevention of hyperkalemia in adults", section on 'Patients with a hyperkalemic emergency'.)

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 kidney 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 a bladder catheter has not been placed before hospitalization, it should be inserted to all crush victims, after excluding urethral bleeding and/or laceration (which is characterized by blood at the urethral meatus), to follow urine flow [28]. Catheters carry a risk of infection, especially in the chaos accompanying most disasters. Therefore, unless there is an obligatory indication, such as unconsciousness, pelvic trauma, possible urethral obstruction, immobilization, or surgery, the catheter should be removed once the patient has established oligoanuric AKI or achieves normal kidney function and monitoring urine production provides no further useful information.

If the urine output goal is achieved, intravenous fluids should be administered until the disappearance of myoglobinuria (either clinically or biochemically). This usually requires several days.

Therapy should be based on physical examination and biochemical analysis, close monitoring of fluid intake and output, and body weight. Although frequently used to determine volume status, absolute central venous pressure (CVP) values can be misleading and often do not predict the response to volume infusion, especially in critically ill patients [41]. Absolute values are increased not only in hypervolemia, but also in other disease states, such as cardiac failure. For that reason, relative changes may be more useful than absolute values in reflecting intravascular volume status [42]. A stable weight may also suggest that the appropriate amount of fluid is being administered to the patient.

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 acute kidney injury' 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 in the early phase since extreme amounts of fluids can diffuse into the damaged muscles. Fluids 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 [4]. 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 [21]. 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 older adults, and in those who are anuric [43].

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 [44,45]. (See "Possible prevention and therapy of ischemic 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 [22,27]. Despite these concerns, however, judicious use of loop diuretics may be justified in older patients, especially if volume overloaded.

TREATMENT OF ESTABLISHED ACUTE KIDNEY INJURY — 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 "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

Intermittent hemodialysis is suggested over other kidney 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 [3]. (See "Acute hemodialysis prescription".)

The other kidney replacement modalities have the following additional limitations [46]:

●Peritoneal dialysis 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. Peritoneal dialysis 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, peritoneal dialysis 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 (PD) for the treatment of acute kidney injury (AKI) in adults".)

●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 "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and "Continuous kidney replacement therapy in acute kidney injury".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

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SUMMARY AND RECOMMENDATIONS

●Development of crush-related AKI – Hypovolemia due to various reasons and high circulating levels in the plasma of myoglobin secondary to rhabdomyolysis can directly cause acute tubular necrosis (ATN), resulting in acute kidney injury (AKI). Rhabdomyolysis-associated AKI due to crush injury is a major source of morbidity and mortality in natural or manmade disasters. (See 'Introduction' above.)

●Before and during extrication – To prevent crush-related AKI, we suggest starting intravenous (IV) fluid replacement prior to and during extrication of the victim whenever possible (Grade 2B). Among crush victims of mass disasters, we suggest giving isotonic saline rather than an isotonic alkaline solution (Grade 2C). Although the exact rate has not been defined by controlled studies, we suggest administering fluid at 1 L/hour initially. After two liters are given, the rate of administration should be decreased to 500 mL/hour to avoid volume overload (algorithm 1). (See 'Before and during extrication' above.)

●After extrication – If no IV fluid was given prior to extraction, IV isotonic saline at a rate of 1000 mL/hour for adults should be initiated as soon as possible after rescue (algorithm 1). After the victim has been removed from the rubble and urine output has been documented, isotonic saline may be switched to an isotonic bicarbonate solution if such fluids are available and alkalosis has been excluded. (See 'Use of bicarbonate' above.)

●Fluid and monitoring strategy – The optimal composition and rate of administration of IV fluids are unknown. Following extrication, we administer intravenous crystalloid at 500 mL/hour for the first day if there is no evidence of fluid overload and the patient can be closely monitored. We closely monitor serum bicarbonate, calcium, and serum and urine pH. We discontinue the alkaline solution if alkalemia or symptomatic hypocalcemia develops. (See 'Use of bicarbonate' above.)

•Mannitol – The use of mannitol to prevent AKI in the setting of crush injury is controversial. However, mannitol may be used as an adjunct to intravenous crystalloid in nonoliguric patients with traumatic rhabdomyolysis, provided close monitoring is possible. (See 'Use of mannitol' above.)

•Goal urine output – The administration of intravenous fluid should be adjusted to maintain the urinary output at approximately 200 to 300 mL/hour. If the urine output goal is achieved, we suggest continuing fluid therapy until the disappearance of myoglobinuria (either clinically or biochemically). This usually requires several days. (See 'Urine output goal' above.)

•Total fluid goal – The total amount of volume administered depends upon the clinical scenario. We closely monitor input and all losses (urinary volume plus other losses together) of the previous day. In this setting, therapy should be based on physical examination, biochemical analysis, close monitoring of fluid intake and output, and body weight. (See 'Total volume administered' above.)

●Hyperkalemia and hypocalcemia – We monitor plasma potassium and calcium several times daily until stabilized. We treat hyperkalemia as discussed elsewhere. We generally reserve calcium supplementation for patients with symptomatic hypocalcemia. (See "Treatment and prevention of hyperkalemia in adults" and "Treatment of hypocalcemia", section on 'Therapeutic approach'.)

●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. Among patients with heme pigment-induced AKI due to crush injury, we suggest intermittent hemodialysis rather than other kidney replacement modalities (Grade 2C). (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and "Acute hemodialysis prescription".)