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Axiom or Myth? Always Start a Bicarbonate Drip for Rhabdomyolysis

2005; Lippincott Williams & Wilkins; Volume: 27; Issue: 6 Linguagem: Inglês

10.1097/00132981-200506000-00042

1552-3624

David Wein,

Cardiovascular Effects of Exercise

Rhabdomyolysis is a syndrome defined by damage to skeletal muscle and the release of cellular contents into the blood. Rhabdomyolysis can be caused by external compression of the muscle, compartment syndrome, vascular compromise, toxins, or exercise. Acute renal failure is one of the most severe consequences of rhabdomyolysis, and occurs in four percent to 33 percent of cases. (Crit Care Clinics 2004;20:171.) Victims of crush injuries who require dialysis demonstrate calculated mortality rates up to 40 percent (J Trauma: Injury, Infection, Crit Care 1997;42[3]:470), and rhabdomyolysis accounts for five percent to seven percent of all cases of acute renal failure in the United States. (Crit Care Clinics 2004;20:171.) In disaster situations such as earthquakes, acute renal failure secondary to rhabdomyolysis is the second most frequent cause of mortality. (J Am Soc Nephrol 2004;15[7]:1862.) The classic triad of muscle pain, weakness, and dark-colored urine was first reported in modern times during World War II. After the bombing of London, Bywater and Beall described the association of renal failure and crush injury when they reported on five patients who had one or more of their extremities trapped following a building collapse. The diagnosis of rhabdomyolysis is made by measuring serum creatine kinase (CK) as an indicator of muscle breakdown. CK may be a better marker than myoglobin because of myoglobin's short half-life. (Medicine 1982;62:141.) It remains unclear precisely what level of CK leads to renal failure, and ranges from 500 U/L to 75,000 U/L have been associated with a significant increase in the rate of renal failure. (J Trauma: Injury, Infection, Crit Care 2004;56[6]:1191.) The pathophysiology of rhabdomyolysis is multifactorial. The mechanical stress of muscle compression leads to calcium influx via stretch receptor channel opening. The increase in intracellular calcium leads to an increase in protease and nuclease activity, along with calcium-dependant phosphorylases, resulting in cell membrane degradation and release of intracellular products. Ischemic and subsequent reperfusion injuries contribute to the degradation of muscle primarily via free radical formation. The release of muscle cell contents into the circulation causes several electrolyte and lab abnormalities, and the release of intracellular potassium can cause hyperkalemia. The cardiotoxic effects of these high potassium levels are subsequently exacerbated by hypocalcemia, hypovolemia, and acidemia. Calcium levels are low because of the influx of calcium into the injured muscle tissue. Hyperphosphatemia also results from muscle breakdown and exacerbates hypocalcemia by furthering the increase in intracellular calcium. These metabolic derangements also lead to calcium deposition in muscle and other viable tissue (metastatic calcification). (Crit Care Clinics 2004;20:171.) Renal Failure In general, skeletal muscle can tolerate up to two hours of warm ischemia without permanent damage. Irreversible functional injury occurs between two and four hours, with necrosis occurring usually at about six hours. Maximal injury takes place after approximately 24 hours of compression. (Crit Care Clinics 2004;20:171.) The pathogenesis of renal failure in crush syndrome is not completely clear, but it is certainly multifaceted. Hypotension plays a prominent role in the development of renal failure following a crush injury and rhabdomyolysis. Large volumes of plasma which accumulate in the injured muscle result in decreased intravascular volume. Additionally, there is decreased renal perfusion from the stimulation of the sympathetic system and the renin-angiotensin-aldosterone axis. Myoglobin from muscle breakdown also causes the release of vasoconstrictors, including endothelin-1 and platelet activating factor. These effects have been primarily demonstrated in animal models. (Crit Care Clinics 2004;20:171.) Also the inflammatory response leads to free radical formation and lipid peroxidation mediated renal damage. Finally, myoglobin precipitates in an acidic urine, forming casts in the renal tubules and tubular obstruction. (Crit Care Clinics 2004;20:171.) Based primarily on these physiologic factors, the standard of care for the prevention of renal failure in rhabdomyolysis has always assumed a three-pronged strategy: early aggressive fluid resuscitation to maintain renal perfusion and dilution of myoglobin, alkalinization of the urine with bicarbonate to prevent precipitation of myoglobin in the tubules, and mannitol for diuresis, vasodilation, and scavenging free radicals. (J Trauma: Injury, Infection, Crit Care 2004;56[6]:1191.) One of the initial studies showing a benefit to this treatment was a retrospective analysis performed by Better et al who observed 15 patients in two groups who suffered similar lower extremity crush injuries. The first group consisted of seven mass casualty patients who received no aggressive fluid resuscitation for at least six hours post extraction, and subsequently received adequate volume replacement until CVP began to rise. All seven of these men developed acute renal failure and required dialysis. Early studies of bicarbonate therapy for rhabdomyolysis may have shown a benefit because of early, aggressive fluid administration The second group was eight men from a mass casualty event three years later; seven of them were given intravenous saline before extrication was completed. They were then evacuated to a hospital within two hours and received mannitol-alkaline diuresis for a target urine output of 300 mL/hour. None of these seven men, all with CK <30,000 U/L, developed renal failure or azotemia. The eighth man developed rhabdomyolysis 24 hours later, with resulting renal failure. The authors concluded that aggressive early volume resuscitation followed by alkaline-mannitol therapy may be protective against ARF in patients with traumatic rhabdomyolysis. (N Engl J Med 1990:322[12]:825.) It is unclear whether a particular component of this therapy, the combination, or some other factor was responsible for the outcome. Nonetheless, animal studies as well as retrospective clinical trials with small sample sizes support urinary alkalinization with intravenous bicarbonate infusion. Nonclinical studies have shown that urinary alkalinization decreases cast formation and lessens direct toxic effects of myoglobin. Large amounts of bicarbonate are required to alkalinize urine in rhabdomyolysis. In one study, an average of 685 mEq bicarbonate was administered over the initial 60 hours of treatment to keep urinary pH <6.5. In this particular study, an average of 375 mg acetazolamide also was administered to prevent alkalemia, although this was not considered standard of care. (Arch Intern Med 1984;144[2]:277.) Diuresis vs. Saline A recent retrospective analysis of 24 patients with various causes of rhabdomyolysis examined the benefit of saline plus mannitol-alkaline diuresis versus saline alone. Both therapies appeared equally effective; no patients developed renal dysfunction. Although the average degree of muscle injury in these patients was relatively low when measured by CK values (rhabdomyolysis was defined as a CK <500), it appeared that saline therapy alone was sufficient to prevent renal failure. (Crit Care Clinics 2004;20:171.) A larger retrospective study examined 1,771 patients with rhabdomyolysis (85% of all trauma ICU admissions to a Level I trauma center from January 1997 to September 2002). The decision to treat patients with bicarbonate-mannitol therapy was made at the discretion of the attending surgeon. The authors determined that the rate of renal failure increased when the CK exceeded 5000 U/L. Among patients with peak CK greater than 5,000 U/L, there was no difference in the rate of renal failure, need for dialysis, or mortality between patients who received bicarbonate-mannitol therapy and those who did not. Only when CK values reached 30,000 U/L did subgroup analysis reveal a trend toward improved outcomes in the mannitol-bicarbonate group. There were only 32 patients in the study with CK <30,000, and 24 received bicarbonate-mannitol while eight did not. The small sample size of this single subgroup makes it difficult to draw definitive conclusions. (J Trauma: Injury, Infection, Crit Care 2004;56[6]:1191.) Although the use of bicarbonate-mannitol stems logically from nonclinical physiological studies, the majority of clinical studies are limited by their small sample size and their retrospective design. In addition, and maybe more importantly, the early studies which seem to reflect a benefit did not control for the use of early fluid resuscitation as an independent variable. Bicarbonate-mannitol therapy has inherent risks, including alkalemia because of the high amounts of bicarbonate required to raise urine pH to a sufficient level. There is a lack of adequate data to support the routine administration of bicarbonate-mannitol therapy to all patients with traumatic rhabdomyolysis. In fact, the largest study to date showed no benefit in mortality or in the rate of hemodialysis with bicarbonate-mannitol therapy. (J Trauma: Injury, Infection, Crit Care 2004;56[6]:1191.) There is only limited evidence to support its use in patients with CK <30,000 U/L. Early, aggressive fluid resuscitation is likely beneficial, and should be started in the emergency department, if not earlier, at least to correct hypotension and hypovolemia. Nearly all of the studies which showed a benefit with bicarbonate-mannitol also noted that the patients who developed renal failure had a lengthy delay in the initiation of fluid resuscitation. Early aggressive fluid resuscitation should be a mainstay of traumatic rhabdomyolysis treatment. Bicarbonate-mannitol therapy has an unproven role in the prevention of renal failure caused by traumatic rhabdomyolysis, particularly in patients with very elevated CK levels. In conclusion, it is not an axiom always to initiate bicarbonate therapy for rhabdomyolysis. Early studies which appeared to show a benefit may have done so because early, aggressive fluid administration is the more critical component of this therapy. The precise role of fluid therapy with regard to amount, rate, and type needs to be validated in further studies. Axioms for Residents Axioms in Emergency Medicine is written specifically for emergency medicine residents to dispel myths and misconceptions about different clinical entities. The column is written each month by a resident from the Emergency Medicine Residency Program at Drexel University College of Medicine in Philadelphia.