ORIGINAL ARTICLE
Rhabdomyolysis and acute kidney injury in the injured war fighter Joel Elterman, MD, David Zonies, MD, MPH, Ian Stewart, MD, Raymond Fang, MD, and Martin Schreiber, MD, Cincinnati, Ohio
Rhabdomyolysis is a recognized complication of traumatic injury. The correlation of an elevated creatine kinase (CK) level and the development of acute kidney injury (AKI) has been studied in the civilian population. We sought to review the prevalence of rhabdomyolysis in injured war fighters and determine if peak CK levels correlate with AKI. METHODS: This is a retrospective cohort study of patients admitted at a US military treatment facility from January to November 2010. Inclusion criteria were active duty patients transported after explosive, penetrating, or blunt injury. Patients with burns or nonYtrauma-related admissions were excluded. Rhabdomyolysis was defined as a CK level greater than 5,000 U/L. AKI was defined using the Kidney Disease: Improving Global Outcomes classification. Mann-Whitney U-tests were used to determine the significance for continuous data. Correlations were determined using Spearman’s Q. Significance was set at p G 0.05. RESULTS: Of the 318 patients included in our analysis, 310 (98%) were male, and the median age was 24 years (21Y28 years). Blast was the predominant mechanism of injury (71%), with a median Injury Severity Score (ISS) of 22 (16Y29). Rhabdomyolysis developed in 79 patients (24.8%). The median peak CK for all patients was 4,178 U/L and ranged from 208 U/L to 120,000 U/L. Stage 1, 2, and 3 AKI developed in 56 (17.6%), 3 (0.9%), and 7 (2.2%) patients, respectively. There was a weak but statistically significant correlation between peak CK and AKI (r = 0.26, p G 0.05). CONCLUSION: Elevated peak CK levels in the injured war fighter are weakly associated with the development of AKI but are not predictive. The development of clinical practice guidelines would help standardize treatment for rhabdomyolysis in combat casualties and would allow for standardized comparisons in future work. (J Trauma Acute Care Surg. 2015;79: S171YS174. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved.) LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. KEY WORDS: Rhabdomyolysis; acute kidney injury; combat casualties. BACKGROUND:
R
habdomyolysis has been recognized as a complication of traumatic injury since World War II.1 It results from the disturbances in the intracellular ion gradients, leading to increased intracellular calcium ion concentrations.2 The clinical manifestations of rhabdomyolysis range from asymptomatic elevations in serum myoglobin and creatinine kinase (CK) levels to acute kidney injury (AKI) and disseminated intravascular coagulation.3 The correlation between elevated creatine kinase level and the development of renal insufficiency has been studied in the civilian population and used to determine treatment algorithms.4Y7 However, mechanisms of injury and transport times differ significantly in the injured war fighter of today’s current conflicts. The predominant mechanism of injury has been blast injury from improvised explosive devices.8 Furthermore, patients injured in the wars in Afghanistan and Iraq are transported through multiple echelons of care over several days Submitted: October 19, 2014, Revised: December 1, 2014, Accepted: December 16, 2014, Printed online: June 30, 2015. From the University of Cincinnati Medical Center (J.E.), Cincinnati, Ohio; Oregon Health & Science University (D.Z., M.S.), Portland, Oregon; San Antonio Military Medical Center (I.S.), San Antonio, Texas; Uniformed Services University of the Health Sciences (J.E., D.Z., I.S., R.F.); and Baltimore Shock Trauma (RF), Baltimore, Maryland. This study was presented at the 2014 Military Health Systems Research Symposium (MHSRS), August 21, 2014, in Fort Lauderdale, Florida. Address for reprints: Joel Elterman, MD, University of Cincinnati Medical Center, 231 Albert Sabin Way, Mail Code: ML0558, Cincinnati, OH 45267; email: [email protected]. DOI: 10.1097/TA.0000000000000572
en route to the continental United States.9 Taken together, these factors may make work done in civilian trauma populations less generalizable to combat casualties. In an effort to improve patient care, routine screening of creatine kinase level was initiated at the Level IV military treatment facility in Landstuhl, Germany. The goal was to identify patients with rhabdomyolysis early and therefore limit complications. We sought to establish the prevalence of rhabdomyolysis in this patient population and hypothesized that peak CK levels would be associated with AKI in injured war fighters.
PATIENTS AND METHODS A retrospective study of all patients admitted to the intensive care unit at a US military Level IV treatment facility (Landstuhl Regional Medical Center) from January 2010 to November 2010 was performed. This study was approved by Institutional Review Board at Brooke Army Medical Center. Inclusion criteria were all active duty patients transported from the deployed theater after explosive, penetrating, or blunt injury and admitted directly to the intensive care unit. Patients with burns and nonYtrauma-related admissions were excluded. Rhabdomyolysis was defined as a CK level greater than 5,000 U/L to be consistent with values associated with AKI in civilian studies.6 AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) classification by the AKI Working Group. Stage 1 was defined as a 1.5-fold to 1.9-fold increase in creatinine above baseline or 0.3 or greater rise from
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TABLE 1. Demographics Patient Characteristics
N = 318
Age, mean (SD), y Sex Male, n (%) Female, n (%) Mechanism of injury Gunshot wound, n (%) Blast injury, n (%) Crush injury, n (%) Blunt mechanism, n (%) Initial vital signs Initial SBP, mean (SD) Initial SBP not detectable, n (%) Initial HR, mean (SD) Initial lactate, mean (SD) Initial base excess, mean (SD) ISS ISS, mean (SD) Head AIS score, mean (SD) Face AIS score, mean (SD) Chest AIS score, mean (SD) Abdomen AIS score, mean (SD) Extremity AIS score, mean (SD) External AIS score, mean (SD) Massive transfusion, n (%)
25.5 (5.6) 310 (98.1) 8 (1.9) 58 (18.5) 223 (71.0) 2 (0.6) 31 (9.9) 118.2 (30.7) 5 (1.7) 106.3 (31.9) 2.1 (1.8) j2.6 (5.5) 23.3 (11.8) 2.4 (1.7) 1.0 (1.1) 2.2 (1.6) 2.0 (1.5 2.6 (1.3) 2.6 (1.3) 124 (39)
AIS, Abbreviated Injury Scale; HR, heart rate; SBP, systolic blood pressure.
the first available creatinine within 48 hours. Stage 2 was defined as a 2.0-fold to 2.9-fold increase from baseline. Stage 3 was defined as a greater than threefold increase from baseline.10 All patients requiring renal replacement therapy (RRT) were classified as Stage 3. The baseline creatinine was calculated using the Modification of Diet in Renal Disease study equation assuming an estimated glomerular filtration rate of 75 mL/min per 1.73 m2.11 Nonnormally distributed data were examined using the Mann-Whitney U-test to determine significance of continuous data. Correlations were determined using Spearman’s Q. Statistical significance was set at p G 0.05.
majority of patients were male (98%), with a median age of 25 (T5.6). Blast was the predominant mechanism of injury (71%), with a median Injury Severity Score (ISS) of 22 (interquartile range, 16Y29). Notably, five patients arrived in cardiac arrest with an undetectable blood pressure. Thirty-nine percent of patients required a massive transfusion, defined as more than 10 U of packed red blood cells transfused within the first 24 hours. The median time from injury until arrival at Landstuhl Regional Medical Center was 38 hours (interquartile range, 25.3Y50.3) during the study period.12 Of the 318 patients studied, 79 (24.8%) developed rhabdomyolysis. The median peak CK for all patients was 4,178 U/L with a range of 208 U/L to 120,000 U/L. Fifty-six patients met criteria for Stage 1 AKI. Of those patients, 33 had a peak CK greater than 5,000 U/L and 23 did not. There were only three patients meeting criteria for Stage 2 and seven patients with Stage 3 AKI. Of note, six of the seven patients with Stage 3 AKI required RRT. All patients with Stage 2 and 3 AKI had peak CK levels greater than 5,000 U/L. The mean peak CK for patients who required RRT was 37,314. The median peak CK for each of the stages of AKI is listed in Table 2. The box plot in Figure 1 further illustrates the relationship of peak CK to the development of AKI. There was a weak but statistically significant correlation between peak CK and AKI (r = 0.27, p G 0.05). Figure 2 demonstrates the receiver operating characteristic curve for the development of AKI based on the peak CK. Rhabdomyolysis was 60% sensitive and 62% specific for the development of AKI.
DISCUSSION Rhabdomyolysis represents a common complication in both civilian trauma patients and combat casualties. The classic description by Bywaters and Beall1 described victims of bombings in London during World War II and became known as the crush syndrome. AKI represents an important potential complication of rhabdomyolysis because it is associated with worse outcomes.13 Myoglobin was identified in 1944 in the urinary sediment and has been implicated in the development
RESULTS After applying the inclusion and exclusion criteria, there were 318 injured war fighters included for analysis. Thirty patients met exclusion criteria. Table 1 lists the patient characteristics to include demographics and initial physiology. The TABLE 2. Median Peak CK Per KDIGO Stage All Stage 0 Stage 1 Stage 2 Stage 3
S172
Patients, n
Peak CK, Median (Range), U/L
318 183 56 3 7
3,481 (208Y58,357) 5,000 (481Y120,000) 6,071 (5,000Y47,400) 42,478 (14,550Y67,000)
Figure 1. Relationship between KDIGO classification and peak CK level. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Trauma Acute Care Surg Volume 79, Number 4, Supplement 1
Elterman et al.
Figure 2. Receiver operating characteristic curve for the development of AKI based on peak CK.
of subsequent AKI.14 The pathogenesis of AKI in rhabdomyolysis is thought to involve myoglobin-induced intrarenal vasoconstriction, direct ischemic injury, and tubular obstruction.15 Although it is possible to measure serum myoglobin, creatine kinase has become a surrogate laboratory marker for rhabdomyolysis because it is a sensitive and inexpensive test to screen for muscle damage.16 The true incidence of rhabdomyolysis is unknown because the clinical definition has not been standardized. In the largest population of trauma patients published, the incidence of rhabdomyolysis was 85%, defined by an abnormal CK level greater than 521 U/L.6 The subsequent development of renal failure in trauma patients with rhabdomyolysis has ranged from 4% to 33%, with an associated mortality rate of 3% to 50%.17 While recognizing that the consensus definition for AKI continues to evolve over time, a weak correlation has been demonstrated between peak creatine kinase levels and the development of AKI in trauma patients with both penetrating and blunt mechanisms.5,6,18 This relationship has not yet been evaluated in contemporary combat casualties, where 74% of casualties sustain a mechanism of injury associated with a blast.8 In this study of 318 injured war fighters, the prevalence of rhabdomyolysis was 24.8%. By using the most recent consensus definition, 66 (21%) of the 318 patients developed AKI. Ten patients developed Stage 2 and 3 AKI, with six going on to require RRT. Unfortunately, the number of patients who eventually returned to a normal renal function is unknown. Peak CK levels were associated with the development of AKI in this population of injured war fighters. Further defining the incidence of rhabdomyolysis and development of AKI is important in the development of treatment strategies. The optimal treatment for trauma patients with rhabdomyolysis remains unclear. The mainstay therapy has involved early hydration with intravenous fluids (IVFs), alkalinization of the urine with sodium bicarbonate, and mannitol. Early hydration with IVF was one of the first treatments identified to be beneficial because this improved renal perfusion.19 Alkalinization of the urine with sodium bicarbonate decreases cast formation and subsequent tubular obstruction, which occurs in
an acidic environment.20 Moreover, precipitation of proteins, which causes tubular obstruction, does not occur in a basic environment.13 Mannitol induces an osmotic diuresis and may protect the kidney from the direct cytotoxic effects of myoglobin because of its effectiveness as a hydroxyl-free radical scavenger.21 Despite these therapies being common in the treatment of rhabdomyolysis, studies have failed to show a benefit with the use of mannitol and sodium bicarbonate over hydration alone.6,22 It should be noted that mannitol and sodium bicarbonate therapy have not been evaluated in trauma patients exclusive of one another and there may be negative effects associated with mannitol in the setting of hypovolemic shock. In addition, the use of antioxidants and free-radical scavengers such as pentoxifylline, deferoxamine, and vitamin C has been suggested for the treatment of AKI related to myoglobinuria but has not been studied in rhabdomyolysis secondary to trauma.4,13 In this study, the individual providers determined the clinical management strategy. All 79 patients identified as having rhabdomyolysis were treated with IVF hydration to a goal urine output of 100 mL/hr. Fourteen of the 79 patients received mannitol in addition to IVF. Eleven received sodium bicarbonate in addition to IVF hydration, and only 1 of the 79 patients received all three treatments. Anecdotally, the one patient who received all three treatments had a peak CK of 40,857 and did not develop AKI. There are several important limitations to discuss related to this study. First, this was a retrospective study and is subject to the inherent biases of the study design. Second, of the 318 patients, only 10 patients met criteria for Stage 2 and 3 AKI, thus representing a relatively small sample size. Third, while the individual providers determined the treatment strategy for rhabdomyolysis, we were unable to determine if the treatment goals were met, for example, a goal urine output of greater than 100 mL/h. Lastly, there were important cofounders to recognize. Five patients arrived in pulseless electrical activity arrest, and of those, four developed AKI, which may have been related to ischemic injury. In addition, 28 of the 66 patients with AKI had received a massive transfusion during the first 24 hours after injury. Despite these limitations, this study provides further insight into the prevalence and complications associated with rhabdomyolysis in combat casualties. While further study is required to identify the optimal treatment of rhabdomyolysis, we believe that the development of clinical practice guidelines in the setting of consensus definitions related to AKI and rhabdomyolysis will allow for more meaningful future comparisons. AUTHORSHIP J.E., R.F., and M.S. designed the study. J.E., D.Z., and I.S. contributed to the statistical analysis and interpretation. All authors contributed to the preparation of the manuscript and final revision.
DISCLOSURE The authors declare no conflicts of interest.
REFERENCES 1. Bywaters E, Beall D. Crush injuries with impairment of renal function. Br Med J. 1941;1:427Y432.
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2. Giannoglou GD, Chazizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90Y100. 3. Huerta-Alardin AL, Varon J, Marik PE. Bench-to bedside review: rhabdomyolysisVand overview for clinicians. Crit Care. 2005;9(2):158Y169. 4. Malinoski DJ, Slater MS, Mullins RJ. Crush injury and rhabdomyolysis. Crit Care Clin. 2004;20:171Y192. 5. Brown CV, Rhee P, Evans K, Demetriades D, Velmahos G. Rhabdomyolysis after penetrating trauma. Am Surg. 2004;70:890Y892. 6. Brown CV, Rhee P, Chan L, Evans K, Demetriades D, Velmahos G. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma. 2004;56:1191Y1196. 7. Stewart IJ, Cotant CL, Tilley MT, Huzar TF, et al. Association of rhabdomyolysis with renal outcomes and mortality in burn patients. J Burn Care Res. 2013;34(3):318Y325. 8. Belmont PJ, McCriskin BJ, Sieg RN, Burks R, Schoenfeld AJ. Combat wounds in Iraq and Afghanistan from 2005 to 2009. J Trauma Acute Care Surg. 2012;73(1):3Y12. 9. Fang R, Pruitt VM, Dorlac GR, Silvey SV, Osborn EC, Flaherty SF, et al. Critical care at Landstuhl Regional Medical Center. Crit Care Med. 2008;36(Suppl.):S383YS387). 10. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter. 2012;2(Suppl):1Y138. 11. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461Y470.
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12. Ingalls N, Zonies D, Bailey JA, Martin KD, Iddins BO, Carlton PK, Hanseman D, Branson R, Dorlac W, Johannigman J. A review of the first 10 years of critical care aeromedical transport during Operation Iraqi Freedom and Operation Enduring Freedom. JAMA Surg. 2014;149(8): 807Y813. 13. Bosch XB, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361:62Y72. 14. Bywaters E, Stead J. The production of renal failure following injection of solutions containing myohaemoglobin. Q J Exp Physiol. 1944;33:53. 15. Zager RA, Gamelin LM. Pathogenic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256:F446YF455. 16. Gabow PA, Kaehney WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine. 1982;61:141Y152. 17. Slater M, Mullins R. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998;186(6):693Y716. 18. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine. 2005;84:377Y385. 19. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med. 1990;322(12):825Y829. 20. Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest. 1989;60(5):619Y629. 21. Zager RA. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications. J Clin Invest. 1992;90(3):711Y719. 22. Homsi E, Barrerio MF, Orlando JM, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail. 1997;19(2):283Y288.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Rhabdomyolysis and acute kidney injury in the injured war fighter Joel Elterman, MD, David Zonies, MD, MPH, Ian Stewart, MD, Raymond Fang, MD, and Martin Schreiber, MD, Cincinnati, Ohio
Rhabdomyolysis is a recognized complication of traumatic injury. The correlation of an elevated creatine kinase (CK) level and the development of acute kidney injury (AKI) has been studied in the civilian population. We sought to review the prevalence of rhabdomyolysis in injured war fighters and determine if peak CK levels correlate with AKI. METHODS: This is a retrospective cohort study of patients admitted at a US military treatment facility from January to November 2010. Inclusion criteria were active duty patients transported after explosive, penetrating, or blunt injury. Patients with burns or nonYtrauma-related admissions were excluded. Rhabdomyolysis was defined as a CK level greater than 5,000 U/L. AKI was defined using the Kidney Disease: Improving Global Outcomes classification. Mann-Whitney U-tests were used to determine the significance for continuous data. Correlations were determined using Spearman’s Q. Significance was set at p G 0.05. RESULTS: Of the 318 patients included in our analysis, 310 (98%) were male, and the median age was 24 years (21Y28 years). Blast was the predominant mechanism of injury (71%), with a median Injury Severity Score (ISS) of 22 (16Y29). Rhabdomyolysis developed in 79 patients (24.8%). The median peak CK for all patients was 4,178 U/L and ranged from 208 U/L to 120,000 U/L. Stage 1, 2, and 3 AKI developed in 56 (17.6%), 3 (0.9%), and 7 (2.2%) patients, respectively. There was a weak but statistically significant correlation between peak CK and AKI (r = 0.26, p G 0.05). CONCLUSION: Elevated peak CK levels in the injured war fighter are weakly associated with the development of AKI but are not predictive. The development of clinical practice guidelines would help standardize treatment for rhabdomyolysis in combat casualties and would allow for standardized comparisons in future work. (J Trauma Acute Care Surg. 2015;79: S171YS174. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved.) LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. KEY WORDS: Rhabdomyolysis; acute kidney injury; combat casualties. BACKGROUND:
R
habdomyolysis has been recognized as a complication of traumatic injury since World War II.1 It results from the disturbances in the intracellular ion gradients, leading to increased intracellular calcium ion concentrations.2 The clinical manifestations of rhabdomyolysis range from asymptomatic elevations in serum myoglobin and creatinine kinase (CK) levels to acute kidney injury (AKI) and disseminated intravascular coagulation.3 The correlation between elevated creatine kinase level and the development of renal insufficiency has been studied in the civilian population and used to determine treatment algorithms.4Y7 However, mechanisms of injury and transport times differ significantly in the injured war fighter of today’s current conflicts. The predominant mechanism of injury has been blast injury from improvised explosive devices.8 Furthermore, patients injured in the wars in Afghanistan and Iraq are transported through multiple echelons of care over several days Submitted: October 19, 2014, Revised: December 1, 2014, Accepted: December 16, 2014, Printed online: June 30, 2015. From the University of Cincinnati Medical Center (J.E.), Cincinnati, Ohio; Oregon Health & Science University (D.Z., M.S.), Portland, Oregon; San Antonio Military Medical Center (I.S.), San Antonio, Texas; Uniformed Services University of the Health Sciences (J.E., D.Z., I.S., R.F.); and Baltimore Shock Trauma (RF), Baltimore, Maryland. This study was presented at the 2014 Military Health Systems Research Symposium (MHSRS), August 21, 2014, in Fort Lauderdale, Florida. Address for reprints: Joel Elterman, MD, University of Cincinnati Medical Center, 231 Albert Sabin Way, Mail Code: ML0558, Cincinnati, OH 45267; email: [email protected]. DOI: 10.1097/TA.0000000000000572
en route to the continental United States.9 Taken together, these factors may make work done in civilian trauma populations less generalizable to combat casualties. In an effort to improve patient care, routine screening of creatine kinase level was initiated at the Level IV military treatment facility in Landstuhl, Germany. The goal was to identify patients with rhabdomyolysis early and therefore limit complications. We sought to establish the prevalence of rhabdomyolysis in this patient population and hypothesized that peak CK levels would be associated with AKI in injured war fighters.
PATIENTS AND METHODS A retrospective study of all patients admitted to the intensive care unit at a US military Level IV treatment facility (Landstuhl Regional Medical Center) from January 2010 to November 2010 was performed. This study was approved by Institutional Review Board at Brooke Army Medical Center. Inclusion criteria were all active duty patients transported from the deployed theater after explosive, penetrating, or blunt injury and admitted directly to the intensive care unit. Patients with burns and nonYtrauma-related admissions were excluded. Rhabdomyolysis was defined as a CK level greater than 5,000 U/L to be consistent with values associated with AKI in civilian studies.6 AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) classification by the AKI Working Group. Stage 1 was defined as a 1.5-fold to 1.9-fold increase in creatinine above baseline or 0.3 or greater rise from
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J Trauma Acute Care Surg Volume 79, Number 4, Supplement 1
Elterman et al.
TABLE 1. Demographics Patient Characteristics
N = 318
Age, mean (SD), y Sex Male, n (%) Female, n (%) Mechanism of injury Gunshot wound, n (%) Blast injury, n (%) Crush injury, n (%) Blunt mechanism, n (%) Initial vital signs Initial SBP, mean (SD) Initial SBP not detectable, n (%) Initial HR, mean (SD) Initial lactate, mean (SD) Initial base excess, mean (SD) ISS ISS, mean (SD) Head AIS score, mean (SD) Face AIS score, mean (SD) Chest AIS score, mean (SD) Abdomen AIS score, mean (SD) Extremity AIS score, mean (SD) External AIS score, mean (SD) Massive transfusion, n (%)
25.5 (5.6) 310 (98.1) 8 (1.9) 58 (18.5) 223 (71.0) 2 (0.6) 31 (9.9) 118.2 (30.7) 5 (1.7) 106.3 (31.9) 2.1 (1.8) j2.6 (5.5) 23.3 (11.8) 2.4 (1.7) 1.0 (1.1) 2.2 (1.6) 2.0 (1.5 2.6 (1.3) 2.6 (1.3) 124 (39)
AIS, Abbreviated Injury Scale; HR, heart rate; SBP, systolic blood pressure.
the first available creatinine within 48 hours. Stage 2 was defined as a 2.0-fold to 2.9-fold increase from baseline. Stage 3 was defined as a greater than threefold increase from baseline.10 All patients requiring renal replacement therapy (RRT) were classified as Stage 3. The baseline creatinine was calculated using the Modification of Diet in Renal Disease study equation assuming an estimated glomerular filtration rate of 75 mL/min per 1.73 m2.11 Nonnormally distributed data were examined using the Mann-Whitney U-test to determine significance of continuous data. Correlations were determined using Spearman’s Q. Statistical significance was set at p G 0.05.
majority of patients were male (98%), with a median age of 25 (T5.6). Blast was the predominant mechanism of injury (71%), with a median Injury Severity Score (ISS) of 22 (interquartile range, 16Y29). Notably, five patients arrived in cardiac arrest with an undetectable blood pressure. Thirty-nine percent of patients required a massive transfusion, defined as more than 10 U of packed red blood cells transfused within the first 24 hours. The median time from injury until arrival at Landstuhl Regional Medical Center was 38 hours (interquartile range, 25.3Y50.3) during the study period.12 Of the 318 patients studied, 79 (24.8%) developed rhabdomyolysis. The median peak CK for all patients was 4,178 U/L with a range of 208 U/L to 120,000 U/L. Fifty-six patients met criteria for Stage 1 AKI. Of those patients, 33 had a peak CK greater than 5,000 U/L and 23 did not. There were only three patients meeting criteria for Stage 2 and seven patients with Stage 3 AKI. Of note, six of the seven patients with Stage 3 AKI required RRT. All patients with Stage 2 and 3 AKI had peak CK levels greater than 5,000 U/L. The mean peak CK for patients who required RRT was 37,314. The median peak CK for each of the stages of AKI is listed in Table 2. The box plot in Figure 1 further illustrates the relationship of peak CK to the development of AKI. There was a weak but statistically significant correlation between peak CK and AKI (r = 0.27, p G 0.05). Figure 2 demonstrates the receiver operating characteristic curve for the development of AKI based on the peak CK. Rhabdomyolysis was 60% sensitive and 62% specific for the development of AKI.
DISCUSSION Rhabdomyolysis represents a common complication in both civilian trauma patients and combat casualties. The classic description by Bywaters and Beall1 described victims of bombings in London during World War II and became known as the crush syndrome. AKI represents an important potential complication of rhabdomyolysis because it is associated with worse outcomes.13 Myoglobin was identified in 1944 in the urinary sediment and has been implicated in the development
RESULTS After applying the inclusion and exclusion criteria, there were 318 injured war fighters included for analysis. Thirty patients met exclusion criteria. Table 1 lists the patient characteristics to include demographics and initial physiology. The TABLE 2. Median Peak CK Per KDIGO Stage All Stage 0 Stage 1 Stage 2 Stage 3
S172
Patients, n
Peak CK, Median (Range), U/L
318 183 56 3 7
3,481 (208Y58,357) 5,000 (481Y120,000) 6,071 (5,000Y47,400) 42,478 (14,550Y67,000)
Figure 1. Relationship between KDIGO classification and peak CK level. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Trauma Acute Care Surg Volume 79, Number 4, Supplement 1
Elterman et al.
Figure 2. Receiver operating characteristic curve for the development of AKI based on peak CK.
of subsequent AKI.14 The pathogenesis of AKI in rhabdomyolysis is thought to involve myoglobin-induced intrarenal vasoconstriction, direct ischemic injury, and tubular obstruction.15 Although it is possible to measure serum myoglobin, creatine kinase has become a surrogate laboratory marker for rhabdomyolysis because it is a sensitive and inexpensive test to screen for muscle damage.16 The true incidence of rhabdomyolysis is unknown because the clinical definition has not been standardized. In the largest population of trauma patients published, the incidence of rhabdomyolysis was 85%, defined by an abnormal CK level greater than 521 U/L.6 The subsequent development of renal failure in trauma patients with rhabdomyolysis has ranged from 4% to 33%, with an associated mortality rate of 3% to 50%.17 While recognizing that the consensus definition for AKI continues to evolve over time, a weak correlation has been demonstrated between peak creatine kinase levels and the development of AKI in trauma patients with both penetrating and blunt mechanisms.5,6,18 This relationship has not yet been evaluated in contemporary combat casualties, where 74% of casualties sustain a mechanism of injury associated with a blast.8 In this study of 318 injured war fighters, the prevalence of rhabdomyolysis was 24.8%. By using the most recent consensus definition, 66 (21%) of the 318 patients developed AKI. Ten patients developed Stage 2 and 3 AKI, with six going on to require RRT. Unfortunately, the number of patients who eventually returned to a normal renal function is unknown. Peak CK levels were associated with the development of AKI in this population of injured war fighters. Further defining the incidence of rhabdomyolysis and development of AKI is important in the development of treatment strategies. The optimal treatment for trauma patients with rhabdomyolysis remains unclear. The mainstay therapy has involved early hydration with intravenous fluids (IVFs), alkalinization of the urine with sodium bicarbonate, and mannitol. Early hydration with IVF was one of the first treatments identified to be beneficial because this improved renal perfusion.19 Alkalinization of the urine with sodium bicarbonate decreases cast formation and subsequent tubular obstruction, which occurs in
an acidic environment.20 Moreover, precipitation of proteins, which causes tubular obstruction, does not occur in a basic environment.13 Mannitol induces an osmotic diuresis and may protect the kidney from the direct cytotoxic effects of myoglobin because of its effectiveness as a hydroxyl-free radical scavenger.21 Despite these therapies being common in the treatment of rhabdomyolysis, studies have failed to show a benefit with the use of mannitol and sodium bicarbonate over hydration alone.6,22 It should be noted that mannitol and sodium bicarbonate therapy have not been evaluated in trauma patients exclusive of one another and there may be negative effects associated with mannitol in the setting of hypovolemic shock. In addition, the use of antioxidants and free-radical scavengers such as pentoxifylline, deferoxamine, and vitamin C has been suggested for the treatment of AKI related to myoglobinuria but has not been studied in rhabdomyolysis secondary to trauma.4,13 In this study, the individual providers determined the clinical management strategy. All 79 patients identified as having rhabdomyolysis were treated with IVF hydration to a goal urine output of 100 mL/hr. Fourteen of the 79 patients received mannitol in addition to IVF. Eleven received sodium bicarbonate in addition to IVF hydration, and only 1 of the 79 patients received all three treatments. Anecdotally, the one patient who received all three treatments had a peak CK of 40,857 and did not develop AKI. There are several important limitations to discuss related to this study. First, this was a retrospective study and is subject to the inherent biases of the study design. Second, of the 318 patients, only 10 patients met criteria for Stage 2 and 3 AKI, thus representing a relatively small sample size. Third, while the individual providers determined the treatment strategy for rhabdomyolysis, we were unable to determine if the treatment goals were met, for example, a goal urine output of greater than 100 mL/h. Lastly, there were important cofounders to recognize. Five patients arrived in pulseless electrical activity arrest, and of those, four developed AKI, which may have been related to ischemic injury. In addition, 28 of the 66 patients with AKI had received a massive transfusion during the first 24 hours after injury. Despite these limitations, this study provides further insight into the prevalence and complications associated with rhabdomyolysis in combat casualties. While further study is required to identify the optimal treatment of rhabdomyolysis, we believe that the development of clinical practice guidelines in the setting of consensus definitions related to AKI and rhabdomyolysis will allow for more meaningful future comparisons. AUTHORSHIP J.E., R.F., and M.S. designed the study. J.E., D.Z., and I.S. contributed to the statistical analysis and interpretation. All authors contributed to the preparation of the manuscript and final revision.
DISCLOSURE The authors declare no conflicts of interest.
REFERENCES 1. Bywaters E, Beall D. Crush injuries with impairment of renal function. Br Med J. 1941;1:427Y432.
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Elterman et al.
2. Giannoglou GD, Chazizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90Y100. 3. Huerta-Alardin AL, Varon J, Marik PE. Bench-to bedside review: rhabdomyolysisVand overview for clinicians. Crit Care. 2005;9(2):158Y169. 4. Malinoski DJ, Slater MS, Mullins RJ. Crush injury and rhabdomyolysis. Crit Care Clin. 2004;20:171Y192. 5. Brown CV, Rhee P, Evans K, Demetriades D, Velmahos G. Rhabdomyolysis after penetrating trauma. Am Surg. 2004;70:890Y892. 6. Brown CV, Rhee P, Chan L, Evans K, Demetriades D, Velmahos G. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma. 2004;56:1191Y1196. 7. Stewart IJ, Cotant CL, Tilley MT, Huzar TF, et al. Association of rhabdomyolysis with renal outcomes and mortality in burn patients. J Burn Care Res. 2013;34(3):318Y325. 8. Belmont PJ, McCriskin BJ, Sieg RN, Burks R, Schoenfeld AJ. Combat wounds in Iraq and Afghanistan from 2005 to 2009. J Trauma Acute Care Surg. 2012;73(1):3Y12. 9. Fang R, Pruitt VM, Dorlac GR, Silvey SV, Osborn EC, Flaherty SF, et al. Critical care at Landstuhl Regional Medical Center. Crit Care Med. 2008;36(Suppl.):S383YS387). 10. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter. 2012;2(Suppl):1Y138. 11. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461Y470.
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12. Ingalls N, Zonies D, Bailey JA, Martin KD, Iddins BO, Carlton PK, Hanseman D, Branson R, Dorlac W, Johannigman J. A review of the first 10 years of critical care aeromedical transport during Operation Iraqi Freedom and Operation Enduring Freedom. JAMA Surg. 2014;149(8): 807Y813. 13. Bosch XB, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361:62Y72. 14. Bywaters E, Stead J. The production of renal failure following injection of solutions containing myohaemoglobin. Q J Exp Physiol. 1944;33:53. 15. Zager RA, Gamelin LM. Pathogenic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256:F446YF455. 16. Gabow PA, Kaehney WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine. 1982;61:141Y152. 17. Slater M, Mullins R. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998;186(6):693Y716. 18. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine. 2005;84:377Y385. 19. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med. 1990;322(12):825Y829. 20. Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest. 1989;60(5):619Y629. 21. Zager RA. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications. J Clin Invest. 1992;90(3):711Y719. 22. Homsi E, Barrerio MF, Orlando JM, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail. 1997;19(2):283Y288.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
