RESEARCH PAPER
High Risk of Rhabdomyolysis and Acute Kidney Injury After Traumatic Limb Compartment Syndrome Wei-Hsuan Tsai, MD,* Shih-Tsai Huang, MD,* Wen-Chung Liu, MD,*† Lee-Wei Chen, MD, PhD,*† Kuo-Chung Yang, MD,*† Kuei-Chang Hsu, MD,* Cheng-Ta Lin, MD,*† and Yen-Yi Ho, MD* Purpose: Rhabdomyolysis often occurs after traumatic compartment syndrome, and high morbidity and mortality have been reported with the acute kidney injury that develops subsequently. We focused on the risk factors for rhabdomyolysis and acute kidney injury in patients with traumatic compartment syndrome. We also analyzed the relation between renal function and rhabdomyolysis in these patients. Materials and Methods: A retrospective chart review was conducted from January 2006 to March 2012. Inpatients with traumatic compartment syndrome were included. We evaluated patients' demographics, history of illicit drugs use or alcohol consumption, mechanism of injury, symptoms, serum creatine kinase levels, and kidney function. Results: A total of 52 patients with a mean age of 40.9 years were included; 23 patients had rhabdomyolysis (44.2%), of which 9 patients developed acute kidney injury (39.1%). Significant predictive factors for rhabdomyolysis were history of illicit drugs or alcohol use (P = 0.039; odds ratio, 5.91) and ischemic injury (P = 0.005). We found a moderate correlation between serum creatine kinase levels and serum creatinine levels (R = 0.57; P < 0.0001). The correlation coefficient (R) between serum creatine kinase levels and the estimated creatinine clearance rate was −0.45. Rhabdomyolysis was a predisposing factor for acute kidney injury (P = 0.011; odds ratio, 8.68). Four patients with rhabdomyolysis required a short period of renal replacement therapy. Conclusion: A high percentage of patients with traumatic compartment syndrome developed rhabdomyolysis (44.2%). Patients with rhabdomyolysis had a higher possibility of developing acute kidney injury (39.1%), and rhabdomyolysis was correlated to renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment. Key Words: trauma, compartment syndrome, rhabdomyolysis, acute kidney syndrome (Ann Plast Surg 2015;74: S158–S161)
C
ompartment syndrome is diagnosed when increased pressure within a limited space compromises the circulation and function of the supplied tissues.1 Trauma is the leading cause of acute compartment syndrome of the limbs,2 and it is commonly considered a surgical emergency requiring immediate decompression. Compartment syndrome is a clinical diagnosis that can often be made based on 5 common symptoms and signs: pain, pallor, paresthesia, pulselessness, and paralysis (ie, the 5 P's). A previous meta-analysis reported that the probability of correct diagnosis increased as the number of clinical findings increased.3
Received September 11, 2014, and accepted for publication, after revision, December 17, 2014. From the *Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China; and †National Yang-Ming University, Taipei, Taiwan, Republic of China. Conflicts of interest and sources of funding: none declared. Reprints: Wen-Chung Liu, MD, Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China. Email: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7402–S158 DOI: 10.1097/SAP.0000000000000460
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Rhabdomyolysis is characterized by skeletal muscle necrosis and release of muscle cell contents into the circulation. It is a common complication of compartment syndrome. Myoglobinuria is the most serious consequence, which leads to acute kidney injury (AKI) in 15% to 50% of cases. Increased morbidity and mortality have been described among patients with AKI.4 The etiology, management, and prognosis of rhabdomyolysis and AKI have been extensively studied. However, reports seldom focus on these conditions in the subgroup of patients with traumatic compartment syndrome. This study aimed to identify the risk factors for rhabdomyolysis and AKI in patients with traumatic compartment syndrome, as well as the relation between renal function and the rhabdomyolysis.
MATERIALS AND METHODS A retrospective chart review was conducted from January 2006 to March 2012 in Kaohsiung Veterans General Hospital. Inpatients with traumatic compartment syndrome were included. Exclusion criteria were as follows: active infectious disease, active cardiovascular disease, peripheral artery disease, animal bites, and patients partially treated at other hospitals. Patients' demographics, history of illicit drug use or alcohol consumption, trauma mechanism, symptoms, and affected limbs as well as the levels of serum creatinine kinase (CK), blood urea nitrogen (BUN), and creatinine (Cr) were recorded. Compartment syndrome was diagnosed mainly by clinical presentation. The etiology of compartment syndrome was classified into 4 categories: soft tissue injury, fracture, vascular causes, and electric burn. Soft tissue injury included those with contusion or crush injury. Patients with a history of compromised circulation, such as severed arteries and prolonged immobilization, were classified as vascular causes. Patients with fractures in the affected compartments without additional vascular injury were classified in one group. The traditional symptoms and signs were evaluated (pain, pallor, paresthesia, paralysis, and pulselessness). The characteristics of the affected limbs were documented. Body mass index was defined as the individual's body mass divided by the square of their height (kg/m2). The estimated creatinine clearance rate was calculated using the Cockcroft-Gault formula.5 Rhabdomyolysis was diagnosed when the serum CK level was 5 times the upper limit of the reference range (male: >840 U/L; female: >600 U/L).6 Acute kidney injury was diagnosed according to the Acute Kidney Injury Network criteria.4 Categorical variables were examined using the χ2 test when appropriate (number, >5); otherwise, a Fisher exact test was used. The relations among continuous variables were correlated using the Pearson correlation with logarithmic transformation of the values. Simple logistic regression analysis was introduced for both categorical and continuous variables. A probability value of P < 0.05 was considered statistically significant. All analyses and graphics were made using MedCalc 11.3 and Microsoft 2000.
RESULTS A total of 52 patients with traumatic compartment syndrome were included (Fig. 1): 41 men and 11 women with a mean age of 40.9 years and a mean body mass index of 25.0 kg/m2. Most affected compartments were in the low legs (n = 34), although the thighs and Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
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Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
Acute Kidney Injury and Compartment Syndrome
TABLE 2. Symptoms Number
P
36 5 7 3 7
0.389 0.644 0.219 0.080 0.035
Pain Pale Paresthesia Paralysis Pulseless
More patients developed rhabdomyolysis when presenting with pulseless; P = 0.035.
FIGURE 1. Diagram of patient number. A total of 52 patients were included. Twenty-three patients (44.2%) had rhabdomyolysis, of which 9 patients (39.1%) developed AKI. Four patients received renal replacement therapy.
therapy groups were 15.1 and 14.4, respectively (P = 0.77). There was no mortality in the rhabdomyolysis patient group.
DISCUSSION arms were also affected (n = 7 and 11, respectively). Nine patients had a history of illicit drug use or alcohol consumption before the trauma. The etiology was soft tissue injury in 14 patients, fracture in 31 patients, and vascular causes in 6 patients; only 1 patient presented with fourth-degree electric burns (Table 1). The clinical symptoms and signs (ie, the 5 P's) are summarized in Table 2. Rhabdomyolysis was documented in 23 patients (44.2%). A history of illicit drug use or alcohol consumption was a significant predictive factor for rhabdomyolysis [P = 0.039; odds ratio (OR), 5.91; Table 3]. Patients with vascular injury had higher incidences of rhabdomyolysis than those in the other etiology groups (P = 0.005; Table 1). There was statistic significant correlation between the number of P's and CK [P = 0.013; correlation coefficient (R), 0.34]. Similarly, there was a trend that rhabdomyolysis was associated with higher number of P's (OR, 1.94; P = 0.085). In the clinical finding (ie, the 5 P's), more patients developed rhabdomyolysis when presenting with pulselessness than when not presenting with it (P = 0.035). Although all 3 patients with paralyzed limbs had rhabdomyolysis, no statistical significance was found (P = 0.08; Table 2). Moderate correlations existed between serum CK levels and serum Cr levels/estimated creatinine clearance rate (R,0.57; P < 0.0001; and R, −0.45; P = 0.001) (Figs. 2A and 2B, respectively), suggesting that serum CK level was inversely proportional to renal function. Eleven patients developed AKI, for which rhabdomyolysis was the predisposing factor (P = 0.011; OR, 8.68) (Table 4). The ratios of BUN to Cr in the AKI and non-AKI groups were 14.7 and 15.0, respectively (P = 0.87). Renal replacement therapy was necessary for 4 patients with rhabdomyolysis and 1 patient without rhabdomyolysis. The ratios of BUN to Cr in the renal replacement therapy and nonrenal replacement
TABLE 1. Trauma Mechanism
Soft tissue injury Fracture Vascular causes 4th degree electric injury
Number
P
14 31 6 1
0.539 0.160 0.005 0.442
Patients with vascular causes had significant higher incidence of rhabdomyolysis: P = 0.005.
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Trauma potentially causes rhabdomyolysis through direct skeletal muscle injury; and with increased pressure in the compartment, the muscle damages more. Common causes of rhabdomyolysis are trauma, drugs, muscle disease, and excessive muscular activity. Trauma is one of the major causes of rhabdomyolysis, which accounts for 8.8% to 26.7% of all cases.6–8 Limb compartment syndrome is often associated with rhabdomyolysis. In our study, 44.2% of the patients with traumatic compartment syndrome developed rhabdomyolysis. Although this value seems high, few studies have discussed it before. It is difficult to estimate the true incidence because the diagnosis of compartment syndrome relies on clinical judgment, and missed diagnosis is possible. Several techniques have been developed to measure the intracompartmental pressure.9 These techniques provide objective values for diagnosis, but the critical level of intracompartmental pressure remains controversial.3 In most clinical practices, these devices are not always available. Moreover, time plays an important role in the management of acute compartment syndrome: If there is a strong clinical suspicion, early intervention is required despite minimal changes in early intracompartmental pressures. We found several risk factors associated with developing rhabdomyolysis in patients with traumatic compartment syndrome: (a) pulseless limbs, (b) vascular causes, and (c) history of alcohol consumption or illicit drug use before the trauma. Of the clinical manifestations of compartment syndrome (ie, the 5 P's), more patients with pulselessness eventually developed rhabdomyolysis than those who did not. It is important to note that it is not only a late sign of TABLE 3. Risk Factors of Rhabdomyolysis Rhabdomyolysis (Mean or Number)
Sex Male Female Age, yrs BMI, kg/m2 Alcohol/Drug Yes No
Yes
No
20 3 37.3 25.9
21 8 43.8 24.5
7 16
2 27
Simple Logistic Regression Analysis OR
95% CI
P
0.39
0.091–1.698
0.211
0.98 1.075 5.91
0.953–1.011 0.941–1.229 1.09–31.97
0.221 0.289 0.039
A history of illicit drug use or alcohol consumption was a significant predictive factor for rhabdomyolysis; P = 0.039.
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Tsai et al
FIGURE 2. A, Logistic regression with logit transformation of serum CK and Cr level (R,0.57; P < 0.0001). Moderate correlations existed between serum CK levels and serum Cr levels. (The dash lines indicate 95% confidence interval). B, Logistic regression with logit transformation of serum CK level and estimated creatinine clearance rate (R, −0.45; P = 0.001). Moderate correlations existed between serum CK levels and estimated creatinine clearance rate. (The dash lines indicate 95% confidence interval).
compartment syndrome. In fact, it implies a vascular injury and potentially severe tissue ischemia. All patients with paralyzed limbs developed rhabdomyolysis in our study, although this did not reach statistical significance (P = 0.08). Limb paralysis is considered a late symptom of compartment syndrome and may be irreversible. We also found that the number of P's was correlated with serum CK (P = 0.013; R = 0.34). This result suggests that the number of P's could serve as a predictive factor of compartment syndrome. All patients in the present study with vascular causes developed rhabdomyolysis. This is biologically plausible because decreased oxygen delivery results in inadequate production of adenosine triphosphate, and prolonged tissue hypoxia eventually leads to muscle necrosis. In general, muscle cell damage started after a 2-hour ischemia. Profound and irreversible injury is noted after 6 to 7 hours of ischemia.10,11 We found that patients with traumatic compartment syndrome had a higher risk of developing rhabdomyolysis if they had a history of alcohol or illicit drug use. Alcohol and illicit drug use is reported to be present in 12.4% to 67% of rhabdomyolysis cases.6–8 These substances typically have direct toxic effects on the muscle cell through several pathways: (a) inhibition of calcium accumulation in the sarcoplasmic reticulum, (b) disruption of muscle cell membranes, (c) inhibition of the sodium-potassium adenosine triphosphatase that maintains cellular integrity, and (d) alterations in carbohydrate metabolism.12,13 Furthermore, these patients may have experienced prolonged immobilization, drug-related involuntary muscle contracture, vasospasm, dehydration, and electrolyte imbalance as secondary effects.12,14 Acute kidney injury is the most serious complication of rhabdomyolysis. The reported incidence of AKI in rhabdomyolysis ranges from 14.4% to 46%.6–8,15 The diversity of incidence is caused by the differences in patient populations, etiology, and diagnostic criteria. The Acute Kidney Injury Network criteria were used for the diagnosis of AKI in this study, and all patients were admitted with diagnoses of traumatic compartment syndrome. Of the patients with rhabdomyolysis, 39.1% developed AKI, compared with 6.9% of those without rhabdomyolysis. Rhabdomyolysis was therefore a significant risk factor for developing AKI. Blood urea nitrogen reabsorption rate can be regulated by the renal tubules, whereas Cr reabsorption rate remains the same. Thus, a ratio of BUN to Cr greater than 20 is considered prerenal AKI owing to the increase in the passive reabsorption of BUN that follows reabsorption of water. The BUN-to-Cr ratios in AKI and non-AKI groups were comparable (14.7 and 15.0, respectively; P = 0.87). The ratios of BUN to Cr in the renal replacement therapy and nonrenal replacement therapy groups were 15.1 and 14.4, respectively (P = 0.77). These data indicted a low possibility of dehydration-related prerenal AKI. Besides, moderate correlation was found between serum CK level and renal function, confirming that rhabdomyolysis was the main factor responsible for AKI in patients with compartment syndrome. S160
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The exact mechanism of rhabdomyolysis leading to AKI remains unclear. Myoglobin is a muscle constituent known to be released into the circulation when skeletal muscle was damaged. It is nephrotoxic only when the urine is acidic.16 Several pathophysiological mechanisms were proposed, including the following: (a) direct tubular toxicity mediated by myoglobin-associated oxidative injury, (b) distal tubule obstruction because of the precipitation of the TammHorsfall protein-myoglobin complex, and (c) myoglobin-induced renal vasoconstriction. Furthermore, volume depletion is common in traumatic injury, which is also associated with renal function impairment.16,17 Serum CK levels are considered a marker of muscle damage. A retrospective study that included all inpatients with rhabdomyolysis showed low correlation between CK levels and kidney function7 (R2 = 0.12). The correlation was higher in our study (R = 0.57 and −0.45), where we only included those with rhabdomyolysis that was related to traumatic compartment syndrome. This suggests that rhabdomyolysis is the most important factor affecting renal function in patients experiencing trauma. In addition, other factors influence renal function in nontraumatic rhabdomyolysis. Since serum CK is associated with renal function, aggressive treatment and close monitoring are suggested when the level is high. A short period of hemodialysis was needed for 4 (44.4%) of the 9 patients with rhabdomyolysis-related AKI. The reported rate of renal replacement therapy8,18,19 is 8.3% to 30%, and the mortality rate for rhabdomyolysis-related AKI6,15,20,21 is reportedly 20% to 42.3%. Compared with previous literature, there was a high rate of renal replacement therapy and less mortality (none) in our study. Thus, rhabdomyolysis due to traumatic compartment syndrome seems to have a greater effect on renal function, necessitating more aggressive intervention. However, the overall prognosis remains good after appropriate treatment. Our study is limited by its retrospective nature. We focus only on the predisposing factors and correlations between rhabdomyolysis
TABLE 4. Risk Factors of AKI Simple Logistic Regression Analysis
Age Sex BMI Drug Rhabdomyolysis
OR
95% CI
P
1.0346 0.790 1.088 4.114 8.679
0.996–1.075 0.144–4.331 0.925–1.280 0.878–19.270 1.646–45.763
0.070 0.786 0.308 0.073 0.011
Rhabdomyolysis was the risk factor of AKI in traumatic compartment syndrome patient group; P = 0.011.
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Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
and AKI. There was no standardized treatment or monitoring protocol, which might have influenced the result. Furthermore, time plays a very important role in compartment syndrome. The intracompartmental pressure changes with time, and the exact time when compartment syndrome starts is hard to detect. However, delayed treatment can result in severe consequences. The diagnosis of compartment syndrome relies on the clinical presentation. A meta-analysis pointed that clinical findings (ie, the 5 P's) have low sensitivity and positive predictive value.3 Thus, more objective and accurate diagnostic methods are required in the future. Serum CK measurement is a common clinical practice that represents a simple and useful marker for the diagnosis of rhabdomyolysis. We found a close relation between serum CK levels and renal function. However, myoglobin is the primary nephrotoxic agent from muscle breakdown and was reported to be more predictive of AKI than CK.18,22 However, a large retrospective study showed that both serum CK and myoglobin were similar in predicting AKI.23 In addition, the half-life of serum CK is longer than that of myoglobin.24 Thus, serum CK is a good marker for monitoring rhabdomyolysis.
CONCLUSION A high percentage (44.2%) of patients with traumatic compartment syndrome developed rhabdomyolysis. Vascular causes and a history of either illicit drug use or alcohol consumption were each significant risk factors for developing rhabdomyolysis. In addition, patients with rhabdomyolysis were more likely to develop AKI (39.1%), and the serum CK level was correlated with renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment. REFERENCES 1. Matsen FA 3rd. Compartmental syndrome. An unified concept. Clin Orthop Relat Res. 1975;113:8–14. 2. Kostler W, Strohm PC, Sudkamp NP. Acute compartment syndrome of the limb. Injury. 2005;36:992–998. 3. Ulmer T. The clinical diagnosis of compartment syndrome of the lower leg: are clinical findings predictive of the disorder? J Orthop Trauma. 2002;16:572–577.
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Acute Kidney Injury and Compartment Syndrome
4. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365–3370. 5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. 6. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine. 1982;61:141–152. 7. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine. 2005;84:377–385. 8. Chen CY, Lin YR, Zhao LL, et al. Clinical factors in predicting acute renal failure caused by rhabdomyolysis in the ED. Am J Emerg Med. 2013;31:1062–1066. 9. Elliott KG, Johnstone AJ. Diagnosing acute compartment syndrome. J Bone Joint Surg Br. 2003;85:625–632. 10. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg. 2002;10:620–630. 11. Harris K, Walker PM, Mickle DA, et al. Metabolic response of skeletal muscle to ischemia. Am J Physiol. 1986;250:H213–220. 12. Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010;48:749–756. 13. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr. 2004; 16:206–210. 14. Prendergast BD, George CF. Drug-induced rhabdomyolysis—mechanisms and management. Postgrad Med J. 1993;69:333–336. 15. Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med. 1988;148:1553–1557. 16. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361:62–72. 17. Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998;186:693–716. 18. Kasaoka S, Todani M, Kaneko T, et al. Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis. J Crit Care. 2010;25:601–604. 19. Sharp LS, Rozycki GS, Feliciano DV. Rhabdomyolysis and secondary renal failure in critically ill surgical patients. Am J Surg. 2004;188:801–806. 20. Mohaupt MG. [Rhabdomyolysis]. Therapeutische Umschau Revue therapeutique. 2003;60:391–397. 21. Woodrow G, Brownjohn AM, Turney JH. The clinical and biochemical features of acute renal failure due to rhabdomyolysis. Ren Fail. 1995;17:467–474. 22. Premru V, Kovac J, Ponikvar R. Use of myoglobin as a marker and predictor in myoglobinuric acute kidney injury. Ther Apher Dial. 2013;17:391–395. 23. El-Abdellati E, Eyselbergs M, Sirimsi H, et al. An observational study on rhabdomyolysis in the intensive care unit. Exploring its risk factors and main complication: acute kidney injury. Ann Intensive Care. 2013;3:8. 24. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90–100.
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High Risk of Rhabdomyolysis and Acute Kidney Injury After Traumatic Limb Compartment Syndrome Wei-Hsuan Tsai, MD,* Shih-Tsai Huang, MD,* Wen-Chung Liu, MD,*† Lee-Wei Chen, MD, PhD,*† Kuo-Chung Yang, MD,*† Kuei-Chang Hsu, MD,* Cheng-Ta Lin, MD,*† and Yen-Yi Ho, MD* Purpose: Rhabdomyolysis often occurs after traumatic compartment syndrome, and high morbidity and mortality have been reported with the acute kidney injury that develops subsequently. We focused on the risk factors for rhabdomyolysis and acute kidney injury in patients with traumatic compartment syndrome. We also analyzed the relation between renal function and rhabdomyolysis in these patients. Materials and Methods: A retrospective chart review was conducted from January 2006 to March 2012. Inpatients with traumatic compartment syndrome were included. We evaluated patients' demographics, history of illicit drugs use or alcohol consumption, mechanism of injury, symptoms, serum creatine kinase levels, and kidney function. Results: A total of 52 patients with a mean age of 40.9 years were included; 23 patients had rhabdomyolysis (44.2%), of which 9 patients developed acute kidney injury (39.1%). Significant predictive factors for rhabdomyolysis were history of illicit drugs or alcohol use (P = 0.039; odds ratio, 5.91) and ischemic injury (P = 0.005). We found a moderate correlation between serum creatine kinase levels and serum creatinine levels (R = 0.57; P < 0.0001). The correlation coefficient (R) between serum creatine kinase levels and the estimated creatinine clearance rate was −0.45. Rhabdomyolysis was a predisposing factor for acute kidney injury (P = 0.011; odds ratio, 8.68). Four patients with rhabdomyolysis required a short period of renal replacement therapy. Conclusion: A high percentage of patients with traumatic compartment syndrome developed rhabdomyolysis (44.2%). Patients with rhabdomyolysis had a higher possibility of developing acute kidney injury (39.1%), and rhabdomyolysis was correlated to renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment. Key Words: trauma, compartment syndrome, rhabdomyolysis, acute kidney syndrome (Ann Plast Surg 2015;74: S158–S161)
C
ompartment syndrome is diagnosed when increased pressure within a limited space compromises the circulation and function of the supplied tissues.1 Trauma is the leading cause of acute compartment syndrome of the limbs,2 and it is commonly considered a surgical emergency requiring immediate decompression. Compartment syndrome is a clinical diagnosis that can often be made based on 5 common symptoms and signs: pain, pallor, paresthesia, pulselessness, and paralysis (ie, the 5 P's). A previous meta-analysis reported that the probability of correct diagnosis increased as the number of clinical findings increased.3
Received September 11, 2014, and accepted for publication, after revision, December 17, 2014. From the *Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China; and †National Yang-Ming University, Taipei, Taiwan, Republic of China. Conflicts of interest and sources of funding: none declared. Reprints: Wen-Chung Liu, MD, Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China. Email: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/15/7402–S158 DOI: 10.1097/SAP.0000000000000460
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Rhabdomyolysis is characterized by skeletal muscle necrosis and release of muscle cell contents into the circulation. It is a common complication of compartment syndrome. Myoglobinuria is the most serious consequence, which leads to acute kidney injury (AKI) in 15% to 50% of cases. Increased morbidity and mortality have been described among patients with AKI.4 The etiology, management, and prognosis of rhabdomyolysis and AKI have been extensively studied. However, reports seldom focus on these conditions in the subgroup of patients with traumatic compartment syndrome. This study aimed to identify the risk factors for rhabdomyolysis and AKI in patients with traumatic compartment syndrome, as well as the relation between renal function and the rhabdomyolysis.
MATERIALS AND METHODS A retrospective chart review was conducted from January 2006 to March 2012 in Kaohsiung Veterans General Hospital. Inpatients with traumatic compartment syndrome were included. Exclusion criteria were as follows: active infectious disease, active cardiovascular disease, peripheral artery disease, animal bites, and patients partially treated at other hospitals. Patients' demographics, history of illicit drug use or alcohol consumption, trauma mechanism, symptoms, and affected limbs as well as the levels of serum creatinine kinase (CK), blood urea nitrogen (BUN), and creatinine (Cr) were recorded. Compartment syndrome was diagnosed mainly by clinical presentation. The etiology of compartment syndrome was classified into 4 categories: soft tissue injury, fracture, vascular causes, and electric burn. Soft tissue injury included those with contusion or crush injury. Patients with a history of compromised circulation, such as severed arteries and prolonged immobilization, were classified as vascular causes. Patients with fractures in the affected compartments without additional vascular injury were classified in one group. The traditional symptoms and signs were evaluated (pain, pallor, paresthesia, paralysis, and pulselessness). The characteristics of the affected limbs were documented. Body mass index was defined as the individual's body mass divided by the square of their height (kg/m2). The estimated creatinine clearance rate was calculated using the Cockcroft-Gault formula.5 Rhabdomyolysis was diagnosed when the serum CK level was 5 times the upper limit of the reference range (male: >840 U/L; female: >600 U/L).6 Acute kidney injury was diagnosed according to the Acute Kidney Injury Network criteria.4 Categorical variables were examined using the χ2 test when appropriate (number, >5); otherwise, a Fisher exact test was used. The relations among continuous variables were correlated using the Pearson correlation with logarithmic transformation of the values. Simple logistic regression analysis was introduced for both categorical and continuous variables. A probability value of P < 0.05 was considered statistically significant. All analyses and graphics were made using MedCalc 11.3 and Microsoft 2000.
RESULTS A total of 52 patients with traumatic compartment syndrome were included (Fig. 1): 41 men and 11 women with a mean age of 40.9 years and a mean body mass index of 25.0 kg/m2. Most affected compartments were in the low legs (n = 34), although the thighs and Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
Acute Kidney Injury and Compartment Syndrome
TABLE 2. Symptoms Number
P
36 5 7 3 7
0.389 0.644 0.219 0.080 0.035
Pain Pale Paresthesia Paralysis Pulseless
More patients developed rhabdomyolysis when presenting with pulseless; P = 0.035.
FIGURE 1. Diagram of patient number. A total of 52 patients were included. Twenty-three patients (44.2%) had rhabdomyolysis, of which 9 patients (39.1%) developed AKI. Four patients received renal replacement therapy.
therapy groups were 15.1 and 14.4, respectively (P = 0.77). There was no mortality in the rhabdomyolysis patient group.
DISCUSSION arms were also affected (n = 7 and 11, respectively). Nine patients had a history of illicit drug use or alcohol consumption before the trauma. The etiology was soft tissue injury in 14 patients, fracture in 31 patients, and vascular causes in 6 patients; only 1 patient presented with fourth-degree electric burns (Table 1). The clinical symptoms and signs (ie, the 5 P's) are summarized in Table 2. Rhabdomyolysis was documented in 23 patients (44.2%). A history of illicit drug use or alcohol consumption was a significant predictive factor for rhabdomyolysis [P = 0.039; odds ratio (OR), 5.91; Table 3]. Patients with vascular injury had higher incidences of rhabdomyolysis than those in the other etiology groups (P = 0.005; Table 1). There was statistic significant correlation between the number of P's and CK [P = 0.013; correlation coefficient (R), 0.34]. Similarly, there was a trend that rhabdomyolysis was associated with higher number of P's (OR, 1.94; P = 0.085). In the clinical finding (ie, the 5 P's), more patients developed rhabdomyolysis when presenting with pulselessness than when not presenting with it (P = 0.035). Although all 3 patients with paralyzed limbs had rhabdomyolysis, no statistical significance was found (P = 0.08; Table 2). Moderate correlations existed between serum CK levels and serum Cr levels/estimated creatinine clearance rate (R,0.57; P < 0.0001; and R, −0.45; P = 0.001) (Figs. 2A and 2B, respectively), suggesting that serum CK level was inversely proportional to renal function. Eleven patients developed AKI, for which rhabdomyolysis was the predisposing factor (P = 0.011; OR, 8.68) (Table 4). The ratios of BUN to Cr in the AKI and non-AKI groups were 14.7 and 15.0, respectively (P = 0.87). Renal replacement therapy was necessary for 4 patients with rhabdomyolysis and 1 patient without rhabdomyolysis. The ratios of BUN to Cr in the renal replacement therapy and nonrenal replacement
TABLE 1. Trauma Mechanism
Soft tissue injury Fracture Vascular causes 4th degree electric injury
Number
P
14 31 6 1
0.539 0.160 0.005 0.442
Patients with vascular causes had significant higher incidence of rhabdomyolysis: P = 0.005.
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Trauma potentially causes rhabdomyolysis through direct skeletal muscle injury; and with increased pressure in the compartment, the muscle damages more. Common causes of rhabdomyolysis are trauma, drugs, muscle disease, and excessive muscular activity. Trauma is one of the major causes of rhabdomyolysis, which accounts for 8.8% to 26.7% of all cases.6–8 Limb compartment syndrome is often associated with rhabdomyolysis. In our study, 44.2% of the patients with traumatic compartment syndrome developed rhabdomyolysis. Although this value seems high, few studies have discussed it before. It is difficult to estimate the true incidence because the diagnosis of compartment syndrome relies on clinical judgment, and missed diagnosis is possible. Several techniques have been developed to measure the intracompartmental pressure.9 These techniques provide objective values for diagnosis, but the critical level of intracompartmental pressure remains controversial.3 In most clinical practices, these devices are not always available. Moreover, time plays an important role in the management of acute compartment syndrome: If there is a strong clinical suspicion, early intervention is required despite minimal changes in early intracompartmental pressures. We found several risk factors associated with developing rhabdomyolysis in patients with traumatic compartment syndrome: (a) pulseless limbs, (b) vascular causes, and (c) history of alcohol consumption or illicit drug use before the trauma. Of the clinical manifestations of compartment syndrome (ie, the 5 P's), more patients with pulselessness eventually developed rhabdomyolysis than those who did not. It is important to note that it is not only a late sign of TABLE 3. Risk Factors of Rhabdomyolysis Rhabdomyolysis (Mean or Number)
Sex Male Female Age, yrs BMI, kg/m2 Alcohol/Drug Yes No
Yes
No
20 3 37.3 25.9
21 8 43.8 24.5
7 16
2 27
Simple Logistic Regression Analysis OR
95% CI
P
0.39
0.091–1.698
0.211
0.98 1.075 5.91
0.953–1.011 0.941–1.229 1.09–31.97
0.221 0.289 0.039
A history of illicit drug use or alcohol consumption was a significant predictive factor for rhabdomyolysis; P = 0.039.
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Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
Tsai et al
FIGURE 2. A, Logistic regression with logit transformation of serum CK and Cr level (R,0.57; P < 0.0001). Moderate correlations existed between serum CK levels and serum Cr levels. (The dash lines indicate 95% confidence interval). B, Logistic regression with logit transformation of serum CK level and estimated creatinine clearance rate (R, −0.45; P = 0.001). Moderate correlations existed between serum CK levels and estimated creatinine clearance rate. (The dash lines indicate 95% confidence interval).
compartment syndrome. In fact, it implies a vascular injury and potentially severe tissue ischemia. All patients with paralyzed limbs developed rhabdomyolysis in our study, although this did not reach statistical significance (P = 0.08). Limb paralysis is considered a late symptom of compartment syndrome and may be irreversible. We also found that the number of P's was correlated with serum CK (P = 0.013; R = 0.34). This result suggests that the number of P's could serve as a predictive factor of compartment syndrome. All patients in the present study with vascular causes developed rhabdomyolysis. This is biologically plausible because decreased oxygen delivery results in inadequate production of adenosine triphosphate, and prolonged tissue hypoxia eventually leads to muscle necrosis. In general, muscle cell damage started after a 2-hour ischemia. Profound and irreversible injury is noted after 6 to 7 hours of ischemia.10,11 We found that patients with traumatic compartment syndrome had a higher risk of developing rhabdomyolysis if they had a history of alcohol or illicit drug use. Alcohol and illicit drug use is reported to be present in 12.4% to 67% of rhabdomyolysis cases.6–8 These substances typically have direct toxic effects on the muscle cell through several pathways: (a) inhibition of calcium accumulation in the sarcoplasmic reticulum, (b) disruption of muscle cell membranes, (c) inhibition of the sodium-potassium adenosine triphosphatase that maintains cellular integrity, and (d) alterations in carbohydrate metabolism.12,13 Furthermore, these patients may have experienced prolonged immobilization, drug-related involuntary muscle contracture, vasospasm, dehydration, and electrolyte imbalance as secondary effects.12,14 Acute kidney injury is the most serious complication of rhabdomyolysis. The reported incidence of AKI in rhabdomyolysis ranges from 14.4% to 46%.6–8,15 The diversity of incidence is caused by the differences in patient populations, etiology, and diagnostic criteria. The Acute Kidney Injury Network criteria were used for the diagnosis of AKI in this study, and all patients were admitted with diagnoses of traumatic compartment syndrome. Of the patients with rhabdomyolysis, 39.1% developed AKI, compared with 6.9% of those without rhabdomyolysis. Rhabdomyolysis was therefore a significant risk factor for developing AKI. Blood urea nitrogen reabsorption rate can be regulated by the renal tubules, whereas Cr reabsorption rate remains the same. Thus, a ratio of BUN to Cr greater than 20 is considered prerenal AKI owing to the increase in the passive reabsorption of BUN that follows reabsorption of water. The BUN-to-Cr ratios in AKI and non-AKI groups were comparable (14.7 and 15.0, respectively; P = 0.87). The ratios of BUN to Cr in the renal replacement therapy and nonrenal replacement therapy groups were 15.1 and 14.4, respectively (P = 0.77). These data indicted a low possibility of dehydration-related prerenal AKI. Besides, moderate correlation was found between serum CK level and renal function, confirming that rhabdomyolysis was the main factor responsible for AKI in patients with compartment syndrome. S160
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The exact mechanism of rhabdomyolysis leading to AKI remains unclear. Myoglobin is a muscle constituent known to be released into the circulation when skeletal muscle was damaged. It is nephrotoxic only when the urine is acidic.16 Several pathophysiological mechanisms were proposed, including the following: (a) direct tubular toxicity mediated by myoglobin-associated oxidative injury, (b) distal tubule obstruction because of the precipitation of the TammHorsfall protein-myoglobin complex, and (c) myoglobin-induced renal vasoconstriction. Furthermore, volume depletion is common in traumatic injury, which is also associated with renal function impairment.16,17 Serum CK levels are considered a marker of muscle damage. A retrospective study that included all inpatients with rhabdomyolysis showed low correlation between CK levels and kidney function7 (R2 = 0.12). The correlation was higher in our study (R = 0.57 and −0.45), where we only included those with rhabdomyolysis that was related to traumatic compartment syndrome. This suggests that rhabdomyolysis is the most important factor affecting renal function in patients experiencing trauma. In addition, other factors influence renal function in nontraumatic rhabdomyolysis. Since serum CK is associated with renal function, aggressive treatment and close monitoring are suggested when the level is high. A short period of hemodialysis was needed for 4 (44.4%) of the 9 patients with rhabdomyolysis-related AKI. The reported rate of renal replacement therapy8,18,19 is 8.3% to 30%, and the mortality rate for rhabdomyolysis-related AKI6,15,20,21 is reportedly 20% to 42.3%. Compared with previous literature, there was a high rate of renal replacement therapy and less mortality (none) in our study. Thus, rhabdomyolysis due to traumatic compartment syndrome seems to have a greater effect on renal function, necessitating more aggressive intervention. However, the overall prognosis remains good after appropriate treatment. Our study is limited by its retrospective nature. We focus only on the predisposing factors and correlations between rhabdomyolysis
TABLE 4. Risk Factors of AKI Simple Logistic Regression Analysis
Age Sex BMI Drug Rhabdomyolysis
OR
95% CI
P
1.0346 0.790 1.088 4.114 8.679
0.996–1.075 0.144–4.331 0.925–1.280 0.878–19.270 1.646–45.763
0.070 0.786 0.308 0.073 0.011
Rhabdomyolysis was the risk factor of AKI in traumatic compartment syndrome patient group; P = 0.011.
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Annals of Plastic Surgery • Volume 74, Supplement 2, May 2015
and AKI. There was no standardized treatment or monitoring protocol, which might have influenced the result. Furthermore, time plays a very important role in compartment syndrome. The intracompartmental pressure changes with time, and the exact time when compartment syndrome starts is hard to detect. However, delayed treatment can result in severe consequences. The diagnosis of compartment syndrome relies on the clinical presentation. A meta-analysis pointed that clinical findings (ie, the 5 P's) have low sensitivity and positive predictive value.3 Thus, more objective and accurate diagnostic methods are required in the future. Serum CK measurement is a common clinical practice that represents a simple and useful marker for the diagnosis of rhabdomyolysis. We found a close relation between serum CK levels and renal function. However, myoglobin is the primary nephrotoxic agent from muscle breakdown and was reported to be more predictive of AKI than CK.18,22 However, a large retrospective study showed that both serum CK and myoglobin were similar in predicting AKI.23 In addition, the half-life of serum CK is longer than that of myoglobin.24 Thus, serum CK is a good marker for monitoring rhabdomyolysis.
CONCLUSION A high percentage (44.2%) of patients with traumatic compartment syndrome developed rhabdomyolysis. Vascular causes and a history of either illicit drug use or alcohol consumption were each significant risk factors for developing rhabdomyolysis. In addition, patients with rhabdomyolysis were more likely to develop AKI (39.1%), and the serum CK level was correlated with renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment. REFERENCES 1. Matsen FA 3rd. Compartmental syndrome. An unified concept. Clin Orthop Relat Res. 1975;113:8–14. 2. Kostler W, Strohm PC, Sudkamp NP. Acute compartment syndrome of the limb. Injury. 2005;36:992–998. 3. Ulmer T. The clinical diagnosis of compartment syndrome of the lower leg: are clinical findings predictive of the disorder? J Orthop Trauma. 2002;16:572–577.
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Acute Kidney Injury and Compartment Syndrome
4. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365–3370. 5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. 6. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine. 1982;61:141–152. 7. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine. 2005;84:377–385. 8. Chen CY, Lin YR, Zhao LL, et al. Clinical factors in predicting acute renal failure caused by rhabdomyolysis in the ED. Am J Emerg Med. 2013;31:1062–1066. 9. Elliott KG, Johnstone AJ. Diagnosing acute compartment syndrome. J Bone Joint Surg Br. 2003;85:625–632. 10. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg. 2002;10:620–630. 11. Harris K, Walker PM, Mickle DA, et al. Metabolic response of skeletal muscle to ischemia. Am J Physiol. 1986;250:H213–220. 12. Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010;48:749–756. 13. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr. 2004; 16:206–210. 14. Prendergast BD, George CF. Drug-induced rhabdomyolysis—mechanisms and management. Postgrad Med J. 1993;69:333–336. 15. Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med. 1988;148:1553–1557. 16. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361:62–72. 17. Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998;186:693–716. 18. Kasaoka S, Todani M, Kaneko T, et al. Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis. J Crit Care. 2010;25:601–604. 19. Sharp LS, Rozycki GS, Feliciano DV. Rhabdomyolysis and secondary renal failure in critically ill surgical patients. Am J Surg. 2004;188:801–806. 20. Mohaupt MG. [Rhabdomyolysis]. Therapeutische Umschau Revue therapeutique. 2003;60:391–397. 21. Woodrow G, Brownjohn AM, Turney JH. The clinical and biochemical features of acute renal failure due to rhabdomyolysis. Ren Fail. 1995;17:467–474. 22. Premru V, Kovac J, Ponikvar R. Use of myoglobin as a marker and predictor in myoglobinuric acute kidney injury. Ther Apher Dial. 2013;17:391–395. 23. El-Abdellati E, Eyselbergs M, Sirimsi H, et al. An observational study on rhabdomyolysis in the intensive care unit. Exploring its risk factors and main complication: acute kidney injury. Ann Intensive Care. 2013;3:8. 24. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90–100.
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