American Journal of Emergency Medicine 32 (2014) 1259–1262
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Red cell distribution width is an independent predictor of mortality in necrotizing fasciitis Chia-Lung Weng, MD, Cheng-Hsien Wang, MD, I-Chuan Chen, MD, Kuang-Yu Hsiao, MD, Kung-Pin Chang, MD, Shih-Yun Wu, MD, Hong-Mo Shih, MD ⁎ Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi, and Chang Gung University College of Medicine, Taiwan (ROC)
a r t i c l e
i n f o
Article history: Received 22 May 2014 Received in revised form 31 July 2014 Accepted 1 August 2014
a b s t r a c t Introduction: Necrotizing fasciitis (NF) is a rapidly progressing and potentially lethal infectious disease of the soft tissue. An elevated red blood cell distribution width (RDW) is associated with increased risk of death in patients with heart disease and infectious disease. We retrospectively assessed the association of elevated RDW with in-hospital mortality due to NF. Methods: All patients had diagnoses of NF and were admitted to the emergency department of a single institution in Taiwan over a 4-year period. Demographics, comorbidities, clinical presentations, and laboratory parameters were retrospectively reviewed. Red blood cell distribution width was categorized as elevated (N 14.5%) or not elevated. Multivariate regression analysis was used to identify risk factors associated with mortality. Results: A total of 98 patients were enrolled, and the mortality rate was 23%. Univariate analysis indicated that advanced age, initial hypotension, low hemoglobin level, and elevated RDW (69.6% vs 20%, OR = 9.14, P b .001) were significantly associated with mortality. Multivariate analysis indicated that RDW was a significant and independent predictor of mortality in enrolled patients. Conclusions: Elevated RDW is a significant and independent predictor of in-hospital mortality for patients with NF. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Necrotizing fasciitis (NF) is a rare but rapidly progressing and potentially lethal infection of soft tissue that was first named by Wilson [1] in 1952. Despite recent improvements in the medical care of patients with NF, the mortality rate remains high [2–4]. Previous research has identified several risk factors, including diabetes mellitus (DM), liver cirrhosis, Aeromonas infection, old age, Vibrio infection, cancer, hypotension, and the presence of more than 10% band neutrophils in a whole blood sample [4–6]. Early recognition of patients with increased risk for NF allows earlier and more aggressive care. In particular, early surgical intervention is crucial for prevention of mortality [7–10]. Red blood cell distribution width (RDW) is a quantitative measure of anisocytosis, the variability in size of circulating erythrocytes, and is routinely reported in complete blood cell count panels. An elevated RDW is associated with severe morbidity and mortality in the presence of chronic heart failure [11–15] and is also a prognostic factor for infectious diseases, such as infection by gram-negative ⁎ Corresponding author. Chang Gung Memorial Hospital, Chiayi No. 6, W Sec, Jiapu Rd, Puzi City, Chiayi County 613, Taiwan (ROC). Tel.: +886 5 3621000x2805; fax: +886 5 362 3002. E-mail addresses: [email protected] (C.-L. Weng), [email protected] (C.-H. Wang), [email protected] (I.-C. Chen), [email protected] (K.-Y. Hsiao), [email protected] (K.-P. Chang), [email protected] (S.-Y. Wu), [email protected] (H.-M. Shih). http://dx.doi.org/10.1016/j.ajem.2014.08.001 0735-6757/© 2014 Elsevier Inc. All rights reserved.
bacteria, severe sepsis, septic shock, and community-acquired pneumonia [16–18]. No previous studies have examined the association between NF and RDW. The purpose of the present retrospective study is to investigate the association between RDW and NF at a single institution in Taiwan over a period of 4 years. 2. Materials and method We performed a retrospective analysis of the records of patients diagnosed with NF who were admitted to our hospital through the emergency department (ED) from the period of January 1, 2008, to December 31, 2012. Chang-Gung Memorial Hospital, in the city of Chayi, is a university teaching hospital in south-central Taiwan. As a general hospital, there are approximately 1000 beds in the general ward, 120 beds in the intensive care unit, and more than 60,000 annual visits to the ED. We used a coding system to assure the anonymity of all enrolled patients. 2.1. Inclusion criteria An electronic search was used to identify all adult patients (older than 18 years) who were admitted to our ED during the 4-year study period. All enrolled patients had diagnoses of NF (code 72886; International Classification of Diseases, Ninth Revision). In addition, all
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patients received surgical debridement; and the surgical findings were compatible with a diagnosis of NF. 2.2. Exclusion criteria Patients were excluded if they were not admitted to the ED, if they were readmitted to the hospital with 30 days of discharge following NF, if they were younger than 18 years, if the diagnosis of NF was excluded after surgery, or if they were discharged from our hospital before complete treatment. 2.3. Data collection Age, sex, and comorbidities such as DM, hypertension, previous stroke, chronic obstructive pulmonary disease (COPD), liver cirrhosis, cancer, coronary artery disease, chronic kidney disease, and congestive heart failure were recorded. We also reviewed symptoms and signs at ED presentation and laboratory findings at admission, including white blood cell and differential count, hemoglobin, RDW, creatinine, alanine aminotransferase, blood sugar, and microbiology results of wound and blood cultures. The in-hospital mortality rate was considered the primary outcome measure. Initial hypotension was defined as systolic blood pressure less than 90 mm Hg at ED triage. Bandemia was defined as the presence of more than 10% band white blood cells. Red blood cell distribution width was defined as (standard deviation of mean corpuscular volume/mean corpuscular volume) × 100%, and a level of 14.5% is the normal upper limit for our hospital. All data collection was by a single researcher who was blinded to the purpose of study. 2.4. Statistical analysis Patients were divided into 2 groups based on in-hospital survival. The differences between the 2 groups were analyzed using the χ 2 test for categorical variables and the independent-samples t test for continuous variables. To identify variables associated with mortality, data were initially analyzed by univariate analysis. Significant variables were then entered into a stepwise backward logistic regression analysis. We also compared the characteristics of patients with normal and abnormal RDW. All statistical assessments were 2-sided. A P value less than .05 was considered statistically significant. All statistical analyses were performed using SPSS (ver. 17.0; SPSS, Chicago, IL) software. 3. Results One hundred twenty cases who had ED diagnosis of NF during the 4-year study period were initially enrolled to our study. Sixteen patients were excluded because the diagnosis of NF was excluded before discharge. One patient who received operation and was treated in other hospital before being transferred to our hospital was excluded. Three patients who refused surgery were also excluded. We also excluded 2 patients who were discharged before complete treatment. We finally enrolled 98 cases (67 men and 31 women), and their demographic data and comorbidities were summarized in Table 1. A total of 23 patients (23%) died during their hospitalization. Patients who died were significantly older than survivors (75.2 ± 11.84 vs 68.23 ± 13.60 years, P = .028). Table 2 lists the major symptoms and signs of the 2 groups. Patients who died were more likely to have hypotension at initial presentation (33.3% vs 60.9%, P = .018). Table 3 compares the laboratory results of the 2 groups. Patients who died had lower levels of hemoglobin (12.90 ± 2.10 vs 11.79 ± 2.59 mg/dL, P = .039) and were more likely to have elevated RDW levels (20% vs 69.6%, P b .001). Variables that were significantly associated with in-hospital death in our study and previous studies [4–6], including age, initial
Table 1 Demographic data and comorbidities
⁎Ageb Malea DMa Hypertensiona Strokea COPDa Liver cirrhosisa Cancera Coronary artery diseasea Chronic kidney diseasea Congestive heart failurea
Survivor(75)
Mortality(23)
P
68.23 ± 13.60 50 (66.7%) 27 (36%) 32 (42.7%) 4 (5.3%) 6 (8%) 10 (13.3%) 9 (12%) 2 (2.7%) 9 (12%) 2 (2.7%)
75.26 ± 11.84 17 (73.9%) 9 (39.1%) 9 (39.1%) 3 (13%) 2 (8.7%) 7 (30.4%) 4 (17.4%) 3 (13%) 6 (26.1%) 2 (8.7%)
.028 .513 .785 .764 .209 .915 .058 .505 .083 .111 .234
a
Categorical data expressed as number (%). Continuous data expressed as mean ± standard deviations. ⁎ P b .05. b
hypotension, liver cirrhosis, RDW greater than 14.5%, hemoglobin, positive blood culture, and bandemia, were examined by a stepwise backward logistic regression analysis. The results indicate that an RDW greater than 14.5% and hypotension at ED triage were significantly and independently associated with mortality (Table 4). Finally, we compared patients with normal and elevated RDW (Table 5). The group with elevated RDW had significantly lower hemoglobin levels (13.25 ± 1.97 vs 11.33 ± 2.32 mg/dL, P b .001). In addition, the group with elevated RDW was older and more likely to have hypotension and bandemia, although these 3 differences were not statistically significant. The group with elevated RDW also had more comorbidities, although liver cirrhosis was the only comorbidity with statistical significance.
4. Discussion The major result of our study is that an elevated RDW is significantly and independently associated with increased risk of in-hospital mortality in patients who present to the ED with NF. Previous studies reported an association of elevated RDW with mortality in patients with heart failure, stroke, sepsis, and pancreatitis [11–20]. To our knowledge, the present study is the first to examine the relationship of RDW and NF. Although our results did not identify the pathophysiologic mechanism for this association, we believe that there are several possible explanations based on review of the literature. First, an elevated RDW indicates the presence of a severe systemic inflammatory state. Inflammation increases bone marrow function, iron metabolism, and the expression of some proinflammatory cytokines, such as tumor necrosis factor–α, interleukin-6, and interleukin-1β. This could lead to the suppression of red blood cell (RBC) maturation, a decrease in the half-life of RBCs, and progression of sepsis, thereby leading to the presence of newer and larger reticulocytes in the circulation and an increase in the RDW [17,19,21–23]. Patients with
Table 2 Comparison of clinical presentation
Swelling Pain Erythema Hemorrhagic bullae Fever ⁎Initial hypotension Tachycardia Altered mental status
Survivor (75)
Mortality (23)
P
70 (93.3%) 63 (84%) 51 (68%) 22 (29.3%) 31 (41.3%) 25 (33.3%) 38 (50.7%) 2 (2.7%)
18 (78.3%) 15 (65.2%) 13 (56.5%) 8 (34.8%) 5 (21.7) 14 (60.9%) 13 (56.5%) 2 (8.7%)
.052 .074 .312 .615 .088 .018 .623 .234
Categorical data expressed as number (%). ⁎ P b .05.
C.-L. Weng et al. / American Journal of Emergency Medicine 32 (2014) 1259–1262 Table 3 Comparison of laboratory result
WBC (103/μL)b Band N10%a ⁎Hemoglobin (g/dL)b Hematocrit (%)b ⁎RDW N14.5a Platelet (103/μL)b Creatinineb Sugarb ALTb Positive blood culturea Vibrio infectiona
Table 5 Comparison of patients with normal or abnormal RDW
Survivor (75)
Mortality (23)
P
16.1 ± 7.48 19 (25.3%) 12.90 ± 2.10 39.3 ± 11.31 15 (20%) 163.17 ± 83.86 1.72 ± 1.53 184.88 ± 158.34 46.35 ± 33.83 24 (32%) 23 (30.7%)
13.95 ± 10.52 10 (43.5%) 11.79 ± 2.59 35.12 ± 7.45 16 (69.6%) 137.57 ± 88.27 2.10 ± 0.92 161.17 ± 191.34 42.67 ± 29.47 12 (52.2%) 6 (26.1%)
.27 .09 .039 .10 b.0001 .209 .27 .628 .677 .079 .674
ALT: alanine aminotransferase. a Categorical data expressed as number (%). b Continuous data expressed as mean ± standard deviations. ⁎ P b .05.
Initial hypotensiona Band N10%a ⁎Hemoglobin (g/dL)b DMa Hypertensiona Strokea COPDa ⁎Liver cirrhosisa Cancera Coronary artery diseasea Chronic kidney diseasea Congested heart failurea
Normal RDW (67)
Elevated RDW (31)
P
24 (35.8%) 17 (25.4%) 13.25 ± 1.97 23 (34.3%) 31 (46.3%) 3 (4.5%) 4 (6%) 5 (7.5%) 9 (13.4%) 2 (3.0%) 10 (14.9%) 1 (1.5%)
15 (48.4%) 12 (38.7%) 11.33 ± 2.32 13 (41.9%) 10 (32.3%) 4 (12.9%) 4 (12.9%) 12 (38.7%) 4 (12.9%) 3 (9.7%) 5 (16.1%) 3 (9.7%)
.272 .179 b.001 .468 .191 .132 .244 b.001 .943 .322 .878 .092
a
Categorical data expressed as number (%). Continuous data expressed as mean ± standard deviations. ⁎ P b .05. b
severe sepsis or septic shock experience a high level of oxidative stress, and this reduces survival of RBCs [24,25] and also leads to an elevated RDW. The results of our study are consistent with this explanation. In agreement, we also found that hypotension and bandemia were more common (although not significantly) in patients with elevated levels of RDW. Thus, an elevated RDW may be associated with a more severe systemic inflammatory state; and this may explain the increased risk for mortality. On the other hand, an elevated RDW level might indicate the presence of severe tissue hypoxia. Necrotizing fasciitis is a lifethreatening soft tissue infection that is accompanied by a rapid increase of inflammation and necrosis of the skin, subcutaneous fat, and fascia, and can rapidly progress to severe sepsis or septic shock with circulatory abnormalities, ultimately leading to global tissue hypoxia [26,27]. In addition to stimulating the systemic inflammatory response syndrome, global tissue hypoxia independently contributes to endothelial activation and disruption of the homeostatic balance of coagulation, vascular permeability, and vascular tone [28], ultimately leading to hemolysis. This response may have contributed to the decreased hemoglobin and elevated RDW in our group of NF patients who died. As discussed above, an elevated RDW indicates a decreased number of RBCs in circulation and the presence of more immature RBCs. Anemia and the presence of more immature RBCs would worsen tissue hypoxia in patients with severe sepsis or septic shock and ultimately lead to increased mortality [29,30]. Our results also indicated an association of elevated RDW with decreased hemoglobin. A low hemoglobin level often reflects the presence of premorbidities, including malnutrition, chronic kidney disease, liver disease, iron deficiency, and malignancy [11,31–33]. The findings of our study (Table 5) agree with this interpretation. In particular, patients with more premorbidities might be more likely to develop anemia; and this could lead to an elevated RDW [14] and poor overall prognosis [34,35]. Thus, this is another possible explanation for our observed association between RDW elevation and mortality in patients with NF.
Table 4 Final model of stepwise backward logistic regression analysis of factors associated with mortality Multivariate (adjusted)
Initial hypotension RDW N14.5
1261
ORs
P
2.996 8.576
.047 b.001
Note: Age, initial hypotension, liver cirrhosis, RDW greater than 14.5%, hemoglobin, positive blood culture, and bandemia were put into logistic regression initially. OR: odds ratio.
The major limitation of our study is that it was retrospective. Medical records are not designed for research purposes, do not include all variables of interest to researchers, and may contain inaccurate or imprecise descriptions. Second, RDW elevation may be due to a deficiency of iron, folate, or vitamin B12; but these data were not available in medical records. Third, we did not investigate and cannot prove the pathogenic mechanism for our observed association of elevated RDW and mortality in patients with NF. Last, all of our patients were from a single medical center in Taiwan. The value of RDW in prediction of clinical outcomes may be different for other populations of NF patients. Further prospective studies with larger patient populations involving multiple centers are necessary to more accurately assess the role of elevated RDW as a predictor of mortality in patients with NF. 5. Conclusions In conclusion, the present study indicated that an elevated RDW is independently and significantly associated with increased in-hospital mortality in patients with NF. Future studies of other populations are needed to verify these results. Conflicts of interest statement None declared. References [1] Wilson B. Necrotizing fasciitis. Am Surg 1952;18:416–31. [2] Hung CC, Chang SC, Lin SF, Fang CT, Chen YC, Hsieh WC. Clinical manifestations, microbiology and prognosis of 42 patients with necrotizing fasciitis. J Formos Med Assoc 1996;95:917–22. [3] Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg 2007;119:1803–7. [4] Hsiao CT, Weng HH, Yuan YD, Chen CT, Chen IC. Predictors of mortality in patients with necrotizing fasciitis. Am J Emerg Med 2008;26:170–5. [5] Lee CY, Kuo LT, Peng KT, Hsu WH, Huang TW, Chou YC. Prognostic factors and monomicrobial necrotizing fasciitis: gram-positive versus gram-negative pathogens. BMC Infect Dis 2011;11:5. [6] Huang KF, Hung MH, Lin YS, Lu CL, Liu C, Chen CC, Lee YH. Independent predictors of mortality for necrotizing fasciitis: a retrospective analysis in a single institution. J Trauma 2011;71:467–73 [discussion 473]. [7] Voros D, Pissiotis C, Georgantas D, Katsaragakis S, Antoniou S, Papadimitriou J. Role of early and extensive surgery in the treatment of severe necrotizing soft tissue infection. Br J Surg 1993;80:1190–1. [8] Qazi SA, Mohammed AA, Saber EI, Mirza SM. Necrotizing fasciitis. Role of early surgical intervention. Saudi Med J 2004;25:890–4. [9] Boyer A, Vargas F, Coste F, Saubusse E, Castaing Y, Gbikpi-Benissan G, Hilbert G, Gruson D. Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 2009;35:847–53. [10] Chao WN, Tsai CF, Chang HR, Chan KS, Su CH, Lee YT, Ueng KC, Chen CC, Chen SC, Lee MC. Impact of timing of surgery on outcome of Vibrio vulnificus–related necrotizing fasciitis. Am J Surg 2013;206:32–9.
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[11] Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, Swedberg K, Wang D, Yusuf S, Michelson EL, Granger CB, CHARM Investigators. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol 2007;50:40–7. [12] Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol 2010;105:312–7. [13] Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, Lenihan DJ, Oren RM, Wagoner LE, Schwartz TA, Adams Jr KF. Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure. J Card Fail 2010;16:230–8. [14] Akin F, Kose N, Ayca B, Katkat F, Duran M, Uysal OK, Arinc H. Relation between red cell distribution width and severity of coronary artery disease in patients with acute myocardial infarction. Angiology 2013;64:592–6. [15] Aung N, Ling HZ, Cheng AS, Aggarwal S, Flint J, Mendonca M, Rashid M, Kang S, Weissert S, Coats CJ, Richards T, Thomas M, Woldman S, Okonko DO. Expansion of the red cell distribution width and evolving iron deficiency as predictors of poor outcome in chronic heart failure. Int J Cardiol 2013;168:1997–2002. [16] Braun E, Domany E, Kenig Y, Mazor Y, Makhoul BF, Azzam ZS. Elevated red cell distribution width predicts poor outcome in young patients with community acquired pneumonia. Crit Care 2011;15:R194. [17] Ku NS, Kim HW, Oh HJ, Kim YC, Kim MH, Song JE, Oh DH, Ahn JY, Kim SB, Jeong SJ, Han SH, Kim CO, Song YG, Kim JM, Choi JY. Red blood cell distribution width is an independent predictor of mortality in patients with gram-negative bacteremia. Shock 2012;38:123–7. [18] Jo YH, Kim K, Lee JH, Kang C, Kim T, Park HM, et al. Red cell distribution width is a prognostic factor in severe sepsis and septic shock. Am J Emerg Med 2013;31:545–8. [19] Şenol K, Saylam B, Kocaay F, Tez M. Red cell distribution width as a predictor of mortality in acute pancreatitis. Am J Emerg Med 2013;31(4):687–9. [20] Ani C, Ovbiagele B. Elevated red blood cell distribution width predicts mortality in persons with known stroke. J Neurol Sci 2009;15(277):103–8. [21] Pierce CN, Larson DF. Inflammatory cytokine inhibition of erythropoiesis in patients implanted with a mechanical circulatory assist device. Perfusion 2005;20:83–90. [22] Scharte M, Fink MP. Red blood cell physiology in critical illness. Crit Care Med 2003;31:S651–7.
[23] Chiari MM, Bagnoli R, De Luca PD, Monti M, Rampoldi E, Cunietti E. Influence of acute inflammation on iron and nutritional status indexes in older inpatients. J Am Geriatr Soc 1995;43:767–71. [24] Kolls JK. Oxidative stress in sepsis: a redox redux. J Clin Invest 2006;116:860–3. [25] Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid Redox Signal 2006;10:1923–40. [26] Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA 1995;273:117–1232. [27] Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s: systemic inflammatory response and organ dysfunction. JAMA 1994;271:226–33. [28] Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation: biology and clinical implications. Intensive Care Med 2001;27:19–31. [29] Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–77. [30] Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion in critical care. Tansfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409–17. [31] Ozkalemkas F, Ali R, Ozkocaman V, Ozcelik T, Ozan U, Ozturk H, Kurt E, Evrensel T, Yerci O, Tunali A. The bone marrow aspirate and biopsy in the diagnosis of unsuspected nonhematologic malignancy: a clinical study of 19 cases. BMC Cancer 2005;5:144. [32] Spell DW, Jones J, Harper WF, Bessman DJ. The value of a complete blood count in predicting cancer of the colon. Cancer Detect Prev 2004;28:37–42. [33] Felker GM, Adams Jr KF, Gattis WA, O’Connor CM. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol 2004;44:959–66. [34] Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher KB. Red cell distribution width and all cause mortality in critically ill patients. Crit Care Med 2011;39:1913–21. [35] Kim J, Kim K, Lee JH, Jo YH, Rhee JE, Kim TY, Kang KW, Kim YJ, Hwang SS, Jang HY. Red blood cell distribution width as an independent predictor of all-cause mortality in out of hospital cardiac arrest. Resuscitation 2012;83:1248–52.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Red cell distribution width is an independent predictor of mortality in necrotizing fasciitis Chia-Lung Weng, MD, Cheng-Hsien Wang, MD, I-Chuan Chen, MD, Kuang-Yu Hsiao, MD, Kung-Pin Chang, MD, Shih-Yun Wu, MD, Hong-Mo Shih, MD ⁎ Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi, and Chang Gung University College of Medicine, Taiwan (ROC)
a r t i c l e
i n f o
Article history: Received 22 May 2014 Received in revised form 31 July 2014 Accepted 1 August 2014
a b s t r a c t Introduction: Necrotizing fasciitis (NF) is a rapidly progressing and potentially lethal infectious disease of the soft tissue. An elevated red blood cell distribution width (RDW) is associated with increased risk of death in patients with heart disease and infectious disease. We retrospectively assessed the association of elevated RDW with in-hospital mortality due to NF. Methods: All patients had diagnoses of NF and were admitted to the emergency department of a single institution in Taiwan over a 4-year period. Demographics, comorbidities, clinical presentations, and laboratory parameters were retrospectively reviewed. Red blood cell distribution width was categorized as elevated (N 14.5%) or not elevated. Multivariate regression analysis was used to identify risk factors associated with mortality. Results: A total of 98 patients were enrolled, and the mortality rate was 23%. Univariate analysis indicated that advanced age, initial hypotension, low hemoglobin level, and elevated RDW (69.6% vs 20%, OR = 9.14, P b .001) were significantly associated with mortality. Multivariate analysis indicated that RDW was a significant and independent predictor of mortality in enrolled patients. Conclusions: Elevated RDW is a significant and independent predictor of in-hospital mortality for patients with NF. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Necrotizing fasciitis (NF) is a rare but rapidly progressing and potentially lethal infection of soft tissue that was first named by Wilson [1] in 1952. Despite recent improvements in the medical care of patients with NF, the mortality rate remains high [2–4]. Previous research has identified several risk factors, including diabetes mellitus (DM), liver cirrhosis, Aeromonas infection, old age, Vibrio infection, cancer, hypotension, and the presence of more than 10% band neutrophils in a whole blood sample [4–6]. Early recognition of patients with increased risk for NF allows earlier and more aggressive care. In particular, early surgical intervention is crucial for prevention of mortality [7–10]. Red blood cell distribution width (RDW) is a quantitative measure of anisocytosis, the variability in size of circulating erythrocytes, and is routinely reported in complete blood cell count panels. An elevated RDW is associated with severe morbidity and mortality in the presence of chronic heart failure [11–15] and is also a prognostic factor for infectious diseases, such as infection by gram-negative ⁎ Corresponding author. Chang Gung Memorial Hospital, Chiayi No. 6, W Sec, Jiapu Rd, Puzi City, Chiayi County 613, Taiwan (ROC). Tel.: +886 5 3621000x2805; fax: +886 5 362 3002. E-mail addresses: [email protected] (C.-L. Weng), [email protected] (C.-H. Wang), [email protected] (I.-C. Chen), [email protected] (K.-Y. Hsiao), [email protected] (K.-P. Chang), [email protected] (S.-Y. Wu), [email protected] (H.-M. Shih). http://dx.doi.org/10.1016/j.ajem.2014.08.001 0735-6757/© 2014 Elsevier Inc. All rights reserved.
bacteria, severe sepsis, septic shock, and community-acquired pneumonia [16–18]. No previous studies have examined the association between NF and RDW. The purpose of the present retrospective study is to investigate the association between RDW and NF at a single institution in Taiwan over a period of 4 years. 2. Materials and method We performed a retrospective analysis of the records of patients diagnosed with NF who were admitted to our hospital through the emergency department (ED) from the period of January 1, 2008, to December 31, 2012. Chang-Gung Memorial Hospital, in the city of Chayi, is a university teaching hospital in south-central Taiwan. As a general hospital, there are approximately 1000 beds in the general ward, 120 beds in the intensive care unit, and more than 60,000 annual visits to the ED. We used a coding system to assure the anonymity of all enrolled patients. 2.1. Inclusion criteria An electronic search was used to identify all adult patients (older than 18 years) who were admitted to our ED during the 4-year study period. All enrolled patients had diagnoses of NF (code 72886; International Classification of Diseases, Ninth Revision). In addition, all
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patients received surgical debridement; and the surgical findings were compatible with a diagnosis of NF. 2.2. Exclusion criteria Patients were excluded if they were not admitted to the ED, if they were readmitted to the hospital with 30 days of discharge following NF, if they were younger than 18 years, if the diagnosis of NF was excluded after surgery, or if they were discharged from our hospital before complete treatment. 2.3. Data collection Age, sex, and comorbidities such as DM, hypertension, previous stroke, chronic obstructive pulmonary disease (COPD), liver cirrhosis, cancer, coronary artery disease, chronic kidney disease, and congestive heart failure were recorded. We also reviewed symptoms and signs at ED presentation and laboratory findings at admission, including white blood cell and differential count, hemoglobin, RDW, creatinine, alanine aminotransferase, blood sugar, and microbiology results of wound and blood cultures. The in-hospital mortality rate was considered the primary outcome measure. Initial hypotension was defined as systolic blood pressure less than 90 mm Hg at ED triage. Bandemia was defined as the presence of more than 10% band white blood cells. Red blood cell distribution width was defined as (standard deviation of mean corpuscular volume/mean corpuscular volume) × 100%, and a level of 14.5% is the normal upper limit for our hospital. All data collection was by a single researcher who was blinded to the purpose of study. 2.4. Statistical analysis Patients were divided into 2 groups based on in-hospital survival. The differences between the 2 groups were analyzed using the χ 2 test for categorical variables and the independent-samples t test for continuous variables. To identify variables associated with mortality, data were initially analyzed by univariate analysis. Significant variables were then entered into a stepwise backward logistic regression analysis. We also compared the characteristics of patients with normal and abnormal RDW. All statistical assessments were 2-sided. A P value less than .05 was considered statistically significant. All statistical analyses were performed using SPSS (ver. 17.0; SPSS, Chicago, IL) software. 3. Results One hundred twenty cases who had ED diagnosis of NF during the 4-year study period were initially enrolled to our study. Sixteen patients were excluded because the diagnosis of NF was excluded before discharge. One patient who received operation and was treated in other hospital before being transferred to our hospital was excluded. Three patients who refused surgery were also excluded. We also excluded 2 patients who were discharged before complete treatment. We finally enrolled 98 cases (67 men and 31 women), and their demographic data and comorbidities were summarized in Table 1. A total of 23 patients (23%) died during their hospitalization. Patients who died were significantly older than survivors (75.2 ± 11.84 vs 68.23 ± 13.60 years, P = .028). Table 2 lists the major symptoms and signs of the 2 groups. Patients who died were more likely to have hypotension at initial presentation (33.3% vs 60.9%, P = .018). Table 3 compares the laboratory results of the 2 groups. Patients who died had lower levels of hemoglobin (12.90 ± 2.10 vs 11.79 ± 2.59 mg/dL, P = .039) and were more likely to have elevated RDW levels (20% vs 69.6%, P b .001). Variables that were significantly associated with in-hospital death in our study and previous studies [4–6], including age, initial
Table 1 Demographic data and comorbidities
⁎Ageb Malea DMa Hypertensiona Strokea COPDa Liver cirrhosisa Cancera Coronary artery diseasea Chronic kidney diseasea Congestive heart failurea
Survivor(75)
Mortality(23)
P
68.23 ± 13.60 50 (66.7%) 27 (36%) 32 (42.7%) 4 (5.3%) 6 (8%) 10 (13.3%) 9 (12%) 2 (2.7%) 9 (12%) 2 (2.7%)
75.26 ± 11.84 17 (73.9%) 9 (39.1%) 9 (39.1%) 3 (13%) 2 (8.7%) 7 (30.4%) 4 (17.4%) 3 (13%) 6 (26.1%) 2 (8.7%)
.028 .513 .785 .764 .209 .915 .058 .505 .083 .111 .234
a
Categorical data expressed as number (%). Continuous data expressed as mean ± standard deviations. ⁎ P b .05. b
hypotension, liver cirrhosis, RDW greater than 14.5%, hemoglobin, positive blood culture, and bandemia, were examined by a stepwise backward logistic regression analysis. The results indicate that an RDW greater than 14.5% and hypotension at ED triage were significantly and independently associated with mortality (Table 4). Finally, we compared patients with normal and elevated RDW (Table 5). The group with elevated RDW had significantly lower hemoglobin levels (13.25 ± 1.97 vs 11.33 ± 2.32 mg/dL, P b .001). In addition, the group with elevated RDW was older and more likely to have hypotension and bandemia, although these 3 differences were not statistically significant. The group with elevated RDW also had more comorbidities, although liver cirrhosis was the only comorbidity with statistical significance.
4. Discussion The major result of our study is that an elevated RDW is significantly and independently associated with increased risk of in-hospital mortality in patients who present to the ED with NF. Previous studies reported an association of elevated RDW with mortality in patients with heart failure, stroke, sepsis, and pancreatitis [11–20]. To our knowledge, the present study is the first to examine the relationship of RDW and NF. Although our results did not identify the pathophysiologic mechanism for this association, we believe that there are several possible explanations based on review of the literature. First, an elevated RDW indicates the presence of a severe systemic inflammatory state. Inflammation increases bone marrow function, iron metabolism, and the expression of some proinflammatory cytokines, such as tumor necrosis factor–α, interleukin-6, and interleukin-1β. This could lead to the suppression of red blood cell (RBC) maturation, a decrease in the half-life of RBCs, and progression of sepsis, thereby leading to the presence of newer and larger reticulocytes in the circulation and an increase in the RDW [17,19,21–23]. Patients with
Table 2 Comparison of clinical presentation
Swelling Pain Erythema Hemorrhagic bullae Fever ⁎Initial hypotension Tachycardia Altered mental status
Survivor (75)
Mortality (23)
P
70 (93.3%) 63 (84%) 51 (68%) 22 (29.3%) 31 (41.3%) 25 (33.3%) 38 (50.7%) 2 (2.7%)
18 (78.3%) 15 (65.2%) 13 (56.5%) 8 (34.8%) 5 (21.7) 14 (60.9%) 13 (56.5%) 2 (8.7%)
.052 .074 .312 .615 .088 .018 .623 .234
Categorical data expressed as number (%). ⁎ P b .05.
C.-L. Weng et al. / American Journal of Emergency Medicine 32 (2014) 1259–1262 Table 3 Comparison of laboratory result
WBC (103/μL)b Band N10%a ⁎Hemoglobin (g/dL)b Hematocrit (%)b ⁎RDW N14.5a Platelet (103/μL)b Creatinineb Sugarb ALTb Positive blood culturea Vibrio infectiona
Table 5 Comparison of patients with normal or abnormal RDW
Survivor (75)
Mortality (23)
P
16.1 ± 7.48 19 (25.3%) 12.90 ± 2.10 39.3 ± 11.31 15 (20%) 163.17 ± 83.86 1.72 ± 1.53 184.88 ± 158.34 46.35 ± 33.83 24 (32%) 23 (30.7%)
13.95 ± 10.52 10 (43.5%) 11.79 ± 2.59 35.12 ± 7.45 16 (69.6%) 137.57 ± 88.27 2.10 ± 0.92 161.17 ± 191.34 42.67 ± 29.47 12 (52.2%) 6 (26.1%)
.27 .09 .039 .10 b.0001 .209 .27 .628 .677 .079 .674
ALT: alanine aminotransferase. a Categorical data expressed as number (%). b Continuous data expressed as mean ± standard deviations. ⁎ P b .05.
Initial hypotensiona Band N10%a ⁎Hemoglobin (g/dL)b DMa Hypertensiona Strokea COPDa ⁎Liver cirrhosisa Cancera Coronary artery diseasea Chronic kidney diseasea Congested heart failurea
Normal RDW (67)
Elevated RDW (31)
P
24 (35.8%) 17 (25.4%) 13.25 ± 1.97 23 (34.3%) 31 (46.3%) 3 (4.5%) 4 (6%) 5 (7.5%) 9 (13.4%) 2 (3.0%) 10 (14.9%) 1 (1.5%)
15 (48.4%) 12 (38.7%) 11.33 ± 2.32 13 (41.9%) 10 (32.3%) 4 (12.9%) 4 (12.9%) 12 (38.7%) 4 (12.9%) 3 (9.7%) 5 (16.1%) 3 (9.7%)
.272 .179 b.001 .468 .191 .132 .244 b.001 .943 .322 .878 .092
a
Categorical data expressed as number (%). Continuous data expressed as mean ± standard deviations. ⁎ P b .05. b
severe sepsis or septic shock experience a high level of oxidative stress, and this reduces survival of RBCs [24,25] and also leads to an elevated RDW. The results of our study are consistent with this explanation. In agreement, we also found that hypotension and bandemia were more common (although not significantly) in patients with elevated levels of RDW. Thus, an elevated RDW may be associated with a more severe systemic inflammatory state; and this may explain the increased risk for mortality. On the other hand, an elevated RDW level might indicate the presence of severe tissue hypoxia. Necrotizing fasciitis is a lifethreatening soft tissue infection that is accompanied by a rapid increase of inflammation and necrosis of the skin, subcutaneous fat, and fascia, and can rapidly progress to severe sepsis or septic shock with circulatory abnormalities, ultimately leading to global tissue hypoxia [26,27]. In addition to stimulating the systemic inflammatory response syndrome, global tissue hypoxia independently contributes to endothelial activation and disruption of the homeostatic balance of coagulation, vascular permeability, and vascular tone [28], ultimately leading to hemolysis. This response may have contributed to the decreased hemoglobin and elevated RDW in our group of NF patients who died. As discussed above, an elevated RDW indicates a decreased number of RBCs in circulation and the presence of more immature RBCs. Anemia and the presence of more immature RBCs would worsen tissue hypoxia in patients with severe sepsis or septic shock and ultimately lead to increased mortality [29,30]. Our results also indicated an association of elevated RDW with decreased hemoglobin. A low hemoglobin level often reflects the presence of premorbidities, including malnutrition, chronic kidney disease, liver disease, iron deficiency, and malignancy [11,31–33]. The findings of our study (Table 5) agree with this interpretation. In particular, patients with more premorbidities might be more likely to develop anemia; and this could lead to an elevated RDW [14] and poor overall prognosis [34,35]. Thus, this is another possible explanation for our observed association between RDW elevation and mortality in patients with NF.
Table 4 Final model of stepwise backward logistic regression analysis of factors associated with mortality Multivariate (adjusted)
Initial hypotension RDW N14.5
1261
ORs
P
2.996 8.576
.047 b.001
Note: Age, initial hypotension, liver cirrhosis, RDW greater than 14.5%, hemoglobin, positive blood culture, and bandemia were put into logistic regression initially. OR: odds ratio.
The major limitation of our study is that it was retrospective. Medical records are not designed for research purposes, do not include all variables of interest to researchers, and may contain inaccurate or imprecise descriptions. Second, RDW elevation may be due to a deficiency of iron, folate, or vitamin B12; but these data were not available in medical records. Third, we did not investigate and cannot prove the pathogenic mechanism for our observed association of elevated RDW and mortality in patients with NF. Last, all of our patients were from a single medical center in Taiwan. The value of RDW in prediction of clinical outcomes may be different for other populations of NF patients. Further prospective studies with larger patient populations involving multiple centers are necessary to more accurately assess the role of elevated RDW as a predictor of mortality in patients with NF. 5. Conclusions In conclusion, the present study indicated that an elevated RDW is independently and significantly associated with increased in-hospital mortality in patients with NF. Future studies of other populations are needed to verify these results. Conflicts of interest statement None declared. References [1] Wilson B. Necrotizing fasciitis. Am Surg 1952;18:416–31. [2] Hung CC, Chang SC, Lin SF, Fang CT, Chen YC, Hsieh WC. Clinical manifestations, microbiology and prognosis of 42 patients with necrotizing fasciitis. J Formos Med Assoc 1996;95:917–22. [3] Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg 2007;119:1803–7. [4] Hsiao CT, Weng HH, Yuan YD, Chen CT, Chen IC. Predictors of mortality in patients with necrotizing fasciitis. Am J Emerg Med 2008;26:170–5. [5] Lee CY, Kuo LT, Peng KT, Hsu WH, Huang TW, Chou YC. Prognostic factors and monomicrobial necrotizing fasciitis: gram-positive versus gram-negative pathogens. BMC Infect Dis 2011;11:5. [6] Huang KF, Hung MH, Lin YS, Lu CL, Liu C, Chen CC, Lee YH. Independent predictors of mortality for necrotizing fasciitis: a retrospective analysis in a single institution. J Trauma 2011;71:467–73 [discussion 473]. [7] Voros D, Pissiotis C, Georgantas D, Katsaragakis S, Antoniou S, Papadimitriou J. Role of early and extensive surgery in the treatment of severe necrotizing soft tissue infection. Br J Surg 1993;80:1190–1. [8] Qazi SA, Mohammed AA, Saber EI, Mirza SM. Necrotizing fasciitis. Role of early surgical intervention. Saudi Med J 2004;25:890–4. [9] Boyer A, Vargas F, Coste F, Saubusse E, Castaing Y, Gbikpi-Benissan G, Hilbert G, Gruson D. Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 2009;35:847–53. [10] Chao WN, Tsai CF, Chang HR, Chan KS, Su CH, Lee YT, Ueng KC, Chen CC, Chen SC, Lee MC. Impact of timing of surgery on outcome of Vibrio vulnificus–related necrotizing fasciitis. Am J Surg 2013;206:32–9.
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