Red cell distribution width and red cell distribution width to total serum calcium ratio as major predictors of severity and mortality in acute pancreatitis

A retrospective case-control study was conducted at the Centro Hospitalar e Universitário de Coimbra from January 2014 to December 2016, including a total of 312 consecutive admissions with AP in our gastroenterology department. Inclusion criteria were age over 18 years-old, a minimum hospital stay of 24 h and a diagnosis of AP according to the RAC [3] (at least two criteria: typical clinical presentation including acute persistent abdominal pain, serum amylase exceeding 3 times the upper limit of normal (100 IU/L) and characteristic findings on abdominal ultrasonography and/or computed tomography). Exclusion criteria included patients with incomplete data and the presence of underlying factors that could change RDW, such as infectious or immunosuppressive conditions/therapy, active malignancy, chronic use of erythropoietin, recent transfusion history, pregnancy or trauma [10, 16]. Ninety-one patients with severe AP were identified during the study period (cases), who were compared with patients with mild AP (controls), in the 1:1 proportion. We randomly selected 91 patients from a total of 146 patients with mild AP to incorporate the control group, using Microsoft Excel (Microsoft, Redmon, WA, USA), and therefore avoid statistical bias. AP severity was also defined according to the RAC in severe, based on the presence of single or multiple persistent organ failure (> 48 h) and/or local complications [3]. Organ failure was classified according to MM including cardiovascular, respiratory and renal failures [3]. In addition, patients who died as a result of AP were compared with AP survivor patients (Fig. 1). Variables evaluated included age, gender, AP etiology, organ failure and local/systemic complications AP-associated, comorbidities, smoking habits (more than 10 cigars/day) and alcohol consumption (more than 20 g alcohol/day). Biochemical and arterial blood gas (ABG) tests at admission were also registered, including white blood cells (WBC) count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, platelet count, blood urea nitrogen (BUN), creatinine, international normalized ratio (INR), albumin, lactate dehydrogenase (LDH), serum glucose, hemoglobin, hematocrit, serum amylase, C-reactive protein at 0 h (CRP_0h), CRP at 24 h (CRP_24h), arterial lactate, arterial partial pressure of oxygen, D-dimers, TSC, RDW at 0 h (RDW_0h), RDW at 24 h (RDW_24h). Additionally, RDW_0h-to-TSC ratio and RDW_0h-to-platelets ratio were evaluated. RDW was also compared with validated and widely used AP prognostic scores at first 24 h, including Ranson, BISAP and MM scores. The primary endpoints were severity and in-hospital mortality associated with AP.

Statistical analysis was carried out using social package for social sciences version 22.0 for Windows (SPSS Inc., Chicago, IL, USA). The level of significance was set at p value less than 0.05. Normality of data distribution was assessed with Kolmogorov-Smirnov or Shapiro-Wilk test. Continuous data were expressed as mean and standard deviation (SD) or median and interquartile range based on the normality of distribution. Groups were compared using Student’s t-test or Mann-Whitney test. Categorical variables were expressed as frequency and percentage and compared using Χ²-test or Fisher’s exact test. Multivariate logistic regression analysis with the determination of adjusted odds ratio (aOR) and area under the receiver operating characteristic curve (AUROC) were also applied, assigning the best cut-off in terms of sensitivity and specificity.

A total of 312 eligible patients were admitted with AP during three consecutive years. One-hundred and forty-six patients had mild AP, 75 (24.0%) moderately severe AP and 91 (29.2%) severe AP. Of the total of 182 enrolled patients (91 with severe AP and 91 with mild AP after random selection), 54.9% (n = 100) were males with mean age of 66.3 ± 15.1 years. Most patients (n = 102; 56.0%) had gall bladder stones. The most common cause of acalculous AP was alcohol (n = 61; 76.2%). An abdominal computed tomography (CT) was performed in 96.7% (n = 88) of patients with severe AP. Among these patients, necrotizing pancreatitis was present in 31 patients (34.1%). Twenty-seven (29.7%) patients developed systemic inflammatory response syndrome and 42 (46.2%) patients presented organ failure, the most common being due to respiratory failure (n = 30;33.0%) followed by renal failure (n = 10;11.0%).

Both groups of patients with severe and mild AP were comparable in terms of age (64.8 ± 16.3 years vs 67.9 ± 13.7 years; p = 0.239) and gender (males: 58.2% vs 51.6%; p = 0.228), as described in Table 1. After multivariate analysis of significant risk factors in univariate analysis, no significant differences were verified in relation to hospital stay or comorbidities between two groups. Concerning laboratory parameters, there was a significant association of severe AP with high BUN (26.6 ± 17.1 vs 19.4 ± 8.8 years;aOR = 1.002; p < 0.004), serum glucose (168.0 ± 72.6 vs 130.9 ± 35.5; aOR = 1.002; p < 0.001), RDW_0h (14.6 ± 1.3 vs 12.7 ± 0.5; aOR = 1.129; p < 0.001), RDW_24h (14.3 ± 1.9 vs 12.8 ± 0.5; aOR = 1.015; p = 0.005) and RDW_0h-to-TSC ratio (1.8 ± 0.4 vs 1.3 ± 0.1; aOR = 1.556; p < 0.001). In addition, there was also a significant association of severe AP with conventional prognostic scores, namely Ranson (2.6 ± 1.2 years vs 1.5 ± 0.9; aOR = 1.043; p < 0.001), BISAP (1.7 ± 0.9 vs 1.0 ± 0.7; aOR = 1.028; p < 0.001) and MM (0.8 ± 0.7 vs 0.0 ± 0.0; aOR = 1.184; p < 0.001) scores (Table 1).

The overall mortality rate was 8.8% (16/182), all cases associated with severe AP, corresponding to a mortality rate of 17.6% (16/91) in the severe AP group. As described in Table 2, cases and controls were similar and therefore comparable in terms of age (71.6 ± 14.3 years vs 65.8 ± 15.1 years; p = 0.123) and gender (68.8% vs 53.6%; p = 0.245). After multivariate analysis, there were no significant differences between survivors and nonsurvivors regarding hospital stay and comorbidities. Nonetheless, nonsurvivors had higher lactate at admission (3.6 ± 1.8 vs 2.0 ± 1.4; aOR = 1.164; p = 0.019), RDW_0h (15.3 ± 1.4 vs 13.5 ± 1.3; aOR = 1.038; p < 0.001), RDW_24h (15.1 ± 1.4 vs 13.4 ± 1.6; aOR = 1.006; p = 0.005) and RDW_0h-to-TSC ratio (2.0 ± 0.3 vs 1.6 ± 0.3; aOR = 1.018; p < 0.001) than survivors. Concerning usual prognostic scores, Ranson (2.7 ± 1.2 vs 2.0 ± 1.2; aOR = 1.019; p < 0.001), BISAP (2.0 ± 1.0 vs 1.3 ± 0.8; aOR = 1.010; p < 0.001) and MM (1.2 ± 1.0 vs 0.6 ± 0.3; aOR = 1.109; p = 0.020) scores were also significantly higher in nonsurvivors.

In order to assess the discriminant performance of RDW in terms of severity and mortality in AP and to establish a comparison with other independent risk factors, an AUROC analysis was performed. RDW_0h (AUROC:0.960; p < 0.001) and RDW_0h-to-TSC ratio (AUROC:0.973; p < 0.001) were major predictors of severe AP to a cut-off value of 13.0 (S-92.7%; Sp-84.3%) and 1.4 (S-96.3%; Sp-84.3%), respectively. These factors were superior to well-stablished prognostic scores as Ranson (AUROC: 0.777; p < 0.001; cut-off:3.0), MM (AUROC: 0.756; p < 0.001; cut-off:1.0) and BISAP (AUROC: 0.732; p < 0.001; cut-off:2.0) (Fig. 2).

Relatively to mortality in AP and as verified for AP severity, RDW at 0 h and 24 h post-admission were the best predictors for mortality in AP (AUROC: 0.842; p < 0.001; cut-off: 14.0 and AUROC: 0.848; p < 0.001; cut-off:13.8, respectively), followed by RDW_0h-to-TSC ratio (AUROC: 0.820; p < 0.001; cut-off: 1.7). All of these parameters were better predictors of AP mortality than MM (AUROC: 0.806; p < 0.001; cut-off:1.0), BISAP (AUROC: 0.693; p = 0.017; cut-off:2.0) or Ranson (AUROC: 0.640; p = 0.003; cut-off: 3.0) scores (Fig. 3).