Association between Red Blood Cell Distribution Width and Short-Term Mortality in Patients with Paralytic Intestinal Obstruction: Retrospective Data Analysis Based on the MIMIC-III Database

Objective Elevated red cell distribution (RDW) has been reported to be associated with mortality in patients with acute pancreatitis and cholecystitis admitted to the intensive care unit (ICU). However, evidence for the relationship between RDW and paralytic intestinal obstruction is lacking. Therefore, the article aims to investigate the relationship between RDW and 28-day mortality of the patients with paralytic intestinal obstruction. Patients and Methods. This is a single-center retrospective study. Based on a particular screening criterion, 773 patients with paralytic intestinal obstruction were selected from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Indicators of the first 24 h into the ICU were used to analyze the relationship between RDW and 28-day death from paralytic intestinal obstruction by Kaplan−Meier (K-M) analysis, logistic regression analysis, and stratification analysis. Results The curve fitting exhibited a nonlinear relationship. The K-M curve showed that groups with higher RDW values had lower survival rates. The logistic regression analysis revealed that RDW increased with 28-day mortality in patients with paralytic intestinal obstruction in the fully adjusted model. In the fully adjusted model, OR value and 95% CI from the second to the third quantiles compared to the first quartile (reference group) were 1.89 (1.04, 3.44) and 3.29 (1.82, 5.93), respectively. The results of stratified analysis of each layer had the same trend as those of regression analysis, and the interaction results were not significant. Conclusion Elevated RDW was associated with increased 28-day mortality from paralytic intestinal obstruction in the ICU. This study can help to further explore the relationship between RDW and death in patients with paralytic intestinal obstruction.


Introduction
In intensive care units (ICU), gastrointestinal failures, including paralytic intestinal obstruction, are common in patients [1].Paralytic intestinal obstruction is a paralysis of the intestine without power, mainly caused by the disorder of the intestinal autonomic nervous system, block of local nerve conduction in the intestine, and obstruction of the contraction of the smooth muscle of the intestine, subsequently resulting in the powerlessness of dilation and peristalsis of the intestinal tube.If the diagnosis and treatment of intestinal obstruction are not timely, the disease can develop seriously and even induce intestinal necrosis, perforation, bacterial peritonitis, and other serious complications, consequently endangering the patients' lives [2].
Red cell distribution (RDW) is a routine blood test indicator, varying in value from 11% to 15%, which represents the degree of uniformity of red blood cell (RBC) size and can refect the heterogeneity of erythrocyte volume in circulation [3].RDW is an ideal laboratory test indicator and is also essential for the diagnosis and diferential diagnosis of anemia due to its features of efciency, efectivity, and low cost [4].Studies have shown that the size of RDW is not only gradually increasing with age [5] but also positively correlated with HbA1c [6].Te risk factors of increased RDW include physical training, senility, erythropoietic stimulation, black race, and pregnancy [4].Besides, the RDW index was reported to be related to the prognosis of some diseases, for instance, acute heart failure [7], cancer [8], acute kidney injury [3], and gastrointestinal disorders [9].RDW is also an independent risk for mortality in the general population [4,10,11].Moreover, RDW has also been linked to the death of patients with digestive-related illnesses in ICU, such as acute pancreatitis [12] and cholecystitis [13].In ICU, the stratifcation of patients is more helpful to understand the prognosis of patients [14].More and more literature has studied specifc diseases and their specifc indicators in ICU [12,13,15].Doctors have a more accurate grasp of diseases and laboratory indicators, which is conducive to understanding the patients' conditions more accurately, having earlier communication with the patient's family members, relieving their anxiety, and providing favorable help for later diagnosis and treatment.In clinical studies, RDW has been proven to afect the prognosis of many diseases, but there is a lack of research on paralytic intestinal obstruction.Many studies confrmed that MIMIC-III plays an important role in clinical studies [16][17][18][19].
Studies have shown that the mortality rate of paralytic intestinal obstruction is 5%-6%, and the average cost of hospitalization is increasing [20].Patients with paralytic intestinal obstruction in the ICU tend to have more severe symptoms, so short-term mortality is also increasing.Terefore, it is imperative to study the factors associated with the death of this disease.Infammation plays a vital role in the progression of paralytic intestinal obstruction.In addition, some infammation factors are to be associated with mortality from intestinal obstruction [21].RDW has a high recognition ability for iron defciency and iron defciency anemia [22].Serum ferritin is the most efective test for the diagnosis of iron defciency.In addition, ferritin can be elevated in response to infammation [22].Terefore, our study aims to investigate whether RDW is associated with death in patients with paralytic intestinal obstruction after their entry into the ICU.

Te Database.
Te retrospective cohort study explored the correlation between RDW and paralytic intestinal obstruction.All the data in this work were acquired from the Medical Information Mart for Intensive Care III (MIMIC-III).In this study, data analysis and publication comply with the statement of strengthening the reporting of observational studies in epidemiology.Jiahui Yin participated in the online course of the National Institutes of Health and passed the exam of the protection Human Research Participants (No. 40089742).Ultimately, she successfully accessed the MIMIC-III database, which is a unicentric and cost-free available database of multiple patients from the Beth Israel Deaconess Medical Center in Boston.

Inclusion and Exclusion Criteria for the Study Population.
Te database contained an aggregate of 58,976 patients admitted to the ICU.In our research, 773 participants were selected through the screening criteria shown in Figure 1 for a fow chart.Patients over 18-years old with paralytic intestinal obstruction who were frst hospitalized in the ICU for more than one day were enrolled.If patients had multiple hospital admissions in the database, we extracted the frst admission.Patients with the following standards were excluded: (1)

Subject Characteristics.
Te diagram of selection for patients showed that 773 patients with paralytic intestinal obstruction were included in our study population.Te features of the study population were shown in Table 1.Tere were three groups of RDW indicators as follows: the low group (12.0-14.1%), the middle group (14.2-15.7%),and the high group (15.8-23.0%).Tere was no diference in sex, serum potassium, WBC, serum glucose, qSOFA, chronic pulmonary disease, and time in ICU among low, middle, and high RDW.Tere was signifcance in age, admission type, ethnicity, SBP, DBP, hematocrit, BUN, platelet count, hemoglobin, serum creatinine, serum anion gap, APS III, OASIS, MLODS, CHF, hypertension, renal failure, liver disease, coagulopathy, pulmonary circulation disease, and time in hospital.In the scoring system, the values of APS III, OASIS, and MLODS increased with RDW, and the results showed obvious signifcance (p < 0.05).Patients in the RDW high group had more comorbidities and higher values of MLODS, qSOFA, OASIS, and APSIII.Higher values of BUN, serum creatinine, and serum anion gap and lower values of hematocrit, WBC, hemoglobin, serum glucose, and platelet were observed in the high group.Increased 28-day mortality was noted in these patients.

Univariate Analysis.
Te results of the univariate analysis were shown in Table 2 in detail.Univariate analysis showed that qSOFA, congestive heart failure, liver disease, coagulopathy, and chronic pulmonary disease were positively correlated with 28-day mortality in patients with paralytic intestinal obstruction.In contrast, elective admission type was negatively associated with the mortality.Tere were indicators independent of 28-day mortality for patients with paralytic intestinal obstruction, including, DBP, serum potassium, BUN, WBC, platelet count, serum creatinine, serum anion gap, APS III, qSOFA, and MLODS.

Overall Survival.
Te K-M curve displayed survival rates of subjects with diferent RDW levels.Te K-M curves explained that patients in the RDW high group had shorter lifetime and higher death rates than those in the RDW medium and low groups (p < 0.001) (Figure 3).

Subgroup Analysis.
In this study, the following indicators were hierarchically analyzed: age, sex, admission type, ethnicity, renal failure, CHF, pulmonary circulatory disease, hypertension, chronic pulmonary disease, liver disease, and coagulopathy (Table 4).Te trend of each subgroup was parallel to the regression analysis.No signifcant interaction was observed in diferent layers (p > 0.05).

Discussion
Paralytic intestinal obstruction is a clinical syndrome in which intestinal motility dysfunction results in the inability to discharge the contents normally, often secondary to severe bowel surgery [23].Te disease not only delays the patient's discharge but also increases the risk of readmission.Although laxatives, cholinergic agonists, and other drugs can be used to treat this disease, there are still some side efects [24].Te mechanism responsible for the relationship between RDW and paralytic intestinal obstruction is unclear.
Previous studies have illustrated that the mortality during the progression of intestinal obstruction is related to infammation indicated by many hematological parameters, such as WBC, neutrophile granulocyte [25], mononuclear leucocyte [21], C-reactive protein, erythrocyte sedimentation rate (ESR), and interleukin-6.Tese indicators are also prognostic characteristics of intestinal obstruction.For example, proinfammatory cytokines are associated with gastrointestinal motility retardation [26].In addition, the preoperative stimulation of the vagus inhibiting infammatory factors can alleviate postoperative intestinal obstruction [27].Recently, it has been shown that RDW can serve as a marker of infammatory response and a key indicator for diagnosing and observing the therapeutic efects of iron defciency anemia [22].Anemia resulting from systemic infammatory response might exacerbate paralytic intestinal obstruction.Furthermore, patients with higher RDW values are more likely to have systemic symptoms and sufer more severe anemia, which leads to more serious diseases.Te increase of RDW refects the abnormality of RBC production, metabolism, and survival, caused by abnormal erythropoietin function, hypertension, oxidative stress, poor nutritional status, dyslipidemia, infammation, RBC fragmentation, and shortened telomere length [4].Figure 2: Association between RDW and 28 day mortality for patients with paralytic intestinal obstruction.Notes: A relationship between them was detected after adjusting for sex, ethnicity, age, SBP, DBP, BUN, WBC, serum glucose, creatinine, serum anion gap, APS III, OASIS, MLODS, congestive heart failure, chronic pulmonary disease, renal failure, and liver disease.A nonlinear relationship was found between RDW and paralytic intestinal obstruction mortality in the curve ftting diagram.Te solid line in the middle represents the smooth curve ftting between variables.Imaginary lines represent the 95% of confdence interval from the ft.Abbreviations: RDW: red cell distribution width, BUN: blood urea nitrogen, SBP: systolic blood pressure, DBP: diastolic blood pressure, WBC: white blood cell, APS III: acute physiology score III, OASIS: Oxford acute severity of illness score, MLODS: modifed logistic organ dysfunction system.6 Emergency Medicine International Accordingly, in addition to the infammation marker, RDW may also be associated with death in patients with intestinal obstruction and could refect microenvironment changes within the patients' bodies.Likewise, further investigation should be performed to examine the RDW's role in the mortality of paralytic intestinal obstruction.
Te mortality of patients with paralytic intestinal obstruction can be afected by many factors.For example, a Ushape relationship between bicarbonate and mortality in ICU patients with paralytic intestinal obstruction was found [28].In one study [29], fungal infection was associated with death in patients with pseudo-obstruction.Additionally, the high value of BUN at admission could lead to a poor prognosis in ICU patients [30].At the same time, serum creatinine changes impacted on the outcomes of critically ill patients [31].Studies have shown that many indicators can serve as risk factors for postoperative intestinal obstruction, including age, preoperative hemoglobin, operation time, American Society of Anesthesiologist score, surgical complexity, and RBC infusion [32].For instance, age is positively correlated to RDW [10].Gastrointestinal surgery is the most signifcant risk factor for paralytic intestinal obstruction.In addition, physical therapy can alleviate postoperative complications of emergency abdominal surgery, including paralytic intestinal obstruction [33].Recently, it was reported that severe COVID-19 (coronavirus disease 2019) infection could also cause paralytic intestinal obstruction, which may be related to the virus entry mediated by the angiotensin-converting enzyme 2 receptor on cells in the gut and subsequent infammation [34].Additionally, RDW was found to be an independent risk factor by logistic regression analysis, which was also validated by substantive clinical observation.Tis fnding applies to the guidance of clinical treatment.RDW is generally improved by defective hematopoietic material or increased RBC destruction.High baseline RDW is signifcantly associated with hemoglobin, bone marrow plasma cell infltration, and cytogenetic risk stratifcation [35].Past studies showed a link between RDW and mortality from digestive diseases in the ICU [12,13].However, the role of RDW in the 28-day mortality of paralytic intestinal obstruction is still unclear.Terefore, it is worth exploring the relationship between short-term mortality and RDW index changes in patients with paralytic intestinal obstruction.
Te purpose of this study is to investigate the relationship between RDW and mortality in patients with Emergency Medicine International paralytic intestinal obstruction.Our study found that the short-term mortality after admission in patients with paralytic intestinal obstruction increased with RDW.In this study, patients with metastatic cancer [36], lymphoma [37], valvular disease, and urgent admission [5] were excluded due to the independence of RDW to the survival time of these diseases.A previous retrospective study [13] on the ICU showed an increase in short-30-day mortality in patients with cholecystitis with increasing RDW (HR 1.183, 95% CI 1.080, 1.295).Tis analysis observed a nonlinear relationship between changes in RDW and 28-day all-cause mortality in patients with paralytic intestinal obstruction.Te study in this paper also had a similar trend, and the diference in efect size between the two was not signifcant.It may be because both of them were digestive system diseases, so the two directions were similar.In the K-M curve, we observed that higher RDW levels had lower survival rates than lower RDW levels.Multiple regression equations indicated that an increase in RDW was associated with an increase in 28-day mortality in patients with paralytic intestinal obstruction after admission to the ICU.In addition, after adjusting for confounding factors, the link remained.High levels of RDW were signifcantly associated with mortality in these patients.Terefore, this study can help medical staf to explore further the relationship between RDW and death in patients with paralytic intestinal obstruction.In each stratum of the subgroup analysis, increased RDW was associated with increased mortality in patients with paralytic intestinal obstruction.In addition, the interaction results were not signifcant.Terefore, stratifed analysis results excluded CHF, hypertension, chronic pulmonary disease, renal failure, liver disease, and coagulopathy on mortality.All these results suggested that the relationship between RDW and 28-day mortality in patients with paralytic intestinal obstruction in the ICU is stable.Paralytic intestinal obstruction can cause or aggravate malnutrition, water, and electrolyte imbalance, which further increases the risk of severe systemic infection, bleeding, organ failure, and indirectly increases the risk of death.
In the present work, a strong association between RDW changes and the mortality of patients with paralytic intestinal obstruction was found and fully supported by However, there are still some limitations to this study.First, conclusions drawn from this work cannot be extrapolated to people with metastatic cancer, urgent admission, lymphoma, valvular disease, or RDW record ≥23, due to the exclusion criteria.Second, since the database of this study is from the United States, the results of this study are not applicable to other populations.Data from diferent regions should have been included.Tird, RDW is a time-varying variable and its causal associations with the outcome should be explored with more advanced techniques [38].But only a single measure of RDW was used in this work, so there is a lack of research on causality.Fourth, the data of this study were obtained from the MIMIC database, which needs to be verifed by more ICU databases.Fifth, laboratory indicators of some patients are missing or abnormal.Sixth, since this database has been continuously updated, new databases are needed for continuous verifcation to ensure the accuracy of experimental results.A possible next step would be to conduct additional research in MIMIC-IV.

Conclusion
Trough analysis of the MIMIC database, we found that RDW was associated with 28-day of admission to the ICU in patients with paralytic intestinal obstruction.More research is needed to explore further the relationship between the two.

Table 1 :
Baseline characteristics of the study population.

Table 2 :
Univariate analysis for 28-day mortality in critically ill patients with paralytic intestinal obstruction.
Notes: normally distributed data are presented as the mean (SD) (analysis of variance); non-normally distributed data are presented as median (IQR) (nonparametric Wilcoxon test); categorical variables are presented as n (%) (Chi-square test).Abbreviations: RDW, red cell distribution width; BUN, blood urea nitrogen; SBP, systolic blood pressure; DBP, diastolic blood pressure; APS III, acute Physiology Score III; OASIS, Oxford acute severity of illness score; qSOFA, quick sequential organ failure assessment score; MLODS, modifed logistic organ dysfunction system; ICU, intensive care unit; SD, standard deviation; IQR, interquartile ranges.95% CI 1.15, 3.60, p � 0.015).High RDW was also associated with increased mortality in the minimally adjusted model (OR 3.90, 95% CI 2.27, 6.68, p < 0.001).In the fully adjusted model, the relationship between the RDW and mortality was similar to that in the minimally adjusted model (OR 1.89, 95% CI 1.04, 3.44, p � 0.036 in the middle RDW; OR 3.29, 95% CI 1.82, 5.93, p < 0.001 in the high RDW).Te p values of the trend tests are all less than 0.001 in all models.

Table 3 :
OR (95% CI) for 28-day mortality across groups of RDW.Notes: For the crude model, we did not adjust other covariants.For the minimally adjusted model, we adjusted age, sex, and ethnicity.For the full adjusted model, we adjust sex, ethnicity, age, SBP, DBP, BUN, WBC, serum glucose, creatinine, serum anion gap, APS III, OASIS, MLODS, congestive heart failure, chronic pulmonary disease, renal failure, and liver disease.Abbreviations: CI, confdence interval; OR, odds ratio; RDW, red cell distribution width; SD, standard deviation.

Table 4 :
Efect size of RDW on 28 day mortality in prespecifed and exploratory subgroups.Emergency Medicine International substantial data analysis, which is vital for the short-term prognosis of patients with paralytic intestinal obstruction.