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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 66-73

Red blood cell distribution width as a prognostic factor in mechanically ventilated patients with severe sepsis in comparison with Sequential Organ Failure Assessment score


Critical Care Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission03-Jun-2015
Date of Acceptance23-Jun-2015
Date of Web Publication6-Sep-2016

Correspondence Address:
Mohab S Mohamed
Critical Care Department, Faculty of Medicine, Alexandria University, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.189784

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  Abstract 


Background Sepsis is a major health concern worldwide. Within the last decade, several trials and protocols have focused on this condition, aiming to establish better measures for its management and prevention of potential complications. Higher values of red blood cell distribution width (RDW) have been found to be associated with sepsis severity and early mortality function and activation.
Patients and methods A sample of 50 patients with severe sepsis who were admitted to Alexandria University Hospital were selected. The patients were divided into two groups: group A and group B. Group A patients met the inclusion and exclusion criteria with high RDW and group B patients met the inclusion and exclusion criteria with normal RDW. Both groups were compared with Sequential Organ Failure Assessment (SOFA) score as a prognostic marker. RDW was measured every other day. Patients were followed up until death or discharge from the ICU for a total of 28 days.
Results A total of 50 adult patients with severe sepsis were enrolled in the study, comprising 12 women (48.0%) and 13 men (52.0%) in group A and 11 women (44.0%) and 14 men (56.0%) in group B. Chest infection was the most common source of sepsis in both group A (36%) and group B (44%). High RDW was associated with prolonged duration of mechanical ventilation (MV) of 13.60±4.76 days, compared with 9.96±3.91 days for normal RDW. High RDW was associated with prolonged ICU stay of 20.0±4.43 days compared with 14.20±3.34 days for normal RDW. High RDW was associated with poor outcome (68% mortality) compared with normal RDW (40% mortality). There was a positive correlation between high RDW with SOFA on day 0 (P=0.002), day 2 (P≤0.001), day 4 (P<0.001), day 6 (P≤0.001), day 14 (P≤0.001), day 20 (P≤0.001), and on average (P=0.001), and in normal RDW on day 0 (P=0.045), day 2 (P=0.033), day 4 (P=0.003), day 6 (P=0.008), day 14 (P=0.042), day 20 (P=0.005), and on average (P=0.010). There was a negative correlation between high RDW and platelet count on day 0 (P=0.0001), day 2 (P=0.002), day 4 (P=0.002), day 6 (P=0.005), and on average (P=0.001), as well as in normal RDW on day 0 (P=0.008), day 2 (P=0.010), day 4 (P=0.029), day 6 (P=0.015), and on average (P=0.012).
Conclusion RDW at admission is an important biomarker in severe sepsis with increased mortality, prolonged duration of MV, and prolonged ICU stay in patients with high RDW at admission. There was positive correlation between RDW and SOFA on days 0, 2, 4, 6, 14, 20, and on average and negative correlation between RDW and platelet on days 0, 2, 4, 6, and on average.

Keywords: red blood cell distribution width, Sequential Organ Failure Assessment, severe sepsis


How to cite this article:
Megahed MM, Shehata SA, Mohamed MS. Red blood cell distribution width as a prognostic factor in mechanically ventilated patients with severe sepsis in comparison with Sequential Organ Failure Assessment score. Res Opin Anesth Intensive Care 2016;3:66-73

How to cite this URL:
Megahed MM, Shehata SA, Mohamed MS. Red blood cell distribution width as a prognostic factor in mechanically ventilated patients with severe sepsis in comparison with Sequential Organ Failure Assessment score. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:66-73. Available from: http://www.roaic.eg.net/text.asp?2016/3/2/66/189784




  Introduction Top


Sepsis is a potentially fatal whole-body inflammation [a systemic inflammatory response syndrome (SIRS)] caused by severe infection [1]. According to the American College of Chest Physicians and the Society of Critical Care Medicine, there are different levels of sepsis [2].

  1. SIRS is the presence of two or more of the following: abnormal body temperature, heart rate, respiratory rate or blood gas, and white blood cell count.
  2. Sepsis is defined as SIRS in response to an infectious process.
  3. Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output).
  4. Septic shock is severe sepsis plus persistently low blood pressure following the administration of intravenous fluid.


Early classification of patients presenting with sepsis by means of objective scoring systems is desirable to determine the prognosis of patients. However, none of the existing scoring systems has fulfilled all expectations. The most commonly used scoring system is the Sequential Organ Failure Assessment (SOFA) score, or just SOFA score, which is used to track a patient’s status during the stay in an ICU. The SOFA score is a scoring system to determine the extent of a person’s organ function or rate of failure [3]. Acute Physiology and Chronic Health Evaluation II (APACHE II) is a severity-of-disease classification system [4]. It is applied within 24 h of admission of a patient to an ICU: an integer score from 0 to 71 is computed on the basis of several measurements; higher scores correspond to more severe disease and a higher risk of death.

Sepsis has a great impact on complete blood count result, and red blood cell distribution width (RDW) is widely available to clinicians because it is routinely reported as part of the complete blood count. The RDW represents an index of the heterogeneity of erythrocytes (anisocytosis), which is calculated by dividing the SD of erythrocyte volume by the mean corpuscular volume (MCV) and multiplying by 100 to express the result as a percentage [5].

For several decades, RDW has been typically used in combination with MCV to differentiate the cause of underlying anemia in clinical practice [6]. Recently, highly significant associations have been described between RDW value and all-cause, noncardiac, and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism, and pulmonary artery hypertension [7]. Moreover, several studies have reported that RDW shows the predictive value of all-cause mortality in critically ill or ICU patients [8].

The mechanism of elevated RDW in these patients is not known, but it has been suggested that the inflammatory process is associated with elevated RDW, and it has been reported that elevated RDW is associated with inflammatory markers such as interleukin-6 and tumor necrosis factor and that proinflammatory cytokines could suppress the maturation of red blood cells and decrease the half-life of red blood cells, which in turn results in elevated RDW [8].


  Aim of the work Top


The aim of the work was to evaluate RDW as a prognostic marker in severely septic patients with respect to mortality, outcome, length of stay, and duration of mechanical ventilation in comparison with the SOFA score.


  Patients and methods Top


Patients

The study was carried out on 50 critically ill adult patients of both sexes with severe sepsis, who were admitted to the Critical Care Medicine Department in Alexandria Main University Hospital.

Approval of the medical ethics committee of Alexandria Faculty of Medicine and informed consent from every patient or from next of kin were taken before conducting the study. Patients were followed up until death or discharge from the ICU.

Inclusion criteria

  1. Age more than 16 years.
  2. Being subjected to mechanical ventilation.
  3. Having severe sepsis.


Exclusion criteria

  1. Presence of iron deficiency anemia.
  2. Presence of folate or vitamin B12 deficiency.
  3. Presence of immune hemolytic anemia.
  4. Having uncured cancer (during chemotherapy).
  5. Presence of malignant hematological disease.
  6. Having immune suppression.
  7. Having hemoglobinopathy.


Materials

RDW was measured using an ADVIA 2120 Hematology system, which was introduced by Bayer HealthCare (now Siemens).

The patients were divided into two groups:

  1. Group A: This group comprised patients who met the inclusion and exclusion criteria with high RDW.
  2. Group B: This group comprised patients who met the inclusion and exclusion criteria with normal RDW.


Both groups were compared with the SOFA score as a prognostic marker.

Period of the study: Patients were followed up until death or discharge from the ICU for a duration of 28 days.

All patients included in the study were subjected on admission to complete history taking, clinical examination, laboratory investigations, the SOFA score, radiological examination, and sepsis workup, including cultures.

Statistical analysis

Data were fed into the computer using the Predictive Analysis Software (PASW Statistics 18). Receiver operating characteristic (ROC) curve [9] was drawn; the ROC area under the curve (AUC) denoted the diagnostic performance of the tests.


  Results Top


The current study was carried out on 50 adult patients of both sexes with a diagnosis of severe sepsis admitted to the Critical Care Department of Alexandria Main University Hospital.

Both groups were homogenous, as seen in [Table 1].
Table 1 Comparison between high RDW and normal RDW

Click here to view


The studied patients ranged in age from 45.0 to 95.0 years, with a mean of 70.76±13.43 years, in group A, and from 19.0 to 94.0 years, with a mean of 68.24±14.0 years, in group B. There were 12 female (48.0%) and 13 male (52.0%) patients in group A, whereas in group B there were 11 female (44.0%) and 14 male (56.0%) patients.

The source of infection in group A was occult in one patient (4.0%), intra-abdominal in five patients (20%), soft tissue in three patients (12%), the urinary tract in five patients (20%), the respiratory tract in nine patients (36%), and the blood stream in two patients (8%), whereas the source of infection in group B was occult in one patient (4%), intra-abdominal in four patients (16%), soft tissue in one patient (4%), the urinary tract in six patients (24%), the respiratory tract in 11 patients (44%), and the blood stream in two patients (8%).

The duration of mechanical ventilation ranged from 6.0 to 20.0 days, with a mean of 13.60±4.76 days, in group A, and from 3.0 to 18.0 days, with a mean of 9.96±3.91 days, in group B. There was significant difference between the two groups as regards the duration of MV.

The duration of ICU stay ranged from 10.0 to 28.0 days, with a mean of 20.0±4.43 days, in group A, and from 8.0 to 20.0 days, with a mean of 14.20±3.34 days, in group B. There was significant difference between the two groups as regards ICU stay.

Regarding outcome, in group A 17 (68%) patients died and eight patients (32%) survived, whereas in group B 10 patients (40%) died and 15 patients (60%) survived. There was significant difference between the two groups as regards outcome.

Regarding the correlation between RDW and SOFA score in group A there was a positive correlation between RDW and SOFA on day 0 (P=0.002), day 2 (P<0.001), day 4 (P<0.001), day 6 (P≤0.001), day 14 (P<0.001), day 20 (P<0.001), and on average (P=0.001), whereas in group B there was a positive correlation between RDW with SOFA on day 0 (P=0.045), day 2 (P=0.033), day 4 (P=0.003), day 6 (P=0.008), day 14 (P=0.042), day 20 (P=0.005), and on average (P=0.010).

Regarding the correlation between RDW and platelets in group A, there was negative correlation between RDW and platelet count on day 0 (P=0.0001), day 2 (P=0.002), day 4 (P=0.002), day 6 (P=0.005), and on average (P=0.001). In group B as well there was a negative correlation between RDW and platelet count on day 0 (P=0.008), day 2 (P=0.010), day 4 (P=0.029), day 6 (P=0.015), and on average (P=0.012).

On day 0 the ROC curves showed that the AUCs to predict 28-day mortality were 0.709 for RDW and 0.770 for SOFA score, and the best cutoff values on day 0 to predict 28-day mortality were 14.5% for RDW, with sensitivity 62.96, specificity 65.22, and accuracy 64.0, and 10 for SOFA score with sensitivity 74.07, specificity 65.22, and accuracy 70.0.

On day 2 the ROC curves showed that the AUCs to predict 28-day mortality were 0.729 for RDW and 0.779 for SOFA score, and the best cutoff values on day 1 to predict 28-day mortality were 15.5% for RDW, with sensitivity 81.48, specificity 56.5, and accuracy 70.0, and 10 for SOFA score with sensitivity 88.89, specificity 60.87, and accuracy 76.0.

On day 4 the ROC curves showed that the AUCs to predict 28-day mortality were 0.707 for RDW and 0.819 for SOFA score, and the best cutoff values on day 3 to predict 28-day mortality were 15.5% for RDW, with sensitivity 74.07, specificity 74.07, and accuracy 70.0, and 11 for SOFA score with sensitivity 88.89, specificity 69.57, and accuracy 80.0.

On day 6 the ROC curves showed that the AUCs to predict 28-day mortality were 0.775 for RDW and 0.780 for SOFA score, and the best cutoff values on day 7 to predict 28-day mortality were 15.5% for RDW, with sensitivity 74.07, specificity 65.22 and accuracy 70.0, and 12 for SOFA score, with sensitivity 81.48, specificity 73.91, and accuracy 73.91.

On average the ROC curves showed that the AUCs to predict 28-day mortality were 0.873 for RDW and 0.903 for SOFA score, and the best cutoff values on average to predict 28-day mortality were 15.5% for RDW, with sensitivity 77.78, specificity 82.6, and accuracy 80.0, and 12.3 for SOFA, with sensitivity 81.48, specificity 86.96, and accuracy 84.0.


  Discussion Top


Sepsis is a major health concern worldwide. In the last decade, several trials and protocols have focused on this condition, aiming to establish better measures for its management and prevention of potential complications. Therapeutic measures with considerable positive impacts have been largely emphasized; however, assessing the prognosis of sepsis remains difficult. Assessing the prognosis of diseases and therapies is part of regular medical care [10]. Mastering this challenge is largely related to the art of medical practice and leads to more objective care of the patient [10].

Prognostic score variables have been shown to be effective for the assessment of septic patients, especially the sequential assessments provided by the SOFA. Several physiological and blood chemistry parameters are used in daily practice in ICUs.

For several decades, RDW has been typically used in combination with the MCV to differentiate the cause of underlying anemia in clinical practice [4]. Recently, highly significant associations have been described between RDW value and all-cause, noncardiac, and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism, and pulmonary artery hypertension [11]. Moreover, several studies have reported that RDW shows the predictive value of all-cause mortality in critically ill or ICU patients [3].

The aim of the work was to evaluate the RDW as a prognostic marker in severely septic patients with respect to mortality, outcome, length of stay, and duration of mechanical ventilation.

The current study was a prospective observational study conducted on 50 adult male and female patients admitted to the Critical Care Medicine Departments in Alexandria Main University Hospital with a diagnosis of severe sepsis and septic shock.

The patients were categorized on ICU admission into two groups

Group A: This group comprised patients who met the inclusion and exclusion criteria with high RDW.

Group B: This group comprised patients who met the inclusion and exclusion criteria with normal RDW.

In our study, regarding demographic characteristics, there were more male than female patients (52% of patients were male in group A and 56% were male in group B). This was the same as in the study by Martin et al. [12], who found that men are more likely than women to develop sepsis. However, this difference could be due to a higher prevalence of comorbidities in men, or because women are protected against the inflammatory changes that occur in severe sepsis and septic shock [13],[14].

The mean age in this study was high (70.76±13.43 years in group A and 68.24±14.0 years in group B) and this was almost the same as in the study by Becchi et al. (2006) [15], who had patients with a mean age of 71 years [13],[14],[16]. Age, male sex, and increased burden of chronic health conditions are important risk factors for severe sepsis [17]. The incidence of severe sepsis increases disproportionately in older adults, and more than half of the severe sepsis cases occur in adults over 65 years of age [18].

Patients with severe sepsis and septic shock frequently have underlying comorbidities that predispose them to infections and may have an additive contribution to mortality [19]. In this study, regarding associated comorbidities, all patients had associated diseases, with the highest proportion of patients having diabetes mellitus; other diseases included hypertension, ischemic heart disease, chronic kidney disease, liver disease, and chronic obstructive pulmonary disease. However, the incidence of comorbidities in this study was higher than in other studies, as in the study by Angus et al. (2001) [13], who had 55% of their patients with comorbidities, and in the study by Blanco et al. (2008) [20], who also had 55% of their patients with comorbidities. The higher incidence of comorbidities in our study may be explained by the higher mean age in our study, and the greater prevalence of comorbidities in Egypt, which may be related to poorer healthcare compared with developed countries.

In agreement with other researchers such as Kumar et al. (2010) [21], Annane et al. (2003) [22], and Blanco et al. (2008) [20], in this study, the lung was the most common primary source of infection in severe sepsis. The most common source of sepsis was chest infection in 36% of patients in group A and 44% in group B. Other sources of sepsis included urinary infection.

We also found that SOFA score in survived cases was significantly lower than SOFA score in nonsurvivors, on admission (P=0.005) and on average (P<0.001). In agreement with the present study Desai et al. [23] studied the prognostic value of SOFA score of patients with sepsis, severe sepsis, and multiorgan dysfunction syndrome. Jain et al. [24] also found that the baseline severity of SOFA was significantly higher among nonsurvivors than among survivors.

Regarding the correlation between RDW and both white blood cells and C-reactive protein (CRP) there was no correlation between them in group A and group B on day 0, day 2, day 4, day 6, and on average. Our study was in agreement with that by Meynaar et al. [25], who studied patients admitted to the ICU in the Netherlands between May 2005 and December 2011 for whom RDW was available. Inflammation was measured by CRP and leukocyte count. Analyses included correlation, logistic regression analysis, and ROC curves; these found no correlation between RDW and CRP or between RDW and leukocyte count.

We also found no correlation between RDW and APACHE II at admission in groups A and B. Our study was in agreement with that by Esper et al. [26], who studied two groups of patients admitted to the ICU: one group consisted of patients with sepsis, severe sepsis, and septic shock; the second group comprised patients without sepsis. The variables studied included RDW, APACHE II, and SOFA scores. During the first 24 h of admission we found that RDW was correlated with SOFA score, but not APACHE II score. This result could be explained because SOFA score is better for evaluating organ dysfunctions compared with APACHE II [27],[28].

As regards platelet count we found a negative correlation in both groups between platelet count and RDW: in group A on day 0 (P=0.012*), day 2 (P=0.023*), day 4 (P=0.002*), day 6 (P=0.005*), and on average (P=0.018*), and in group B on day 0 (P=0.005*), day 2 (P=0.005*), day 4 (P=0.005*), day 6 (P=0.010*), and on average (P=0.007*).

Our study was in agreement with that of Gao et al. (2014) [29], who reported that platelet count was inversely related to mortality in septic patients. Boechat et al. (2012) [30] reported that platelet count reduction by greater than 50% is a strong indicator of mortality. This drop presumably arises from depletion of coagulation factors and platelet consumption during the septic process, and is a significant prognostic indicator of mortality.

ICU length of stay and duration of mechanical ventilation were higher in group A than in group B. In agreement with our study, Zhang et al. [31] found that higher RDW (>14.8%) was associated with prolonged ICU stay. Regarding short-term mortality, the present study found that RDW was a good predictor of short-term mortality. In agreement with our study, Lorente et al. [32], who performed a prospective, observational, multicenter study in six Spanish ICUs with 297 severely septic patients, found that patients with RDW higher than 15.5% had a lower probability of survival at day 30 than did patients with a lower percentage.

Also Zhang et al. [31], who conducted a retrospective study in a 24-bed ICU of a tertiary teaching hospital, found that higher RDW was associated with increased in-hospital mortality.

Again, Sadaka et al. [33], who conducted a study on 279 patients with septic shock, found that RDW on day 1 of septic shock is a robust predictor of mortality. The RDW is inexpensive and commonly measured. The RDW fared better than either APACHE II or SOFA, and the sum of RDW and APACHE II was a stronger predictor of mortality than either one alone.

Also Topeli et al. [34], who performed a prospective study on patients who were admitted into the ICU between 1 January 2003 and 31 December 2005, found that ICU admission RDW value might be a prognostic indicator for hospital mortality in critically ill patients.

Again, Bazick et al. [8], who performed a multicenter observational study with a total of 51 413 patients to study the prevalence of increased RDW and its significance in the ICU, found that RDW is a robust predictor of the risk of all-cause patient mortality in the critically ill.

Hunziker et al. [35], who performed an observational cohort study including 17 922 ICU patients with available RDW measurements from different types of ICUs, found RDW to be a promising independent short-term and long-term prognostic marker in ICU patients.

The ROC curve for mortality showed that RDW value on admission was more or less comparable to SOFA scores in predicting 28-day mortality in sepsis, where the AUC was 0.709 for RDW and 0.770 for SOFA score, on day 2 the AUC was 0.729 for RDW and 0.779 for SOFA, on day 4 the AUC was 0.707 for RDW and 0.819 for SOFA, on day 6 the AUC was 0.775 for RDW and 0.780 for SOFA, and on average the AUC was 0.873 for RDW and 0.903 for SOFA. There was significant positive correlation between RDW and SOFA on admission, at day 2, day 4, day 6, day 14, day 20, and on average. In agreement with our study Lorente et al. [32] found in their multicenter study conducted on severely septic patients that RDW showed a positive correlation with SOFA score on days 1, 4, and 8 (P=0.007, 0.002, and P<0.001, respectively), and that RDW predicts mortality at 30 days in septic patients with AUC 0.62, 0.63, and 0.63 on days 1, 4, and 8, respectively.

Sadaka et al. [33], in their study conducted on patients with septic shock, found that RDW on day 1 of septic shock was a strong predictor of hospital mortality, and by estimating the ROC AUC RDW showed a very good discriminative power for hospital mortality (AUC=0.74) and for SOFA (0.69); in our study the accuracy of RDW on admission was lower than that of SOFA score in predicting 28-day mortality.

RDW was associated with increased mortality; the underlying mechanism is still unclear and represents an important avenue for future ‘bedside-to-bench’ research. A possible pathophysiologic explanation is that RDW is a surrogate of inflammation, which is known to increase RDW. Several studies found RDW to be associated with blood markers of inflammation, such as interleukin-6 [36], as well as impaired iron mobilization [37]. Also, oxidative stress has been shown to increase anisocytosis by disrupting erythropoiesis, and to alter blood cell membrane deformability and red blood cell circulation half-life, ultimately leading to increased RDW [8],[36],[38].

Previous research found that adjusting for inflammation (for example, CRP) did not substantially reduce the prognostic value of RDW, demonstrating its effect beyond these factors [8],[36],[39].

RDW may also reflect the patient’s degree of physiological reserve, one of three main determinants of clinical outcome, as suggested by Bion [40]. The physiological reserve represents cellular response to acute stress and the resultant tissue hypoxia. Ischemia activates cellular systems that would reduce oxygen demand and physiologic processes that would improve tissue oxygen delivery, such as increased production and release of mature red cells into the peripheral bloodstream. How well this process of reactive erythropoiesis is carried out under oxidative stress may represent the patient’s ability to handle acute physiological insult. Release of large immature red cells with poor oxygen-binding capacity, which results in an increased RDW, implies suboptimal response to oxidative stress. This may explain why the association between RDW and clinical outcome is independent of the severity of acute illness as well as the degree of inflammation. It may well represent the genetic factors that determine how well the body withstands physiological stress, whether from a severe infection, multitrauma, burns, or acute pancreatitis [41].

The reason may also be that inflammation has an impact on bone marrow function and iron metabolism [42],[43], and inflammatory cytokines such as proinflammatory cytokines have been found to inhibit erythropoietin-induced erythrocyte maturation and proliferation and to downregulate erythropoietin receptor expression, leading to suppression of erythrocyte maturation, accentuated with sepsis, which allows newer, larger reticulocytes to enter the circulation, which is associated with RDW increase [43],[44]. Elevated RDW has also been noted to be associated with oxidative stress [45],[46] and activation of the renin–angiotensin–aldosterone system [47],[48]. These conditions can be associated with increased mortality even in acutely ill patients.


  Conclusion Top


RDW at admission is an important biomarker in severe sepsis with increased mortality, prolonged duration of MV, and prolonged ICU stay in patients with high RDW at admission. There was a positive correlation between RDW and SOFA on days 0, 2, 4, 6, 14, and 20 and on average and a negative correlation between RDW and platelets on days 0, 2, 4, and 6 and on average.

Financial support and sponsorship

Nil.Conflicts of interest

There are no conflicts of interest.

 
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