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Mean platelet volume to platelet count ratio as a predictor of mortality in septic patients

Sepsis is one of the leading causes of death in the ICU patients. Despite the extensive research over the last two decades, few specific treatments have been shown to improve the outcome but great inroads have been attained in identifying various correctable abnormalities and markers within the disease process. The sepsis syndrome represents a progression in clinical and pathophysiological severity. However, it is a continuum with definable, albeit arbitrary, phases that place the patients at risk for morbidity and mortality. The complex pathophysiology of sepsis involve infection with systemic inflammatory response. Thrombocytopenia may arise from reduced central production or from peripheral destruction. Among its multiple causes, Sepsis is a clear risk factor with an incidence of more than 35 %.


INTRODUCTION
Sepsis is one of the leading causes of death in the ICU patients. 1 Despite the extensive research over the last two decades, few specific treatments have been shown to improve the outcome but great inroads have been attained in identifying various correctable abnormalities and markers within the disease process. The sepsis syndrome represents a progression in clinical and pathophysiological severity. However, it is a continuum with definable, albeit arbitrary, phases that place the patients at risk for morbidity and mortality. 2 The complex pathophysiology of sepsis involve infection with systemic inflammatory response. 3 Thrombocytopenia may arise from reduced central production or from peripheral destruction. Among its multiple causes, Sepsis is a clear risk factor with an incidence of more than 35 %. 4 The mean platelet volume (MPV) describes the average size of platelets in a blood sample and is routinely measured by automated hematology analyzers using either electrical impedance or optical fluorescence method measured by automated hematology analyzers using either electrical impedance or optical fluorescence method The mean platelet volume describes the average size of platelet in blood sample and represents the reactivity of the platelets. It is measured automated hematology analyzers employing impedance and optical effects. 5 Platelets with high mean platelet volume and usually larger and active.
Their prothrombotic nature results in platelet adhesion and aggregation. 6 Several studies suggest that changes in MPV are nonspecific and are seen in severe clinical conditions such during infection, sepsis and chronic inflammatory conditions. 7,8 There are few studies that are done on the effects of MPV in sepsis and are found to have conflicting results. Moreover, only little is known of the MPV on mortality in patients with sepsis. Hence, in our study, we aimed to look at the response of Mean Platelet volume to platelet count ratio in patients admitted with sepsis and its capability in prognostication.

METHODS
This was a case control study and was carried out over a 2year period from 2018-2020, at Amrita Institute of Medical Sciences and Research Center, Kochi, Kerala.

Selections and description of the participants
A total of 200 patients with sepsis were admitted into the Medical ICU directly from the ER, were chosen for the study randomly. The patients were followed up for 28 days and were divided into two categories based on survival.

Inclusion criteria
Minimum age requirement was 18 years of age. No maximum age limit was set. Patients were identified in the emergency room (ER) on arrival as cases of sepsis and septic shock as per the guidelines provided by the Society of critical care medicine's latest recommendations provided with the sepsis care bundle on survivingsepsiscampaign.org

Exclusion criteria
Patients with suspected or known case of haematological malignancies or primary marrow disorders, known case of Immune Thrombocytopenic Purpura (ITP), Acute Splenic sequestration, known case of platelet structural and functional disorders, those on chemotherapy and those patients who require Linezolid for their treatment during the ICU stay.
Only direct admissions into the ICU meeting the above inclusion and exclusion criteria were chosen for the study.

Sample size calculation
Based on the results of mean Mean Platelet volume to platelet count ratio after admission, of survivors and non survivors (0.26±0.89, 0.80±1.30) among septic patients observed in an earlier publication9 and with 90 % power and 95 % confidence, the minimum sample size comes to 200. Sample size would be in the ratio of 1:5, non survivors to survivors

Methods of data collection
After identification of such cases in the ER, their details were entered into a software developed by the IT department. The patient's lab details were automatically stored and pulled into the database.
Clinical details of the patient were followed up during their hospital stay and further up to 28 days. These details were entered into the software and stored on the database for further analysis manually.
Individual SOFA and APACHE II score elements were assessed and entered into the software which was stored for later evaluation.

Sample collection
The day 1 samples of MPV and CRP were taken on admission from the ER and sent to the lab within 15 minutes of admission. The sample for MPV was the same sample for CBC and were collected in EDTA vaccutainers at admission. The samples for Complete Blood Count (CBC) which includes the MPV were analysed in the Hematology lab using Abott Cell-Dyn model 3700 hematology analyzer and reported within 40 minutes of sample collection.
SOFA score on admission were calculated within 2 hours of admission after initial evaluation and emergency management including fluid resuscitation, mechanical ventilation (invasive/ non-invasive) The outcome was taken as either death of the patient (in this study referred to as "non survivors") or the patients who were alive during their hospital stay and at follow up at 28 days (referred to as "survivor"). All the details were stored in the date base until the required sample size was reached and was then taken for analysis. Data analysis was done with the help of a statistician.

Statistical analysis
The statistical analysis was done using the IBM SPSS version 20.0 software. The categorical variables were expressed using percentage and frequency. Numerical variables were denoted using mean and standard deviation. ROC curve analysis was used to determine the cut-off values for change in Mean platelet volume.
Chi-square was used to test the statistical significance of the association of all categorical variables with mortality. Independent sample t test was used to study the statistical significance of the difference in the mean values of all continuous variables with mortality. Multivariate logistic regression analysis was used to identify the independent predictor of mortality. A p value of<0.05 was considered to be statistically significant.

Demographic data
Total of 200 patients were selected after passing through the inclusion criteria. Of these patients, there were 127 male patients and 73 female patients (Table 1). Patient's outcome was followed for 28 days. Outcome taken were the death to the patient due to sepsis and septic shock.
The most common reason for admission to the hospital was pneumonia (83 patients), followed by urinary tract infection (61 patients). 18 patients with pneumonia expired with 21 patients having other sources of sepsis.
Mean platelet volume was taken on the day of admission and on the 72 hours post admission. Mean platelet volume on day 1 in expired patients was 9.64 with standard deviation of 0.95, mean MPV at 72 hours was 11.48 with standard deviation of 1.09 and mean change in MPV (72 hours-adm) was 1.81 with standard deviation of 0.66 (Table 2). SOFA was also calculated on Day 1. In the "nonsurvivors" category, SOFA Day 1 mean was found to be 7.41 with standard deviation of 2.66 (Table 2).  With the above date, we can conclude safely that basic demographic does not influence the MPV levels and therefore will not be a variable in the rest of the study.

Main study results
Among the total 39 patients, who have expired, Mean Platelet Volume day 1 had a mean of 9.64 with standard deviation of 0.95. Among the survivors the Mean Platelet Volume at admission was mean of 9.60 with standard deviation of 0.99. Comparison done with student's t'test showed no statistical difference between the two groups with p value of 0.838 (Table 2).
Meanwhile, mean platelet volume at 72 hours, change is mean platelet volume and mean platelet volume to platelet count ratio showed promising results with mean of 11.48 with standard deviation of 1.09, 1.81 with standard deviation of 0.66 and mean of 9.197 with standard deviation of 5.106 respectively in the "non-survivors" category. These variables were found to be statistically significant p<0.01 (Table 2).
Mean APACHE scoring and SOFA score calculated at admission in "non-survivors "category was 29.38 with standard deviation of 17.36 and mean of 7.41 with standard deviation of 2.66 respectively ( Table 2). Both the variables were found to be statistically significant.
As we can see above mean platelet volume at 72 hours, change in mean platelet volume, mean platelet volume to Platelet count ratio, APACHE and SOFA score had significant differences in the mean values among the two groups suggesting these variables better predicted their respective outcomes.
An ROC curve analysis was done, after ascertaining that Mean Platelet Volume showed a significant difference between the "survivors" and "non survivors" group. The ROC curve analysis was done, cut off for mean platelet volume to platelet count ratio was 5.3, with sensitivity of 84 %, specificity of 84 and positive predictive value of 55%.
A logistic regression analysis was done to find out the best predictor of outcomes. On analysis the B (Beat) value of MPV to platelet count ratio was found to be significant (p value<0.005) as compared to APACHE and SOFA scoring (p value 0.15, 0.41) ( Table 4). This shows that mean platelet volume to platelet count ratio are better predictors of mortality as compared to SOFA and APACHE.
It was also decided to see if the change in mean platelet volume, mean platelet volume to platelet count ratio, SOFA and APACHE had an influence on the duration of hospital stay. On analysis, it was found that none of the variables were found to be significant p>0.05. This means the duration of hospital stay was independent of change in mean platelet volume, mean platelet volume to platelet count ratio, and SOFA and APACHE II scores.  In figure 1 area under the curve (AUC) of MPV 72h, ΔMPV72h-adm and MPV/Platelet ratio were 0.86, 0.98 and 0.92, and the cutoffs chosen are 11.9, 1.45 and 53.5 respectively.
The above table 4 shows that APACHE, SOFA, MPV/ platelet ratio are all predictors of mortality. But as we can clearly see that MPV/ platelet ratio is superior to APACHE and SOFA in predicting mortality.

DISCUSSION
Sepsis and Septic shock remains as one of the most challenging problems in ICU settings. Despite the extensive knowledge regarding the patient response to sepsis, only limited studies have been done in evaluating the potential for platelet indices to be used as a marker in sepsis or assess its value in prognostication. Platelet count in itself though, has found its way into the SOFA scoring as one of the variables assessing coagulation parameters in those with sepsis.
Early detection of sepsis helps in risk stratification, allocation of resources and assess the efficacy of therapeutic interventions.
During the clinical course of sepsis, platelets undergo wide variations, which initially respond with hyperstimulation followed by exhaustion. The causes of thrombocytopenia, can be centrally mediated or from peripheral destruction. 10 There is an inverse relationship between Mean platelet volume and platelet count, this can be seen in several physiological and pathological situations. 11 This inverse relationship was also found in our study.
There are several studies that have looked into MPV for critically ill patients. Zampieti et al studied 87 critically ill patients and found that MPV at 24 hours were significantly higher in the non-survivor group. They found no relationship between the prognosis and the MPV taken at admission. They also were able to conclude that MPV was better at predicting outcome than the difference in the platelet count within the first 24 hours. 11 Similar results were also observed by a European study done by by Eberhardt et al. 12 Another study by Beechi et al published in 2008 in Italy, showed conflicting results with their analysis showing a 3 times increase in death probability (95 % CL, OR=3.04, P<0.05) of patient with an MPV>9.7 fl at recruitment time. The rational given for this was that sepsis resulted in a marrow disturbance which ultimately reduced platelet production. 12 In the previous studies that were done, we have seen that MPV does in fact predict mortality in patients with sepsis. Most of the studies which has been listed above shows that a high MPV, whether at admission or through the course, was indicative of a poor prognosis. One study showed a contradicting report of a low MPV being indicative of poor prognosis.
This is a prospective study, to evaluate the usefulness of MPV to platelet count ratio on day as a mortality predictor in septic patients. We found that the mean platelet volume increased within the first 72 hours of hospital stay. This increase was high for both survivors and non survivors. But the non survivors had a much steeper rise as compared to the survivors. MPV to platelet count ratio also was found to be higher in the non survivors. Through Multivariate logistic regression, we can conclude MPV to platelet count ratio is an independent predictor of mortality. These findings were similar to the earlier publications. 9,13 Limitations It doesn't entirely reflect the population of India since the patient samples only reflect a possible local subset. MPV has not been studied in the conditions included in the exclusion criteria. At this point MPV cannot be used to evaluate the prognosis in patients who are in the exclusion criteria. This study does not take into account, the other conditions that can affect MPV such as smoking, Cerebrovascular accidents (CVA) and acute coronary syndromes (ACS).

CONCLUSION
MPV/Platelet ratio, which is a part and parcel of a complete blood count, is a hidden gem in our diagnostic arsenal and can help identify a patient with a possible poor outcome on admission. MPV/ Platelet ratio more than 5.3, suggest a higher chance of mortality in patients with sepsis and septic shock. It will also help us to convey a prognosis to the patient's relatives. But for MPV to be accepted in this light, requires much larger and broader studies involving different patient groups. Meanwhile it would be prudent to keep a close watch on the MPV of these patients and tailor the treatment regimens to the possible predicted outcomes.