In this study, we examined the association between the severity of organ failure and the efficacy of PMX by using the Japanese nationwide inpatient database, the DPC data. After adjusting the patient background characteristics by propensity score matching, we found that PMX significantly improves the survival of sepsis patients in the SOFA score ranges of 7–9 and 10–12. On the other hand, there was no significant difference in the survival rate in SOFA score ranges of 0–6, 13–15, and 16–24. In the analysis of organ support-free days, PMX was also effective in the SOFA ranges of 7–9 and 10–12, compared to 0–6, 13–15, and 16–24.
Several previous studies have examined the effectiveness of PMX using the DPC data. In one study focused on septic shock due to lower gastrointestinal perforation, the 28 day-mortality rates for patients with and without PMX were 17.1% and 16.3%, respectively, which were not significantly different [9]. Conversely, in a study on septic shock with AKI who required CRRT, the 28 day-mortality rates with and without PMX were 40.2% and 46.7%, respectively, with a significant improvement with PMX treatment [10]. Our recent study on noradrenaline-treated septic shock patients showed a substantial improvement of 28 day-survival rates by PMX treatment, 77.9% for the PMX group and 71.1% for the non-PMX group [11]. In addition, our analysis of data from patients with sepsis requiring CHDF showed that PMX significantly improved mortality and shortened hospital and ICU stays [12]. All studies used the propensity score matching technique to adjust the patient background between PMX-treated and non-treated groups. However, none of the studies used the SOFA score as an adjustment factor of patient background or as a subgroup stratification factor since the database did not include the SOFA score before March 2018.
This study, which used the DPC data after April 2018, is the first to utilize the SOFA score recorded in the DPC database to analyze the efficacy of sepsis treatment. The SOFA score, which reflects the degree of damage to multiple organs, has been widely used as a factor reflecting the severity of sepsis in patients. Many studies have reported that it is highly associated with mortality. Using the SOFA scores is a powerful method for analyzing large-scale registry data such as DPC and examining the effectiveness of various treatments for critically ill patients in actual clinical practice in detail.
Several multicenter RCTs have been conducted to evaluate the efficacy of PMX on septic shock. However, they showed inconsistent findings regarding the survival benefit. We assume that one reason for the lack of apparent efficacy of PMX in those RCTs may be that the included patients were heterogeneous with varied severity of the disease. In the EUPHRATES trial, the largest RCT of PMX conducted so far, the analysis of all enrolled patients showed no difference in the mortality between the PMX group and control group [13]. But a post-hoc study showed a significant benefit of PMX in the patients with multiple organ dysfunction scores (MODS) of 10 or more and endotoxin activity assay (EAA) level in the range of 0.6 to 0.9 [14]. Although EAA is a measurement of endotoxin levels, it is also considered a marker that reflects the degree of organ damage [15]. Thus, the post-hoc analysis of the EUPHRATES trial is consistent with the results of this study using the SOFA score. The research confirmed that PMX is the most effective in patients with an intermediate range of organ damage.
Our previous study on the analysis of noradrenaline-administered septic shock patients showed that PMX efficacy is less pronounced in the subgroup of patients with the highest maximum daily dose of noradrenaline [11]. Furthermore, several reports indicate that PMX treatment is more effective when the time between the onset of shock and the administration of PMX is shorter [16, 17]. The present analysis results using the SOFA score suggest that it is vital to use PMX at an appropriate time when organ damage does not progress too far.
In the stratified analysis using individual SOFA score components of each organ, the survival benefit of PMX tended to be higher in patients with central nervous system SOFA scores of less than two than in patients with scores of two or more. On the other hand, the effect tended to be higher in patients with scores of 2 or more for respiration, coagulation, liver, cardiovascular, and renal SOFA score. This result suggests that optimal timing may vary depending on the type of organ that is impaired. However, the present analysis did not consider the correlation between each organ damage. Further study is needed to determine the impacts of individual organ damage on the efficacy of PMX.
One study aimed to identify the optimal population for PMX using the sepsis database, which could not show the correlation between PMX efficacy and SOFA score [18]. However, only 92 patients received PMX in that study. It may not have enough power to analyze the precise relationship of PMX to various patient conditions. The strength of our research is that we analyzed data containing more than 2000 cases of PMX treatment, which enabled more in-depth analysis.
The SOFA score is widely used as an indicator of organ damage in critically ill patients. There are many reports on the association of SOFA score and the prognosis of sepsis patients [19, 20]. The latest definition of sepsis, Sepsis-3, also uses an increase in SOFA score as an indicator of organ damage [21]. The SOFA score is relatively easy and quick to obtain. It is an item routinely assessed in daily clinical settings. This study provides helpful information for the selection of suitable patients for PMX treatment in real-world clinical settings.
This study has several limitations. First, the study is a retrospective analysis of data. Although we adjusted for possible background factors by propensity score matching, we cannot rule out the presence of confounding factors. These include vital signs or laboratory data, which are not available in the DPC database. Second, the disease code of sepsis is based on clinical judgment and not always based on the international definition of Sepsis-3.