Journal Article

Targeted therapy using polymyxin B hemadsorption in patients with sepsis: a post-hoc analysis of the JSEPTIC-DIC study and the EUPHRATES trial

Yamakawa, Kazuma, Foster, Debra M., Doi, Kent, Kudo, Daisuke, Goto, Tadahiro, Kellum, John A., Osawa, Itsuki, Kushimoto, Shigeki, Hayakawa, Mineji

2023

Overview

Background Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We sought to identify patient subgroups likely to benefit from PMX-HA. Methods We retrospectively identified 1911 patients with sepsis from a retrospective observational study in Japan (the JSEPTIC-DIC study) and 286 patients with endotoxemic septic shock from a randomized controlled trial in North America that restricted patients to those with high endotoxin activity (the EUPHRATES trial). We applied the machine learning-based causal forest model to the JSEPTIC-DIC cohort to investigate heterogeneity in treatment effects of PMX-HA on 28-day survival after adjusting for potential confounders and ascertain the best criteria for PMX-HA use. The derived criteria for targeted therapy by PMX-HA were validated using the EUPHRATES trial cohort. Results The causal forest model revealed heterogeneity in treatment effects of PMX-HA. Since patients having higher treatment effects were more likely to have severe coagulopathy and hyperlactatemia, we identified the potential treatment targets of PMX-HA as patients with PT-INR > 1.4 or lactate > 3 mmol/L. In the EUPHRATES trial cohort, PMX-HA use on the targeted subpopulation (75% of all patients) was significantly associated with higher 28-day survival (PMX-HA vs. control, 68% vs. 52%; treatment effect of PMX-HA, + 16% [95% CI + 2.2% to + 30%], p  = 0.02). Conclusions Abnormal coagulation and hyperlactatemia in septic patients with high endotoxin activity appear to be helpful to identify patients who may benefit most from PMX-HA. Our findings will inform enrollment criteria for future interventional trials targeting patients with coagulopathy and hyperlactatemia.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Algorithms / Analysis / Anti-Bacterial Agents / Blood / Care and treatment / Critical care / Critical Care Medicine / Diagnosis / Dosage and administration / Emergency Medicine / Endotoxemia / Endotoxin / Endotoxins / Failure / Hemadsorption / Hemoperfusion / Humans / Hyperlactatemia - etiology / Infection / Intensive / Lactates / Machine learning / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Methods / Molecular targeted therapy / Mortality / Observational Studies as Topic / Patient outcomes / Patients / Personalized medicine in the ICU / Polymyxin B / Polymyxin B - pharmacology / Polymyxin B - therapeutic use / Randomized Controlled Trials as Topic / Retrospective Studies / Sepsis / Septic shock / Shock, Septic / Survival analysis