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Background: Equipoise exists regarding the implementation of evidence-based guidelines for nutritional therapy in critical illness because some previous cluster-randomised controlled trials (cRCTs) demonstrate patient benefits whilst others do not. We aimed to resolve this issue by initiating an appropriately powered cRCT to assess whether active implementation of an evidence-based guideline for nutrition therapy in critical illness could reduce mortality. Methods: We did a multicentre, cluster-randomised, parallel-controlled trial in 97 intensive care units (ICUs) throughout China. We developed an up-to-date, evidence-based nutrition guideline. ICUs randomly allocated to implement the guideline formed a local "intervention team", which actively implemented the guideline using standardized educational materials. ICUs assigned to the control group remained unaware of the guideline. All ICUs enroled critically ill patients who were expected to stay longer than seven days. The primary outcome was all-cause mortality within 28 days of enrolment . Findings Between March, 2018 and July, 2019, we enrolled 1,373 patients at 48 guideline ICUs and 1,399 patients at 49 control ICUs. Implementation of the nutrition guideline resulted in significantly earlier enteral nutrition (EN) initiation (1.20 vs. 1.55 mean days to initiation of EN; difference -0.40 [95% CI, -0.71 to -0.09]; P=0.01) and delayed parenteral nutrition (PN) initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI, 0.44 to 1.67]; P=0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference -1.6% [95% CI -4.3% to 1.2%]; p=0.42) between study groups. Interpretation: Active implementation of an evidence-based guideline can change practice. Our active implementation strategy improved the provision of nutrition therapy to critically ill patients. However, in our cRCT, this improvement in care did not translate to a reduction in mortality. We did not identify any safety concerns associated with the active implementation of our evidence-based guideline for nutrition therapy. Trial Registration: The study was registered in the ISRCTN registry before enrolment commenced (No. ISRCTN12233792). Funding Statement: The study was funded by the Key Research and Development Program Foundation of Jiangsu Province of China (no. BE2015685) and Nutricia, Wuxi, China. Declaration of Interests: Dr. GSD reported receiving academic research grants related to nutrition in critical illness from the Australian National Health and Medical Research Council, Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland and Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. Dr. AvZ reports personal fees from Baxter, personal fees from Nestle, personal fees from Fresenius Kabi, grants and personal fees from Nutricia, grants from Cardinal Health grants from Mermaid grants from Lyric, outside the submitted work. Dr. WqL reported receiving speakers honoraria from Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. No other disclosures were reported. Ethics Approval Statement: The study was approved by the local hospital ethics committees of all the participating ICUs. At each site, informed consent was obtained from the patients or their next of kin before enrolment.

Acute lung injury (ALI) is a severe disease with high morbidity and mortality, and is characterized by devastating inflammation of the lung and increased production of reactive oxygen species (ROS). Recent studies have indicated that fatty acid binding protein (FABP4) is important in the regulation of inflammation. However, the role of FABP4 in sepsis-related ALI, and the specific mechanism of action have not been examined. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) and recombinant FABP4 (hrFABP4) resulted in the production of pro-inflammatory cytokines, inflammatory cytokines, and ROS, while these changes were ameliorated by pretreatment with the FABP4 inhibitor BMS309403 and FABP4 siRNA. Sequentially, treatment of A549 cells with N-acetylcysteine (NAC) significantly attenuated LPS and hrFABP4-induced the generation of ROS and the release of inflammatory cytokines. In vivo, a cecal ligation and puncture (CLP)-induced ALI murine model was successfully established. Then, the mice were treated with FABP4 inhibitor BMS309403. The results showed treatment with BMS309403 improved the survival rate of CLP-induced ALI mice, and prevented lung inflammation, histopathological changes, and increase of FABP4 induced by CLP. These data indicate that FABP4 plays an important role in lung inflammation of sepsis-induced ALI. Blockade of FABP4 signaling exhibits a protective effect in a CLP-induced ALI mouse model, and in A549 cell LPS specifically induces enhanced expression of FABP4, which then causes inflammatory cytokine production by elevating the ROS level.