The role of TIM-3 in sepsis: a promising target for immunotherapy?

Sepsis remains a significant cause of mortality and morbidity worldwide, with limited effective treatment options. The T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) has emerged as a potential therapeutic target in various immune-related disorders. This narrative review aims to explore the role of TIM-3 in sepsis and evaluate its potential as a promising target for immunotherapy. We discuss the dynamic expression patterns of TIM-3 during sepsis and its involvement in regulating immune responses. Furthermore, we examine the preclinical studies investigating the regulation of TIM-3 signaling pathways in septic models, highlighting the potential therapeutic benefits and challenges associated with targeting TIM-3. Overall, this review emphasizes the importance of TIM-3 in sepsis pathogenesis and underscores the promising prospects of TIM-3-based immunotherapy as a potential strategy to combat this life-threatening condition.

Intraoperative intensive blood pressure management strategy and the outcome of patients who had an acute ischaemic stroke undergoing endovascular treatment under general anaesthesia: study protocol for a prospective randomised controlled trial.

BackgroundEndovascular thrombectomy is the recommended treatment for acute ischaemic stroke, but the optimal blood pressure management strategy during the procedure under general anaesthesia remains controversial. In this study protocol, we propose an intraoperative intensive blood pressure range (110-140 mm Hg systolic blood pressure) based on a retrospective analysis and extensive literature review. By comparing the outcomes of patients who had an acute ischaemic stroke undergoing mechanical thrombectomy under general anaesthesia with standard blood pressure management (140-180 mm Hg systolic blood pressure) versus intensive blood pressure management, we aim to determine the impact of intraoperative intensive blood pressure management strategy on patient prognosis. METHODS AND ANALYSIS: The study is a double-blinded, randomised, controlled study, with patients randomised into either the standard blood pressure management group or the intensive blood pressure management group. The primary endpoint of the study will be the sequential analysis of modified Rankin Scale scores at 90 days after mechanical thrombectomy. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of Shanghai Changhai Hospital with an approval number CHEC2023-015. The results of the study will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: ChiCTR2300070764.

Understanding COVID-19-associated endothelial dysfunction: role of PIEZO1 as a potential therapeutic target.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Due to its high infectivity, the pandemic has rapidly spread and become a global health crisis. Emerging evidence indicates that endothelial dysfunction may play a central role in the multiorgan injuries associated with COVID-19. Therefore, there is an urgent need to discover and validate novel therapeutic strategies targeting endothelial cells. PIEZO1, a mechanosensitive (MS) ion channel highly expressed in the blood vessels of various tissues, has garnered increasing attention for its potential involvement in the regulation of inflammation, thrombosis, and endothelial integrity. This review aims to provide a novel perspective on the potential role of PIEZO1 as a promising target for mitigating COVID-19-associated endothelial dysfunction.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

High-dose ascorbic acid potentiates immune modulation through STAT1 phosphorylation inhibition and negative regulation of PD-L1 in experimental sepsis.

Sepsis is a complex, multifactorial syndrome characterized by a dysregulated host response to infection, leading to severe organ dysfunction and high mortality rates among critically ill patients. Hypovitaminosis C and vitamin C deficiency are frequently observed in septic patients, prompting interest in the potential therapeutic role of ascorbic acid. Although intravenous administration of ascorbic acid has been investigated in multiple clinical trials for sepsis treatment, the specific immunomodulatory mechanisms underlying its effects remain elusive. This study aimed to investigate the protective effects of high-dose ascorbic acid on experimental sepsis. Results show that intravenous administration of high-dose ascorbic acid (250 mg/kg) attenuated sepsis-induced organ dysfunctions in a cecal ligation and puncture (CLP)-induced septic mouse model. Ascorbic acid improved splenic cell apoptosis and increased the number of CD3+ T cells in septic mice induced by CLP. Furthermore, ascorbic acid downregulated PD-L1 expression in livers, reduced PD-1 expression in spleens, and inhibited the phosphorylation of STAT1 at Y701 in multiple organs of CLP-induced septic mice. The in vitro experiments also revealed that 800 µM ascorbic acid suppressed STAT1 phosphorylation and inhibited lipopolysaccharide (LPS) and IFN-γ-induced PD-L1 expression in macrophages. These findings suggest that ascorbic acid prevents sepsis-associated organ dysfunction through the p-STAT1/PD-L1 signaling pathway. Our study provides new insights into the potential therapeutic use of ascorbic acid in sepsis.

Interpretable machine-learning model for real-time, clustered risk factor analysis of sepsis and septic death in critical care.

BACKGROUND AND OBJECTIVE: Interpretable and real-time prediction of sepsis and risk factor analysis could enable timely treatment by clinicians and improve patient outcomes. To develop an interpretable machine-learning model for the prediction and risk factor analysis of sepsis and septic death. METHODS: This is a retrospective observational cohort study based on the Medical Information Mart for Intensive Care (MIMIC-IV) dataset; 69,619 patients from the database were screened. The two outcomes include patients diagnosed with sepsis and the death of septic patients. Clinical variables from ICU admission to outcomes were analyzed: demographic data, vital signs, Glasgow Coma Scale scores, laboratory test results, and results for arterial blood gasses (ABGs). Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Model interpretations were based on the Shapley additive explanations (SHAP), and the clustered analysis was based on the combination of K-means and dimensionality reduction algorithms of t-SNE and PCA. RESULTS: For the analysis of sepsis and septic death, 47,185 and 2480 patients were enrolled, respectively. The XGBoost model achieved a predictive value of area under the curve (AUC): 0.745 [0.731-0.759] for sepsis prediction and 0.8 [0.77, 0.828] for septic death prediction. The real-time prediction model was trained to predict by day and visualize the individual or combined risk factor effects on the outcomes based on SHAP values. Clustered analysis separated the two phenotypes with distinct risk factors among patients with septic death. CONCLUSION: The proposed real-time, clustered prediction model for sepsis and septic death exhibited superior performance in predicting the outcomes and visualizing the risk factors in a real-time and interpretable manner to distinguish and mitigate patient risks, thus promising immense potential in effective clinical decision making and comprehensive understanding of complex diseases such as sepsis.

Punicalin attenuates LPS-induced acute lung injury by inhibiting inflammatory cytokine production and MAPK/NF-κB signaling in mice.

Background: Acute lung injury (ALI) remains a significant cause of morbidity and mortality in critically ill patients. Novel therapies interfering with the inflammatory response has been an area of focus for infectious disease treatment. Punicalin has shown strong anti-inflammatory and antioxidative properties; however, its effect in ALI has not been previously explored. Purpose: To investigate the effects of punicalin in lipopolysaccharide (LPS)-induced ALI and explore the underlying mechanisms. Methods: LPS (10 mg/kg) was administered intratracheally to create the ALI model in mice. Punicalin (10 mg/kg) was administered intraperitoneally shortly after LPS to investigate survival rate, lung tissue pathological injury, oxidative stress, levels of inflammatory cytokines in BALF and lung tissue, neutrophil extracellular trap (NET) formation and its effects on NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. In vitro studies were performed to evaluate the inflammatory cytokine release and NET formation in LPS-induced (1 µg/ml) and punicalin-treated mouse neutrophils derived from the bone marrow. Results: In vivo, punicalin reduced mortality, lung injury score, lung wet-to-dry (W/D) weight ratio, protein concentrations in BALF and malondialdehyde (MDA) levels in lung tissues, and increased superoxide dismutase (SOD) levels in lung tissues of LPS-induced ALI mice. Increased secretion of TNF-α, IL-1ß, and IL-6 in the BALF and the lungs of ALI mice was reversed by punicalin, whereas IL-10 was upregulated. Neutrophil recruitment and NET formation were also decreased by punicalin. Inhibition of NF-κB and MAPK signaling pathways was observed in punicalin-treated ALI mice. In vitro co-incubation with punicalin (50 µg/ml) inhibited the production of inflammatory cytokines and NET formation in LPS-treated neutrophils derived from mouse bone marrow. Conclusion: Punicalin reduces inflammatory cytokine production, prevents neutrophil recruitment and NET formation, and inhibits the activation of NF-κB and MAPK signaling pathways in LPS-induced ALI.

Risk factors for postoperative pulmonary complications in elderly patients receiving elective colorectal surgery: A retrospective study.

Study objective: Postoperative pulmonary complications (PPCs) are common and associated with adverse outcomes impairing long-term survival and quality of recovery. This single-centered retrospective study aimed to examine factors associated with PPCs in patients receiving elective colorectal surgery aged ≥60 years. Methods: Between January 2019 and December 2019, 638 patients at the Shanghai Changhai Hospital who had received elective surgery for colorectal cancer were enrolled in this study. Patients were divided into the PPC group (n=38) and non-PPC group (n=600). Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), red blood cell distribution width (RDW), and systemic inflammatory index (SII) were selected and caculated to indicate preoperative and postoperative inflammatory status. Receiver operating characteristic curve and bivariate correlation analyses were performed to evaluate the identified risk factors. Main results: The overall incidence of PPCs was approximately 5.96%. Multivariate regression analysis identified age (OR = 1.094, 95%CI 1.038-1.153, P = 0.001), preoperative RDW (OR = 1.159, 95%CI 1.025-1.309, P = 0.018), and preoperative SII (OR = 1.001, 95%CI 1.000-1.003, P = 0.035) as independent risk factors for PPCs. The cut-off values of age, preoperative RDW, and preoperative SII for predicting PPCs were 69.5 (sensitivity 0.658, specificity 0.653), 13.2 (sensitivity 0.789, specificity 0.552) and 556.1 (sensitivity 0.579, specificity 0.672), respectively. Conclusions: Age, preoperative RDW, and preoperative SII were identified as independent risk factors for PPC occurrence in elderly patients receiving elective colorectal surgery. Further studies are warranted to evaluate whether normalization of preoperative RDW and SII, as modifiable risk factors, are associated with improved surgical outcomes.

Personality, Preoperative Anxiety, and Postoperative Outcomes: A Review.

Research has shown that personality is associated with anxiety levels in the general population. However, little is known about the relationship between personality and preoperative anxiety and the subsequent health outcomes in patients undergoing surgery. Therefore, this review aimed to identify studies that explored the relationship between personality traits and preoperative anxiety, as well as their association with postoperative outcomes. Existing literature shows that anxiety may play an intermediary role in the relationship between personality and postoperative outcomes. Severe anxiety may partially explain the adverse effects of certain personality traits, such as neuroticism, on postoperative outcomes. However, the relationship between personality traits, preoperative anxiety, and postoperative outcomes remains unclear. Interventions such as clinical evaluation, preoperative counseling, and management strategies can be of great value in identifying and resolving patients' anxiety and negative emotions to improve postoperative outcomes.

Childbirth Pain, Labor Epidural Analgesia, and Postpartum Depression: Recent Evidence and Future Directions.

Pregnancy and childbirth are major life events for women and their families, characterized by physical, psychological, and emotional changes that can trigger anxiety, depression, and mental disorders in susceptible individuals. Acute labor pain is an independent risk factor for persistent pain in the postpartum period and is associated with depressive disorders. Epidural analgesia is a well-established technique that has commonly been regarded as the gold standard in pain management during labor. Although the relationships between labor pain, labor epidural analgesia, and postpartum depression have been studied by many investigators, the results of these studies are conflicting. Some literature suggest that labor epidural analgesia is associated with a reduction in the incidence of postpartum depression; however, other studies have failed to demonstrate this association. Unmet analgesic needs expectations, unmet birth expectations, and/or the quality of social support during labor may contribute to postpartum depression. The limitations of the published studies included differential misclassification of study variables and residual confounding, variations in the diagnosis of depression, and incomplete history data. Thus, future studies should include information on sociodemographic and patient-level variables and assessments of pain during labor or in the postpartum period. Better management of labor pain should be provided to prevent long-term morbidity and improve maternal and neonatal outcomes. Anesthesiologists could collaboratively work with obstetricians and perinatal psychiatrists to ensure that hospitals prioritize screening and treatment for postpartum depression.

The effect of prehabilitation on the postoperative outcomes of patients undergoing colorectal surgery: A systematic review and meta-analysis.

Study objective: Prehabilitation is analogous to marathon training and includes preoperative preparation for exercise, as well as nutrition and psychology. However, evidence-based recommendations to guide prehabilitation before colorectal surgery are limited. We aimed to evaluate the effect of prehabilitation on the postoperative outcomes of patients undergoing colorectal surgery. Design: This study is a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane databases were searched for studies reporting the effect of prehabilitation strategies versus standard care or rehabilitation in patients undergoing colorectal surgery. The primary outcomes were overall postoperative complications and length of hospital stay (LOS), and the secondary outcome was functional capacity (measured using the 6-min walk test [6MWT]) at 4 and 8 weeks after surgery. Main results: Fifteen studies with 1,306 participants were included in this meta-analysis. The results showed no significant reduction in the number of overall postoperative complications (risk ratio = 1.02; 95% confidence interval [CI] = 0.79-1.31; p = 0.878) or LOS (standardized mean difference = 0.04; 95% CI = -0.11 to 0.20; p = 0.589) in patients who underwent colorectal surgery with or without prehabilitation strategy. Additionally, there were no significant differences in the functional capacity estimated using the 6MWT at 4 and 8 weeks postoperatively. Conclusions: Prehabilitation did not significantly affect the number of postoperative complications, LOS, or functional capacity of patients undergoing colorectal surgery. Whether prehabilitation should be recommended deserves further consideration. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=290108, identifier CRD42021290108.

Research Progress on Risk Factors of Preoperative Anxiety in Children: A Scoping Review.

BACKGROUND: Preoperative anxiety has adverse effects on children and negative impacts on postoperative rehabilitation. Anesthesiologists can accurately identify children with preoperative anxiety, and individualized intervention can effectively improve their psychological state and clinical prognosis. However, a comprehensive summary of the current available evidence has yet to be conducted. Searches were conducted in Medline databases from inception to March 2022. Primary studies that reported preoperative anxiety in children and its attendant effects on postoperative recovery and prognosis were screened and included. Among the 309 publications identified, 12 related studies (n = 3540 patients) met the eligibility criteria. The incidence of preoperative anxiety in children in the included studies ranged from 41.7% to 75.44%. While 16 influencing factors were identified, only 5 factors had a significant impact on preoperative anxiety in children: younger age (n = 8), parental anxiety (n = 7), negative previous hospitalizations (n = 3), less sociableness (n = 2), and surgical setting (n = 1). The current scoping review identified risk factors for preoperative anxiety in children. Healthcare workers should identify and manage preoperatively anxious children. There are still some factors that are controversial, and large-scale clinical studies are needed.

Methane-rich saline protects against sepsis-associated cognitive deficits in mice.

Sepsis is associated with multiple organ dysfunction, and the brain is particularly vulnerable. Sepsis-associated encephalopathy (SAE) increases the mortality of patients with sepsis; however, the pathogenesis of SAE remains unclear. Methane, the simplest aliphatic hydrocarbon, has been reported to have anti-inflammatory and organ-protective effects. This study aimed to investigate the effects of methane on the cognitive deficits in mice with experimental sepsis. We randomly divided C57BL/6 male mice into sham, cecal ligation and puncture (CLP), and CLP + methane-rich saline (MS) groups. Twenty-four hours after surgery, behavioral tests were conducted on surviving mice and the hippocampus were collected for biochemical analysis. We found that CLP resulted in cognitive deficits in septic mice. A physiological mechanistic investigation revealed that microglia in the hippocampus are largely activated, coupled with the production of inflammatory cytokines and reactive oxygen species (ROS). Notably, methane inhibited the activation of microglia in the hippocampus, reduced the severity of inflammation, diminished the generation of ROS, and ultimately alleviated behavioral impairment in septic mice. Together, these show that treatment with methane ameliorated cognitive deficits in septic mice, which is partly related to the anti-inflammatory and antioxidative effects in the hippocampus.

Effect of Perioperative Intravenous Lidocaine on Postoperative Recovery in Patients Undergoing Ileostomy Closure: Study Protocol for a Randomized Controlled Trial.

Introduction: Opioids have been widely used clinically as the first choice for pain management. Ileostomy closure usually leads to temporary intestinal paralysis, which manifests as abdominal distension and pain, delayed defecation, nausea, and vomiting. Intraoperative and postoperative use of opioids inhibit gastrointestinal function and aggravate intestinal paralysis, and are notoriously addictive. Thus, reducing perioperative opioid use is important for patients undergoing ileostomy closure to restore the continuity and integrity of the intestine. Intravenous lidocaine has been shown to have anti-inflammatory properties and analgesic effects. We consider minimizing the use of opioids for such patients, and perioperative intravenous injection of lidocaine may be beneficial to the recovery of intestinal function in patients with ileostomy closure. Methods and Analysis: This is a randomized double-blind placebo-controlled trial to investigate the effectiveness and safety of intravenous lidocaine in patients undergoing ileostomy closure. The time of first postoperative anal venting, postoperative opioids use, postoperative recovery, intraoperative adverse effects and postoperative complications will be collected and analyzed.

Neurofilament Light Chain: A Candidate Biomarker of Perioperative Stroke.

Perioperative stroke is defined as a brain infarction of ischemic or hemorrhagic etiology that occurs during surgery or within 30 days after surgery. However, identifying perioperative stroke is challenging. Thus, the discovery and validation of neurological biomarkers for perioperative stroke are urgently needed. Neurofilament forms part of the neuronal cytoskeleton and is exclusively expressed in neurons. After disease-related neuroaxonal damage occurs, neurofilament light chain protein is released into the cerebrospinal fluid and blood. Blood neurofilament light chain has recently been shown to serve as a potential marker of interest during the perioperative period. Therefore, the aim of the present review was to give an overview of the current understanding and knowledge of neurofilament light chain as a potential biomarker of perioperative stroke.

Tim-3 Blockade Decreases the Apoptosis of CD8+ T Cells and Reduces the Severity of Sepsis in Mice.

INTRODUCTION: The T cell immunoglobulin and mucin domain 3 (Tim-3) mediated immunosuppressive pathway has been shown to play an essential role in the development of sepsis. However, the influence of Tim-3 blockade during sepsis and the possible effects on T cells' function remains largely unknown. Our study investigates the role of Tim-3 in cecal ligation and puncture (CLP)-induced sepsis in mice. METHODS: Sepsis was induced in C57BL/6 male mice via CLP. The expression of Tim-3 in CD8+ T cells after CLP challenge was measured. A dose of 50 µg anti-Tim-3 antibodies was injected intraperitoneally 30 min after surgery. Postoperative survival, bacterial clearance in the blood and peritoneal lavage fluid, cytokine secretion in the blood, and lung and liver histology were evaluated. In addition, the apoptosis of immune cells in the spleen and thymus was examined, respectively. RESULTS: Tim-3 expression was elevated in the splenic CD8+ T cells of septic mice. At the early stage of CLP-induced sepsis, blocking Tim-3 with anti-Tim-3 antibodies reduced the severity of sepsis. The anti-Tim-3 antibodies alleviated the morphology of lung and liver injuries in septic mice. The anti-Tim-3 antibodies also reduced the severity of the inflammatory responses and lymphocyte apoptosis in septic mice. CONCLUSIONS: Anti-Tim-3 antibodies might be a potential therapeutic strategy for sepsis.

Risk Factors for Delirium after Deep Brain Stimulation Surgery under Total Intravenous Anesthesia in Parkinson's Disease Patients.

BACKGROUND: Postoperative delirium (POD) is associated with perioperative complications and mortality. Data on the risk factors for delirium after subthalamic nucleus deep brain stimulation (STN-DBS) surgery is not clarified in Parkinson's disease (PD) patients receiving total intravenous anesthesia. We aimed to investigate the risk factors for delirium after STN-DBS surgery in PD patients. METHODS: The retrospective cohort study was conducted, including 131 PD patients who underwent STN-DBS for the first time under total intravenous anesthesia from January to December 2021. Delirium assessments were performed twice daily for 7 days after surgery or until hospital discharge using the confusion assessment method for the intensive care unit. Multivariate logistic regression analysis was used to determine the risk factor of POD. RESULTS: In total, 22 (16.8%) of 131 patients were in the POD group, while the other 109 patients were in the Non-POD group. Multivariate logistic regression analysis showed that preoperative Mini-mental State Examination score [odds ratio = 0.855, 95% confidence interval = 0.768-0.951, p = 0.004] and unified Parkinson's disease rating scale part 3 (on state) score (odds ratio = 1.061, 95% confidence interval = 1.02-1.104, p = 0.003) were independently associated with delirium after surgery. CONCLUSIONS: In this retrospective cohort study of PD patients, a lower Mini-mental State Examination score and a higher unified Parkinson's disease rating scale part 3 (on state) score were the independent risk factors for delirium after STN-DBS surgery in PD patients under total intravenous anesthesia.

Extubation in the operating room results in fewer composite mechanical ventilation-related adverse outcomes in patients after liver transplantation: a retrospective cohort study.

BACKGROUND: To investigate the effect of extubation in the operating room (OR) on mechanical ventilation-related adverse outcomes in patients who undergo liver transplantation. METHODS: Patients who underwent liver transplantation between January 2016 and December 2019 were included. According to the timing of extubation, patients were divided into OR extubation group and intensive care unit (ICU) extubation group. The propensity score was used to match OR extubation group and ICU extubation group at a 1:2 ratio by demographical and clinical covariates. The primary outcome was a composite of mechanical ventilation-related adverse outcomes, including 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), and in-hospital moderate to severe pulmonary complications. Secondary outcomes included in-hospital moderate to severe infectious complications, unplanned reintubation rates, ICU and postoperative hospital lengths of stay, and total hospital cost. RESULTS: A total of 438 patients were enrolled. After propensity score matching, 94 patients were in OR extubation group and 148 patients were in ICU extubation group. Incidence of the composite mechanical ventilation-related adverse outcomes was significantly lower in OR extubation group than ICU extubation group, even after adjusting for confounding factors (19.1% vs. 31.8%; Odds Ratio, 0.509; 95% Confidence Index [CI], 0.274-0.946; P=0.031). The duration of ICU stay was much shorter in OR extubation group than ICU extubation group (median 4, Interquartile range [IQR] (3 ~ 6) vs. median 6, IQR (4 ~ 8); P<0.001). Meanwhile, extubation in the OR led to a significant reduction of total hospital cost compared with extubation in the ICU (median 3.9, IQR (3.5 ~ 4.6) 10000 US dollars vs. median 4.1, IQR (3.8 ~ 5.1) 10000 US dollars; P=0.021). However, there were no statistically significant differences in moderate to severe infectious complications, unplanned reintubation rates, and the length of postoperative hospital stay between groups. CONCLUSIONS: Among patients who underwent liver transplantation, extubation in the OR compared with extubation in the ICU, significantly reduced the primary composite outcome of 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), or in-hospital moderate to severe pulmonary complications. TRIAL REGISTRATION: The trial was registered at www.clinicaltrials.gov with registration number NCT04261816. Retrospectively registered on 1st February 2020.