Background: Remimazolam besylate is a novel ultra-short-acting benzodiazepine which offers rapid sedation onset, predictable metabolism, and reduced hemodynamic instability compared to traditional agents. This trial aims to evaluate the sedation efficacy and safety of remimazolam besylate compared to midazolam in acute respiratory distress syndrome (ARDS) patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). Methods: This is a multicenter, randomized, single-blind, pilot trial that enrolls adults with ARDS on VV-ECMO. Patients will be randomized 1:1 to protocol-directed sedation with either remimazolam besylate or midazolam, targeting a Richmond Agitation-Sedation Scale (RASS) score of-4. A standardized rescue sedation protocol with dexmedetomidine is predefined. The primary outcome is the percentage of time within the target sedation range (TTR) without rescue sedation. Secondary outcomes are difference in time to awakening between the two groups, ECMO duration, 28-day mortality, delirium incidence, and comprehensive safety evaluation, analyzed using modified intention-to-treat and safety analyses. Discussion: This multicenter, randomized controlled pilot trial evaluates the safety and efficacy of remimazolam besylate versus midazolam for sedation in ARDS patients supported by VV-ECMO. As the first prospective study in this population, it aims to evaluate comparative sedation efficacy while characterizing hemodynamic stability and recovery profiles. The results are expected to offer significant evidence to guide future trials and optimize sedation practices in complex intensive care unit settings. Trial Registration: ChiCTR2500108567.

Background: Despite the widespread use of voriconazole in antifungal treatment, its high pharmacokinetic and pharmacodynamic variability may lead to suboptimal efficacy, especially in intensive care unit (ICU) patients. Machine learning (ML), an artificial intelligence modeling approach, is increasingly being applied to personalized medicine. The effectiveness of ML models for predicting voriconazole blood concentrations in ICU patients, compared to traditional population pharmacokinetics (popPK) models, has been uncertain until now. This study aims to identify the most effective modeling strategy for voriconazole. Methods: We developed six ML models using 244 concentrations from 62 patients in our previous popPK dataset. Another additional dataset, consisting of 282 trough concentrations from 177 patients, was used to externally evaluate both ML models and five other published popPK models, utilizing prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. Results: The XGBoost model exhibited superior predictive performance among the six ML models, achieving an R2 of 0.73. Its performance metrics (RMSE%: 127.21 %, median absolute prediction error: 29.65 %, median prediction error: 9.82 %, F20: 34.04 %, F30: 50.71 %) outperformed those of the best popPK model (RMSE%: 152.41 %, median absolute prediction error: 44.75 %, median prediction error: -0.99 %, F20: 23.40 %, F30: 36.88 %), suggesting greater accuracy and precision in predicting pharmacokinetics. Conclusions: Both ML and popPK models can be utilized for individualized voriconazole therapy. Our comparative study provides insights into the most effective methods for modeling and predicting voriconazole concentrations. (c) 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:Coagulopathy frequently complicates venovenous extracorporeal membrane oxygenation (VV ECMO) procedures, yet its underlying mechanism remains elusive. This retrospective study aimed to identify factors contributing to coagulopathy during VV ECMO by analyzing clinical data and employing proteomic approaches. A prospective cohort was also examined for validation. METHODS:We retrospectively analyzed clinical data from 51 patients undergoing VV ECMO between January 2015 and April 2021, categorizing them into coagulopathy(n = 21), defined by elevated levels of D-dimer and decreased fibrinogen in plasma that were reversible by circuit exchange, and non-coagulopathy(n = 30) groups. Plasma samples collected on days 0-2(D1), days 3-5(D4), and days 6-8(D7) were subjected to proteomics and Luminex assay. Additionally, oxygenator fiber samples were collected from a prospective cohort between May 2022 and August 2022 for scanning electron microscopy. RESULTS:Inflammation emerged as a pivotal factor in coagulopathy development during VV ECMO, as evidenced by elevated interleukin-6 levels on D1 and increased leukocyte and neutrophil counts on D4. Proteomics analysis identified a significant elevation of S100A8 and S100A9 in the plasma of coagulopathy patients throughout VV ECMO, findings confirmed by Luminex assay. In the prospective cohort, thrombosis and leukocyte accumulation were observed on oxygenator fibers from coagulopathy patients, along with elevated levels of S100A8 and S100A9 in plasma. CONCLUSIONS:Coagulopathy during VV ECMO is associated with heightened levels of proinflammatory proteins S100A8 and S100A9 in plasma, accompanied by leukocyte accumulation on oxygenator fibers. These findings emphasize the potential therapeutic target against coagulopathy during VV ECMO.

Mucosal antigen-specific T cells are pivotal for pathogen clearance and immune modulation in respiratory infections. Dysregulated T cell responses exacerbate coronavirus disease 2019 severity, marked by cytokine storms and respiratory failure. Despite extensive description in peripheral blood, the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in the lungs remain elusive. Here we conducted integrated single-cell profiling of SARS-CoV-2-specific T cells in 122 bronchoalveolar lavage fluid (BALF) and 280 blood samples from 159 patients, including 27 paired BALF and blood samples from 24 patients. SARS-CoV-2-specific T cells were robustly elicited in BALF irrespective of prior vaccination, correlating with diminished viral loads, lessened systemic inflammation and improved respiratory function. SARS-CoV-2-specific T cells in BALF exhibited profound activation, along with proliferative and multi-cytokine-producing capabilities and a glycolysis-driven metabolic signature, which were distinct from those observed in peripheral blood mononuclear cells. After viral clearance, these specific T cells maintained a polyfunctional tissue-resident memory phenotype, highlighting their critical roles in infection control and long-term protection. The authors show that SARS-CoV-2-specific T cells in the lung are key to fighting infection and persist after viral clearance, contributing to long-term immunity and protection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, encodes several accessory proteins that have been shown to play crucial roles in regulating the innate immune response. However, their expressions in infected cells and immunogenicity in infected humans and mice are still not fully understood. This study utilized various techniques such as luciferase immunoprecipitation system (LIPS), immunofluorescence assay (IFA), and western blot (WB) to detect accessory protein-specific antibodies in sera of COVID-19 patients. Specific antibodies to proteins 3a, 3b, 7b, 8 and 9c can be detected by LIPS, but only protein 3a antibody was detected by IFA or WB. Antibodies against proteins 3a and 7b were only detected in ICU patients, which may serve as a marker for predicting disease progression. Further, we investigated the expression of accessory proteins in SARS-CoV-2-infected cells and identified the expressions of proteins 3a, 6, 7a, 8, and 9b. We also analyzed their ability to induce antibodies in immunized mice and found that only proteins 3a, 6, 7a, 8, 9b and 9c were able to induce measurable antibody productions, but these antibodies lacked neutralizing activities and did not protect mice from SARS-CoV-2 infection. Our findings validate the expression of SARS-CoV-2 accessory proteins and elucidate their humoral immune response, providing a basis for protein detection assays and their role in pathogenesis.

Active cytomegalovirus (CMV) infection is associated with poor prognosis in septic patients with critical illness. Patients of septic category are highly likely to benefit from prophylactic antiviral therapy. Nevertheless, the clinical characteristics for CMV reactivation are lacking among septic patients requiring mechanical ventilation. The aim of this study was to investigate the incidence, risk factors, and clinical outcomes regarding active CMV infection in mechanically ventilated patients with sepsis. A single-center, retrospective cohort study conducted from January 2021 to December 2023 that included septic patients on mechanical ventilation at the intensive care unit (ICU) of a national hospital. Study participants were divided into active and non-active CMV infection groups based on CMV DNAemia within a 28-day hospitalization period in ICU. Clinical features, laboratory findings, treatment measures, and clinical outcomes were compared between the two groups. Among 118 septic patients, 21 (17.8

The vastly spreading COVID-19 pneumonia is caused by SARS-CoV-2. Lymphopenia and cytokine levels are tightly associated with disease severity. However, virus-induced immune dysregulation at cellular and molecular levels remains largely undefined. Here, the leukocytes in the pleural effusion, sputum, and peripheral blood biopsies from severe and mild patients were analyzed at single-cell resolution. Drastic T cell hyperactivation accompanying elevated T cell exhaustion was observed, predominantly in pleural effusion. The mechanistic investigation identified a group of CD14+ monocytes and macrophages highly expressing CD163 and MRC1 in the biopsies from severe patients, suggesting M2 macrophage polarization. These M2-like cells exhibited up-regulated IL10, CCL18, APOE, CSF1 (M-CSF), and CCL2 signaling pathways. Further, cell type specific dysregulation of transposable elements was observed in Severe COVID-19 patients. Together, our results suggest that severe SARS-CoV-2 infection causes immune dysregulation by inducing M2 polarization and subsequent T cell exhaustion. This study improves our understanding of COVID-19 pathogenesis.

Background Chronic obstructive pulmonary disease (COPD) is one of most common comorbidities in acute respiratory distress syndrome (ARDS). There are few specific studies on the appropriate ventilation strategy for patients with ARDS comorbid with COPD, especially regarding on positive end-expiratory pressure (PEEP) titration. Methods To compare the respiratory mechanics in mechanical ventilated ARDS patients with or without COPD and to determine whether titration of PEEP based on electrical impedance tomography (EIT) is superior to the ARDSnet protocol. This is a single center, perspective, repeated measure study. ARDS patients requiring mechanical ventilation who were admitted to the intensive care unit between August 2017 and December 2020 were included. ARDS patients were divided according to whether they had COPD into a COPD group and a non-COPD group. Respiratory mechanics, gas exchange, and hemodynamics during ventilation were compared between the groups according to whether the PEEP level was titrated by EIT or the ARDSnet protocol. Results A total of twenty-seven ARDS patients including 14 comorbid with and 13 without COPD who met the study eligibility criteria were recruited. The PEEP levels titrated by EIT and the ARDSnet protocol were lower in the COPD group than in the non-COPD group (6.93 ± 1.69 cm H 2 O vs. 12.15 ± 2.40 cm H 2 O, P < 0.001 and 10.43 ± 1.20 cm H 2 O vs. 14.0 ± 3.0 cm H 2 O, P < 0.001, respectively). In the COPD group, the PEEP level titrated by EIT was lower than that titrated by the ARDSnet protocol (6.93 ± 1.69 cm H 2 O vs. 10.43 ± 1.20 cm H 2 O, P < 0.001), as was the global inhomogeneity (GI) index (0.397 ± 0.040 vs. 0.446 ± 0.052, P = 0.001), plateau airway pressure (16.50 ± 4.35 cm H 2 O vs. 20.93 ± 5.37 cm H 2 O, P = 0.001), dead space ventilation ratio (48.29 ± 6.78% vs. 55.14 ± 8.85%, P < 0.001), ventilation ratio (1.63 ± 0.33 vs. 1.87 ± 0.33, P < 0.001), and mechanical power (13.92 ± 2.18 J/min vs. 15.87 ± 2.53 J/min, P < 0.001). The cardiac index was higher when PEEP was treated by EIT than when it was titrated by the ARDSnet protocol (3.41 ± 0.50 L/min/m 2 vs. 3.02 ± 0.43 L/min/m 2 , P < 0.001), as was oxygen delivery (466.40 ± 71.08 mL/min/m 2 vs. 411.10 ± 69.71 mL/min/m 2 , P = 0.001). Conclusion Titrated PEEP levels were lower in patients with ARDS with COPD than in ARDS patients without COPD. In ARDS patient comorbid with COPD, application of PEEP titrated by EIT was lower than those titrated by the ARDSnet protocol, which contributed to improvements in the ventilation ratio, mechanical energy, cardiac index, and oxygen delivery with less of an adverse impact on hemodynamics.

BackgroundViral causes of acute respiratory distress syndrome (ARDS) are mostly limited to influenza. However, adenovirus has been emerging as a cause of ARDS with a high mortality rate and described in adults are rare.MethodsWe conducted a prospective, single-center observational study of viral pneumonia with ARDS and confirmed adenovirus-associated ARDS in adults at our quaternary referral institution between March 2019 and June 2020. We prospectively analyzed clinical characteristics, laboratory test results, radiological characteristics, viral load from nasopharyngeal swabs and endotracheal aspirates, treatments, and outcomes for the study participants.ResultsThe study enrolled 143 ARDS patients, including 47 patients with viral pneumonia-related ARDS, among which there were 14 adenovirus-associated ARDS patients, which accounted for 29.79% of the viral pneumonia-related ARDS cases. Among the adenovirus-associated ARDS patients, 78.57% were men with a mean age of 54.93 ± 19.04 years, younger than that of the non-adenovirus associated ARDS patients. Adenovirus-associated ARDS patients had no specific clinical characteristics, but they presented with decrease in the number of CD3+CD4+ T cells and higher serum creatinine during the early stage. The viral load and the positivity rate in the lower respiratory tract were higher than that of the upper respiratory tract in the patients with adenovirus-associated ARDS. All patients required invasive mechanical ventilation treatment. The average time from shortness of breath to the application of invasive ventilation was 24 h. Ten patients (71.43%) complicated by acute kidney injury, while 13 patients (71.43%) in the non-adenovirus associated ARDS group (P = 0.045). Additionally, 85.71% of the 14 adenovirus-associated ARDS patients survived. No significant differences were detected between the two groups regarding duration of ventilation, length of ICU stay and mortality.ConclusionAdenovirus infection is an important cause of virus-related ARDS. The positivity rate of adenovirus infection in lower respiratory tract secretions was higher than that in upper respiratory tract secretions in these patients. Age, lower CD3+CD4+ T cells, and high serum creatinine may be were associated with adenovirus induce ARDS in adults required mechanical ventilation. Early identification and intervention to prevent disease progression are essential for reducing the mortality rate in these patients.

Objectives: To evaluate the relation between metagenomic next-generation sequencing (mNGS) and the prognosis of patients with infectious diseases undergoing mechanical ventilation in the intensive care unit (ICU).Methods: This is a single-center observational study, comparing nonrandomly assigned diagnostic ap-proaches. We analyzed the medical records of 228 patients with suspected infectious diseases undergoing mechanical ventilation in the ICU from March 2018 to May 2020. The concordance of pathogen results was also assessed for the results of mNGS, culture, and polymerase chain reaction assays.Results: The 28-day mortality of the patients in the mNGS group was lower after the baseline difference correction (19.23% (20/104) vs 29.03% (36/124) , P = 0.039). Subgroup analysis showed that mNGS assay was associated with improved 28-day mortality of patients who are not immunosuppressed (14.06% vs 29.82%, P = 0.018). Not performing mNGS assay, higher acute physiology and chronic health evaluation II score, and hypertension are independent risk factors for 28-day mortality. The mNGS assay presented an advantage in pathogen positivity (69.8% double-positive and 25.0% mNGS-positive only), and the concor-dance between these two assays was 79.0%.Conclusion: mNGS survey may be associated with a better prognosis by reducing 28-day mortality of patients with infectious diseases on mechanical ventilation in the ICU. This technique presented an ad-vantage in pathogen positivity over traditional methods.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background. Since 2020 COVID-19 pandemic became an emergent public sanitary incident. The epidemiology data and the impact on prognosis of secondary infection in severe and critical COVID-19 patients in China remained largely unclear. Methods. We retrospectively reviewed medical records of all adult patients with laboratory-confirmed COVID-19 who were admitted to ICUs from January 18 th 2020 to April 26 th 2020 at two hospitals in Wuhan, China and one hospital in Guangzhou, China. We measured the frequency of bacteria and fungi cultured from respiratory tract, blood and other body fluid specimens. The risk factors for and impact of secondary infection on clinical outcomes were also assessed. Results. Secondary infections were very common (86.6%) when patients were admitted to ICU for >72 hours. The majority of infections were respiratory, with the most common organisms being Klebsiella pneumoniae (24.5%), Acinetobacter baumannii (21.8%), Stenotrophomonas maltophilia (9.9%), Candida albicans (6.8%), and Pseudomonas spp. (4.8%). Furthermore, the proportions of multidrug resistant (MDR) bacteria and carbapenem resistant Enterobacteriaceae (CRE) were high. We also found that age ≥60 years and mechanical ventilation ≥13days independently increased the likelihood of secondary infection. Finally, patients with positive cultures had reduced ventilator free days in 28 days and patients with CRE and/or MDR bacteria positivity showed lower 28 day survival rate. Conclusions. In a retrospective cohort of severe and critical COVID-19 patients admitted to ICUs in China, the prevalence of secondary infection was high, especially with CRE and MDR bacteria, resulting in poor clinical outcomes.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.

目的 探讨无创正压通气(NIV)与球囊面罩(BVM)通气相比是否能够改善重症加强治疗病房(ICU)危重患者气管插管前的预氧合.方法 这是一个单中心、前瞻性随机对照研究,研究纳入2015年6月至2017年6月在广州医科大学附属第一医院、广州呼吸健康研究院ICU内需要气管插管的患者.随机将患者分为对照组和NIV组,分别使用BVM或者NIV进行预氧合.比较两组患者各项指标的差异,探讨NIV在危重症患者预氧合中的应用价值.结果 共纳入患者106例,男75例,女31例;平均年龄(65.0±12.6)岁.对照组53例,NIV组53例.对照组和NIV组气管插管的原因分别为:肺炎[40例(75.5％)比39例(73.6％)],慢性阻塞性肺疾病[12例(22.6％)比11例(20.8％)],其他[1例(1.9％)比3例(5.7％)],两组气管插管原因比较差异均无统计学意义(P＞0.05).对照组和NIV组急性生理学和慢性健康状况评分系统Ⅱ评分分别为20(17,26)比20(16,26)分,差异无统计学意义(P=0.86).对照组和NIV组预氧合前脉搏血氧饱和度(SpO2)分别为92％(85％,98％)比91％(85％,98％)(P=0.87).预氧合后,NIV 组的 SpO2显著高于对照组99％(96％,100％)比96％(90％,99％)(P=0.001).在预氧合前SpO2＜90％的亚组患者中,对照组和NIV组的SpO2分别为83％(73％,85％)和81％(75％,86％)(P=0.75);预氧合后,NIV 组的 SpO2明显高于对照组的99％(96％,100％)比94％(90％,99％)(P=0.000).预氧合前SpO2≥90％的亚组患者中,对照组和NIV组的SpO2分别为95.5％(92％,99％)比96％(94％,99％)(P=0.52);预氧合后两组 SpO2相似98％(95％,100％)比99％(96％,100％)(P=0.1).对照组和 NIV 组机械通气时间 17(10,23)d 比 19(11,26)d(P=0.86);28天生存率73.6％比71.7％(P=0.34),ICU 病死率31.3％比31.7％(P=0.66).结论 与传统的BVM比较,NIV辅助预氧合对危重患者是安全有效的,严重低氧血症的危重患者更有可能从NIV预氧合中获益.

床旁重症超声是肺栓塞危险分层和右心功能不全评价的重要方法.本文回顾性描述重症医学科收治1例重症肺炎患者在疾病进展过程中并发高危肺动脉栓塞,因为循环衰竭使患者处于危及生命的状态,行CTPA等检查风险高.应用床旁重症超声识别高危肺动脉栓塞及在治疗过程中的动态监测.经采用谨慎的溶栓方案、抗感染、维持循环稳定等综合处理方案,患者病情好转出院.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) may be a lifesaving rescue therapy for patients with severe coronavirus disease 2019 (COVID-19). However, little is known regarding the efficacy of prolonged ECMO (duration longer than 14 days) in patients with COVID-19. In this case report, we report the successful use of prolonged VV-ECMO (111 days) in a 61-year-old man with severe COVID-19. Given the high mortality rate of severe COVID-19, this case provided evidence for use of prolonged VV-ECMO as supportive care in patients with severe COVID-19.

Background The coronavirus disease 2019 (COVID-19) pandemic has spread all over the world resulting in high mortality, yet no specific antiviral treatment has been recommended. Methods A retrospective descriptive study was conducted involving 19 consecutive critically ill patients during January 27, 2020 to April 18, 2020. Ribavirin was given at 0.15g q8h orally upon ICU admission for 7 to 21 days. Here, 28-day mortality, lower respiratory tract specimens (ETA), and ribavirin side effect on the day of ICU admission (Day 1), Day 7, Day 14 and Day 21 were analyzed. Results All the nineteen critically ill COVID-19 patients (14 males and 5 females, median age 56yr) survived through to the 28th day of observations with 6 patients (31.58%) being discharged from the ICU. The SARS-CoV-2 viral positivity in sputum/ETA was 100% (19/19) on Day 1, 73.68% (14/19) on Day 7, 57.89% (11/19) on Day 14 and 36.84% (7/19) on Day 21. Ribavirin side effect was not observed in these patients. Conclusion Ribavirin is well tolerated in critically ill patients with COVID-19 and may benefit COVID-19 patients through increasing the virus clearance.

Abstract Background: Metagenomic Next-Generation Sequencing (mNGS) has gradually shown its advantages in pathogen identification for clinical infectious disease. However, few studies were conducted on the evaluation between this technique and conventional methods like culture and PCR and the prognosis of patients with infectious diseases on mechanical ventilation in ICUMethods: We conducted this retrospective study from March 2018 to May 2020 in the first Affiliated Hospital of Guangzhou Medical University, a total of 228 patients with suspected infectious diseases on mechanical ventilation were included, including 104 cases of mNGS group and 124 cases of non-mNGS. Statistical analyses were performed between the two groups and subgroup of whether were immunocompromised. The concordance between mNGS, culture and PCR was also assessed.Results: The 28-day mortality rate of the patients in the mNGS group was lower after the baseline difference correction (19.23% vs. 29.03%，p=0.039), indicating that mNGS may improve the prognosis of patients in ICU. And subgroup analysis showed that mNGS could improve the 28-day mortality of nonimmunosuppressive patients（14.06% vs. 29.82%, p=0.018）. According to the analysis of Logistic Regression, not performing mNGS, high APACHE II score and hypertension were independent risk factors for 28-day mortality, which strongly suggested that mNGS was one of the key factors affecting prognosis. A total of 157 samples performed mNGS, 116 of them received both mNGS and culture. mNGS presented advantages of positivity (69.8% double positive and 25.0% mNGS positive only) and concordance (79.0%, match and partly match).Conclusions: mNGS may improve the prognosis and reduce the 28-day mortality rate of patients with infectious diseases on mechanical ventilation in ICU. This technique has shown its advantages comparing with conventional methods, and will be wildly used as a promising technology for infectious disease.