Effects of tidal volume on physiology and clinical outcomes in patients with one­lung ventilation undergoing surgery: A meta­analysis of randomized controlled trials.

There is no detailed study on how tidal volume (VT) affects patients during one-lung ventilation (OLV). The present study conducted a meta-analysis to assess the effect of VT on physiology and clinical outcomes in OLV patients. Databases until February 2023 were retrieved from PubMed, Cochrane Library and Web of Science. Randomized controlled trials comparing the application of low and high VT ventilation in adults with OLV were performed. Demographic variables, VT, physiology, and clinical outcomes were retrieved. The random-effects model calculated the summary of odds ratios with 95% confidence intervals (CI) and mean difference with standard deviation. A total of 12 studies involving a total of 876 participants met the inclusion criteria. Low VT ventilation was associated with decreased risk of acute lung injury [relative risk 0.50, 95% CI (0.28, 0.88), P=0.02]. Low VT ventilation decreased the driving pressure (ΔP) and peak pressure (Ppeak) and improved arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2). Furthermore, the present study suggested that a significant difference in blood IL-6 was observed between low and high VT ventilation [mean difference, -35.51 pg/ml, 95% CI (-66.47, -4.54 pg/ml), P=0.02]. A decrease in the length of stay at the hospital occurred in the low VT group when set to 4-5 ml/kg. In the OLV patients, low VT ventilation decreased the risk of acute lung injury, blood IL-6, ΔP and Ppeak, and improved PaO2/FiO2. Furthermore, when low VT was set to 4-5 ml/kg, the length of stay at the hospital decreased.

Development of genomic phenotype and immunophenotype of acute respiratory distress syndrome using autophagy and metabolism-related genes.

Background: Distinguishing ARDS phenotypes is of great importance for its precise treatment. In the study, we attempted to ascertain its phenotypes based on metabolic and autophagy-related genes and infiltrated immune cells. Methods: Transcription datasets of ARDS patients were obtained from Gene expression omnibus (GEO), autophagy and metabolic-related genes were from the Human Autophagy Database and the GeneCards Database, respectively. Autophagy and metabolism-related differentially expressed genes (AMRDEGs) were further identified by machine learning and processed for constructing the nomogram and the risk prediction model. Functional enrichment analyses of differentially expressed genes were performed between high- and low-risk groups. According to the protein-protein interaction network, these hub genes closely linked to increased risk of ARDS were identified with CytoHubba. ssGSEA and CIBERSORT was applied to analyze the infiltration pattern of immune cells in ARDS. Afterwards, immunologically characterized and molecular phenotypes were constructed according to infiltrated immune cells and hub genes. Results: A total of 26 AMRDEGs were obtained, and CTSB and EEF2 were identified as crucial AMRDEGs. The predictive capability of the risk score, calculated based on the expression levels of CTSB and EEF2, was robust for ARDS in both the discovery cohort (AUC = 1) and the validation cohort (AUC = 0.826). The mean risk score was determined to be 2.231332, and based on this score, patients were classified into high-risk and low-risk groups. 371 differential genes in high- and low-risk groups were analyzed. ITGAM, TYROBP, ITGB2, SPI1, PLEK, FGR, MPO, S100A12, HCK, and MYC were identified as hub genes. A total of 12 infiltrated immune cells were differentially expressed and have correlations with hub genes. According to hub genes and implanted immune cells, ARDS patients were divided into two different molecular phenotypes (Group 1: n = 38; Group 2: n = 19) and two immune phenotypes (Cluster1: n = 22; Cluster2: n = 35), respectively. Conclusion: This study picked up hub genes of ARDS related to autophagy and metabolism and clustered ARDS patients into different molecular phenotypes and immunophenotypes, providing insights into the precision medicine of treating patients with ARDS.

Early decrease of ventilatory ratio after prone position ventilation may predict successful weaning in patients with acute respiratory distress syndrome: A retrospective cohort study.

Background: Previous studies usually identified patients who benefit the most from prone positioning by oxygenation improvement. However, inconsistent results have been reported. Physiologically, pulmonary dead space fraction may be more appropriate in evaluating the prone response. As an easily calculated bedside index, ventilatory ratio (VR) correlates well with pulmonary dead space fraction. Hence, we investigated whether the change in VR after prone positioning is associated with weaning outcomes at day 28 and to identify patients who will benefit the most from prone positioning. Materials and methods: This retrospective cohort study was performed in a group of mechanically ventilated, non-COVID ARDS patients who received prone positioning in the ICU at Zhongda hospital, Southeast University. The primary outcome was the rate of successful weaning patients at day 28. Arterial blood gas results and corresponding ventilatory parameters on five different time points around the first prone positioning were collected, retrospectively. VR responders were identified by Youden's index. Competing-risk regression models were used to identify the association between the VR change and liberation from mechanical ventilation at day 28. Results: One hundred and three ARDS patients receiving prone positioning were included, of whom 53 (51%) successfully weaned from the ventilator at day 28. VR responders were defined as patients showing a decrease in VR of greater than or equal to 0.037 from the baseline to within 4 h after prone. VR responders have significant longer ventilator-free days, higher successful weaning rates and lower mortality compared with non-responders at day 28. And a significant between-group difference exists in the respiratory mechanics improvement after prone (P < 0.05). A linear relationship was also found between VR change and compliance of the respiratory system (Crs) change after prone (r = 0.32, P = 0.025). In the multivariable competing-risk analysis, VR change (sHR 0.57; 95% CI, 0.35-0.92) was independently associated with liberation from mechanical ventilation at day 28. Conclusion: Ventilatory ratio decreased more significantly within 4 h after prone positioning in patients with successful weaning at day 28. VR change was independently associated with liberation from mechanical ventilation at day 28.

Hepatocyte growth factor protects pulmonary endothelial barrier against oxidative stress and mitochondria-dependent apoptosis.

BACKGROUND: Pulmonary microvascular endothelial cells (PMVECs) were not complex, and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Previous studies have demonstrated that hepatocyte growth factor (HGF), which was secreted by bone marrow mesenchymal stem cells, could decrease endothelial apoptosis. We investigated whether mTOR/STAT3 signaling acted in HGF protective effects against oxidative stress and mitochondria-dependent apoptosis in lipopolysaccharide (LPS)-induced endothelial barrier dysfunction and ALI mice. METHODS: In our current study, we introduced LPS-induced PMEVCs with HGF treatment. To investigate the effects of mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) pathway in endothelial oxidative stress and mitochondria-dependent apoptosis, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 were, respectively, used to inhibit mTOR/STAT3 signaling. Moreover, lentivirus vector-mediated mTORC1 (Raptor) and mTORC2 (Rictor) gene knockdown modifications were introduced to evaluate mTORC1 and mTORC1 pathways. Calcium measurement, reactive oxygen species (ROS) production, mitochondrial membrane potential and protein, cell proliferation, apoptosis, and endothelial junction protein were detected to evaluate HGF effects. Moreover, we used the ALI mouse model to observe the mitochondria pathological changes with an electron microscope in vivo. RESULTS: Our study demonstrated that HGF protected the endothelium via the suppression of ROS production and intracellular calcium uptake, which lead to increased mitochondrial membrane potential (JC-1 and mitochondria tracker green detection) and specific proteins (complex I), raised anti-apoptosis Messenger Ribonucleic Acid level (B-cell lymphoma 2 and Bcl-xL), and increased endothelial junction proteins (VE-cadherin and occludin). Reversely, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 could raise oxidative stress and mitochondria-dependent apoptosis even with HGF treatment in LPS-induced endothelial cells. Similarly, mTORC1 as well as mTORC2 have the same protective effects in mitochondria damage and apoptosis. In in vivo experiments of ALI mouse, HGF also increased mitochondria structural integrity via the mTOR/STAT3 pathway. CONCLUSION: In all, these reveal that mTOR/STAT3 signaling mediates the HGF suppression effects to oxidative level, mitochondria-dependent apoptosis, and endothelial junction protein in ARDS, contributing to the pulmonary endothelial survival and barrier integrity.

Isolation of Primary Mouse Pulmonary Microvascular Endothelial Cells and Generation of an Immortalized Cell Line to Obtain Sufficient Extracellular Vesicles.

Pulmonary microvascular endothelial cells (PMECs) and the extracellular vesicles (EVs) derived from PMECs participate in maintaining pulmonary homeostasis and mediating the inflammatory response. However, obtaining a high-purity population of PMECs and their EVs from mouse is still notoriously difficult. Herein we provide a method to isolate primary mouse PMECs (pMPMECs) and to transduce SV40 lentivirus into pMPMECs to establish an immortalized cell line (iMPMECs), which provides sufficient quantities of EVs for further studies. pMPMECs and iMPMECs can be identified using morphologic criteria, a phenotypic expression profile (e.g., CD31, CD144, G. simplicifolia lectin binding), and functional properties (e.g., Dil-acetylated low-density protein uptake, Matrigel angiogenesis). Furthermore, pMPMEC-EVs and iMPMEC-EVs can be identified and compared. The characteristics of pMPMEC-EVs and iMPMEC-EVs are ascertained by transmission electron microscopy, nanoparticle tracking analysis, and specific protein markers. iMPMECs produce far more EVs than pMPMECs, while their particle size distribution is similar. Our detailed protocol to isolate and immortalize MPMECs will provide researchers with an in vitro model to investigate the specific roles of EVs in pulmonary physiology and diseases.

Association of Frailty With the Risk of Mortality and Resource Utilization in Elderly Patients in Intensive Care Units: A Meta-Analysis.

Background: The associations of frailty with the risk of mortality and resource utilization in the elderly patients admitted to intensive care unit (ICU) remain unclear. To address these issues, we performed a meta-analysis to determine whether frailty is associated with adverse outcomes and increased resource utilization in elderly patients admitted to the ICU. Methods: We searched PubMed, EMBASE, ScienceDirect, and Cochrane Central Register of Controlled Trials through August 2021 to identify the relevant studies that investigated frailty in elderly (≥ 65 years old) patients admitted to an ICU and compared outcomes and resource utilization between frail and non-frail patients. The primary outcome was mortality. We also investigated the prevalence of frailty and the impact of frailty on the health resource utilization, such as hospital length of stay (LOS) and resource utilization of ICU. Results: A total of 13 observational studies enrolling 64,279 participants (28,951 frail and 35,328 non-frail) were finally included. Frailty was associated with an increased risk of short-term mortality (10 studies, relative risk [RR]: 1.70; 95% CI: 1.45-1.98), in-hospital mortality (five studies, RR: 1.73; 95% CI: 1.55-1.93), and long-term mortality (six studies, RR: 1.86; 95% CI: 1.44-2.42). Subgroup analysis showed that retrospective studies identified a stronger correlation between frailty and hospital LOS (three studies, MD 1.14 d; 95% CI: 0.92-1.36). Conclusions: Frailty is common in the elderly patients admitted to ICU, and is associated with increased mortality and prolonged hospital LOS. Trial registration: This study was registered in the PROSPERO database (CRD42020207242).

An optimized method for the induction and purification of mouse bone marrow dendritic cells.

Dendritic cells (DCs) play an essential role in the initiation of adaptive immune responses, but they are rare in all organs. The traditional methods used to increase the yield and purity of DCs are the early removal of granulocyte culture medium and the isolation of high-purity DCs by magnetic-activated cell sorting (MACS). This study provides a more rapid and economical optimization method to obtain more high-purity DCs. (i) We harvested 18% more bone marrow (BM) cells by using forceps to crack the epiphysis instead of cutting it with scissors during BM cell extraction. (ii) When the cells in the culture medium that is discarded on day 3 in the traditional method were centrifuged and then added back to the petri dish, the DC yield on day 5 increased by 61%. (iii) On the third day, the addition of fresh medium and the retention of the original medium rather than discarding it increased the number of DCs harvested on the fifth day by 137%. (i-iii) The improved method cost an average of 74% less than the conventional method and yielded the same number and function of cells. (iv) The initial number of BM cells was increased by 15% in 4-week-old mice compared with 8-week-old mice. (v) The Percoll density centrifugation (PDS) method was used to purify DCs on day 6 after induction, and the purity of the DCs was greater than 90%, which showed no significant difference from the MACS method. However, the yield of the PDS method increased by 21%. In addition, the PDS method has a lower cost, with an average purification cost of 4 CNY ($0.58) compared with 648 CNY ($93.25) for MACS, reducing the cost by 99%. Therefore, high-purity and high-yield DCs can be rapidly obtained through a five-step improvement in the process of BM cell extraction, induction and purification.

Physiological effects of different recruitment maneuvers in a pig model of ARDS.

BACKGROUND: In acute respiratory distress syndrome (ARDS), lung recruitment maneuvers can recruit collapsed alveoli in gravity-dependent lung regions, improving the homogeneity of ventilation distribution. This study used electrical impedance tomography to investigate the physiological effects of different recruitment maneuvers for alveolar recruitment in a pig model of ARDS. METHODS: ARDS was induced in ten healthy male pigs with repeated bronchoalveolar lavage until the ratio of arterial partial pressure of oxygen (PaO2) of fraction of inspired oxygen (P/F) was < 100 mmHg and remained stable for 30 min (TARDS). ARDS pigs underwent three sequential recruitment maneuvers, including sustained inflation, increments of positive end-expiratory pressure (PEEP), and pressure-controlled ventilation (PCV) applied in random order, with 30 mins at a PEEP of 5 cmH2O between maneuvers. Respiratory mechanics, hemodynamics, arterial blood gas, and electrical impedance tomography were recorded at baseline, TARDS, and before and after each recruitment maneuver. RESULTS: In all ten pigs, ARDS was successfully induced with a mean 2.8 ± 1.03 L bronchoalveolar lavages. PaO2, P/F, and compliance were significantly improved after recruitment with sustained inflation, increments of PEEP or PCV (all p < 0.05), and there were no significant differences between maneuvers. Global inhomogeneity index significantly decreased after recruitment with sustained inflation, increments of PEEP, or PCV. There were no significant differences in global inhomogeneity before or after recruitment with the different maneuvers. The decrease in global inhomogeneity index (ΔGI) was significantly greater after recruitment with increments of PEEP compared to sustained inflation (p = 0.023), but there was no significant difference in ΔGI between increments of PEEP and PCV or between sustained inflation and PCV. CONCLUSION: Sustained inflation, increments of PEEP, and PCV increased oxygenation, and regional and global compliance of the respiratory system, and decreased inhomogeneous gas distribution in ARDS pigs. Increments of PEEP significantly improved inhomogeneity of the lung compared to sustained inflation, while there was no difference between increments of PEEP and PCV or between sustained inflation and PCV.

Neurally Adjusted Ventilatory Assist versus Pressure Support Ventilation in Difficult Weaning: A Randomized Trial.

BACKGROUND: Difficult weaning frequently develops in ventilated patients and is associated with poor outcome. In neurally adjusted ventilatory assist, the ventilator is controlled by diaphragm electrical activity, which has been shown to improve patient-ventilator interaction. The objective of this study was to compare neurally adjusted ventilatory assist and pressure support ventilation in patients difficult to wean from mechanical ventilation. METHODS: In this nonblinded randomized clinical trial, difficult-to-wean patients (n = 99) were randomly assigned to neurally adjusted ventilatory assist or pressure support ventilation mode. The primary outcome was the duration of weaning. Secondary outcomes included the proportion of successful weaning, patient-ventilator asynchrony, ventilator-free days, and mortality. Weaning duration was calculated as 28 days for patients under mechanical ventilation at day 28 or deceased before day 28 without successful weaning. RESULTS: Weaning duration in all patients was statistically significant shorter in the neurally adjusted ventilatory assist group (n = 47) compared with the pressure support ventilation group (n = 52; 3.0 [1.2 to 8.0] days vs. 7.4 [2.0 to 28.0], mean difference: -5.5 [95% CI, -9.2 to -1.4], P = 0.039). Post hoc sensitivity analysis also showed that the neurally adjusted ventilatory assist group had shorter weaning duration (hazard ratio, 0.58; 95% CI, 0.34 to 0.98). The proportion of patients with successful weaning from invasive mechanical ventilation was higher in neurally adjusted ventilatory assist (33 of 47 patients, 70%) compared with pressure support ventilation (25 of 52 patients, 48%; respiratory rate for neurally adjusted ventilatory assist: 1.46 [95% CI, 1.04 to 2.05], P = 0.026). The number of ventilator-free days at days 14 and 28 was statistically significantly higher in neurally adjusted ventilatory assist compared with pressure support ventilation. Neurally adjusted ventilatory assist improved patient ventilator interaction. Mortality and length of stay in the intensive care unit and in the hospital were similar among groups. CONCLUSIONS: In patients difficult to wean, neurally adjusted ventilatory assist decreased the duration of weaning and increased ventilator-free days.

Terlipressin for the treatment of septic shock in adults: a systematic review and meta-analysis.

BACKGROUND: Catecholamines are the first-line vasopressors used in patients with septic shock. However, the search for novel drug candidates is still of great importance due to the development of adrenergic hyposensitivity accompanied by a decrease in catecholamine activity. Terlipressin (TP) is a synthetic vasopressin analogue used in the management of patients with septic shock. In the current study, we aimed to compare the effects of TP and catecholamine infusion in treating septic shock patients. METHODS: A systematic review and meta-analysis was conducted by searching articles published in PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials between inception and July 2018. We only selected randomized controlled trials evaluating the use of TP and catecholamine in adult patients with septic shock. The primary outcome was overall mortality. The secondary outcomes were the ICU length of stay, haemodynamic changes, tissue perfusion, renal function, and adverse events. RESULTS: A total of 9 studies with 850 participants were included in the analysis. Overall, no significant difference in mortality was observed between the TP and catecholamine groups (risk ratio(RR), 0.85 (0.70 to 1.03); P = 0.09). In patients < 60 years old, the mortality rate was lower in the TP group than in the catecholamine group (RR, 0.66 (0.50 to 0.86); P = 0.002). There was no significant difference in the ICU length of stay (mean difference, MD), - 0.28 days; 95% confidence interval (CI), - 1.25 to 0.69; P = 0.58). Additionally, TP improved renal function. The creatinine level was decreased in patients who received TP therapy compared to catecholamine-treated participants (standard mean difference, SMD), - 0.65; 95% CI, - 1.09 to - 0.22; P = 0.003). No significant difference was found regarding the total adverse events (Odds Ratio(OR), 1.48(0.51 to 4.24); P = 0.47), whereas peripheral ischaemia was more common in the TP group (OR, 8.65(1.48 to 50.59); P = 0.02). CONCLUSION: The use of TP was associated with reduced mortality in septic shock patients less than 60 years old. TP may also improve renal function and cause more peripheral ischaemia. PROSPERO registry: CRD42016035872.

Neural versus pneumatic control of pressure support in patients with chronic obstructive pulmonary diseases at different levels of positive end expiratory pressure: a physiological study.

INTRODUCTION: Intrinsic positive end-expiratory pressure (PEEPi) is a "threshold" load that must be overcome to trigger conventional pneumatically-controlled pressure support (PSP) in chronic obstructive pulmonary disease (COPD). Application of extrinsic PEEP (PEEPe) reduces trigger delays and mechanical inspiratory efforts. Using the diaphragm electrical activity (EAdi), neurally controlled pressure support (PSN) could hypothetically eliminate asynchrony and reduce mechanical inspiratory effort, hence substituting the need for PEEPe. The primary objective of this study was to show that PSN can reduce the need for PEEPe to improve patient-ventilator interaction and to reduce both the "pre-trigger" and "total inspiratory" neural and mechanical efforts in COPD patients with PEEPi. A secondary objective was to evaluate the impact of applying PSN on breathing pattern. METHODS: Twelve intubated and mechanically ventilated COPD patients with PEEPi ≥ 5 cm H2O underwent comparisons of PSP and PSN at different levels of PEEPe (at 0 %, 40 %, 80 %, and 120 % of static PEEPi, for 12 minutes at each level on average), at matching peak airway pressure. We measured flow, airway pressure, esophageal pressure, and EAdi, and analyzed neural and mechanical efforts for triggering and total inspiration. Patient-ventilator interaction was analyzed with the NeuroSync index. RESULTS: Mean airway pressure and PEEPe were comparable for PSP and PSN at same target levels. During PSP, the NeuroSync index was 29 % at zero PEEPe and improved to 21 % at optimal PEEPe (P < 0.05). During PSN, the NeuroSync index was lower (<7 %, P < 0.05) regardless of PEEPe. Both pre-trigger (P < 0.05) and total inspiratory mechanical efforts (P < 0.05) were consistently higher during PSP compared to PSN at same PEEPe. The change in total mechanical efforts between PSP at PEEPe0% and PSN at PEEPe0% was not different from the change between PSP at PEEPe0% and PSP at PEEPe80%. CONCLUSION: PSN abolishes the need for PEEPe in COPD patients, improves patient-ventilator interaction, and reduces the inspiratory mechanical effort to breathe. TRIAL REGISTRATION: Clinicaltrials.gov NCT02114567 . Registered 04 November 2013.