The gut-lung axis in critical illness: microbiome composition as a predictor of mortality at day 28 in mechanically ventilated patients.

BACKGROUND: Microbial communities are of critical importance in the human host. The lung and gut microbial communities represent the most essential microbiota within the human body, collectively referred to as the gut-lung axis. However, the differentiation between these communities and their influence on clinical outcomes in critically ill patients remains uncertain. METHODS: An observational cohort study was obtained in the intensive care unit (ICU) of an affiliated university hospital. Sequential samples were procured from two distinct anatomical sites, namely the respiratory and intestinal tracts, at two precisely defined time intervals: within 48 h and on day 7 following intubation. Subsequently, these samples underwent a comprehensive analysis to characterize microbial communities using 16S ribosomal RNA (rRNA) gene sequencing and to quantify concentrations of fecal short-chain fatty acids (SCFAs). The primary predictors in this investigation included lung and gut microbial diversity, along with indicator species. The primary outcome of interest was the survival status at 28 days following mechanical ventilation. RESULTS: Sixty-two mechanically ventilated critically ill patients were included in this study. Compared to the survivors, the diversity of microorganisms was significantly lower in the deceased, with a significant contribution from the gut-originated fraction of lung microorganisms. Lower concentrations of fecal SCFAs were detected in the deceased. Multivariate Cox regression analysis revealed that not only lung microbial diversity but also the abundance of Enterococcaceae from the gut were correlated with day 28 mortality. CONCLUSION: Critically ill patients exhibited lung and gut microbial dysbiosis after mechanical ventilation, as evidenced by a significant decrease in lung microbial diversity and the proliferation of Enterococcaceae in the gut. Levels of fecal SCFAs in the deceased served as a marker of imbalance between commensal and pathogenic flora in the gut. These findings emphasize the clinical significance of microbial profiling in predicting the prognosis of ICU patients.

Lesson of urgent bilateral lobar lung transplantation for acute fibrinous and organizing pneumonia: a case report.

Background: Acute fibrinous and organizing pneumonia (AFOP) is one of acute expiratory diseases, which occurs rarely with a difficult diagnosis. AFOP is related to an idiopathic cause or autoimmune disease, drug use, infection, cancer, or transplantation. Variation of treatment depends on different institutions. To date, no evidence shows that lobar lung transplantation is applied in an urgent situation such as AFOP. Case Description: A 33-year-old female patient experienced fever, cough, and dyspnea four days prior to admission. She had no underlying health conditions. Initially, she received oxygen therapy and empiric antimicrobial treatment, but later developed pulmonary consolidation. Pathological examination confirmed the diagnosis of AFOP. Despite receiving standardized treatment involving extracorporeal membrane oxygenation (ECMO) and mechanical ventilation, the patient's respiratory function remained compromised. Consequently, an urgent lobar lung transplantation was performed. However, the patient encountered several challenges including carbapenem-resistant Pseudomonas aeruginosa pneumonia, exophytic granulation tissue, anastomotic stenosis, bronchopleural fistulae, anastomotic infections, septic shock, bacteremia, reperfusion syndrome, primary graft dysfunction, severe renal failure, and critical illness myopathy. Although the patient ultimately recovered and had a favorable survival outcome over 1-year post-discharge through multidisciplinary care, there are several key points to consider. Based on the findings from a systematic review, urgent transplantation may be a potential alternative treatment for AFOP. However, peri-transplantation programs should be enhanced, particularly regarding criteria selection, ECMO management, and the role of enhanced recovery after transplantation. Conclusions: The case demonstrates the feasibility of bilateral lobar lung transplantation in patients with AFOP, especially in an urgent situation.

Sestrin2 suppresses ferroptosis to alleviate septic intestinal inflammation and barrier dysfunction.

OBJECTIVE: Alterations in intestinal function play a crucial role in the pathogenesis of sepsis, and the repair of the intestinal barrier is a potential strategy for the treatment of sepsis. Sestrin2 (SESN2), a highly conserved stress-responsive protein, can be induced in response to stress. AIM: This paper aimed to explore the role and mechanism of SESN2 in septic intestinal dysfunction. METHODS: Blood samples were collected from patients with septic intestinal dysfunction, and Caco-2 cells were subjected to lipopolysaccharide (LPS) to construct in vitro models. The expression level of SESN2 was determined in the blood samples and cells. The impacts of SESN2 overexpression on cell inflammation, oxidative stress, barrier integrity, and MAPK/Nrf2 signaling were evaluated. To determine the mediated role of MAPK signaling and ferroptosis, AMPK inhibitor (Compound C) and ferroptosis inducer (erastin) were separately used to treat cells, and the influences on the above aspects in cells were assessed. RESULTS: The expression level of SESN2 was down-regulated in patients with septic intestinal dysfunction and LPS-induced cells. SESN2 overexpression was found to suppress cell inflammation and oxidative stress, maintain barrier integrity, and activate AMPK/Nrf2 signaling. Following the AMPK signaling was inhibited or the ferroptosis was triggered, the effects of SESN2 overexpression on the cells were both reversed. CONCLUSION: Reduced SESN2 contributed to inflammatory response and barrier dysfunction in septic intestinal dysfunction by promoting ferroptosis via activating the AMPK/Nrf2 signaling pathway.

Evaluation and Validation of the Limited Sampling Strategy of Polymyxin B in Patients with Multidrug-Resistant Gram-Negative Infection.

Polymyxin B (PMB) is the final option for treating multidrug-resistant Gram-negative bacterial infections. The acceptable pharmacokinetic/pharmacodynamic target is an area under the concentration-time curve across 24 h at a steady state (AUCss,24h) of 50-100 mg·h/L. The limited sampling strategy (LSS) is useful for predicting AUC values. However, establishing an LSS is a time-consuming process requiring a relatively dense sampling of patients. Further, given the variability among different centers, the predictability of LSSs is frequently questioned when it is extrapolated to other clinical centers. Currently, limited data are available on a reliable PMB LSS for estimating AUCss,24h. This study assessed and validated the practicability of LSSs established in the literature based on data from our center to provide reliable and ready-made PMB LSSs for laboratories performing therapeutic drug monitoring (TDM) of PMB. The influence of infusion and sampling time errors on predictability was also explored to obtain the optimal time points for routine PMB TDM. Using multiple regression analysis, PMB LSSs were generated from a model group of 20 patients. A validation group (10 patients) was used to validate the established LSSs. PMB LSSs from two published studies were validated using a dataset of 30 patients from our center. A population pharmacokinetic model was established to simulate the individual plasma concentration profiles for each infusion and sampling time error regimen. Pharmacokinetic data obtained from the 30 patients were fitted to a two-compartment model. Infusion and sampling time errors observed in real-world clinical practice could considerably affect the predictability of PMB LSSs. Moreover, we identified specific LSSs to be superior in predicting PMB AUCss,24h based on different infusion times. We also discovered that sampling time error should be controlled within -10 to 15 min to obtain better predictability. The present study provides validated PMB LSSs that can more accurately predict PMB AUCss,24h in routine clinical practice, facilitating PMB TDM in other laboratories and pharmacokinetics/pharmacodynamics-based clinical studies in the future.

Plasma fibronectin can affect the cytokine profile and monocytes/macrophages function in addition to predicting the prognosis of advanced sepsis.

The value of plasma fibronectin (pFN) in the diagnosis and prognosis of sepsis has not been fully established. Previous studies finding that pFN is significantly reduced in sepsis, however, whether reduced pFn affects the prognosis of sepsis has not been clarified. Here, we detected and analyzed pFN and other conventional inflammatory markers in advanced sepsis patients and performed correlation analysis with SOFA score. We also used Fn gene conditional knockout mice which were performed by cecum ligation and puncture (CLP) to investigate the effect of FN deficiency on sepsis prognosis. We found, compared with procalcitonin, c-reactive protein, and interleukin-6, pFN was more correlated with SOFA score in advanced sepsis patients (r -.720, p < .001). In animal experiments, Fn gene knockout mice showed significantly greater mortality after CLP compared with the control group because of inhibited phagocytosis and bacterial clearance ability of macrophages, with double cytokine storm. Furthermore, FN can regulate macrophages through the integrin α5ß1/Fak/Src signaling pathway. Overall, we found pFN can more accurately reflect the severity and prognosis of advanced sepsis. The absence of FN altered the cytokine storm and phagocytic function of macrophages, suggesting that FN could be a potential therapeutic target in sepsis.

[Clinical study on intravenous combined with aerosol inhalation of polymyxin B for the treatment of pneumonia caused by multidrug-resistant Gram-negative bacteria].

OBJECTIVE: To investigate the efficacy of intravenous combined with aerosol inhalation of polymyxin B for the treatment of pneumonia caused by multidrug-resistant Gram-negative (G-) bacteria. METHODS: A observational study was conducted. The clinical data of 45 patients with pneumonia due to multidrug-resistant G- bacteria admitted to intensive care unit of Fujian Medical University Union Hospital from January to October in 2020 were analyzed. According to the different use methods of polymyxin B, 25 patients who received single intravenous drip (the first dose was 2.0 mg/kg, then 1.25 mg/kg, once every 12 hours) from January to April in 2020 were enrolled in the routine group, and 20 patients who received intravenous drip combined with aerosol inhalation (25 mg once every 12 hours, sputum in the airway was sucked and then sprayed aerosol) from May to October in 2020 were enrolled in the combination group. After the treatment course of polymyxin B, the total bacterial clearance rate, total clinical efficiency rate, recovery time of body temperature, time of bacterial clearance and the change of serum procalcitonin (PCT) level before and after treatment were compared between the two groups. Moreover, the incidence of adverse reactions during treatment in the two groups was observed. RESULTS: The results of sputum culture in the routine group were Acinetobacter baumannii in 13 patients, Klebsiella pneumoniae in 5 patients, Pseudomonas aeruginosa in 6 patients, Enterobacter cloacae in 1 patient; the sputum culture results of the combination group showed that there were 5 patients of Acinetobacter baumannii, 9 Klebsiella pneumoniae and 6 Pseudomonas aeruginosa. There was no significant difference in the results of sputum culture between the two groups (P > 0.05). The total bacterial clearance rate and the total clinical efficiency rate of the combination group were significantly higher than those in the routine group (total bacterial clearance rate: 70.0% vs. 40.0%, total clinical efficiency rate: 75.0% vs. 40.0%, both P < 0.05). The recovery time of body temperature and the time of bacterial clearance of the combination group were significantly shorter than those in the routine group [recovery time of body temperature (days): 6.0±3.9 vs. 10.2±7.3, time of bacterial clearance (days): 6.1±5.2 vs. 11.5±6.8, both P < 0.05]. No significant difference was found in serum PCT level before treatment between the two group. There was no significant difference in serum PCT level before and after treatment in the routine group [µg/L: 0.85 (0.44, 2.87) vs. 1.43 (0.76, 5.30), P > 0.05]. The serum PCT level after treatment in the combination group was significantly lower than that before treatment [µg/L: 0.27 (0.10, 0.70) vs. 0.91 (0.32, 3.53), P < 0.05], and it was significantly lower than that in the routine group [µg/L: 0.27 (0.10, 0.70) vs. 0.85 (0.44, 2.87), P < 0.01]. The incidence of renal toxicity of polymyxin B between the combination group and the routine group was not significantly different (5.0% vs. 4.0%, P > 0.05). CONCLUSIONS: The efficacy of intravenous combined with aerosol inhalation of polymyxin B for the treatment of pneumonia due to multidrug-resistant G- bacteria is better than that of intravenous drip of polymyxin B only. The aerosolized polymyxin B will not increase the risk of renal injury.

High positive end expiratory pressure levels affect hemodynamics in elderly patients with hypertension admitted to the intensive care unit: a prospective cohort study.

BACKGROUND: To study the effects of different positive end expiratory pressure (PEEP) on blood pressure and heart function in elderly patients with hypertension. METHODS: Forty elderly patients above 65 years of age treated with mechanical ventilation were divided into two groups: a control group of non-hypertensive subjects (n = 18) and a hypertension group (n = 22) patients with essential hypertension. Changes in blood pressure, central venous pressure (CVP), central venous oxygen saturation (ScvO2), heart rate, and airway pressure were determined in response to different selected PEEP levels of 0, 2, 4, 6, 8, 10 and 12 cm H2O under SIMV(PC) + PSV mode throughout the study. RESULTS: In both groups, the increase in PEEP led to an increase in CVP and airway pressure. When PEEP was above 4 cm H2O in the hypertension group, a decrease in blood pressure and ScvO2, and an increase of heart rate were observed. These results indicated that cardiac output significantly decreased. CONCLUSION: High levels of PEEP can significantly influence changes in blood pressure and heart function in elderly patients with hypertension. TRIAL REGISTRATION: This trial was retrospectively registered, The Chinese trial registration number is ChiCTR-ROC-17012873. The date of registration is 10-2-2017.

Blood purification treatment initiated at the time of sepsis diagnosis effectively attenuates serum HMGB1 upregulation and improves patient prognosis.

The aim of the present study was to investigate the increase in serum and urine levels of high mobility group box protein 1 (HMGB1) during sepsis and the effect of blood purification treatments on HMGB1 levels and patient prognosis. A total of 40 intensive care patients with sepsis were randomly assigned to different groups (n=10 per group): A control group (sepsis group), a continuous renal replacement treatment (CRRT) group, a hemoperfusion (HP) group and an HP+CRRT group. The blood purification treatments using HP and/or CRRT were performed immediately after the diagnosis of sepsis. HMGB1 levels were measured using ELISA, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores and 30-day survival rates were evaluated. Relative to a healthy control group (n=10), HMGB1 levels were observed to be significantly upregulated during sepsis (P<0.05). Following the initiation of sepsis, serum HMGB1 continued to increase in the sepsis group and was significantly elevated at 24 h (P<0.05), whereas urine HMGB1 levels decreased significantly at 12 and 24 h (P<0.05). Serum HMGB1 levels were significantly positively correlated with APACHE II scores (r=0.7284, P<0.01) and significantly negatively correlated with urine HMGB1 levels (r=-0.5103, P=0.026). Serum HMGB1 levels were significantly reduced in the HP and HP+CRRT groups by 12 and 24 h following the initiation of treatment (both P<0.05). Changes in the urine HMGB1 level differed in each group. Relative to the sepsis group, the APACHE II scores of all blood purification groups were significantly reduced (P<0.05) and the 30-day survival rate of the HP+CRRT group was significantly increased (P=0.0107). The results of the present study indicate that blood purification initiated at the point of diagnosis in patients with sepsis may attenuate serum HMGB1 upregulation, promote urinary excretion of HMGB1 and improve the prognosis of sepsis.

Curcumin protects against acute renal injury by suppressing JAK2/STAT3 pathway in severe acute pancreatitis in rats.

The aim of the present study was to investigate the effect of curcumin on acute renal injury in a rat model of severe acute pancreatitis (SAP). A SAP model with acute kidney injury was established in rats by retrograde injection of 5% sodium taurocholate into the pancreatic duct. The serum amylase, creatinine (Cr) and blood urea nitrogen (BUN) levels in rats were measured. Hematoxylin and eosin staining was used to assess pancreatic and renal histological changes. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured using ELISA kits. Renal protein levels of Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway components were determined by western blot assay. The results showed that curcumin significantly decreased serum amylase, Cr and BUN levels, and alleviated pancreatic and renal histological changes in SAP rats. Furthermore, curcumin markedly decreased serum TNF-α and IL-6 levels and downregulated renal protein levels of JAK2/STAT3 pathway components. These results proved that curcumin ameliorates acute renal injury in a rat model of SAP. The molecular mechanism of its effect may be associated with the suppression of the JAK2/STAT3 pathway to reduce TNF-α and IL-6 levels in SAP-induced acute renal injury. Therefore, the findings of the present study revealed the potential use of curcumin for the prevention and treatment of SAP and the associated renal injury.

Association of microRNA polymorphisms with the risk of myocardial infarction in a Chinese population.

MicroRNAs (miRNAs) are involved in the regulation of a variety of biological processes, such as inflammation. Dysregulation of miRNAs have been implicated in many human disease, including cardiovascular diseases. Polymorphisms in miRNA genes may affect the miRNA biogenesis and function, and thus cause changes in the expression of thousands of genes. The aim of this study was to examine whether miRNA polymorphisms (miR-146a rs2910164, miR-149 rs71428439, miR-196a2 rs11614913, miR-218 rs11134527, and miR-499 rs3746444) contribute to the risk for the development of myocardial infarction (MI). Five miRNA polymorphisms were genotyped in a total of 1808 subjects composed of 919 MI patients and 889 control individuals. The GG genotype of rs3746444 was found to be associated with a significantly increased risk of MI (recessive model, adjusted OR = 1.710, 95% CI: 1.058-2.763, P = 0.029). Although the CC genotype of rs2910164 significantly increased the risk of MI under dominant and additive models (P < 0.05), this difference disappeared after adjustment for age, sex, blood pressure, triglycerides, total cholesterol, HDL, LDL and diabetes. In addition, when rs3746444 and rs2910164 were evaluated together by the number of putative high-risk alleles, we found an increased risk of MI for subjects carrying 3-4 risk alleles (3-4 risk alleles vs. 0-1 risk allele, adjusted OR = 1.580, 95% CI: 1.069-2336, P = 0.022; 3-4 risk alleles vs. 0-2 risk allele, adjusted OR = 1.513, 95% CI: 1.031-2.219, P = 0.034). These findings indicate that miR-499 rs3746444 and miR-146a rs2910164 may represent novel markers of MI susceptibility.

[Postoperative monitor of hemodynamics of orthotopic heart transplantation and treatment of its disorders].

OBJECTIVE: To study the postoperative hemodynamics after heart transplantation and treatment for disorders due to denervated transplanted hearts in order to improve the short term outcome of heart transplantation. METHODS: Forty one patients with endstage cardiopathy underwent orthotopic cardiac transplantation. The changes in the graft function were closely monitored during the postoperative period in order to maintain the stability of hemodynamics of the allografts. RESULTS: All recipients received vasoactive drug therapy and 6 recipients died of acute dysfunction of the right ventricle of the allograft during the postoperative period. The remaining patients survived well and led a life with rather good quality. CONCLUSION: The hemodynamic characteristics of a denervated grafted heart are unique. Close monitoring and good nursing care with rational administration of vasoactive drugs are the key measures for the prevention of acute dysfunction of the allograft in the early postoperative period.

[Experience in donor-recipient gender mismatching heart transplantation: analysis of seven female patients receiving male donor hearts].

OBJECTIVE: To summarize the experience in donor-recipient gender mismatching heart transplantation. METHODS: Seven female patients with end-stage cardiopathy aged 13 approximately 44, underwent orthotopic transplantation of hearts from male donors. Fine-tuning immunosuppressive protocols were adopted: Stanford classic therapy was applied on 3 cases and immunosupression induction therapy was applied on 4 cases. The clinical outcomes were observed for an average of 20 months (5 approximately 54 months). RESULTS: No acute reject reaction was found in all 7 cases within 3 months postoperatively. The earliest 2 patients died of refractory rejection 38 and 34 months postoperatively due to immunosuppressive withdrawal because of financial difficulty. The other 5 cases resumed their normal work and daily life. No allograft dysfunction, severe opportunistic infection episodes, and injury of liver and kidney functions were found in all cases. CONCLUSION: Fine-tuning immunosuppressive protocols improve the short-term and long-term clinical effects of donor-recipient gender mismatching heart transplantation.