Survival of COVID-19 Patients With Respiratory Failure is Related to Temporal Changes in Gas Exchange and Mechanical Ventilation.

Background: Respiratory failure due to coronavirus disease of 2019 (COVID-19) often presents with worsening gas exchange over a period of days. Once patients require mechanical ventilation (MV), the temporal change in gas exchange and its relation to clinical outcome is poorly described. We investigated whether gas exchange over the first 5 days of MV is associated with mortality and ventilator-free days at 28 days in COVID-19. Methods: In a cohort of 294 COVID-19 patients, we used data during the first 5 days of MV to calculate 4 daily respiratory scores: PaO2/FiO2 (P/F), oxygenation index (OI), ventilatory ratio (VR), and Murray lung injury score. The association between these scores at early (days 1-3) and late (days 4-5) time points with mortality was evaluated using logistic regression, adjusted for demographics. Correlation with ventilator-free days was assessed (Spearman rank-order coefficients). Results: Overall mortality was 47.6%. Nonsurvivors were older (P < .0001), more male (P = .029), with more preexisting cardiopulmonary disease compared to survivors. Mean PaO2 and PaCO2 were similar during this timeframe. However, by days 4 to 5 values for all airway pressures and FiO2 had diverged, trending lower in survivors and higher in nonsurvivors. The most substantial between-group difference was the temporal change in OI, improving 15% in survivors and worsening 11% in nonsurvivors (P < .05). The adjusted mortality OR was significant for age (1.819, P = .001), OI at days 4 to 5 (2.26, P = .002), and OI percent change (1.90, P = .02). The number of ventilator-free days correlated significantly with late VR (-0.166, P < .05), early and late OI (-0.216, P < .01; -0.278, P < .01, respectively) and early and late P/F (0.158, P < .05; 0.283, P < .01, respectively). Conclusion: Nonsurvivors of COVID-19 needed increasing intensity of MV to sustain gas exchange over the first 5 days, unlike survivors. Temporal change OI, reflecting both PaO2 and the intensity of MV, is a potential marker of outcome in respiratory failure due to COVID-19.

NF-κB and FosB mediate inflammation and oxidative stress in the blast lung injury of rats exposed to shock waves.

Blast lung injury (BLI) is the major cause of death in explosion-derived shock waves; however, the mechanisms of BLI are not well understood. To identify the time-dependent manner of BLI, a model of lung injury of rats induced by shock waves was established by a fuel air explosive. The model was evaluated by hematoxylin and eosin staining and pathological score. The inflammation and oxidative stress of lung injury were also investigated. The pathological scores of rats' lung injury at 2 h, 24 h, 3 days, and 7 days post-blast were 9.75±2.96, 13.00±1.85, 8.50±1.51, and 4.00±1.41, respectively, which were significantly increased compared with those in the control group (1.13±0.64; P<0.05). The respiratory frequency and pause were increased significantly, while minute expiratory volume, inspiratory time, and inspiratory peak flow rate were decreased in a time-dependent manner at 2 and 24 h post-blast compared with those in the control group. In addition, the expressions of inflammatory factors such as interleukin (IL)-6, IL-8, FosB, and NF-κB were increased significantly at 2 h and peaked at 24 h, which gradually decreased after 3 days and returned to normal in 2 weeks. The levels of total antioxidant capacity, total superoxide dismutase, and glutathione peroxidase were significantly decreased 24 h after the shock wave blast. Conversely, the malondialdehyde level reached the peak at 24 h. These results indicated that inflammatory and oxidative stress induced by shock waves changed significantly in a time-dependent manner, which may be the important factors and novel therapeutic targets for the treatment of BLI.

Comparison of two different models of sepsis induced by cecal ligation and puncture in rats.

BACKGROUND: The present study was designed to explore the difference between two rat models of sepsis and to establish a more stable rat model. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into three groups: sham operation group, simple cecal ligation and perforation group (SCLP), and cecal ligation perforation plus drainage group (CLP-DS). The general condition of the rats was observed, and the time of death and survival rate at 72 h were recorded. The arterial blood and lung tissue were obtained 9 h after the operation. RESULTS: The mortality of the CLP-DS group was significantly higher than that of the SCLP group. The limitation package, intestinal adhesion, and poor drainage were detected in the SCLP rats, whereas intestinal edema and hyperemia, bloody water in the abdominal cavity, but no inflammatory package were observed 24 h after the operation in the CLP-DS rats by autopsy. There were significant differences in interleukin-6 and tumor necrosis factor-alpha levels between the SCLP group and the CLP-DS group. Severe pulmonary septal thickening, alveolar wall vascular congestion, and protein debris deposition in the alveolar cavity were observed in the SCLP group, whereas pulmonary bullae were observed in the CLP-DS group using light microscopy, and there were significant difference among groups in Smith lung injury score. CONCLUSIONS: These results suggested that the cecal ligation combined with puncture drainage model of sepsis is more stable than that of the simple cecal ligation and puncture model of sepsis in the rat, which resolved the problem of puncture wrapped in the traditional CLP model of sepsis in rat.

Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome.

BACKGROUND: Hyaluronic acid (HA), an extracellular matrix component, is degraded in response to local tissue injury or stress. In various animal models of lung injury, HA has been shown to play a mechanistic role in modulating inflammation and injury. While HA is present in the lungs of patients with acute respiratory distress syndrome (ARDS), its relationship to patient outcomes is unknown. METHODS: We studied 86 patients with ARDS previously enrolled in the Phase II Randomized Trial of Fish Oil in Patients with Acute Lung Injury (NCT00351533) at five North American medical centers. We examined paired serum and bronchoalveolar lavage fluid (BALF) samples obtained within 48 hours of diagnosis of ARDS. We evaluated the association of HA levels in serum and BALF with local (lung injury score (LIS)) and systemic (sequential organ failure assessment score (SOFA)) measures of organ dysfunction with regression analysis adjusting for age, sex, race, treatment group, and risk factor for ARDS. RESULTS: We found that both day-0 circulating and alveolar levels of HA were associated with worsening LIS (p = 0.04 and p = 0.003, respectively), particularly via associations with degree of hypoxemia (p = 0.02 and p < 0.001, respectively) and set positive end-expiratory pressure (p = 0.01 and p = 0.02, respectively). Circulating HA was associated with SOFA score (p < 0.001), driven by associations with the respiratory (p = 0.02), coagulation (p < 0.001), liver (p = 0.006), and renal (p = 0.01) components. Notably, the alveolar HA levels were associated with the respiratory component of the SOFA score (p = 0.003) but not the composite SOFA score (p = 0.27). CONCLUSIONS: Elevated alveolar levels of HA are associated with LIS while circulating levels are associated with both lung injury and SOFA scores. These findings suggest that HA has a potential role in both local and systemic organ dysfunction in patients with ARDS.

The Impact of Steroid Responder Status on Long-Term Outcomes in Critically Ill Patients With Acute Respiratory Distress Syndrome Receiving High-Dose Glucocorticoids.

Background and objective High-dose intravenous pulsed glucocorticosteroids (GCS) are not part of the standard treatment in acute respiratory distress syndrome (ARDS), and the evidence supporting their use is conflicting. In clinical practice, however, they are used in specialist settings when clinico-patho-radiological features suggest a potentially steroid-responsive pattern, or as a last resort in cases where patients are unable to be weaned off mechanical ventilation. This study aimed to investigate if an early objective response to high-dose GCS treatment in selected critically ill patients is predictive of survival in ARDS. Methods This study involved a case series of 63 patients treated at a tertiary specialist respiratory ICU between 2009 and 2017 who received high-dose GCS for ARDS following a multidisciplinary board agreement. Patients were stratified according to the change in their modified lung injury score (mLIS) between days 0 and 10 following GCS initiation. Changes in mLIS (range: 0-4) were grouped as follows - full responders: ≥2, partial responders: ≥1 and <2, and non-responders: <1. Mortality on discharge and at 6, 12, 18, and 24 months post-ICU discharge was assessed for each group. Data were analysed using logistic regression and a receiver operating curve (ROC) to determine a statistically significant association between the change in mLIS and survival. Results Of the 63 patients, there were seven full responders, 12 partial responders, and 44 non-responders to high-dose GCS. Overall mortality at ICU discharge and 6, 12, 18 and 24 months post-discharge was 29/63 (46.0%), 33/63 (52.4%), 34/63 (54.0%), 34/63 (54.0%), and 35/63 (55.6%) respectively. Mortality was significantly lower in the partial and full-response groups than in the non-response group at all time frames. Logistic regression showed a significant association between the change in mLIS and survival (p<0.001), and a ROC demonstrated that categorising the change in mLIS was a good predictive model for survival (c-statistic 0.86). Conclusions Measuring the change in mLIS by day 10 following high-dose GCS administration for ARDS may be clinically useful in prognosticating such patients. Further research using mLIS as a measure of response to GCS, and larger datasets to enable the evaluation of prognostic factors, may assist clinicians in predicting which patients with persistent ARDS are likely to respond to GCS therapy.

Induced hypernatremia in patients with moderate-to-severe ARDS: a randomized controlled study.

BACKGROUND: Induced hypernatremia and hyperosmolarity is protective in animal models of lung injury. We hypothesized that increasing and maintaining plasma sodium between 145 and 150 mmol/l in patients with moderate-to-severe ARDS would be safe and will reduce lung injury. This was a prospective randomized feasibility study in moderate-to-severe ARDS, comparing standard care with intravenous hypertonic saline to achieve and maintain plasma sodium between 145 and 150 mmol/l for 7 days (HTS group). Both groups of patients were managed with lung protective ventilation and conservative fluid management. The primary outcome was 1-point reduction in lung injury score (LIS) or successful extubation by day 7. RESULTS: Forty patients were randomized with 20 in each group. Baseline characteristics of severity of illness were well balanced. Patients in the HTS group had higher plasma sodium levels during the first 7 days after randomization when compared with the control group (p = 0.04). Seventy five percent (15/20) of patients in the HTS group were extubated or had ≥ 1-point reduction in LIS compared with 35% (7/20) in the control group (p = 0.02). There was also a decrease in length of mechanical ventilation and hospital length of stay in the HTS group. CONCLUSION: We have shown clinical improvement in patients with moderate-to-severe ARDS following induced hypernatremia, suggesting that administration of hypertonic saline is a safe and feasible intervention in patients with moderate-to-severe ARDS. This suggests progress to a phase II study. Clinical Trial Registration Australian and New Zealand Clinical Trials Registry (ACTRN12615001282572).

Dual Effect of Bleomycin on Histopathological Features of Lungs and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model.

Mediastinal fat-associated lymphoid clusters (MFALCs) are novel immune clusters that function in the pathogenesis of bleomycin (BLM)-induced pneumonitis in a C57BL/6 mouse model. However, we lack literature on the effects of BLM in an autoimmune disease mouse model (AIDM). In the present study, BLM sulfate (BLM group) or phosphate-buffered saline (PBS group) were intranasally administered in BXSB/MpJ-Yaa (Yaa) AIDM and its wild-type strains (BXSB/MpJ "BXSB") and the histopathology of MFALCs and lungs were examined on days 7 and 21 days. Immunohistochemical analysis was performed to detect lymphatic vessels (LVs), high endothelial venules (HEVs), proliferating, and immune cells. Furthermore, the mRNA expression of Yaa locus genes (TLR7, TLR8, Arhgap6, Msl3, and Tceanc) was detected in the lung tissues. Here, we show a dual effect of BLM on intra-thoracic immune hemostasis among Yaa AIDM and its corresponding wild-type strain (BXSB mice). The BLM group of BXSB mice displayed significantly higher values of lung injury scores (LIS) and size of MFALCs as compared with the corresponding PBS group. However, an opposite effect was detected in Yaa mice. Furthermore, Yaa mice displayed decreased serum autoantibody titers and downregulated expression of TLR7, TLR8, Msl3, and Tceanc in the lungs following BLM administration, especially on day 21. Interestingly, significant positive correlations were detected in both strains between the LIS and the size of MFALCs, LVs, HEVs, and proliferating cells. Conclusively, our findings revealed a crucial function of HEVs on the extent of lung injury and the development of MFALCs in BLM-administered Yaa AIDM and control BXSB mice with dual effects. Moreover, our data suggest that down regulation of Yaa locus genes could contribute as an important attributing factor leading to decrease in the degree of autoimmunity and lung injury in AIDM. Therefore, we suggest that genetic background contributes to BLM diversity among AIDM and the wild-type strain. Targeting some genes or venules could provide novel therapeutic approaches for some autoimmune-associated respiratory diseases via controlling the MFALCs development.

Significance of vascular endothelium growth factor testing in exhaled breath condensate of patients with acute respiratory distress syndrome.

OBJECTIVE: We aimed to observe and investigate the clinical significance of vascular endothelium growth factor (VEGF) levels in exhaled breath condensate (EBC) from patients with acute respiratory distress syndrome (ARDS). METHODS: An improved EcoScreen condenser was used to collect EBC from 31 ARDS patients on mechanical ventilation and from 22 healthy subjects. Serum and EBC VEGF levels were analyzed with ELISA. VEGF levels in the EBC of patients with different grades of lung injuries were analyzed. The correlation between VEGF levels and clinical indicators was analyzed. RESULTS: Serum and EBC VEGF levels were linearly and positively correlated with a correlation coefficient of 0.694 (P< 0.01). The VEGF level in the EBC of ARDS patients was significantly lower than that in the control group (P< 0.01). The VEGF level in the EBC of the mild ARDS group was higher than that in the moderate-severe ARDS group (P< 0.01). The VEGF level in the EBC of the survival group was higher than that in the mortality group. The VEGF level in the EBC of ARDS patients was positively correlated with PaO2/FiO2 and PaO2 and was negatively correlated with lung injury score (LIS) and A-aDO2/PaO2. CONCLUSION: The changes in VEGF levels in the EBC of ARDS patients can Respiratory Medicine, reflect the severity of lung injury. Therefore, VEGF level in EBC can be used as an auxiliary index for judging the severity and prognosis of ARDS patients.

Assessment of ventilator-associated pneumonia by combining 8-isoprostane and nitric oxide levels in exhaled breath condensate with the clinical pulmonary infection score.

OBJECTIVE: To investigate the effectiveness of combining the 8-isoprostane and nitric oxide (NO) levels in exhaled breath condensate (EBC) with the clinical pulmonary infection score (CPIS) to assess ventilator-associated pneumonia (VAP) in patients on mechanical ventilation. METHODS: Thirty-two patients with VAP served as the observation group and 32 patients without VAP served as the control group. The correlations of 8-isoprostane and NO levels in EBC with CPIS, chest X-ray score, oxygenation index, and lung injury score (LIS) were analyzed. The area under the curve (AUC) was compared with experimental data using the receiver operating characteristic curve (ROC) to predict VAP. RESULTS: The 8-isoprostane and NO levels in EBC of VAP patients on mechanical ventilation were positively correlated with CPIS, chest X-ray score, and LIS, but negatively correlated with oxygenation index. The AUC of simplified CPIS combined with 8-isoprostane and NO levels in EBC for predicting VAP was 0.914, which suggests that this is a highly effective for making a diagnosis. CONCLUSIONS: The simplified CPIS combined with the 8-isoprostane and NO levels in EBC of patients on mechanical ventilation is effective for evaluating and diagnosing VAP. 8-Isoprostane and NO levels in EBC could be used as biomarkers to evaluate VAP.

Pulmonary complement depositions in autopsy of critically ill patients have no relation with ARDS.

BACKGROUND: The complement system has frequently been suggested to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS). The current study explored the association between pulmonary depositions of a complement activation product and the clinical diagnosis of ARDS. METHODS: Lung tissue material from autopsied critically ill patients who died whilst on invasively mechanical ventilation was collected and stained for complement C3d. The diagnosis of ARDS was by the Berlin Definition. Lung injury scores (LIS) and driving pressures were calculated, 48 and 24 h prior to death. A pathologist who remained blinded for the clinical data scored the extent of C3d depositions, using a C3d deposition score (a minimum and maximum score of 0 and 24), and of diffuse alveolar damage (DAD). The primary analysis focused on the association between the C3d deposition score and the clinical diagnosis of ARDS. Secondary analyses focused on associations between the C3d deposition score and the presence of diffuse alveolar damage (DAD) in histopathology, and LIS and driving pressures in the last 2 days before death. RESULTS: Of 36 patients of whom autopsy material was available, 12 were diagnosed as having had ARDS. In all patients, C3d depositions were found in various parts of the lungs, and to a different extent. Notably, C3d deposition scores were similar for patients with ARDS and those without ARDS (4.5 [3.3-6.8] vs. 5.0 [4.0-6.0]; not significant). C3d deposition scores were also independent from the presence or absence of DAD, and correlations between C3d scores and LIS and driving pressures prior to death were poor. CONCLUSION: Pulmonary C3d depositions are found in the lungs of all deceased ICU patients, independent of the diagnosis of ARDS. The presence of complement C3d was not associated with the presence of DAD on histopathology and had a poor correlation with ventilation characteristics prior to death.