Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies

Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects

Between-trial heterogeneity in ARDS research

Purpose Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics

Alkaline phosphatase in pulmonary inflammation-a translational study in ventilated critically ill patients and rats

Background Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. Aim To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats Methods AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. Results BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14–1.20] vs 0.55 [0.21–1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18–3.59] vs 1.01 [0.80–1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. Conclusions In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model

Between-trial heterogeneity in ARDS research

Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I 2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics

Between-trial heterogeneity in ARDS research

Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I 2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics

Incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients: insights from the MARS Study

Objective: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. Design and Setting: This is a post hoc analysis of a prospective multicenter cohort study. Patients: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. Endpoints: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 μmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. Results: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%–confidence interval 1.06–1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%–confidence interval 2.08–3.27]; P Conclusions: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia.</p

Incidence, Clinical Characteristics and Outcomes of Early Hyperbilirubinemia in Critically Ill Patients: Insights From the MARS Study

OBJECTIVE: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. DESIGN AND SETTING: This is a post hoc analysis of a prospective multicenter cohort study. PATIENTS: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. ENDPOINTS: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 μmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. RESULTS: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%-confidence interval 1.06-1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%-confidence interval 2.08-3.27]; P < 0.001) than patients with early hyperbilirubinemia and a normal platelet count (odds ratio, 1.09 [95%-confidence interval 0.75-1.55]; P = 0.655). CONCLUSIONS: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia