Acute respiratory distress syndrome (ARDS) is a common disease entity in critical care medicine and is still associated with a high mortality. Because of the heterogeneous character of ARDS, animal models are an insturment to study pathology in relatively standardized conditions. Rodent models can bridge the gap from in vitro investigations to large animal and clinical trials by facilitating large sample sizes under physiological conditions at comparatively low costs. One of the most commonly used rodent models of acute lung inflammation and ARDS is administration of lipopolysaccharide (LPS), either into the airways (direct, pulmonary insult) or systemically (indirect, extra-pulmonary insult). This narrative review discusses the dynamics of important pathophysiological pathways contributing to the physiological response to LPS-induced injury. Pathophysiological pathways of LPS-induced lung injury are not only influenced by the type of the primary insult (e.g., pulmonary or extra-pulmonary) and presence of additional stimuli (e.g., mechanical ventilation), but also by time. As such, findings in animal models of LPS-induced lung injury may depend on the time point at which samples are obtained and physiological data are captured. This review summarizes the current evidence and highlights uncertainties on the molecular dynamics of LPS-induced lung injury in rodent models, encouraging researchers to take accurate timing of LPS-induced injury into account when designing experimental trials.

To describe and evaluate the effects of the new noisy pressure support ventilation (noisy PSV) on lung physiologic variables. Crossover design with four modes of mechanical ventilation. Experimental research facility of a university hospital. A total of 12 pigs weighing 25.0–36.5 kg. Animals were anesthetized, the trachea was intubated, and lungs were ventilated with a mechanical ventilator (volume-controlled mode). Acute lung injury was then induced by surfactant depletion. Biphasic intermittent airway pressure/airway pressure release ventilation (BIPAP/APRV) was initiated, and anesthesia depth was decreased to allow spontaneous breathing. After that, each animal was ventilated with four different modes of assisted mechanical ventilation (1 hr each, Latin squares sequence): 1) PSV, 2) PSV combined with intermittent sighs (PSV + Sighs), 3) BIPAP/APRV + spontaneous breathing, and 4) noisy PSV with random variation of pressure support (normal distribution). The mean level of pressure support was set identical in all PSV forms. We found that noisy PSV increased tidal volume variability compared with PSV and PSV + Sighs (19% vs. 5% and 7%, respectively, p < .05) independently from the inspiratory effort; improved oxygenation and reduced venous admixture but did not affect the amount of nonaerated lung tissue as compared with other assisted ventilation modes; reduced mean airway pressure at comparable minute ventilation; redistributed pulmonary blood flow toward nondependent lung regions similar to other PSV forms, whereas BIPAP/APRV + spontaneous breathing did not; and reduced the inspiratory effort and cardiac output in comparison with BIPAP/APRV + spontaneous breathing. In the surfactant depletion model of acute lung injury, the new noisy PSV increased the variability of the respiratory pattern and improved oxygenation by a redistribution of perfusion toward the ventilated nondependent lung regions with simultaneous lower mean airway pressure, comparable minute ventilation, and no increase in the inspiratory effort or cardiac output.

Objective: Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care. Data Sources, Study Selection, Data Extraction, and Data Synthesis: Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review. Conclusions: Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.

BACKGROUND. COVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. METHODS. Patients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. Results. The primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P < 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group. Conclusion. CCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies. Trial registration. ClinicalTrials.gov NCT04433910. Funding. Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802.

To explore whether 1) conventional pressure support ventilation improves lung function and attenuates the pulmonary inflammatory response compared to pressure-controlled ventilation and 2) random variation of pressure support levels (noisy pressure support ventilation) adds further beneficial effects to pressure support ventilation. Three-arm, randomized, experimental study. University hospital research facility. Twenty-four juvenile pigs. Acute lung injury was induced by surfactant depletion. Animals were randomly assigned to 6 hrs of mechanical ventilation (n = 8 per group) with either 1) pressure-controlled ventilation, 2) pressure support ventilation, or 3) noisy pressure support ventilation. During noisy pressure support ventilation, the pressure support varied randomly, with values following a normal distribution. In all groups, the driving pressures were set to achieve a mean tidal volume of 6 mL/kg. At the end of experiments, animals were killed and lungs extracted for histologic and biochemical analysis. Respiratory, gas-exchange, and hemodynamics variables were assessed hourly. The diffuse alveolar damage and the inflammatory response of lungs were quantified. Pressure support ventilation and noisy pressure support ventilation improved gas exchange and were associated with reduced histologic damage and interleukin-6 concentrations in lung tissue compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange and decreased the inspiratory effort while reducing alveolar edema and inflammatory infiltration compared to pressure support ventilation. In this model of acute lung injury, pressure support ventilation and noisy pressure support ventilation attenuated pulmonary inflammatory response and improved gas exchange as compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange, reduced the inspiratory effort, and attenuated alveolar edema and inflammatory infiltration as compared to conventional pressure support ventilation.