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Background: Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2. Results: Escalating doses of fecal slurry (0.5–2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups. Conclusions: We demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies. [ABSTRACT FROM AUTHOR]

Background: External chest-wall compression (ECC) is sometimes used in ARDS patients despite lack of evidence. It is currently unknown whether this practice has any clinical benefit in patients with COVID-19 ARDS (C-ARDS) characterized by a respiratory system compliance (Crs) < 35 mL/cmH2O. Objectives: To test if an ECC with a 5 L-bag in low-compliance C-ARDS can lead to a reduction in driving pressure (DP) and improve gas exchange, and to understand the underlying mechanisms. Methods: Eleven patients with low-compliance C-ARDS were enrolled and underwent 4 steps: baseline, ECC for 60 min, ECC discontinuation and PEEP reduction. Respiratory mechanics, gas exchange, hemodynamics and electrical impedance tomography were recorded. Four pigs with acute ARDS were studied with ECC to understand the effect of ECC on pleural pressure gradient using pleural pressure transducers in both non-dependent and dependent lung regions. Results: Five minutes of ECC reduced DP from baseline 14.2 ± 1.3 to 12.3 ± 1.3 cmH2O (P < 0.001), explained by an improved lung compliance. Changes in DP by ECC were strongly correlated with changes in DP obtained with PEEP reduction (R2 = 0.82, P < 0.001). The initial benefit of ECC decreased over time (DP = 13.3 ± 1.5 cmH2O at 60 min, P = 0.03 vs. baseline). Gas exchange and hemodynamics were unaffected by ECC. In four pigs with lung injury, ECC led to a decrease in the pleural pressure gradient at end-inspiration [2.2 (1.1–3) vs. 3.0 (2.2–4.1) cmH2O, P = 0.035]. Conclusions: In C-ARDS patients with Crs < 35 mL/cmH2O, ECC acutely reduces DP. ECC does not improve oxygenation but it can be used as a simple tool to detect hyperinflation as it improves Crs and reduces Ppl gradient. ECC benefits seem to partially fade over time. ECC produces similar changes compared to PEEP reduction. [ABSTRACT FROM AUTHOR]

Purpose: Comparisons of negative versus positive pressure ventilation have imperfectly matched the pressure-time profile or the lung volume history, or have incompletely applied in vivo negative pressure to include the complete thoracic wall and abdomen. Hypothesis: Negative pressure exerts the same pattern of lung distension as positive pressure when the pressure-time and volume history profiles are identical and the application of negative pressure is over the whole lung. Methods: (1) In isolated (ex vivo) and (2) intact (in vivo) mouse lungs ( n = 4/group) (sealed chamber enclosing either the whole lung or whole mouse except for external airway opening), identical and inverse-tidal, square-wave pressure-time profiles were obtained with positive and negative pressure ventilation. (3) Following an identical volume history, surfactant-depleted rabbits ( n = 7) were randomly assigned to sustained, static equivalent positive versus negative pressures. (4) Surfactant-depleted anesthetized rabbits ( n = 10) with identical volume histories were randomized to positive versus negative ventilation with identical pressure-time characteristics. Results: Matched positive and negative pressure time profiles in ex vivo and in vivo mice resulted in identical tidal volumes. Identical (negative vs. positive) sustained static pressures resulted in similar PaO and end expiratory lung volumes. Positive and negative ventilation with identical volume histories and pressure time characteristics showed no difference in oxygenation or lung volumes. Historical comparisons suggested better oxygenation with negative pressure when the volume history was not identical. Conclusions: These data do not support major biological differences between negative and positive pressure ventilation when waveforms and lung volume history are matched. [ABSTRACT FROM AUTHOR]

Permissive hypercapnia is established in lung injury management. Therapeutic hypercapnia causes benefit or harm, depending on the context. Ventilator-associated lung injury has a wide spectrum of candidate mechanisms, affording multiple opportunities for intervention such as hypercapnia to exert benefit or harm. To confirm (1) that hypercapnia attenuates in vivo ventilator-induced lung injury (VILI); (2) biological plausibility of such protection (e.g., dose-response, time series, inflammatory profile); and (3) that the associated biochemical events are consistently beneficial. A mouse model of VILI was established in vivo. Injurious ventilation was established, hypercapnia applied and markers of inflammation measured. Lung injury was quantified by gas exchange, elastance, microvascular leak, histology and levels of cytokines and eicosanoids, cyclooxygenase and tissue nitrotyrosine. Injurious ventilation caused significant lung injury (mechanics, microvascular leak, histology) and release of inflammatory cytokines, chemokines and eicosanoids. Hypercapnia attenuated these responses, with dose-response and time-dependent effects. No adverse effects of hypercapnia were observed in controls. Hypercapnia suppressed the transcription (mRNA) and translation (protein) of the major inducible prostanoid-generating enzyme (COX-2), but the effects on the downstream eicosanoids were modest. However, hypercapnia significantly increased lung tissue nitrotyrosine—at PaCO2 levels that were protective. Hypercapnia provided consistent and biologically plausible in vivo protection against VILI, but elevated lung tissue levels of nitro-tyrosine as previously described in sepsis. Clinicians and those designing clinical trials need to be aware of the potential for detrimental effects when using hypercapnia in order to balance benefits versus harm with this approach. [ABSTRACT FROM AUTHOR]

Negative pressure ventilation via an external device ('iron lung') has the potential to provide better oxygenation with reduced barotrauma in patients with ARDS. This study was designed to see if oxygenation differences between positive and negative ventilation could be explained by CT. Six anaesthetized rabbits had ARDS induced by repeated saline lavage. Rabbits were ventilated with positive pressure ventilation (PPV) and negative pressure ventilation (NPV) in turn. Dynamic CT images were acquired over the respiratory cycle. A computer-aided method was used to segment the lung and calculate the range of CT densities within each slice. Volumes of ventilated lung and atelectatic lung were measured over the respiratory cycle. NPV was associated with an increased percentage of ventilated lung and decreased percentage of atelectatic lung. The most significant differences in ventilation and atelectasis were seen at mid-inspiration and mid-expiration (ventilated lung NPV = 61%, ventilated lung PPV = 47%, p < 0.001; atelectatic lung NPV = 10%, atelectatic lung PPV 19%, p < 0.001). Aeration differences were not significant at end-inspiration. Dynamic CT can show differences in lung aeration between positive and negative ventilation in ARDS. These differences would not be appreciated if only static breath-hold CT was used. [ABSTRACT FROM AUTHOR]

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