Rationale: While inspired fractional inspired oxygen concentrations (FiO2s) > 0.60 are avoided clinically when possible due in large part to animal study findings, FiO2s ≤ 0.60 have generally been thought relatively safe in hypoxemic patients. However, increasing attention is now being focused on the effects of conservative versus liberal therapeutic oxygen protocols in critically ill patients, especially in light of the prolonged courses of oxygen therapy SARS-CoV-2 patients are receiving. Notably, in the development of a lethal ß-coronavirus pneumonia model in mice that produces lung injury and progressive reductions in oxygen saturations like SARS-CoV-2, we found that atmospheric FiO2s as low as 0.30 reduced survival compared to room air. This finding prompted us to systematically examine the literature for the experience with FiO2s ≤0.60 but >0.21 in animal models of lung infection and non-infectious injury. Preliminary results from this review are presented here. Methods: In collaboration with a Biomedical Librarian, we performed a systematic literature search of Pubmed, EMBASE, and the Web of Science for relevant citations of published studies through September 30, 2021, using individualized search strategies for each database. Published studies that investigated animals challenged with a lung infection or other injury, and that compared outcomes, including survival, measures of organ injury or other changes, in animals administered therapeutic oxygen levels (FiO2 ≤0.60 but >0.21) versus ones administered room air (FiO2=0.21) were selected for further review. Results: After preliminary title and review of 12,446 retrieved reports and then removal of 2,049 duplicates, 51 s were found that described studies specifically examining an FiO2 ≤0.60 but >0.21 in a preclinical animal model with or without an infectious or noninfectious challenge. Based on findings, animals were challenged with bacteria in 14 studies, lipopolysaccharide in 2, acid aspiration in 2, mechanical ventilation in 1, while 12 each examined the effects of oxygen alone or oxygen with another pharmacologic agent. No study examined FiO2s ≤0.60 with viral challenge. By contrast, we found 520 s specifically describing investigations of FiO2s >0.60 and 258 describing the use of “hyperoxic” oxygen administration in similar types of models. Conclusions: A large preclinical literature identified the adverse effects of FiO2s ≥0.60 and hyperoxia and informed clinical practice. While similar preclinical studies examining FiO2s ≤0.60 are limited, they may be just as informative and should be encouraged in light of ongoing questions regarding the benefits and risks of conservative versus liberal therapeutic oxygen protocols.

ationale H mmune checkpoint inhibitor CI whether prior ICI treatment worsens or improves outcomes with this virus. To address this issue, we performed a systematic review of studies of cancer patients with COVID-19 that ret

Rationale: Immune stimulation with immune checkpoint inhibitors (ICIs) has emerged as a highly effective treatment for several cancer types. Research also suggests these agents may be therapeutic for viral infections. However, by interrupting inhibitory signaling pathways, ICIs can cause immune-related adverse events including pneumonitis. A critical question during the present SARS-CoV-2 pandemic has been whether prior ICI treatment aggravates or improves virus-associated lung injury. Methods: To address this question, we first developed a lethal coronavirus acute lung injury model in A/J mice by infecting them intratracheally (IT) with mouse hepatitis virus-1 (MHV-1), a betacoronavirus that can be studied at Biosafety Level-2 (Study-1). We then investigated the effects of anti-PD-L1 monoclonal antibody (anti-PD-L1mAb;clone 10F.9G2, Bio X Cell) pretreatment on outcomes with MHV-1 lung challenge (Study-2). Results: In Study 1 testing 8 increasing doses of virus [5 to 2000 plaque forming units (PFU)/mouse], IT administration of 12.5 (n=8), 25 (n=8), or 50 (n=16) PFU/mouse produced lethality rates closest to 50% (Figure A). At 14d, surviving mice receiving any of these three doses had decreased circulating lymphocyte and increased lavage lymphocyte percentages and protein concentrations compared to diluent-challenged control animals (p≤0.04 averaged across the three MHV doses). Experiments in noninfected animals showed that compared to isotype-mAb (control) treatment, 4 doses of anti-PD-L1mAb (300μg/mouse) administered intraperitoneally every 3d significantly reduced lung immune cell PD-L1 expression (normalized mean fluorescence intensity, p=0.04;Figure B) and produced anti-PD-L1mAb levels at 14d consistent with those measured in ICI-treated cancer patients ( 283.2 ± 112.4 ug/mL). Therefore, in Study 2, mice were treated with either isotype-mAb or anti-PD-L1mAb (300ug/mouse, every 3 days) starting 12d before and continuing until 3d after IT challenge with 25 or 50PFU/mouse of MHV-1 (Experiments 1 and 2 respectively). Compared to control animals [12 survivors of 12 total animals in Experiment 1 (100%), and 4 of 12 in Experiment-2 (33%)], survival was decreased with PD-L1-mAb in both experiments [11 of 12, (91%) and 2 of 12 (17%), respectively] but these survival differences were not significant (p>0.05) (Figure C). Conclusions: Intratracheal MHV-1 challenge in A/J mice produced lethality and late changes in circulating lymphocytes and lung lavage lymphocytes and protein that appear consistent with changes observed clinically with SARS-CoV2 infection. Prior treatment with anti-PD-L1mAb in this model did not improve and potentially aggravated the lethal effects of MHV-1, but requires further study.

From December 2009 to December 2010, 47 patients in Scotland presented with confirmed anthrax infection manifested by soft tissue disease related to heroin injection. These cases represent the first known outbreak of a recently recognized form of anthrax, termed injectional anthrax, which appears to be associated with a high mortality rate (28% in confirmed cases from the UK outbreak). While epidemiologic data from this outbreak have been published, no report has systematically described findings in patients at presentation or compared these findings in nonsurvivors and survivors.

I n this issue of Critical Care Medicine, Dr. Wiedermann and colleagues (1) performed a retrospective analysis of the phase III Kybersept trial and demonstrated a beneficial effect of antithrombin (AT) III in the subgroup of patients with a moderate risk of death (40–70% mortality rate) (2). However, over the past 2 decades, beneficial effects of new sepsis therapies identified by such subgroup analysis have not been confirmed in subsequent clinical trials (3). To maximize predictive ability, subgroup analysis of clinical trials should include all patients enrolled in the trial and should test whether treatment effects are altered by important variables. In addition, p values should be corrected for those factors tested that could potentially alter the treatment effect of an agent. Finally, findings should be consistent with known pathophysiologic mechanisms. The analysis by Dr. Wiedermann and colleagues does not meet these requirements. However, their report represents an intriguing application of a previous hypothesis by Knaus and Wagner (4). They postulated that treatments which alter the host inflammatory response, such as AT III, should be beneficial in septic patients with intermediate mortality rates but not the extremes (4). These therapies would have no effect in very low risk patients because host responses are appropriate and of limited harm, and they would be ineffective in very high risk patients because the overall likelihood of death is so great that no treatment would be beneficial. To further test this hypothesis for AT III, we examined the clinical sepsis trials of AT III and two other antithrombotic agents: recombinant human activated protein C (rhAPC) and tissue factor pathway inhibitor (TFPI, Table 1) (2, 5, 6). Examining these three agents separately and combined, we attempted to provide insights into how these agents act as a class, to improve our understanding of the similarities and differences in these agents, and to potentially identify factors that alter their efficacy. This analysis explores additional data not available in prior review of these agents (7).