Compared to FiO2s >0.60, Few Preclinical Animal Studies Have Examined the Effects of Therapeutic FiO2s ≤ 0.60 in Models of Lung Infection or Noninfectious Injury: Preliminary Results of a Planned Systematic Review and Meta-Analysis

ABSTRACT

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.