Liponucleotides Improve Gas Exchange in Dogs with Aspiration Pneumonia

Abstract

RATIONALE.There is an urgent need for new drugs for both COVID-19 patients and those with other forms of the acute respiratory distress syndrome (ARDS). ARDS in influenza-infected mice is associated with reduced levels of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II epithelial cells. We found previously that early or late post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline decreased hypoxemia, pulmonary edema, lung dysfunction, and inflammation without altering viral replication. Because it is a truism that mice with ARDS are far easier to cure than people, we wished to show that parenteral liponucleotide administration could likewise attenuate ARDS in a more clinically-relevant real-world situation. METHODS. Client-owned pet dogs admitted to the Small Animal ICU at The Ohio State University Veterinary Medical Center for aspiration pneumonia were enrolled in a randomized, double-blinded, placebo-controlled trial of treatment with vehicle (0.1 ml/kg sterile 0.9% saline, i.v.; n=8 dogs) or CDP-choline (5 mg/kg in 0.1 ml/kg 0.9% saline, i.v.; n=9 dogs) every 12 hours over the first 48 hours after admission. Dogs received standard of care supportive therapy and supplemental O 2 (in an O 2 tent or via nasal cannula) as deemed necessary by the attending clinician. Vital signs, blood pressure, and peripheral O 2 saturations were recorded every 8 hours. Arterial blood gases were measured every 12 hours. Venous blood was collected on admission and at 48 hours for clinical chemistry and CBC/differential counts. Written consent was obtained from all owners, who received a $400 financial incentive (in the form of a contribution to hospital expenses) to participate. RESULTS. Dogs in the treatment arm were significantly younger, but there were no other significant differences between placebo-and CDP-choline-treated dogs on admission. All dogs exhibited tachycardia, tachypnea, hypertension, hypoxemia, hypocapnia, lymphopenia, and neutrophilia. Administration of CDP-choline resulted in rapid, progressive, and clinically significant increases in P a O 2 :F i O 2 values and declines in alveolararterial (A-a) gradients that did not occur in placebo (saline)-treated animals. CDP-choline treatment also prevented platelet consumption over the first 48 hours after admission but had no detectable detrimental effects in sick dogs. CONCLUSIONS. CDP-choline acts rapidly to promote gas exchange in dogs with spontaneous aspiration pneumonia. Because CDP-choline has been shown to be very safe in human subjects, it should be considered as a potential adjunct therapy in ARDS and/or COVID-19 patients.