Influenza A H1N1 induces declines in alveolar gas exchange in mice consistent with rapid post‐infection progression from acute lung injury to ARDS

Background Patients with severe seasonal or pandemic influenza pneumonia frequently develop acute respiratory distress syndrome (ARDS). One clinical diagnostic criterion for ARDS is the P_aO₂:F_iO₂ ratio, which is an index of alveolar gas exchange. However, effects of H1N1 influenza infection on P_aO₂:F_iO₂ ratios and related pathophysiologic readouts of lung function have not been reported in mice. Methods To develop a method for determining P_aO₂:F_iO₂ ratios, uninfected mice were anesthetized with pentobarbital, diazepam/ketamine, or inhaled isoflurane. Subsequently, they were allowed to breathe spontaneously or were mechanically ventilated. After 15 minutes exposure to room air (F_iO₂ = 0·21) or 100% O₂ (F_iO₂ = 1·0), carotid P_aO₂ was measured. To determine influenza effects on P_aO₂:F_iO₂, mice were challenged with 10 000 p.f..u./mouse influenza A/WSN/33. Results P_aO₂:F_iO₂ ratios were abnormally low (≤400 mmHg) in spontaneously breathing mice. Mechanical ventilation with positive end‐expiratory pressure was required to obtain P_aO₂:F_iO₂ ratios in uninfected mice consistent with normal values in humans (≥600 mmHg). At day 2 following infection P_aO₂:F_iO₂ ratios indicated the onset of acute lung injury. By day 6, P_aO₂:F_iO₂ ratios were <200 mmHg, indicating progression to ARDS. Impaired gas exchange in influenza‐infected mice was accompanied by progressive hemoglobin desaturation, hypercapnia, uncompensated respiratory acidosis, hyperkalemia, and polycythemia. Conclusions Influenza infection of mice results in impairment of alveolar gas exchange consistent with rapid development of acute lung injury and progression to ARDS. P_aO₂:F_iO₂ ratios may be of utility as clinically relevant and predictive outcome measures in influenza pathogenesis and treatment studies that use mouse models.