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(a)O(2):F(i)O(2) ratio, which is an index of alveolar gas exchange. However, effects of H1N1 influenza infection on P(a)O(2):F(i)O(2) ratios and related pathophysiologic readouts of lung function have not been reported in mice.
Methods: To develop a method for determining P(a)O(2):F(i)O(2) 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(i)O(2) = 0·21) or 100% O(2) (F(i)O(2) = 1·0), carotid P(a)O(2) was measured. To determine influenza effects on P(a)O(2):F(i)O(2), mice were challenged with 10,000 p.f..u./mouse influenza A/WSN/33.
Results: P(a)O(2):F(i)O(2) ratios were abnormally low (≤400 mmHg) in spontaneously breathing mice. Mechanical ventilation with positive end-expiratory pressure was required to obtain P(a)O(2):F(i)O(2) ratios in uninfected mice consistent with normal values in humans (≥600 mmHg). At day 2 following infection P(a)O(2):F(i)O(2) ratios indicated the onset of acute lung injury. By day 6, P(a)O(2):F(i)O(2) 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(a)O(2):F(i)O(2) ratios may be of utility as clinically relevant and predictive outcome measures in influenza pathogenesis and treatment studies that use mouse models.
© 2012 Blackwell Publishing Ltd.