ABSTRACT NO: 018
Introduction: Hypoxaemia is common in septic acute respiratory failure. Hypoxic pulmonary vasoconstriction (HPV) optimizes arterial oxygenation by redistributing pulmonary blood flow towards lung regions with high ventilation/perfusion (V/Q) ratios. Sepsis and endotoxaemia impair HPV. NO, produced in large amounts by NOS2 during sepsis and endotoxaemia, is a potent pulmonary vasodilator modulating HPV.
Methods: We studied anaesthetized wild-type and NOS2-deficient mice. Left unilateral alveolar hypoxia was produced by occlusion of the left mainstem bronchus (LMBO). Twenty-two hours after an endotoxin challenge, we measured, at thoracotomy, right pulmonary artery blood flow (QRPA), pulmonary (PPA) and systemic (PSA) artery pressure. In some experiments, animals breathed 40 ppm of NO in air for 22 h. The fractional distribution of total pulmonary blood flow (QPA) and left pulmonary flow (QLPA) were intermittently assessed by transient occlusion of QLPA for 90 s. HPV was assessed as the percentage reduction in fractional blood flow to the hypoxic left lung.
Results: LMBO produced a reduction in QLPA/QPA of −6 ± 5% in wild-type mice and −50 ± 7% in control NOS2-deficient mice (P = NS). Endotoxin-challenged wild-type mice had an attenuated vasoconstrictor response to LMBO with QLPA/QPA −18 ± 5% (P < 0.01 vs control). After endotoxin challenge, NOS2-deficient mice showed a preserved reduction of QLPA/QPA of −51 ± 6% in response to LMBO, which did not differ between untreated wild-type or untreated NOS2-deficient mice. Breathing 40 ppm nitric oxide (NO) for the duration of the endotoxin challenge reversed the protective effect of congenital NOS2-deficiency.
Conclusions: During endotoxaemia, nitric oxide and an inflammatory product appear to act synergistically on the pulmonary vasculature to attenuate HPV and cause hypoxemia.
Acknowledgements: This work was supported by USPHS Grant HL 42397, and a Max Kade Foundation grant to RU.
The publication of this supplement has been supported by the sponsors of the Third ISMG Meeting: Abbott, AGA, AstraZeneca, Dräger, Janssen, Medex Medical, Messer Austria, Ohmeda, Pharmacia & Upjohn, Scott Medical Products, Siemens