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At altitude, reduced barometric pressure lowers PAO₂ and subsequent PaO₂. A PaO₂ of 52 mmHg on FiO₂ 0.4 indicates significant hypoxemia. The priority is to increase oxygen delivery—raise FiO₂, and coordinate with the flight crew to reduce cabin altitude if aircraft performance permits. COPD patients may have V/Q mismatch; moderate PEEP (5–8 cm H₂O) can help, but jumping to 15 risks hyperinflation and hypotension. Hyperventilation to reduce PaCO₂ will not correct hypoxemia and may cause dynamic hyperinflation in COPD. Maintaining current settings accepts inadequate oxygenation that threatens organ perfusion and increases arrhythmia risk. Flight physiology planning should include oxygen reserves, ABG or reliable oximetry trending, and contingency pressurization profiles. Balancing oxygenation while avoiding barotrauma and hemodynamic compromise is central to safe fixed-wing COPD transports.