Phrenic long-term facilitation is robust to hypercapnia and hypocapnia but not hyperventilatory hypotension under PEEP

Phrenic long-term facilitation (LTF) has been extensively studied in anesthetized animals under well-defined physiological conditions but the factors underlying its possible manifestation under clinically relevant conditions are not well understood. Here, we examine the stability of LTF in the face of hypercapnic or hypocapnic challenges in anesthetized, paralyzed and mechanically ventilated rats. Sixty minutes after induction of phrenic LTF by intermittent hypoxia the animal was exposed to one of four conditions for 5 min with or without positive end-expiratory pressure (PEEP, 3–4 cmH2O): hypocapnic apnea, hypocapnia (5 Torr below resting level), 5% CO2 and 10% CO2. LTF at 60 min post-intermittent hypoxia was ∼39% above baseline. Following the above CO2 tests, LTF almost invariably returned to the corresponding pre-test level after recovery for 20 min. The only exception was the combination of hypocapnic apnea and PEEP, which resulted in a marked decrease in mean arterial pressure (to 38–55 mmHg) during test and a subsequent paradoxical sustained attenuation of LTF (to ∼8% above baseline) even after mean arterial pressure had fully recovered. The results suggest that LTF, once developed, is highly robust to changes in CO2 levels and is attenuated only after severe hypotension secondary to excessive hyperventilation under PEEP.