Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial

Abstract

Background The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants, that increase respiratory drive irrespective of its cause. We tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. We hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. Methods In this randomized double-blind cross-over trial, 14 male and female healthy volunteers were randomized to receive placebo, low and high dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. We conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. Results Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/mL at low- and high-dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/mL at low- and high-dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47±0.20 µg/mL. The steady-state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51±0.04 µg/mL. A concentration of 1 µg/mL ENA-001 was required for full reversal of the propofol effect at its C50. Discussion In this pilot study, we demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance, but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.