Reversal of propofol-induced depression of the hypoxic ventilatory response by BK-channel blocker ENA-001: a randomized controlled trial.

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.

Informations de copyright

Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.

Déclaration de conflit d'intérêts

Conflicts: In the last 36 months, AD received consultancy fees from Enalare Therapeutics Inc. (USA), Trevena Inc. (USA), and awards/grants from the US Food and Drug Administration and from the Dutch Research Council (NWO, the Hague, the Netherlands) in the framework of the NWA-ORC Call for research project TAPTOE, Tackling and preventing the opioid epidemic (NWA.1160.18.300). JVP and TM are employees of Enalare, Therapeutics Inc., Princeton, New Jersey, USA.