Document Type
Article
Publication Date
6-1-2024
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. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response.
METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and 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. The authors 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 the propofol concentration that reduced the hypoxic ventilatory response by 50%.
CONCLUSIONS: In this pilot study, the authors 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.
Recommended Citation
Jansen, Simone; van Lemmen, Maarten; Olofsen, Erik; Moss, Laurence; Pergolizzi, Joseph; Miller, Thomas; Colucci, Robert; van Velzen, Monique; Kremer, Philip; Dahan, Albert; van der Schrier, Rutger; and Niesters, Marieke, "Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial" (2024). Department of Medicine Faculty Papers. Paper 453.
https://jdc.jefferson.edu/medfp/453
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
38241294
Language
English
Comments
This article is the author's final published version in Anesthesiology, Volume 140, Issue 6, June 2024, Pages 1076 - 1087.
The published version is available at https://doi.org/10.1097/ALN.0000000000004915.
Copyright © 2024 The Author(s).