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.

Editor’s Perspective
What We Already Know about This Topic
  • The carotid body is the main mammalian oxygen sensor and hypoxia triggers the hypoxic ventilatory response that restores pulmonary oxygen uptake
  • Propofol reduces the ventilatory response to hypoxia
  • ENA-001 is an agnostic respiratory stimulant that increases breathing activity by blocking calcium-activated potassium channels at the carotid bodies
What This Article Tells Us That Is New
  • The hypothesis that ENA-001 can restore the hypoxic ventilatory response during propofol infusion was tested in a double-blind, placebo-controlled crossover study in 12 healthy adults
  • Subjects were randomized to receive placebo, low-dose ENA-001, and high-dose ENA-001 on three separate occasions, during each of which isohypercapnic hypoxic ventilatory responses were measured during placebo, low-dose propofol, and high-dose propofol infusions
  • ENA-001 was effective in restoring the propofol-impaired hypoxic ventilatory response
  • Using a pharmacodynamic model based on the interaction between oxygen sensitivity and carbon dioxide sensitivity, an ENA-001 concentration of 1.5 μg/ml was determined to be able to fully reverse the depressant effects of a steady state propofol concentration of 2 μg/ml