Acute effects of esketamine on hypoxic ventilatory response, haemodynamics, and brain function in healthy volunteers

Background: The acute hypoxic ventilatory response is a critical chemoreflex originating at the carotid bodies. This study investigates the impact of low-dose i.v. esketamine on the ventilatory response to 20 min of isocapnic hypoxia to test the hypothesis that esketamine does not affect hypoxic ventilation.

Methods: In this open-label study, 18 healthy subjects received a 3-h escalating i.v. infusion of esketamine, totalling 1.0 mg kg^-1. Before the esketamine infusion (control condition) and during the last 30 min of infusion, the ventilatory response to 20 min of isocapnic hypoxia (oxygen saturation ∼80%) was measured. We assessed the increase in ventilation from baseline to its peak during the first 5 min of isocapnic hypoxia (hypoxic ventilatory response) and the increase in ventilation from baseline to 20 min of isocapnic hypoxia (sustained hypoxia). Haemodynamics and acute brain function were also measured.

Results: Independent of hypoxia, a small excitatory effect of ketamine on isocapnic ventilation was observed: the mean increase in ventilation (95% confidence interval) was 3.1 (2.4-3.7) L min^-1 (P<0.0001). Esketamine had no effect on the isocapnic ventilatory response to acute and sustained hypoxia but increased MAP (+10 mm Hg) and heart rate (+10 beats min^-1), similarly during normoxia and hypoxia. Esketamine increased anxiety and alertness and affected external perception.

Conclusions: I.V. esketamine up to 1 mg kg^-1 does not affect the ventilatory response to hypoxia, but affects haemodynamics and acute brain function. Increases in anxiety and alertness could be a cause of the sustained ventilatory response to hypoxia during esketamine infusion.

Clinical trial registration: The trial was registered at the ISRCTN registry on June 27, 2023 under identifier ISRCTN 42617929 (https://www.isrctn.com/ISRCTN42617929).