The effect of esketamine on the hypoxic ventilatory response

INTERVENTION: The study intervention is the administration of esketamine. In part 1 of the study the researchers will infuse four esketamine doses and during each dose, they will measure the HVR: In part 1 of the study, for esketamine the dosing regimen is set at dose 0 (control condition for 60 min), followed by dose 16 (16 mg given over 60 min), dose 24 (24 mg given over 60 min) and finally dose 32 (32 mg over 60 min); all doses are per 70 kg. This dosing regimen is identical to that used earlier by (Jonkman et al. BJA 2018; https://clinicaltrialregister.nl/nl/trial/24921). In part 2, the researchers will test the dose that effectively sustains the HVR in part 1, and will perform an RCT (esketamine vs placebo) to determine whether that dose is able to reverse remifentanil‐induced depression of the HVR. Participants will be studied three times with at least 2 days in between study visits. CONDITION: The effect of esketamine on the hypoxic ventilatory response ; Respiratory PRIMARY OUTCOME: Hypoxic ventilatory response as determined from the change in ventilation and the change in oxygen saturation, ie. ?Ventilation/?Saturation with unit L/min per % desaturation, where ? stands for the difference between the variable observed at baseline and observed during hypoxia. Measured through measuring minute ventilation by facemask during the exposure period (i.e. l/min/% desaturation). SECONDARY OUTCOME: ; 1. Plasma esketamine concentrations over time, measured using blood samples at 0, 2, 5, 30, 60, 62, 65 and 75 min following the start of each of the esketamine infusions; 2. Psychomimetic side effects assessed by the Bowdle and Bond & Lader questionnaires during hypoxic breathing; INCLUSION CRITERIA: 1. Aged 18 ‐ 45 years 2. Body mass inde X19‐30 kg/m² 3. Ability to read and understand the subject information in the Dutch language