Devices used to deliver inhaled sedation increase dead space ventilation. We therefore compared ventilatory effects among isoflurane sedation via the Sedaconda ACD-S (internal volume: 50 mL), isoflurane sedation via the Sedaconda ACD-L (100 mL), and propofol sedation with standard mechanical ventilation with heat and moisture exchangers (HME). This is a substudy of a randomized trial that compared inhaled isoflurane sedation via the ACD-S or ACD-L to intravenous propofol sedation in 301 intensive care patients. Data from the first 24 h after study inclusion were analyzed using linear mixed models. Primary outcome was minute ventilation. Secondary outcomes were tidal volume, respiratory rate, arterial carbon dioxide pressure, and isoflurane consumption. In total, 151 patients were randomized to propofol and 150 to isoflurane sedation; 64 patients received isoflurane via the ACD-S and 86 patients via the ACD-L. While use of the ACD-L was associated with higher minute ventilation (average difference (95% confidence interval): 1.3 (0.7, 1.8) L/min,p< 0.001), higher tidal volumes (44 (16, 72) mL,p= 0.002), higher respiratory rates (1.2 (0.1, 2.2) breaths/min,p= 0.025), and higher arterial carbon dioxide pressures (3.4 (1.2, 5.6) mmHg,p= 0.002), use of the ACD-S did not significantly affect ventilation compared to standard mechanical ventilation and sedation. Isoflurane consumption was slightly less with the ACD-L compared to the ACD-S (−0.7 (−1.3, 0.1) mL/h,p= 0.022). The Sedaconda ACD-S compared to the ACD-L is associated with reduced minute ventilation and does not significantly affect ventilation compared to a standard mechanical ventilation and sedation setting. The smaller ACD-S is therefore the device of choice to minimize impact on ventilation, especially in patients with a limited ability to compensate (e.g., COPD patients). Volatile anesthetic consumption is slightly higher with the ACD-S compared to the ACD-L.