During lung-protective ventilation, respiratory rate (RR) is frequently increased to compensate for hypercapnia. Despite its widespread use, however, the physiological consequences of this strategy remain incompletely understood. We aimed to characterize the physiological trade-offs of stepwise RR escalation at fixed tidal volume during controlled ventilation, with a particular focus on dead space partitioning, ventilatory efficiency, and energetic burden.

In this prospective physiological crossover pilot study, 30 mechanically ventilated ICU patients underwent stepwise RR increases from 15 to 33 min ⁻ ¹ (primary analysis restricted to ≤27 min ⁻ ¹) at constant tidal volume (6 mL·kg ⁻ ¹ ideal body weight (IBW)) under two protocols: complete expiration and fixed I:E ratio (1:1.9). Dead space was assessed using the Enghoff modification of the Bohr equation at two predefined minute ventilation targets (100 and 150 mL·kg ⁻ ¹ IBW), with capnographic variables derived from quadratic mixed-effects models. Ventilatory efficiency was quantified using the ventilatory ratio (VR), the expected-to-observed PaCO₂ response derived from the alveolar ventilation equation, and the incremental CO ₂ elimination per unit additional minute ventilation (ΔV̇CO₂/ΔMV).

A 50% increase in minute ventilation (RR 17→25 min ⁻ ¹) reduced PaCO₂ by 5.1 mmHg (95% CI 4.2 to 5.9), systematically less than predicted under the assumption of constant dead space fraction. Alveolar dead space increased from 132 to 189 mL (p  <  0.001) and dead space fraction rose from 0.60 to 0.65. Incremental CO₂ elimination efficiency declined with increasing RR (β = −0.95 ml CO₂/L MV per min ⁻ ¹, 95% CI − 1.41 to −0.49), suggesting plateau formation under complete expiration. Mechanical power increased exponentially, reaching +181% under complete expiration versus +122% under fixed I:E at 27 min ⁻ ¹. Baseline VR moderated V̇CO ₂ trajectories: patients with high VR tended to show declining CO₂ elimination beyond 21–24 min ⁻ ¹, whereas low-VR-patients showed approximately linear increases.

In this physiological study, RR escalation during low-tidal volume ventilation was associated with progressive decline in ventilatory efficiency, driven by increasing dead space fraction and compounded by rising CO₂ rebreathing. These effects were most pronounced in patients with elevated baseline VR, supporting future investigation of individualized ventilation approaches that balance gas exchange efficiency against mechanical cost.