Ventilatory long-term facilitation in humans: systematic review and meta-analysis

Therapeutic acute intermittent hypoxia (tAIH) elicits respiratory motor plasticity in rodents and humans, including ventilatory long-term facilitation (vLTF), a sustained, post-tAIH breathing increase. However, reported human vLTF is variable, and factors contributing to this variability remain unknown. This systematic review and meta-analysis determined: 1) average vLTF across human studies; 2) tAIH protocol characteristics associated with vLTF magnitude; and 3) if vLTF exhibits a diurnal cycle. Since tAIH delivery timing is seldom reported, day vs nighttime tAIH were used as proxies for diurnal active and rest phases. Multilevel random-effects meta-analyses estimated pooled vLTF; CR2-adjusted meta-regression models evaluated associated factors. Daytime tAIH elicited an ∼18% increase in ventilation (42 effect sizes, p < 0.001), with greater vLTF associated with longer cumulative hypoxic exposure (protocols < 50 min; p = 0.016) and greater Petco ₂ elevation above baseline ( p = 0.003). In a combined model, higher average end-tidal Pco ₂ (Petco ₂ ) during tAIH ( p = 0.035) and higher duty cycle (proportion of each cycle spent hypoxic; p = 0.011) were independently associated with greater vLTF. Comparing day and nighttime tAIH, breathing frequency increased more following daytime vs nighttime tAIH ( p < 0.001), whereas tidal volume changes were similar between diurnal phases ( p = 0.585). However, limited independent variation in protocol characteristics and sparse representation across the diurnal cycle constrain interpretation of vLTF variability. Inconsistent reporting of clock time and end-tidal gases further limits interpretation and poses a barrier to the translation of tAIH as a therapeutic modality to improve breathing ability in conditions that threaten ventilator dependence.