Model-based characterization of ventilatory stability using spontaneous breathing

Abstract

Cyclic ventilatory instabilities are widely attributed to an increase in the sensitivity or loop gain of the chemoreflex feedback loop controlling ventilation. A major limitation in the conventional characterization of this feedback loop is the need for labor-intensive methodologies. To overcome this limitation, we developed a method based on trivariate autoregressive modeling using ventilation, end-tidal Pco2 and Po2; this method provides for estimation of the overall “loop gain” of the respiratory control system and its components, chemoreflex gain and plant gain. Our method was applied to recordings of spontaneous breathing in 15 anesthetized, tracheostomized, newborn lambs before and after administration of domperidone (a dopamine D2-receptor antagonist that increases carotid body sensitivity). We quantified the known increase in hypoxic ventilatory sensitivity in response to domperidone; controller gain for O2 increased from 0.06 (0.03, 0.09) l·min−1·mmHg−1 to 0.09 (0.08, 0.13) l·min−1·mmHg−1; median (interquartile-range). We also report that domperidone increased the loop gain of the control system more than twofold [0.14 (0.12, 0.22) to 0.40 (0.15, 0.57)]. We observed no significant changes in CO2 controller gain, or plant gains for O2 and CO2. Furthermore, our estimate of the cycle duration of periodic breathing compared favorably with that observed experimentally [measured: 7.5 (7.2, 9.1) vs. predicted: 7.9 (7.0, 9.2) breaths]. Our results demonstrate that model-based analysis of spontaneous breathing can 1) characterize the dynamics of the respiratory control system, and 2) provide a simple tool for elucidating an individual's propensity for ventilatory instability, in turn allowing potential therapies to be directed at the underlying mechanisms.