title: 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 Pco(2) and Po(2); 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 D(2)-receptor antagonist that increases carotid body sensitivity). We quantified the known increase in hypoxic ventilatory sensitivity in response to domperidone; controller gain for O(2) 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 CO(2) controller gain, or plant gains for O(2) and CO(2). 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.
authors.affiliation: Massachusetts Institute of Technology, Cambridge, MA, USA. shamim@mit.edu
authors.forename: Shamim
authors.initials: S
authors.lastname: Nemati
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Edwards
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sands
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Berger
authors.forename: Andrew
authors.initials: A
authors.lastname: Wellman
authors.forename: George C
authors.initials: GC
authors.lastname: Verghese
authors.forename: Atul
authors.initials: A
authors.lastname: Malhotra
authors.forename: James P
authors.initials: JP
authors.lastname: Butler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D025461:Feedback, Physiological; D006935:Hypercapnia / Q000503:physiopathology; D006985:Hyperventilation / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000294:innervation*; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D010507:Periodicity; D012123:Pulmonary Ventilation / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012018:Reflex; D012119:Respiration / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D012756:Sheep; D014139:Tracheostomy
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D002245:Carbon Dioxide; D004294:Domperidone; D010100:Oxygen