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The effect of remifentanil on respiratory variability, evaluated with dynamic modeling

¹Institute of Communications and Computer Systems, National Technical University of Athens, Athens, Greece; ²Nuffield Department of Anaesthetics, University of Oxford, Oxford, United Kingdom; ³Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, United Kingdom; ⁴Department of Electrical and Computer Engineering, University of Cyprus, Nicosia, Cyprus, and ⁵Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom

Submitted 15 June 2008 ; accepted in final form 2 February 2009

Opioid drugs disrupt signaling in the brain stem respiratory network affecting respiratory rhythm. We evaluated the influence of a steady-state infusion of a model opioid, remifentanil, on respiratory variability during spontaneous respiration in a group of 11 healthy human volunteers. We used dynamic linear and nonlinear models to examine the effects of remifentanil on both directions of the ventilatory loop, i.e., on the influence of natural variations in end-tidal carbon dioxide (PET_CO2) on ventilatory variability, which was assessed by tidal volume (VT) and breath-to-breath ventilation (i.e., the ratio of tidal volume over total breath time VT/TTOT), and vice versa. Breath-by-breath recordings of expired CO₂ and respiration were made during a target-controlled infusion of remifentanil for 15 min at estimated effect site (i.e., brain tissue) concentrations of 0, 0.7, 1.1, and 1.5 ng/ml, respectively. Remifentanil caused a profound increase in the duration of expiration. The obtained models revealed a decrease in the strength of the dynamic effect of PET_CO2 variability on VT (the "controller" part of the ventilatory loop) and a more pronounced increase in the effect of VT variability on PET_CO2 (the "plant" part of the loop). Nonlinear models explained these dynamic interrelationships better than linear models. Our approach allows detailed investigation of drug effects in the resting state at the systems level using noninvasive and minimally perturbing experimental protocols, which can closely represent real-life clinical situations.

nonlinear models; Volterra kernels; opioid; ventilation; chemoreflex

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