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A parsimonious model integrating drug effect on the hypercarbic and hypoxic ventilatory drive


A. Caruso, P.M. Schumacher, M. Luginbühl, M. Morari, T. Bouillon

SGAR - Schweizerische Gesellschaft für Anesthesiologie und Reanimation, Annual Meeting, Interlaken

Background: Multiple studies are available describing i) the effect of oxygen on the hypercarbic respiratory drive (HCRD), ii) the effect of carbon dioxide on the acute hypoxic respiratory drive (AHORD), iii) the effect of drugs on the HCRD and iv) the effect of drugs on the AHORD. Unfortunately, most of them are not suitable for simulation and dose finding as the experimental paradigms are geared towards isolating physiologic phenomena in order to obtain interpretable data of respiratory subsystems . We propose to integrate the available knowledge with a parsimonious interaction model. Methods: The following criteria were defined prior to model building: The model must adequately describe HCRD, AHORD and their interaction in the absence of drug; it must reproduce the measured effect of the major anesthetic drugs on HCRD and AHORD, regardless of the experimental conditions; it must be parameterized completely with published parameters and/or parameters derived from published data. The effects of propofol and opioids on HCRD have been previously integrated. Building on this structure, AHORD was described with a linear model with satO2 as input, drug effects on AHORD expressed as reduction of the slope. The synergism between HCRD and AHORD was expressed as multiplication of the respective terms. Results: The model satisfies the stated requirements and adequately describes data on HCRD and AHORD interaction, drug effects on AHORD at different PCO2. Discussion: This model integrates several isolated pharmacological and physiological aspects of acute drug induced respiratory depression under various conditions. Results from studies on drug effects on the isohypercapnic AHORD and isooxic HCRD can now be meaningfully integrated to yield a picture of drug induced respiratory effects including interactions based on different mechanisms in the clinical situation. Combined with a metabolic model, the model also serves as a test bed for drug tolerability and control issues under non-steady state conditions. The hypoxic respiratory drive serves as a last desperate stopgap with little impact at PaO2>80 mmHg even under severe hypercarbia. Therefore effects of drugs on the hypoxic respiratory drive are of minor significance compared to effects of drugs on the HCRD in the clinical setting.


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M. Morari

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% Autogenerated BibTeX entry
@InProceedings { CarEtal:2007:IFA_2940,
    author={A. Caruso and P.M. Schumacher and M. Luginb{\"u}hl and M. Morari and T.
    title={{A parsimonious model integrating drug effect on the
	  hypercarbic and hypoxic ventilatory drive}},
    booktitle={SGAR - Schweizerische Gesellschaft f{\"u}r Anesthesiologie
	  und Reanimation, Annual Meeting},
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