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A20
October 13, 2007 9:00 AM - 10:30 AM Room Room 302 |
| A Parsimonious Model Integrating Drug Effect on the Hypercarbic and Hypoxic Ventilatory Drive |
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Antonello L.G. Caruso, M.S., Peter M. Schumacher, M.Sc., Ph.D., Martin Luginbuehl, M.D., Manfred Morari, M.Sc., Ph.D., Thomas W. Bouillon, M.D. Automatic Control Laboratory, ETH Zurich, Zurich, Switzerland |
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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, inter/extrapolation and dose finding. This is due to the experimental paradigms geared towards isolating physiologic phenomena in order to obtain reliable and 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 accurately reproduce the measured effect of the major anesthetic drugs (volatile anesthetics, propofol, opioids) 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 [1]. 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 [2]. The synergism between HCRD and AHORD was expressed as multiplication of the respective terms [3]. Results The final structure of the model is:[figure1]The model satisfies the stated requirements and (after transformation of PO2 into satO2 considering the effect of hyper-/hypocarbia on the O2 dissociation curve), adequately describes data on HCRD and AHORD interaction [4], drug effects on AHORD at different PCO2 [5,6]. Discussion This model describes and 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 meaningfully be 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 [7], the model also serves as a simulator/test bed for both drug tolerability and control issues under non-steady state conditions. For drugs influencing both HCRD and AHORD it is possible to experimentally separate drug effects on HCRD from that on AHORD, but not vice versa. As can be clearly inferred from the equations, 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 (breathing an oxygen/air mixture). References [1] Anesthesiology 2004; 100:240-50 [2] Anesthesiology 1996; 85:60-68 [3] Clin Physiol 2001; 21:447-64 [4] J Clin Invest 1970; 49:1061-72 [5] Can Anaesth Soc J 1983; 30:607-14 [6] Anesthesiology 1995; 83:478-90 [7] Ann Biomed Eng 1997; 25:985-99. Anesthesiology 2007; 107: A20 |
Figure 1
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