The inherited intensity of the hypoxic ventilatory response may be important in determining the severity of hypoxaemia in chronic obstructive pulmonary disease (COPD). However, existing methodology does not allow adequate quantification of peripheral chemoreceptor sensitivity in conscious humans. The aim of this project was to validate a new mathematical model and apply this model to investigate the hypoxic ventilatory response of healthy offspring of patients with COPD. The mathematical model (consisting of two linear differential equations in parallel, each with either a fast or slow time constant component, both using the fall in SaO<SUB>2</SUB> as the stimulus and with the equation outputs summed to give the rise in ventilation above the normoxic baseline value) was used to analyse the ventilatory response to transient and step change hypoxic stimuli in normal conscious human volunteers. Ten repeated measurements of the hypoxic ventilatory response in four subjects showed that the model parameter estimation was reproducible within a subject, and capable of distinguishing between subjects. Studies at rest and increasing levels of exercise showed that the hypoxic ventilatory response expressed both as the V<SUB>E</SUB>inst/SaO<SUB>2</SUB> relationship and as the model gain parameters increased with increasing exercise level. No significant effect could be demonstrated upon the ventilatory response of varying the rate of onset of the hypoxic stimulus to give a time course for the fall in SaO2 from 17 to 50 seconds. The central adenosine blocker theophylline given as a slow-release oral preparation did not consistently affect the hypoxic ventilatory response expressed either as the V<SUB>E</SUB>inst/SaO<SUB>2</SUB> relationship or as the model gain parameters of six normal subjects. Thus, the mathematical model appears to quantitate the hypoxic ventilatory response in normal subjects and is capable of reflecting true physiological changes. It may also provide further information regarding the components of the response than conventional methods of analysis. Studies in 35 offspring of patients with COPD showed a significant relationship between the PaO<SUB>2</SUB> of a group of patients with COPD and the hypoxic ventilatory response of their offspring in response to step change hypoxia. However the PaO<SUB>2</SUB> of the patients was best predicted by a combination of the model gain parameters of their offspring (where gain 1 may represent the peripheral chemoreceptor response, and gain 2, the central or combined hypoxic response). Hence the PaO<SUB>2</SUB> of the patients may be determined by hereditary characteristics of the peripheral chemoreceptor and central components of the hypoxic ventilatory response. The hypoxic ventilatory response of the offspring group was no different from that of a group of 26 age and sex-matched control subjects whose parents did not have COPD, suggesting that the offspring group were within the wide range of the normal hypoxic ventilatory response. The studies in the offspring of patients with COPD suggest that the PaO<SUB>2</SUB> in COPD seems to depend on a genetically determined normal variation of both peripheral stimulation and central depression of ventilation by hypoxia.
|Hill, Jane Elizabeth
|University of Edinburgh
|Electronic Thesis or Dissertation
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