He C 02 Response : Usefulness and Uncertainties 613

In 1905, HALDANE and PR.rnsn.EY [1] demonstrated the dramatic sensitivity of human ventilation to small increases in arterial carbon dioxide tension (Paco 2 ), a response now known to be mediated by the intracranial chemoreceptors, with an oxygen-dependent contribution from the peripheral chemoreceptors. Since that time, the response of minute or alveolar ventilation to increases in Paco2, induced by the inhalation of C02, has remained one of the most widely studied relationships in human respiratory physiology. Elucidation of this response is still one of the few techniques available to study respiratory control in man. However, its purpose and limitations are often misunderstood, there is no ideal technique, and doubts have been expressed about its physiological relevance [2, 3]. Until computers became widely available, expired ventilation, measured by means of a gas meter, was one of the few easily measured output variables in man, and more recent attempts to substitute mean inspiratory flow and other components of the respiratory cycle of more relevance to recent models of control of the respiratory cycle [4-6] have still to gain widespread acceptance. The input variable, Paco 2 , is usually approximated by endtidal or alveolar carbon dioxide tension (PETC0 2 or PAco 2 ), measured with great tedium in early studies by Uoyd-Haldane analysis of individual samples of alveolar rur. Carbon dioxide inhalation can be used qualitatively to test for presence or absence of C0 2 sensitivity, and to stress the system as a basis for other studies, or quantitatively to assess chemoreceptor gain under a variety of conditions [7-9]. A background of hyperoxia alveolar oxygen tension (PA02) >approx 200 mmHg) functionally inactivates the peripheral chemoreceptors and allows the C0 2 responsiveness of the intracranial chemoreceptors to be studied in isolation. Use of the C0 2 response to study chemoreceptor gains depends on the assumption that PErco 2 changes at the lungs are proportional to changes of H+ or carbon dioxide tension (Pco 2 ) at the chemoreceptors, but the location of this site for the intercranial chemoreceptors is even less certain than it was 20 yrs ago [10]. Following a step change of Pco2 at the lungs in cats [11], brain extracellular fluid (ECF) H+ changes slowly, with a time constant of nearly a minute, and takes 5 min to stabilize, whilst ventilation lags still further, changing in man as a monoexponential with a half time of 1-1.5 min [12]. The site of chemosensitivity is