Copyright ©ERS Journals Ud 1993 Eur Respir J. 1993, 6, 611-613 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936

EDITORIAL

The C02 response: usefulness and uncertainties

W.N. Gardner

In 1905, HALDANE and PR.rnsn.EY [1] demonstrated the probably closer to the venous than the arterial side of the dramatic sensitivity of human ventilation to small in­ cerebral circulation and is, thus, influenced by cerebral ), creases in arterial carbon dioxide tension (Paco2 a re­ blood flow, which increases dramatically as C02 increases sponse now known to be mediated by the intracranial [13]. The output of the chemoreceptors, thus depends not chemoreceptors, with an oxygen-dependent contribution , only on the amplitude of the increase in Paco2 but also , from the peripheral chemoreceptors. Since that time, the on the rate of change of Pco2 and the time at which response of minute or alveolar ventilation to increases in measurement is made. These vary for the different tech­ Paco , induced by the inhalation of C0 , has remained niques used to determine the C0 resp6nse. 2 2 2 one of the most widely studied relationships in human The traditional steady-state technique usually requires respiratory physiology. Elucidation of this response is an open circuit [6, 8], and offers great flexibility in ma­ still one of the few techniques available to study respi­ nipulation of inspired gases. Inspired C02 is held at a ratory control in man. However, its purpose and limita­ fixed level until ventilation reaches a quasi-plateau (usu­ tions are often misunderstood, there is no ideal technique, ally ~8 min), and the mean of ventilation over the fmal and doubts have been expressed about its physiological minute or two provides one point on the response curve. relevance [2, 3]. Successive levels are studied either by returning to Until computers became widely available, expired ven­ eucapnia between each level, or by continuing up the re­ tilation, measured by means of a gas meter, was one of sponse curve in steps of approximately 1% inspired Pco2 the few easily measured output variables in man, and up to 5-7%. A truly random technique is rarely possi­ more recent attempts to substitute mean inspiratory flow ble, due to time constraints. Ventilation continues to and other components of the respiratory cycle of more change for hours and even days after a step of C02 (14], relevance to recent models of control of the respiratory and thus it is difficult to define a true steady-state. More­ cycle [4-6] have still to gain widespread acceptance. over, as ventilation increases, increasing amounts of C02 , The input variable, Paco2 is usually approximated by end­ are inhaled, imposing a limitation on the range studied. tidal or alveolar carbon dioxide tension (PETC02 or Injection of a fixed amount of C02 per breath overcomes ), PAco2 measured with great tedium in early studies by this limitation, and produces the same responses as stand­ Uoyd-Haldane analysis of individual samples of alveolar ard inhalation techniques [15]. Because of the time re­ rur. quired for one estimation, steady-state techniques are Carbon dioxide inhalation can be used qualitatively to unsuitable for patient studies. test for presence or absence of C02 sensitivity, and to Rebreathing techniques are even more approximate, in , stress the system as a basis for other studies, or quanti­ that rebreathing from zero inspired C02 as used in the tatively to assess chemoreceptor gain under a variety of study of TARDIF et al. in this issue [16] will result in pro­ conditions [7-9]. A background of hyperoxia alveolar gressively changing Pco2 gradients across each of the ) oxygen tension (PA02 >approx 200 mmHg) functionally interfaces between the alveolar air and the chemo­ inactivates the peripheral chemoreceptors and allows the receptors, with even less certainty that changes of Paco 2 C02 responsiveness of the intracranial chemoreceptors to are proportional to changes of H+ at the chemoreceptors. be studied in isolation. Use of the C02 response to study The modification of READ [17], in which the rebreathing chemoreceptor gains depends on the assumption that bag initially contains Pco2 at the mixed venous level, en­

PErco2 changes at the lungs are proportional to changes sures that the gradients are abolished, and partly over­ of H+ or carbon dioxide tension (Pco ) at the chemo­ 2 comes these objections. receptors, but the location of this site for the intercranial Nevertheless, rebreathing results often differ from those chemoreceptors is even less certain than it was 20 yrs ago obtained by steady-state techniques. Recent studies in

[10]. Following a step change of Pco2 at the lungs in which rebreathing was stimulated [18], have documented cats [11], brain extracellular fluid (ECF) H+ changes criteria for the initial step and subsequent rate of increase slowly, with a time constant of nearly a minute, and takes of Paco2 that ensure that rebreathing and steady-state re­ 5 min to stabilize, whilst ventilation lags still further, sponses are the same. These findings should be taken changing in man as a monoexponential with a half into consideration in future studies using rebreathing tech­ time of 1-1.5 min [12]. The site of chemosensitivity is niques. Despite improvements in technique, the physiological Dept of Thoracic Medicine, Kings College School of Medicine and relevance of these responses must stiU be questioned. It Dentisb:y, Bessemer Rd. London SES 9PJ, UK. is generally accepted that the slope of a first degree 612 W.N. GARDNER

regression line fitted to this relationship, when Paco2 is intracranial chemoreceptors have any role at all, and the increased between about 5-20 mmHg (0.7-2.7 kPa) above C02 response may have even less relevance here. resting in hyperoxia, gives a measure of intracranial There are other uncertainties about C02 response. The chemoreceptor sensitivity, with progressive increase in fact that there is a slope at all, reflects the inability of slope oxygen tension (Po ) falls [8] and a horizontal as 2 the control system to fully correct for the imposed in­ shift in the "fan" of lines in acidaemia and alkalaemia • crease in Paco2 It has still not been satisfactorily estab­ [9]. However, breathing 2-6% C0 is rarely physiologi­ lished if, or why, venous loaded C0 (as in exercise) 2 2 cal. The response, line is probably not linear over the results in more complete feedback, and a steeper slope, whole range, and flattens off at higher values. Thus, than inhaled C0 • Recent studies of venous C0 load­ 2 2 the slope may be different if measured from a different ing in haemodialysis (De Backer, personal communica­ starting value, or over a different part of the curve. tion) suggest that they are the same. Another factor, In early studies, the response at and just above resting rarely considered, is the role of post-stimulus potentiation was rarely studied, due to the breath-by-breath variabil­ or "after discharge" [32], which will have a variable ef­ ity in this region, which was assumed to be due to the fect depending on the technique used to increase C0 • 2 influence of "higher centre" noise, in the absence of the Functional residual capacity is rarely measured, but stabilizing effect of the chemoreceptors. Subject aware­ hyperinflation, such as occurs in obstructive lung disease, ness of increase in ventilation at the higher levels of will increase ventilation [33], and may affect the slope

inspired C02 was also offered as at least a partial ex­ of the response. planation for day-by-day shifts in the slope and position In lung disease the situation is even more complex. of the response curves. This effect can be minimized by Because of gas exchange disruption and increased

averaging the responses to small repeated changes in impedence, both PETco2 and ventilation may fail to re­ Paco2 [12, 19). However, recent studies have shown that flect, respectively, the true input and output at the respi­ resting breathing patterns remain unchanged and unique ratory centres, requiring other measures, such as arterial to an individual over many years, even into stage or transcutaneous Pco inputs, and mouth occlusion N 2 as sleep [20], suggesting that breathing may be less random . ) pressure (P0 1 or diaphragmatic electromyographic activ­ and susceptible to higher centre influence than had pre­ ity (EMG) as outputs. Blood gas abnormalities at rest viously been supposed. change the starting point of any determination and, as­

The lower end of the C02 response curve is flattened suming that the response curve is not linear over its into a "dogleg" region in which C02 responsiveness is range, make comparison between subjects difficult. In the greatly reduced or absent [7, 21]. Young described a study by TARDIF et al. [16] use is made of the fact that region of increased instability at the junction of the "dog­ the subjects are on a ventilator to normalize the eucapnic leg" and the steep part of the C0 response curve, sug­ 2 starting values to a fixed point (but not necessarily to the gesting a possible change of mechanism at this point [21] subjects, ftxed point) to allow comparison of responses. Young is referred to in Cunningharn's Review. The work Because of the uncertainties discussed above, their quali­ was done by Young while working for Cunningharn. tative fmdings that patients with acute respiratory failure

Airway chemosensitivity, although of small quantitative retain roughly normal C02 sensitivity is valid, but any importance [22], may also have an increased role in this quantitation of the contribution of C02 to ventilation in region. Animal experiments show C02 sensitivity main­ this situation must be interpreted with more caution. tained down to about l kPa [23], so that this "dogleg" It could be argued that respiratory disease affects the probably reflects some form of central gating, rather than lungs and not the brain stem, and in the absence of neu­ true loss of chemoreceptor sensitivity. In man, apnoea rological lesions, and allowing for chronic acid-base or unstable breathing patterns can be induced by small disturbances, there may be no reason to expect anything reductions in Paco2 below the resting level both in sleep other than normal chemoreceptor function in these [24, 25], and sometimes in the awake state [26-28]. Ve­ patients. However, sleep deprivation, such as occurs in

nous C02 unloading by haemodialysis [29, 30], and en­ many patients with respiratory disease, reduces the slope semble averaging of ventilatory responses to transient eo, of the C02 response without alteration of resting values pulses during recovery from voluntary overbreathing [19], and pattern of ventilation [34], but more recent studies suggest that the apnoeic threshold for Paco2 may be up suggest that this effect may be clinically unimportant to 10 mrnHg (1.3 kPa) below the resting level, but with [35]. wide individual variation. The normal "resting" control point probably lies just around the corner on the "dogleg" [30] and, in that the References role of the intracranial chemoreceptors is probably to limit , 1. Haldane JS, Priestley JG. - Regulation of lung ventila­ natural rises of Paco2 the normal operating range for this feedback control probably lies on this much flatter tran­ tion. J Physiol 1905; 32: 225-266. sitional zone. It is questionable, therefore, whether 2. Dejours P, Puccinelli R, Armand J, Dicharry M. - Con­ cept and measurement of ventilatory sensitivity to carbon di­ the slope of the C0 response curve at much higher Paco 2 2 oxide. J Appl Physiol 1965; 20: 890-897. levels is relevant to control of normal breathing. It 3. Dempsey JA. - C02 response: stimulus definition and may be more physiologically valid to measure the re­ limitations. Chest 1976; 70; 114-118. sponse immediately above resting, something which is 4. Clarke FJ, Euler Cv. - On the regulation of depth and rarely attempted. In exercise, it is uncertain whether the rate of breathing. J Physiol 1972; 222: 267-295. 1HE C02 RESPONSE: USEFULNESS AND UNCERTAINTIES 613

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