PACo2 and to CO2 combined with hypoxia were measured in duplicate with an

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1 THE REPEATABILITY OF VENTILATORY RESPONSES TO EXCESS OF CARBON DIOXIDE AND LACK OF OXYGEN. By J. L. ANDERTON, E. A. HARRIS and K. B. SLAWSON. From the Department of Therapeutics, University of Edinurgh. (Received for pulication 26th June 1963) The ventilatory responses to CO2 without hypoxia, to hypoxia at constant PACo2 and to CO2 comined with hypoxia were measured in duplicate with an interval of 20 min. etween the two sets of measurements. The PAC0O threshold during the second set differed in only random fashion from that during the first set; so did the CO2 sensitivity in the asence of hypoxia. The CO2 sensitivity during hypoxia, however, was significantly greater during the second set of measurements. The relevance of these results to the investigation of drugs which affect respiration is discussed. IN studies of the analeptic drugs ethamivan and prethcamide [Anderton et al., 1962; Anderton and Harris, 1963 ] the ventilatory response to changes in alveolar CO2 tension (Pco2) was measured efore and during administration of the drug. Both drugs were shown to stimulate reathing, as compared with the effect of merely repeating the ventilatory measurements without giving any drug. Susequent experiments were carried out, using ethamivan, to study the ventilatory response to hypoxia at constant alveolar Pco, and these appeared to show that the drug also increases the response to hypoxia. When control experiments were done, however, it was found that repeating the measurements, without giving the drug, resulted in an increased hypoxic response of aout the same magnitude as when ethamivan was given. We therefore decided to undertake further control experiments and the results of these and the previous ones are now presented. METHODS Gas mixtures were supplied to the sujects, and ventilation and alveolar gas tensions measured, y methods and under conditions previously descried [Cunningham et at., 1957; Anderton et al., 1962; Anderton and Harris, 1963 a]. The sujects were all young, healthy volunteers, mostly male medical students; two nurses were the only females studied. All ventilatory measurements were made in the steady state of ventilation and alveolar Pco2. Each experiment consisted of a duplicate set of oservations (periods 1 and 2) separated y an interval of 20 mi. during which the mouthpiece was removed and the suject reathed room air. The total duration of the experiment was practically the same for each suject in any one programme, and the order and duration of administration of gas mixtures were standardized as far as was compatile with the attainment of steady states. The experimental programmes were of three kinds: 1. Response to Hypoxia at Constant PACO (six sujects).-four sujects were studied at low PA (1-2 mm. Hg aove resting) and two at a higher PACO (6-8 mm. Hg aove resting). The first group was first given a mixture containing 02 at 43

2 44 Anderton, Harris and Slawson 150 and CO2 at 20 mm. Hg. In the steady state the PAC0 was noted and for the rest of the experiment maintained y suitaly varying PI00 Two hypoxic mixtures followed the first, at 80 and 65 mm. Hg respectively. The two sujects studied at a higher Pco2 were given gas mixtures as follows: PIC02 (mm. Hg) Suject Mixture P102 (mm. Hg) A -- Period 1 Period 2 I. A. (1) (2) As (3) (3) 65 To maintain PAC02 of (2) As (3) D. C. N. (1) (2) As (3) (3) 65 To maintain PAC02 of (2) As (3) 2. Response to C02 in the Asence of Hypoxia (six sujects).-three mixtures containing 50 per cent 02 and with a PIa0 of etween 20 and 40 mm. Hg were given in succession. One suject had four such mixtures, and another only two, during period Response to C02 and Hypoxia (twelve sujects).-two programmes were followed, using six sujects for each. The sequences of inspired gas tensions are shown in Tale I. Programme (a) gave hypoxic responses at low PAC0, programme () at a higher PAC0. Mixtures 1 and 2 in each programme provided data for the C02-response without hypoxia. The remaining mixtures each gave a single V, PAO0, PAO point at hypoxic levels of PA0. One suject in programme () was studied twice, with an interval of 3 months; with the main ody of data. TABLE I.-RESPONSE TO CO2 AND HYPOXIA: only his first experiment is considered INSPIRED GAS MIXTURES Order P102(mm. Hg) PIC00 (mm. Hg) Programme 3(a) Four males Two females Programme 3() Calculations.-The C02-sensitivity and C02-threshold vary from one suject to another, partly ecause of differences in ody size. When several sujects are grouped it is therefore convenient to standardize the data so that these differences etween individuals are cancelled. For this purpose we have used a modification, suggested y Mr. B. B. Lloyd, of the method we descried previously [Anderton et al., 1962]. The standard to which all sujects are corrected is the V/PAC0 line for the non-hypoxic data of period 1, and all data for oth periods are adjusted y an amount such that this line comes to have a PACO intercept (parameter B) of mm. Hg and a slope (S) of 3*5 l./min./mm. Hg. These values were aritrarily

3 Ventilatory Responses to CO2 and Hypoxia chosen early in our experiments and are not average normal values. The correction is made as follows. From the non-hypoxic data of period 1 a regression line is calculated (least squares) and its parameters B and S are noted. The difference etween B and mm. Hg is added to (or 3utracted from) all PAco values for oth periods, to make B = mm. Hg. All ventilation values are then multiplied y 3-S5 making the new S for the non-ypoxic C02-response line of period 1 equal to TABLE II.-VENTILATORY RESPONSE TO HYPOXIA AT CONSTANT PACO (PROGRAMME 1) Period 1 Period 2 Suject, PAO PACO S* B* PAO2 PAC0, Tested at PACO just aove normal S* B* I. D *2 10* * B. L. (115) (116) * F9 R. F * d1 18* * R. W. W Tested at higher PACO0 I. A D. C. N * S and B are standardized as descried in the text. Bracketed PAO values were assumed. In this and susequent tales, PA0 and PAC00 are in mm. Hg, V in 1./min., B.T.P.S. l./min./mm. Hg. From the corrected data, B for period 2 can then e calculated, together with S for the non-hypoxic line of period 2. The slopes for the hypoxic lines of oth periods are calculated from the V, PACO values in the hypoxic states, assuming that B, in each period, is unaffected y hypoxia; from the work of Lloyd et al. [1958]. this assumption follows RESULTS The results of the experiments in programme 1 are shown in Tale II. All sujects save B. L. had PA values in period 2 which were practically the same as (actually a little lower than) the corresponding values in period 1. B. L.'s PA values were a little higher (y 0.3, 0.5 and 1-1 mm. Hg) in period 2, and at the lowest PA, this could have accounted for the oserved 45

4 46 Anderton, Harris and Slawson a'4 Ir E 3 E PROGRAMME 3a - 60, 50k 40.- Period 1 N45-8 '---' Period 2 \\ DC.N I0-1 ~q-2 'a -3 'w. -4 cr1 I- 30k f \XI \ B.L R.F PA02 -Mmm Hg FIG. l.-ventilatory response to hypoxia at two levels of constant PAC0'PA 02values showni eside each point..2 a-t PROGRAMME 3 - (x D.C.N.) wa ofui/p1 2 lie fro ALVEOLAR P02-mm. Hg FIG. 2.-Change in slopeofvp 0liero period 1 to period 2, in relation to the PA02at which the slope was determinedl. o.5 I.A Prog.1 o x E c E- 0 -c ci ALVEOLAR Pa2 -mm.hg FIG. 3.-Data from three experiments on I. A., plotted as in fig. 2.

5 Ventilatory Responses to CO2 and Hypoxia difference in ventilation etween the two periods. Taking the group as a whole, however, all save R. W. W. showed a higher ventilation during hypoxia in period 2. This was particularly marked in I. A. and D. C. N. whose hypoxic responses were measured at a relatively higher PA o. The magnitude of the increase in ventilatory response is illustrated in fig. 1, in which mean values for I. D., B. L. and R. F., and for I. A. and D. C. N., are plotted and assumed curves drawn. TABLE III.-VENTILATORY RESPONSE TO CO2 IN THE ABSENCE OF HYPOXIA (PROGRAMME 2) Period 1 Period 2 CA- Suject v V S B PACo. (1 a a J. N. 4: *1 17*3 4B *3* * *8 52*6 R. A. S '3 10* L0* ! * D.G * L r4* * *2-1 27* T. R. W * *7 32* B. D J *6 G. C. 3 9* * * l a PACO, * * *1 41* * a, data as determined;, after standardization. S is in I./min./mm. Hg and B in mm. Hg. a 12* * * *6 * *2 26* * * Mean S.E. 4* * * Tale III gives the data from programme 2. Parameters S and B are standardized for period 1 as descried aove. During period 2, S and B show wide individual discrepancies although the mean values for the six sujects are not significantly different from S and B for period 1 (mean S =3-94, S.E., 0.49; mean B =-42, S.E. 1.55). The data from programme 3(a) are presented in Tale IV. The individual results again show that the standardized B during period 2 differed from mm. Hg y a variale amount, although the mean for the six sujects was not significantly different (mean B = 35.15, S.E. 1.44). There was also a change in the standardized S from period 1 to period 2 at each level of PA ut the changes in S were evenly scattered around zero change (fig. 2). It is notale that, in several of the sujects in oth periods, S did not increase

6 48 Anderton, Harris and Slawson consistently as PA fell. In this respect the sujects differed from those in programme 3() whose results are given in Tale V. Apart from D. W. D. (period 1) and I. A. (1.5.63, period 2) in whom S was the same at oth levels of hypoxia, S increased in all as PA0 fell. The differences in S etween period 1 and period 2 are shown for programme 3() in fig. 2, plotted against TABLE IV.-VENTILATORY RESPONSE TO CO2 AND HYPOXIA: HYPoxic DATA AT LOWER PAC0 Suject PAC02 a J. A. R. S S. K. L R. F A. D. A J. A. R. L J. G Period 1 V a A PAO2 * S B PACO0 a a a, data as determined;, after standardization. * At Pio, of 350 mm. Hg, PAO is assumed to e mm. Hg. Period 2 (PROGRAMME 3(a)) V PA S B the mean PA0 at each hypoxic level for the two periods. The difference increases as PA falls and, at the lowest PA0 studied, all differences are positive-i.e. the slope is higher during period 2 than during period 1. We have comined all S-differences for programme 3() plus D. C. N., elow a PAO of 70 mm. Hg, and tested the mean and median of these differences y the t-test. Both differ from zero to a highly significant degree (mean, 1.39, S.E. 0-49, 0.01 > p > 0.005; median 1.30, 0.01 > p > 0.005). The change in B etween periods, although individually wide, is on the average insignificant (mean B =35.62, S.E. 0.76). t

7 Ventilatory Responses to CO2 and Hypoxia Data from the three studies on suject I. A. are comined in fig. 3. Parameter S increases faster in period 2 as Po, is reduced. In sequence, B for these experiments changed y + 1.6, and mm. Hg respectively, from period 1 to period 2. TABLE V.-VENTILATORY RESPONSE TO CO2 AND HYPOXiA: HYPoxic DATA AT HIGHELER PACO (PROGRAMME 3()) Suject I. R. W. D. W. D. I. A K. Y4 B. A.t J. H. N. I. A PACO, a Period 1 Period 2 V PAO, S a * B PACO0 a a $ Female suject. a, data as determined;, after standardization. * At Pi02 of 350 mm. Hg, PA02 is assumed to e mm. Hg. 49 PA02 S B DISCuSSION A suject may show appreciale changes in ventilatory response to CO2 and to hypoxia when retested after an interval of 20 min. Most of this variaility is random, at least with regard to CO2 threshold and to CO2 sensitivity at non-hypoxic levels of PA0. However, although the CO2 sensitivity at low PA0 did not change significantly when tested at low PA (programme 3(a)), at a higher PAC0 (programme 3() and D. C. N. of programme 1) the change in slope elow a PA02 of 70 mm. Hg was predominantly positive and the mean change was significantly different from zero. This VOL. XLIX, NO. L

8 50 Anderton, Harris and Slawson indicates that the response to hypoxia was greater during period 2 than during period 1 in this group. The question arises as to why the increase in the response to hypoxia was not oserved in those sujects tested at a relatively low PAC0 (programme 3(a)). As already mentioned, these sujects did not show, individually, a consistent increase in S with diminishing PA0. This has een noted y the Oxford workers [Cunningham, personal communication] when the response to hypoxia is studied at low ventilation. It seems clear that more consistent results are otained at higher levels of V and PAc02 possily due, in part, to a relatively smaller effect of discrepancies in respiratory frequency upon the proportion of total ventilation reaching the alveoli. Our experiments were primarily concerned with short-term repeataility during an experimental session lasting up to 4 hr. However, long-term repeataility is also important. Suject I. A. was studied three times during the course of 1 year; the programmes used gave results which could e compared and which are shown in Tales II and V. In dealing with the data of (Tale II) the slope and PAC02 intercept at PA02 of mm. Hg have een standardized to l./min./mm. Hg and mm. Hg respectively; in the other two experiments (Tale V) the routine standardization of the data at PA0 mm. Hg has een followed. Thus derived, changes in standardized slope are plotted against mean PAO in fig. 3. This shows an apparent increase in the response to hypoxia during period 2 on each of the days of study. Inspection of Tales II and V shows that I. A. was fairly consistent in his hypoxic responses, as judged y the values of S during hypoxia. One possile reason for the random variation in ventilatory responses of our sujects is the fact that they were not trained to the procedure, though no one was upset y it. Random variation might e expected to diminish as a suject's experience increases. The investigation of drugs, however, cannot ethically e undertaken on a small group of expert sujects; many drugs affecting respiration are hait-forming. We consider that our use of relatively inexperienced sujects is more relevant to this purpose. Two main conclusions can e drawn from these studies. First, while there is a good deal of random variation in the ventilatory responses of a given suject to CO2 and hypoxia, the effect of this may e largely eliminated y using standardized data from groups of six sujects, at least so far as CO2 threshold and CO2 sensitivity with minimal hypoxia are concerned. It follows that drug studies of the test-retest type should e done on a similar numer of sujects and the results averaged. Secondly, in addition to random variation, there seems to e a systematic effect of C02, hypoxia or oth on the susequent response to hypoxia. The reason for this is oscure. One possiility we have considered is the mild metaolic acidosis which accompanies acute hypercapnia, descried y Cunningham et al. [1961 and 1962] and Lamertsen [1963] and confirmed y us. If a metaolic

9 Ventilatory Responses to CO2 and Hypoxia acidosis induced y the hypercapnia of period 1 persisted into period 2, and ecame intensified y it, it might increase the hypoxic responses during period 2. One would also expect a systematic fall in B during period 2 and this did not occur in any of the programmes studied. ACKNOWLEDGMENTS We are grateful to Professor R. H. Girdwood for providing facilities for this work and to Mr. S. A. Sklaroff for statistical advice. E. A. H. held a Grant for Scientific Assistance from the Medical Research Council during the latter part of this work and J. L. A. held a Riker Research Fellowship during its earlier part. We are greatly indeted to our sujects for their co-operation. 51 REFERENCES ANDERTON, J. L., COWIE, J. F., HARRIS, E. A. and SLEET, R. A. (1962). "Effect of ethamivan (vanillic acid diethylamide) on the respiratory response of healthy young men to caron dioxide, in the asence of hypoxia", Brit. J. Pharmacol. 19, ANDERTON, J. L. and HARRIS, E. A. (1963 a). "The changing state of reathing during inhalation of CO,, studied with an inexpensive, recording CO, analyser", Quart. J. exp. Physiol. 48, ANDERTON, J. L. and HARRIS, E. A. (1963 ). "Ventilatory effects of prethcamide in healthy young men", Brit. J. Pharmacol. 20, CUNNINGHAM, D. J. C., CORMACK, R. S., O'RIORDAN, J. L. H., JUKES, M. G. M. and LLOYD, B. B. (1957). "An arrangement for studying the respiratory effects in man of various factors", Quart. J. exp. Physiol. 42, CUNNINGHAM, D. J. C., SHAW, D. G., LAHIRI, S. and LLOYD, B. B. (1961). "The effect of maintained ammonium chloride acidosis on the relation etween pulmonary ventilation and alveolar oxygen and caron dioxide in man", Quart. J. exp. Physiol. 46, CUNNINGHAM, D. J. C., LLOYD, B. B. and MICHEL, C. C. (1962). "Acid ase changes in the lood during hypercapnia and hypocapnia in normal man", J. Physiol. 161, 26P. LLOYD, B. B., JUKES, M. G. M. and CUNNINGHAM, D. J. C. (1958). "The relation etween alveolar oxygen pressure and the respiratory response to caron dioxide in man", Quart. J. exp. Physiol. 43, LAMBERTSEN, C. J. (1963). The Regulation of Human Respiration. Ed. Cunningham and Lloyd. Oxford: Blackwell.

EFFECT OF ETHAMIVAN (VANILLIC ACID DIETHYLAMIDE) ON THE RESPIRATORY RESPONSE OF HEALTHY YOUNG MEN TO CARBON -DIOXIDE, IN THE ABSENCE OF HYPOXIA

Brit. J. Pharmacol. (1962), 19, 142-152. EFFECT OF ETHAMIVAN (VANILLIC ACID DIETHYLAMIDE) ON THE RESPIRATORY RESPONSE OF HEALTHY YOUNG MEN TO CARBON -DIOIDE, IN THE ABSENCE OF HYPOIA BY J. L. ANDERTON,