Cunningham and Gee, 1956, 1957; Lloyd, Jukes and Cunningham, 1956]?

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1 THE EFFECT OF A RSE N THE TEMPERATURE OF THE BODY ON THE RESPRATORY RESPONSE TO CARBON DOXDE AT REST. By D. J. C. CUNNNGHAM and J. L. H. O'RORDAN. From the University Laboratory of Physiology, Oxford. (Received for publication 30th May 1957) Five resting subjects were exposed to a hot humid environment in order to raise their rectal temperatures by C., which were then maintained for min. The rise in each individual produced a definite respiratory response. Pulmonary ventilation and alveolar pco2 were measured throughout, and alveolar pco2 controlled and varied by adding CO2 to the inspired air. A steady raised temperature (1) over a range of alveolar pco2 that included normal and raised values increased CO2 sensitivity approximately twofold, (2) at the normal alveolar pco2 increased the ventilation by /min., and (3) in air-breathing experiments produced only a slight hyperpncea and a fall of the alveolar pco2; over this low range ventilation appeared to be independent of alveolar pco2. This was considered to be consistent with the existence of a CO2 threshold, such as is found in anoxia. When temperature was rising there was apparently no correlation between the magnitude of the response and the rate of rise of temperature. When alveolar PCO2 was allowed to fall, as temperature became steady the ventilation declined from the peak reached in the non-steady state, but when pco2 was controlled the decline was usually small or absent. The greater effect on respiration of a rising than of a steady raised temperature in air-breathing experiments is thought to depend upon two factors: (a) the gradual decline in the CO2 stimulus as CO2 is lost from the body as a result of the hyperpncea; (b) an additional factor, the nature of which is discussed. THE pulmonary ventilation is increased when the temperature of the body is raised at rest [Haldane, 1905; Hill and Flack, 1909; Bazett and Haldane, 1921; Landis, Long, Dunn, Jackson and Meyer, 1926; Barltrop, 1954] and during and after exercise [Cotes, 1955; Bannister, Cunningham and Douglas, 1954]. We have studied steady raised body temperatures and carbon dioxide as stimuli to respiration at rest, and in Part of this paper an attempt is made to answer two questions: (1) are the effects of the two stimuli additive, as are those of experimental acidosis and CO2 [Nielsen, 1936], or is the response to one altered by varying the intensity of the other, as with anoxia and CO2 [Gee, 1949; Nielsen and Smith, 1951; Cormack, Cunningham and Gee, 1956, 1957; Lloyd, Jukes and Cunningham, 1956]? (2) When the alveolar pco2 falls below its normal level as a result of the hyperpncea at raised temperatures, is there any evidence of a " CO2 threshold " below which the ventilation is independent of C02, like that demonstrated in anoxia by Nielsen and Smith [1951] and by Hall [1953]? The observations reported in Part were made while temperature was rising during the transition from one steady state to another. VOL. xl. No

2 330 Cunningham and O'Riordan PART.-THE EFFECTS OF STEADY RASED TEMPERATURES METHODS Subjects.-Five healthy young men acted as subjects. Their ages and body measurements are shown in Table. They came without food to the laboratory, changed into light clothing and sat in a deck chair in the chamber for 30 min. before any measurements were made. TABLE.-AGES AND BODY MEASUREMENTS OF SUBJECTS Subject Age Height Weight years cm. kg Respiratory Measurements.-The respiratory apparatus already described [Cunningham, Cormack, O'Riordan, Jukes and Lloyd, 1957] was used except that the inspired gas was not humidified and respiratory frequency was measured by recording the fluctuations of the mouth pressure. All apparatus, except some for sampling alveolar air, the valves and some short flexible connections, was outside the chamber. For reasons given by Cunningham et al. [1957], values for alveolar pco2 were obtained by the Haldane and Priestley rather than by the Rahn and Otis method, the latter serving only as a guide to the progress of the experiment. The pressure of water vapour in the lungs was taken to be that of water at the rectal temperature. Measurement of Body Temperature.-The rectum was chosen for measuring body temperature because sublingual temperatures are unreliable during hyperpncea. A copper-constantan thermocouple was inserted 7 cm. beyond the external anal sphincter; the thermocouple was calibrated before and after each experiment against a standard thermometer. Because the body temperature is not uniform rectal temperature was expressed to 0.10 C., though the circuit was capable of greater accuracy than this. Raising the Body Temperature. -The chamber was wooden and measured 1 8 x 1 1 x 1 1 m. Through glass windows in one side, the subject and the wet- and dry-bulb thermometers were observed; these were placed near the deck chair and remote from the steam input and the fan. Carbon filament lamps provided light and warmth during observations at normal body temperature, and the environmental temperature and humidity could be raised by steam from a boiler outside the chamber; the air and steam were circulated by a slowly revolving fan. The required temperature was obtained by opening or closing one of the windows. A wet-bulb temperature of 390 C. was sufficient to raise the rectal temperature, and of C. to maintain the raised level. The precise wet-bulb temperature required at any moment was dictated by the readings of the rectal thermometer. Haldane [1905] showed that if the wet-bulb temperature exceeded 890 F. [31-5 C.] in still air, the rectal temperature of a resting subject started to rise, but in our experiments a higher wet-bulb temperature than this was required to maintain a raised rectal temperature, probably because the subjects were breathing cool unsaturated air and so their lungs were effectively outside the heating chamber.

3 Raised Temperature, CO2 and Breathing 331 CONDUCT OF THE EXPERMENTS t was decided to study the effects on each subject of several changes of PCO2 at only one raised temperature because body temperature can be altered only slowly and the subject always knows when steam enters the chamber and when he feels hot, whereas the C02 content of the inspired air can be altered rapidly and repeatedly without knowledge, and the effects of small changes may pass unnoticed. c 5 ' E OC.,, -A rb 40 Q.Q) 0: co Xt CO Jp P1 d E c. 30 * LU 0-20 O. l Alveolar nspired e E d.8 & C.p Reta y36ib ~ _ 1 2 a 1 TME N HOURS 2 3 FGS. la and b.-course of typical experiments. Rahn and Otis PCO2 (not shown) recorded throughout as a check on the steadiness of the response and the progress of the experiment. (a) CO2 sensitivity determined at normal and raised temperatures, (b) an air-breathing experiment. The induced rise of body temperature varied from subject to subject, but, with 2 exceptions, was always the same for any one subject. n the first experiment on any subject the temperature was raised until a clearly recognizable hyperpncea was observed, when the wet-bulb temperature was reduced to allow the body temperature to become steady; the steady-state temperature for each subject was therefore determined by the temperature which produced an obvious hyperpncea in the non-steady state. Because we employed the smallest increase of temperature required to produce a clearly recognizable

4 332 Cunningham and O'Riordan response, our subjects were seldom very uncomfortable in the steady state and tetany never occurred in the heating chamber experiments [cf. Landis et al., 1926]. Short rebreathing experiments [cf. Haldane, Meakins and Priestley, 1919; Cormack et al., 1956] provided valuable preliminary information from which the experiments of the main series were planned. n the first experiment of the main series on each subject, no CO2 was added to the inspired air until a set of respiratory measurements at a steady raised temperature had been completed. As the technique developed, the form of the experiments changed; in the early ones CO2 was added to the inspired air to keep the alveolar pco2 constant at a normal or raised value throughout [cf. Cormack et al., 1957]; later, parts of the CO2-sensitivity curve (the regression of ventilation on alveolar pco2) were determined at raised and normal temperatures, and on 2 subjects CO2 sensitivity was determined in full at both temperatures; comparatively few such experiments were performed. The course of a typical experiment of the last type and of an air-breathing experiment are shown in fig. la and b. Steadiness of Conditions.-When steady-state measurements were being made, the body temperature was kept as constant as possible since a sudden rise or fall might change ventilation considerably (see Part ). t was decided arbitrarily that the temperature would be considered steady only if the difference between extreme values was less than 0 2 C. for at least 20 min. When the alveolar pco2 was changed by a substantial amount, about 20 min. elapsed before a new set of measurements was made, a period usually sufficient for the re-establishment of a respiratory steady state. RESULTS Ventilation, V (B.T.P.S.) is plotted against alveolar pco2 at normal and steady raised temperatures for subjects 1, 2 and 3 in fig. 2a, b and c. The mean temperatures, T, and mean resting alveolar pco2's, R, are also shown. The results on subjects 4 and 5 are dealt with separately in an appendix because, while not conflicting with those shown above, they are less clear-cut. C02 Sensitivity, S, over the Normal and Upper Ranges of Alveolar PC02.- The data from individual experiments were usually insufficient for satisfactory statistical analysis so the results on each subject were pooled. Linear regressions of V on pco2 were calculated for the data at normal and raised temperatures over a range of pco2 extending upwards from the lowest value obtained when air was breathed at ordinary temperature; the points obtained at raised temperature in air-breathing experiments (open circles in fig. 2) were not included in the calculations because there was an obvious discontinuity in the vicinity of R. For each subject the slopes of the 2 regression lines, S, were compared using the Behrens method [Fisher and Yates, 1933], which is applicable when the variances of the quantities to be compared differ significantly.

5 Raised Temperature, CO2 and Breathing 333 A a: Subject. Subject 2. R C z 0 3~~~~T3 x 8~ _~~ 0_ ALVEOLAR9pC42, 0 R4 50 0~~~~~~~~~~~~~~ 3o t. 25 X a T-36-90C x 40 mm.c50c. T3386C.~~~~3-5C xt3663 xxx rase tempertures tempertue. T, mea meneca reta tempeatur teprtr atwihosratoswr 0hc 0bevain weemae ALVue,beOLhngair, p CO2. mm.weto. ALVEOLA pullnsreesisofvnco2mm.ehr to~~~ujet Subec 3nd3 meantalveolar pch w whenbreathingairt oar Tpe atre. i cateorindary Forsubet 1,, b and therelation 3 vetlain,v between si alelrpoth and normpealtand snc ft b Subjesjo dan 1, 2 3. temperature;each cataseda tempertreowimthl pc dnerorbeabovy;,a raisigtedtempert eaure,bhnreath bing air,pco fallwedto(fal Ful lines regressioncsof1 ondpc2, overno atwichitonathnomlavoapc2vr was measured issonioi.3n h asidct standrdl occasions by adjusting the alveolar pco2 at raised temperature to its previous normal value [cf. Cormack et al., 1957] and was increased at raised temperature in all 3 subjects. The adjustment of the pco2 was not always exact and the best estimate of the effect of temperature on VR may be obtained by comparing the intercepts of the regression lines on R (fig. 3b). The increases in VR with temperature were variable, but were significant (Behrens test, P < 0.01) in all 3 cases. The determination of VR at two raised temperatures on subject 5 is described in the appendix. V at Raised Temperature and below the Normal Alveolar pco2.-jn some experiments no CO2 was added to the inspired air during the thermal

6 334 Cunningham and O'Riordan hyperpnoea and so alveolar pco2 fell, usually by more than 5 mm., and sometimes by as much as 15 mm. (fig. 2, open circles). The relation described between V and pco2 over the higher range of pco2 clearly does not hold in this region and the data are fairly well represented by a horizontal line drawn through the means of the open-circle points. n these experiments the increases in V were small. A LU ~~~~~ uil20 B 10 -~/ RECTAL TEMPERATURE, C FGS. 3a and b.-relation between C02 sensitivity (S) and rectal temperature over normal and upper range of alveolar PCO2 for subjects 1, 2 and 3. Bars represent standard errors. (b) Relation between ventilation at the normal alveolar PCO2 (VTR) and rectal temperature for subjects 1, 2, 3 and 5. Bars represent standard errors. Additional Observations.-Before the application of heat the rectal temperature fell progressively by as much as 0 3 C./hr. [cf. Benedict and Slack, 1911]. The fall was more rapid during C02 inhalation [Cormack et al., 1957]. The rectal temperature just before the chamber was heated thus depended to some extent upon the duration and nature of the preceding investigations. Periodic breathing was seen occasionally with rising and steady raised temperatures when the alveolar PCO2 was near its normal value (fig. 4); this was unexpected in view of the conventional explanation of "physiological" periodic breathing which in the past was seen only with a low alveolar PC02 [Haldane and Priestley, 1935; Landis et al., 1926]. However, it has

7 Raised Temperature, CO2 and Breathing 335 previously been seen with normal or raised pco2 by Cormack et al. [1957] during anoxia. n each case it has been a chance observation and we are inclined to attribute its appearance partly to psychological factors of the kind discussed in Part. 'i liii 'ii l U l111l1 1l 1 iuue i ilii ilieiuiir,, 1_11, HUl U 11 1 NU 111 le ri 1l UWtU nlua * *pp p * * * FG. 4.-Periodic breathing observed at raised body temperature and with normal alveolar subject P00; 1. Top and middle tracings (a continuous record), onset of periodic breathing while temperature was rising; bottom tracing, later in the same experiment when temperature was steady. From top to bottom on each tracing, 1, signal marker; 2, signals from gas meter; 3, signals from gas meter; 4, time, 10 sec.; 5, mouth pressure tracing. Top and Bottom middle tracings tracing Rate of rise of rectal temperature, 'C./hr. 2*4 0 Rectal temperature, 'C nspired PCO2, mm. Hg Alveolar PCO2 mm. Hg.... about 42 about 43 Ventilation,./min DsCUSSON The possibility that the effects that we observed may be attributed to psychological factors is considered in some detail in Part, because the responses to a rising temperature are probably more liable to interference from this source. The results of the air-breathing experiments are in agreement with the finding of Bazett and Haldane [1921] and of Barltrop [1954], that the respiratory response to a steady raised temperature is smaller than that to a rising temperature (see Part ). The nteraction between Raised Temperature and C02, and a Comparison with Anoxia.-Gray [1950] mentioned temperature as a possible respiratory stimulus but did not include it in his "chemical ventilation equation". He postulated that the "partial effects" of individual respiratory stimuli could be summed algebraically, and hence in a plot of V against alveolar pco2 the

8 336 Cunningham and O'Riordan application of a second stimulus would displace the regression line upwards or to the left with no change of slope. Grodins [1950] assumed this applied to temperature. Nielsen and Smith [1951] and Cormack et at. [1957] discussed the inadequacy of the theory when applied to the anoxic and CO2 stimuli, and it appears that our results at raised temperature are not in accordance with Gray's assumptions either. However, Cotes [1955] found that the raised temperature of an exercising subject did not affect the slopes of the V/pCO2 lines but displaced them upwards, as predicted by Gray. There are a number of important differences between his experiments and our own; for example, temperature gradients across the skin were large and heat production was increased several fold in his subject, who also inhaled CO2 in oxygen, while ours were given C02-air mixtures. n these circumstances a difference between the 2 sets of results is not surprising. The interactions of raised temperature at rest and of anoxia with the CO2 stimulus have several points in common [cf. Nielsen and Smith, 1951; Lloyd et al., 1956]; at and above the normal alveolar pco2 the relation betweenv and pco2 appears to be linear for anoxia and there is no evidence that this is not the case also for raised temperature. The increase of CO2 sensitivity has been reasonably well established for temperature, as for anoxia. Furthermore, the data in fig. 2 indicate that at raised temperature there is a discontinuity in the relationship between V and pco2 at or slightly below R, similar to the CO2 threshold demonstrated for anoxia by Nielsen and Smith [1951] and by Hall [1953]. Such a threshold would be at the point where the extrapolation of the regression line meets the horizontal line drawn through the points at raised temperature and low pco2, as indicated by the dotted lines in fig. 2b and c. Since the work was completed, Lloyd et al. [1956] have introduced a slightly different method of expressing results of this sort. As with anoxia, the intercepts of the regression lines for the present data extrapolated to the PC02 axis (the constant B of Lloyd et at.) were not displaced consistently in either direction by raising the temperature. f for any one subject, therefore, B is the same for all sets of observations above the C02 threshold, the regression lines might permissibly be redrawn to pass through it, and a change in 1R would then merely be a manifestation of a change in slope. Exercise Hyperpncea.-A discussion of the bearing of these results on the problem of exercise hyperpncea will be given in a later paper. Possible Modes of Action of Raised Temperature on Respiration.-The specialized thermoreceptors may have contributed an additional stimulus to the respiratory centre; Bazett [1951] stressed the importance of the skin receptors, and Lim and Grodins [1955] have examined the relative contributions of the skin and hypothalamus to thermal panting in dogs. n the tongue, where some thermoreceptors in the cat are thought to respond to absolute temperature [Dodt and Zotterman, 1952], the temperature may even have fallen as a result of the hyperpncea while the temperature of the rest of the body rose. There is little evidence that any of these receptors do or do not affect respiration under steady-state conditions in man.

9 Raised Temperature, CO2 and Breathing 337 On the other hand, raising the temperature, besides affecting excitability, alters the environment of cells in the respiratory centre and carotid and aortic bodies in a number of ways, and it is possible that our findings result from effects of change of temperature on receptors normally concerned with the regulation of respiration rather than on specialized thermoreceptors in other regions. The concentrations and rates of diffusion of free C02, carbonic acid and bicarbonate would be altered by raising the temperature; if the temperature of the arterial blood were to change between the lungs and the centres [cf. Gerbrandy, Snell and Cranston, 1954] its pco2 and ph would change also [cf. Brewin, Gould, Nashat and Neil, 1955]. The results of Brewin et al. invalidate, to some extent, the observation of Bernthal and Weeks [1939] that warming the fluid used for perfusion of the carotid body stimulates respiration; the temperature of the perfusate was adjusted after gaseous equilibration and so the pco2 and ph of the fluid as it entered the carotid body is not known for certain [Schmidt and Comroe, 1940; Neil, personal communication]. APPENDX TO PART Results on Subjects 4 and 5 n fig. 5, V is plotted against alveolar pco2 for subject 4, the symbols being the same as in fig. 2. The data on him have been excluded from the main series for F Cd J z J z w 40 Subject 4 Subject 4 T= R T=38 0 C 0 /. T-38-20C _ T=38-1 C. xsexx x,-- l 0 x * ALVEOLAR p C02. mm. Hg. /T=36-6C 50 bc FG. 5.-Relation between ventilation and alveolar pco2 for subject 4. Symbols as in fig. 2. Separate regression lines have been drawn for the 2 experiments at raised temperature in which pco2 was above normal.

10 338 Cunningham and O'Riordan reasons, (1) Pooling of the results obtained at high temperature on separate days was very unsatisfactory so separate regression lines have been calculated for the few points in each experiment; S and VR at ordinary temperature were similar on the 2 days when they were measured, so a single line was calculated for the data at ordinary temperature. (2) VR was not measured at raised temperature and to obtain it by extrapolation of the regression lines would be very misleading. (3) n a later experiment subject 4 showed an hysterical hyperpncea during and after exercise; this, coupled with the unusually large increases in S, suggested that raised temperature and CO2 might not have been the only respiratory stimuli active during some of the determinations shown in fig. 5. There were no more definite reasons for treating the data on him with reserve. Subject 5 found the selected temperature ( C.) uncomfortable and in 2 experiments at this temperature VR, was doubled, the increase being significant (fig. 3b). n 3 more experiments at the more comfortable temperature of C. (±t0-1) the change in VR was small and not significant. S was not determined satisfactorily at any temperature because his respiration was very variable. PART.-THE EFFECTS OF RSNG TEMPERATURES METHODS Besides the observations in the steady states preceding and immediately following the phase of rising temperature, the maximum ventilation while temperature was rising and the corresponding alveolar pco2 were noted and used as an index of the effect of temperature in the non-steady state. RESULTS n 9 air-breathing experiments on 5 subjects we have confirmed that on raising the body temperature there is an increase in ventilation and a fall of alveolar pco2, that the peak response while temperature is rising may be very great [Bazett and Haldane, 1921; Landis et al., 1926] and that the increase in ventilation and depression of alveolar pco2 at a given temperature are nearly always less when temperature is steady than when it is rising [in fig. 6a, x, the non-steady-state increase in ventilation, exceeds y, the steady-state increase; Bazett and Haldane; Barltrop, 1954]. Mean values and standard errors for ventilation, alveolar pco2 and rectal temperature of all subjects during the 3 states are shown in fig. 6a; the mean decline in the ventilation, z, at the transition from the non-steady to the steady state at raised temperature was 11.0 l./min. (S.E. ± 3.2). There was great variation in the results between individuals and between different experiments on the same individual. The ventilation and alveolar pco2 usually reached their steady values at the higher temperature quite suddenly, often within 5 min. of the change of environmental conditions which led to the steady state for temperature; rectal temperature approached its steady value more slowly [cf. Gerbrandy et al., 1954]. n fig. 7a the maximum increase in ventilation, x, while temperature was rising is plotted against the rate of rise of rectal temperature for all experiments. Points obtained on a single subject are joined. Five points obtained

11 Raised Temperature, CO2 and Breathing 339 on 2 subjects by Landis et al. [1926] are also shown; there is no disagreement between our results and theirs, but there is little or no evidence for correlation. The decline, z, at the transition from the non-steady to the steady state is plotted against the rate of rise of temperature in fig. 7b, and the evidence for correlation is no better than for x. 60 A B 01 tn c a O o 2 - -J 00,Q,cj A j...z -E X.,...3V. T.T B b 43 ix 1 37 Ai m ALVEOLAR pc02 FREE TO VARY...***i** E m p CO2 HELD STEADY FG. 6.-Means and standard errors of ventilation, alveolar pco2 and rectal temperature for all subjects;, at ordinary temperature just before the application of heat;, at the moment of the peak response while temperature was rising;, early in the subsequent steady state at raised temperature. (a) 9 air-breathing experiments, (b) 10 experiments in which alveolar pco2 was held at or near its control value. x, y, increases in ventilation in non-steady and steady states respectively above control value at ordinary temperature; z, decline in ventilation at transition from non-steady to steady state at raised temperature. Open circles in b, mean ventilations in 3 other experiments the results of which were qualitatively different from those of the 10 shown by the closed circles. The Effect of C02.-n the air-breathing experiments the initial high ventilation resulted in a considerable loss of CO2 from the body, as judged from the depression of the alveolar pco2. Part or all of the decline, z, in the ventilation might be attributed to the development of acapnia [cf. anoxia, Haldane and Poulton, 1908; Cormack et al., 1957]. To test this possibility, in 13 other experiments the fall of alveolar PCO2, and hence the loss of C02 from

12 340 Cunningham and O'Riordan the body, was largely prevented by the addition of some extra C02 to the inspired air as the hyperpncea developed [cf. Cormack et al., 1957]. Any decline in the ventilation, z, which might persist in spite of this would be evidence for the existence of a response to a rising temperature, as suggested by Landis et al. [1926], over and above the known response to a steady raised temperature described in Part. z 60 0 A C z X, Zuj a z!aui z >;td w z 60 4 B D - 6 ze 20 cd z u 0 - T RATE OF RSE OF RECTAL TEMPERATURE, OC/HR. FGs. 7a, b, c and d.-absence of correlation of rate of rise of rectal temperature with non-steady-state increase in ventilation, x, when pco2 was allowed to fall (a) and when it was held steady (c), and with decline in ventilation at the onset of the steady state, z, (b and d). Points obtained on different occasions on the same subject are joined. Crosses denote observations of Landis et al. [1926] on 2 subjects. An incomplete experiment on subject 1 is included in c and d, making a total of 14 points. The experiments were carried out at normal and raised levels of alveolar pco2; the relation between the steady and the non-steady states was similar at each level so all experiments are considered together as a group. " Setting " the alveolar pco2 is relatively easy in the steady state, but difficult in the nonsteady state; thus, at the steady raised temperature pco2 was within 1 mm. of its selected value in 12 out of 13 experiments, but when temperature was rising, pco2 was within 3 mm. in only 7 out of 12 experiments; in the 13th experiment alveolar pco2 was not recorded at the time of the peak response. A consistent pattern appeared in 10 of the experiments, mean values for the results of which are shown as closed circles in fig. 6b. The values for z lay between - 6 and /min. and were distributed normally about a mean of + 1*7 1./min. (S.E. ± 1-4). n the remaining 3 experiments, z was 32, 50 and

13 Raised Temperature, CO2 and Breathing 57 1./min. These 3 have been excluded from the means in fig. 6b because when they were included [as was done in a preliminary account of this work,- Cunningham and O'Riordan, 1956], mean z lay between the groups and described neither satisfactorily. Means for the 3 are shown in fig. 6b as open circles. The individual values of x and z when pco2 was held steady are plotted against rate of rise of temperature in fig. 7c and d. The responses of a single subject on separate occasions show no correlation with the rate of rise of temperature which does not, therefore, account for the differences between them. The Temperature required to Produce a Response.-The experiments were not designed to elucidate the relation between the rise of temperature and the magnitude of the response; however, as the work proceeded a fairly uniform pattern emerged. Soon after steam was admitted to the chamber there might be a small hyperpncea, sometimes even before the rectal temperature started to rise; the onset of the major response was often delayed until the rectal temperature had risen appreciably, usually by an amount which was characteristic for the subject, though each showed some variation. Fig. lb illustrates an experiment on subject 3 in which temperature was increased in 2 steps; a major increase in the ventilation occurred only during the second rise. The rise before a well-marked respiratory response was observed was C. with subject 1 and C. with subjects 2 and 4. Subject 3 was less consistent; in 3 experiments the initial hyperpncea occurred after rectal temperature had risen 1-2, 1.0 and 0-2 C. The selection of the steady raised temperatures to which the subjects were exposed was based on their responses in the non-steady state; nevertheless, whenever the selected temperature was achieved there was a well-marked effect on VR in the steady state, but when a lower temperature was employed, as with subject 5, the change in VR was trifling (fig. 3b). The data are consistent with the view that for the non-steady state, and possibly also for the steady state, there is a temperature threshold which may be fairly uniform for any one subject. n this respect our results differ from those of Cotes [1955] who showed that the relation between rectal temperature and ventilation in exercise was linear over the whole range studied. 341 DiscussioN The data may be analyzed further by using the regressions of ventilation on pco2 for the steady state from fig. 2. With them it is possible to predict the position on the diagram which should be occupied by a point representing the peak non-steady-state response if the decline, z, is to be accounted for completely by changes in the alveolar pco2. The predicted ventilation is probably a slight overestimate since the rectal temperature on which it is based is slightly higher than that which obtained at the time of the peak response. There may also be some doubt about the data at low pco2 because

14 342 Cunningham and O'Riordan the exact form of the steady-state relationship over this range is uncertain. Nevertheless, if the point representing the observed response lies well above the appropriate regression line, it is reasonable to conclude that an additional stimulus was operating ALVEOLAR p CO2, mm. Hg. FGS. 8a and b.-relation between ventilation and alveolar PCO2 at ordinary temperature ( x ) and with rising (A, A) and steady raised temperatures (0, 0 ). Open symbols denote experiments in which pco2 was free to vary, closed symbols, those in which an attempt was made to control it. Lines with arrows join points from single experiments; thick full and broken lines are the regression lines from fig. 2. (a) subject 1; (b) subject 2. The data for each subject have been plotted in this way and 2 of the diagrams are shown in fig. 8. Three points have been plotted for each experiment, one at ordinary temperature immediately before the application of heat, one at the peak of the non-steady-state response and the 3rd early in the subsequent steady state at raised temperature. The points for a single experiment are joined by arrows. The regression lines for the steady state from fig. 2 are shown for comparison. One extreme is shown by subject 1 in whom, when pco2 was allowed to vary, all the non-steady-state points lay far above the predicted values; at normal and raised pco2, 2 of the points lay far above, while a 3rd lay very near the regression line. Data were incomplete in another 2 experiments with the pco2 held steady, but the

15 Raised Temperature, CO2 and Breathing 343 responses were like the largest shown. The other extreme is illustrated by subject 2 in whom there was one response at low pco2 which lay above the regression line; the other at low pco2, and both those at normal and high pco2, lay within the limits set by the lines. For all subjects, 8 out of 9 responses at low pco2 were substantially greater than the predicted values; at normal and high pco2 6 out of 13 lay very close to or below the regression lines, but the 6 included 3 on subject 5 at a temperature which was near or at his temperature threshold. t is interesting that the 2 subjects whose reponses are illustrated in fig. 8 showed both types of response, though the respiration of one was usually stable and difficult to disturb while the other's was very labile. The second analysis is more rigorous than the first, but they agree in suggesting that there are 2 distinct types of response to a rising temperature, one of which may be explained in terms of the steady temperature and the alveolar pco2 alone, and the other which cannot, and therefore suggests the participation of some additional factor, not present to the same extent in the preceding or subsequent steady states. The additional factor was present in all but one of the experiments in which pco2 was allowed to fall, but was absent in at least 3 of those in which it was held steady and in which the temperature threshold was certainly exceeded. The action of CO2 may, therefore, be either to reduce its effects, sometimes to zero, or occasionally to accentuate them. Subjective interference with the results of respiratory experiments may arise in at least 3 ways: first, by active co-operation from a subject who knows what is expected of him; second, by conditioning; and third, there may be a hyperpnceic response to general discomfort or anxiety. The importance of the first 2 forms has been demonstrated during the infusion of noradrenaline [Barcroft, Basnayake, Celander, Cobbold, Cunningham, Jukes and Young, 1957]. The subject on whom this demonstration was made was our subject 1, whose response to noradrenaline when he knew the plan of the experiments was similar to his response to raised temperature. n preliminary experiments, Barcroft, Cunningham and Jukes [unpublished] found that the nonsteady-state response was particularly susceptible to interference, the steady state being more stable. n the temperature experiments, interference is unlikely to have arisen from either of the first 2 sources. The subjects knew only that they would be exposed to a hot, humid atmosphere, that they might find themselves breathing hard and that the experiments would last 2-4 hrs., during which their breathing would be observed. They knew neither the plan of the experiments nor the results expected. t was inevitable with the method that they should know when the heat was applied; they were uncomfortable while their body temperatures were rising and their breathing was sometimes unpleasantly violent. They also recognized a change before the rectal temperature became steady since the air within the chamber became cooler and less hazy. Their sensations of being overheated disappeared and they sometimes felt cool, even though body temperature was steady at a high level.

16 344 Cunningham and O'Riordan The discomfort of the non-steady state may have contributed to the excess of the response over that to a steady raised temperature. n the air-breathing experiments, however, the peak responses were no greater than those reported previously, whether in a humid tin mine [Haldane, 1905] or in hot baths [Bazett and Haldane, 1921; Landis et al., 1926]. t is unlikely, therefore, that the psychological disturbance was any greater in our experiments. n the steady state it seems likely that in the temperature experiments, as in the noradrenaline infusion experiments, the response was less labile; there may have been an exception to this in the case of subject 4 (see appendix to Part ). The Additional Factor.-The nature of the additional factor responsible for the difference between the steady- and non-steady-state effects is obscure; it might be the effect of a sudden change in the intensity of stimulation of receptors normally concerned in the regulation of respiration, in the medulla or the carotid and aortic bodies, though it is apparently independent of the rate of change of temperature, or it might result from the activation of the specialized thermoreceptors mentioned in Part. f any of them are concerned, it is difficult to see why there may sometimes be no response to a rising temperature over and above that predicted from the steady-state data. On the other hand, a response to general discomfort or anxiety miight be the additional factor; if this is so, the double effect of C02, in augmenting or suppressing the factor's activity, could be explained because there were some indications that CO2 reduced the dizziness and discomfort of thermal hyperpncea and CO2 is also known to make "voluntary " hyperpncea easier to sustain. ACKNOWLEDGMENTS J. L. H. O'R. acknowledges the receipt of a Medical Research Council training grant and is grateful to Professor E. G. T. Liddell for laboratory facilities. We wish to thank Professor C. G. Douglas for his part in some of the experiments and for his advice on numerous occasions. We are grateful to Dr. R. B. Fisher for expert advice on statistics, to Mr. B. B. Lloyd for helpful criticism of the manuscript and to Messrs. T. J. Meadows and A. Austin for technical assistance. We also express our thanks to the subjects for their co-operation. REFERENCES BANNSTER, R. G., CUNNNGHAM, D. J. C. and DOUGLAS, C. G. (1 954). "The carbon dioxide stimulus to breathing in severe exercise", J. Physiol. 125, BARCROFT, H., BASNAYAKE, V., CELANDER, O., COBBOLD, A. F., CUNNNGHAM, D. J. C., JUKES, M. G. M. and YOUNG,. M. (1957). "The effect of carbon dioxide on the respiratory response to noradrenaline in man", J. Physiol. 137, BARLTROP, D. (1954). "The relation between body temperature and respiration ", J. Physiol. 124, P. BAZETT, H. C. (1951). "Theory of reflex controls to explain regulation of body temperature at rest and during exercise", J. appi. Physiol. 4, BAZETT, H. C. and HALDANE, J. B. S. (1921). "Some effects of hot baths on man", J. Physiol. 55, 4-5 P.

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