Ventilatory relief of the sensation of the urge to breathe

Transcription

1 4582 Journal of Physiology (1996), 490.3, pp Ventilatory relief of the sensation of the urge to breathe in humans: are pulmonary receptors important? H. R. Harty, C. J. Mummery*, L. Adams, R. B. Banzett t, I. G. Wright, N. R. Banner*, M. H. Yacoub and A. Guz Department of Medicine, Charing Cross and Westminster Medical School, London W6 8RF, UK, Departments of Cardiothoracic Surgery, t A naesthetics, and *Cardiology and Transplant Medicine, Harefield Hospital, Middlesex UB9 6JH, UK and tphysiology Program, Harvard School Of Public Health, Boston, MA 02115, USA 1. The sensation of an urge to breathe (air hunger) associated with a fixed level of hypercapnia is reduced when ventilation increases. The aim of the present study was to investigate whether pulmonary receptors are important in this mechanism. 2. Five heart-lung transplant (HLT) subjects and five control subjects were studied during periods of mechanical and spontaneous ventilation. End-tidal PCO, (PET,Co2) was increased by altering the level of inspired C02. Throughout, subjects rated sensations of air hunger. Air hunger was also monitored during and immediately following maximal periods of breath-holding. 3. When the level of mechanical ventilation was fixed, both groups experienced a high degree of air hunger when PET,co, was increased by about 10 mmhg. At similar levels of hypercapnia, both groups derived relief from approximately twofold increases in tidal volume, although relief was slightly less effective in HLT subjects. This was reversible, with decreases in the level of mechanical ventilation rapidly giving rise to increased ratings of air hunger. 4. With breath-holding, all subjects obtained some respiratory relief within 2 s of the break point; there was no significant difference between the groups. 5. The results suggest that sensations of an urge to breathe induced by hypercapnia can be modulated by changes in tidal volume in the presumed absence of afferent information from the lung. In humans, it is well documented that if ventilation is constrained below the appropriate level, the degree of respiratory discomfort experienced increases. This has been shown to occur during breath-holding experiments (Hill & Flack, 1908; Fowler, 1954; Flume, Eldridge, Edwards & Houser, 1994), during volitional targeted breathing experiments (Remmers, Brooks & Tenney, 1968; Chonan, Mullholland, Cherniack & Altose, 1987; Schwartzstein, Simon, Weiss, Fencl & Weinberger, 1989) and during studies on mechanically ventilated patients with respiratory muscle paralysis (Opie, Smith & Spalding, 1959). In all of these studies, subjects were able to tolerate a higher level of Pco, when breathing at an increased level of ventilation. These studies would therefore suggest that amelioration of respiratory discomfort can occur independently of changes in blood gases. However, the mechanism by which the act of breathing modulates respiratory discomfort remains unclear. Fowler (1954) suggested that vagal input played a role in the relief of discomfort following breath-holding. Wright & Branscomb (1956) also proposed that impulses from pulmonary stretch receptors were important in the lung volume-related modulation of breathlessness. Further support for this view has been provided from a study on mechanically ventilated quadriplegics in whom afferent information from the chest wall is presumed absent (Manning, Shea, Schwartzstein, Lansing, Brown & Banzett, 1992). These authors found an inverse relationship between the degree of air hunger and the size of the tidal volume (when PET,CO, was held constant), and therefore suggested that pulmonary receptors were important. One method for investigating the importance of pulmonary receptors in the amelioration of respiratory discomfort would be to study a group of subjects who lack afferent feedback from the lungs. Heart-lung transplantation disrupts the neural pathways between the central nervous system and the lungs below the tracheal anastomosis. In a

2 806 H. R. Harty and others J Phy8iol preliminary report on patients following bilateral lung transplantation, there was some evidence to suggest that such individuals do not experience respiratory relief as rapidly as normal subjects when breathing resumes at the end of a period of breath-holding (Flume, Eldridge & Edwards, 1993). The aim of the present study was to investigate whether afferent information from pulmonary receptors is important in the mechanism by which the act of breathing provides relief of respiratory discomfort. By utilizing a study design similar to that used in the quadriplegic subjects mentioned above (Manning et al. 1992), we controlled the level of hypercapnia while defining the relationship between the degree of respiratory discomfort and changes in tidal volume delivered by mechanical ventilation. Using this approach we can explore these relationships under steady-state conditions in a way that is not possible with breath-holding studies. METHODS These studies were undertaken with the approval of the ethical committees of Charing Cross Hospital and Harefield Hospital. All subjects gave informed written consent. None of the subjects was aware of the specific aims of the study. Subjects Five subjects who had previously undergone heart-lung transplantation (HLT) were studied. Five age- and sex-matched healthy volunteers (controls) were also studied. Details of all subjects, including drug treatment in the transplant recipients, are given in Table 1. The HLT subjects were deliberately chosen because they were as near as possible to normal, as assessed by respiratory function testing, arterial oxygen saturation, cardiovascular and exercise testing and their reported ability to lead a 'normal active life'. When questioned, none of the subjects reported experiencing shortness of breath or any respiratory discomfort at rest or during normal activity. None of the HLT subjects were hypoxaemic at rest (oxygen saturation values at rest ranged from 96 to 99 %) and all were clinically stable and active at the time of the study. All control subjects were free from any signs of respiratory infection. All HLT subjects and three of the five control subjects had no previous history of smoking. Data from an additional four HLT subjects and five control subjects were obtained but have not been analysed for the following reasons: two HLT and three control subjects were unable to tolerate mechanical ventilation; two HLT and three control subjects were unable to understand or properly use the air hunger rating scale. Measurement techniques Inspiratory and expiratory airflows were measured using a pneumotachograph-pressure transducer set-up (Fleisch no 2 with Validyne MP cmh2o; Sandhurst Technology Ltd, Surrey, UK; deadspace, 25 ml); from this, inspiratory time, expiratory time, respiratory frequency (fr), tidal volume (VT) and minute ventilation (VE) were obtained. Inspired gas mixtures were humidified and warmed using a servo-controlled humidifier (Concha Therm III; Kendal Company, London, UK) and maintained at an inspired temperature of 'C. End-tidal PCO2 (PET,co2) was measured using an infrared analyser (LB2 medical gas analyser; Beckman Instruments, Fullerton, CA, USA; sample rate, 200 ml min1) on gas sampled from a port in the mouthpiece via a narrow-bore tube. Airway pressure was measured using a pressure transducer (Validyne MP45; + 80 cmh2o) via a separate port in the mouthpiece. An estimate of arterial blood oxygen saturation was monitored continuously using pulse oximetry via a finger probe (Biox 3700; Ohmeda, Herts, UK). Blood pressure was measured non-invasively at 3-5 min intervals using an automated sphygmomanometer (either Omega 1400, Vickers Medical, Hants, UK or Narco BioSystems PE300, Linton Instrumentation, Norfolk, UK). Assessment of respiratory discomfort Subjects were instructed to rate the discomfort caused by their urge to breathe every 15 s on a visual display positioned comfortably within their line of vision. Using a hand-held controller, the subject selected one of seven LEDs, each corresponding to an intensity of discomfort (see below) in response to a rating request. This system for rating respiratory discomfort has been described previously (Banzett et al. 1990). Prior to each of the experimental runs, a standard explanation of the rating scale was read to the subject. Thus 'zero' (Z) was defined as no respiratory discomfort at all, 'slight' (S) as respiratory discomfort which is distinct but not very unpleasant and could be tolerated for a very long time, 'moderate' (M) as very unpleasant respiratory discomfort which could be tolerated for several minutes and 'extreme' (E) as respiratory discomfort which has reached an intolerable level. The subjects were told that they could rate extreme at any time and we would immediately change the experimental conditions to make them feel more comfortable. Three of the seven LEDs were marked with a 'plus' (+) and subjects were told to use this plus rating if they felt that their level of respiratory discomfort fell between two of the defined ratings. Experimental protocols Each subject underwent three sessions (comprising four experimental protocols; see below), each lasting about 20 min; intervals of at least 30 min were allowed between runs. During all studies, the subjects lay supine with their heads slightly elevated; they wore a nose-clip throughout and breathed via a mouthpiece. During the first two sessions, subjects were ventilated using a positive-pressure volume-cycled ventilator (Servo 900B; Siemens, Elema, Sweden). In the third session subjects breathed spontaneously on the same mouthpiece, connected to a T-piece through which a bias airflow was passed. In all three sessions the inspired oxygen level was maintained at 50 %; the fraction of CO2 in inspired air (FI co) was manually controlled using a mixing valve (model 961; Siemens) to achieve the desired levels of PE co (see below). Prior to being studied, and with the aid of verbal feedback from the experimenter, subjects practised how to relax during positive-pressure mechanical ventilation; absence of spontaneous respiratory effort was confirmed by subjectively assessing the shape of the inflation pressure recording and the repeatability of the peak inflation pressure. Before each of the studies, an estimate of PET,co, during relaxed spontaneous breathing was obtained by continuously sampling respired air from a patent nostril using a fine-bore tube held in position by tape on the upper lip; no other transducers were attached at this time.

3 J Physiol Respiratory sensation and pulmonary receptors 807 Subject no. Sex Age Height Weight FEV1 (years) (cm) (kg) (1) A. Heart-lung transplant subjects 1 M M M M F Mean S.D. - 4*9 4.3 B. Control subjects 1 M 32 2 M 35 3 M 24 4 M 35 5 F 42 Mean S.D Table 1. Clinical and anthropometric data for HLT and control subjects *1 3-1 (73%) 3-5 (76%) 4*3 (97%) 4-2 (96%) 3-1 (99%) (85%) (110%) (88%) (88%) (106%) Resting FVC PET,CO2 Diagnosis (I) (mmhg) 3X6 (72%) 3*5(75%) 51 (99%) 5-4 (101%) 3-3(91%) (90%) 4-7 (107%) 4-6(91%) 4-8 (96%) 3*3 (116%) CF CF PA CF-IDDM CF 34 H 38 H 39 H 39 IDDM 35 H Medication CyA, Aza, Pan CyA, Aza, Ran, Pan, Col CyA CyA, Aza, Ran, Ome, Trim, Nif, Pred, Ins CyA, Aza, Trim, Ran, Pan Resting PET'co, was obtained during unencumbered air breathing. Control subjects are listed in the same order as their matched transplant subjects. Abbreviations: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; CF, cystic fibrosis; H, healthy; IDDM, insulin-dependent diabetes mellitus; PA, pulmonary atresia; Aza, azathioprine; Col, colistin; CyA, cyclosporin A; Ins, insulin; Nif, nifedipine; Ome, omeprazole; Pan, pancreatin; Pred, prednisolone; Ran, ranitidine; Trim, co-trimoxazole. Values given in parentheses next to the values in the FEV1 and FVC columns indicate percentage of normal predicted values. Ins Time post surgery (months) Throughout all three sessions, white noise was played to the subject via headphones to minimize the possibility of auditory cues indicating experimental changes in ventilation (see below). First session. Subjects were ventilated at min-' kg-' with a respiratory frequency of 15 breaths min-' and an inspiratory duration of 35% of respiratory cycle time. In some cases these levels were adjusted slightly for subject comfort but for any individual, all respiratory variables were held constant during this run. Experiment 1. Change in steady-state PETC02 at fixed ventilation. When subjects were relaxed they were asked to rate respiratory discomfort every 15 s. FIco2 was increased gradually to attain a PET,C02 close to the resting level during spontaneous breathing (see above). If ratings indicated a level of discomfort greater than zero+, inspired CO2 concentration was reduced so that lower ratings were attained. These conditions were then sustained over a baseline period of -4 min, during which ratings of respiratory discomfort were continued. FI 202 was then increased in stages, each lasting between 2 and 5 min, until ratings of moderate were obtained. These conditions were then sustained over a test period of -4 min. Second session. As in the previous session, subjects were mechanically ventilated throughout this run. Experiment 2. Change in steady-state PET,CO2 with concomitant increase in ventilation. After establishing baseline conditions similar to those used in Experiment 1, ratings of respiratory discomfort were obtained over a period of -4 min. Thereafter, FI C02 was increased to achieve the same level of PET,C02 which had previously induced ratings of moderate respiratory discomfort in Experiment 1. At the same time, the tidal volume delivered from the ventilator was increased; this was done in -100 ml stages so that subjects would not perceive acute (i.e. breath to breath) changes. This was continued until tidal volume had approximately doubled over a period of -- min; there were no changes in respiratory timing. The increased level of ventilation was sustained over a test period of -4 min. Experiment 3. Change in ventilation at fixed elevated P c02. With PET,C02 held constant at the elevated level (see above), tidal volume was reduced, again in stages, until the baseline ventilation was reestablished or until the subject rated moderate+ or extreme; in either case the experiment was terminated at this point. Third session. Experiment 4. Spontaneous ventilatory response to fixed elevated PET,C02* With the respiratory circuit attached, a hyperoxic gas mixture (50% % air) was allowed to flow past the subject's mouthpiece at a rate greater than the maximum peak inspiratory flow anticipated in these studies. We were able to confirm the adequacy of flow from the fact that there was never any fall in inspired CO2 concentration during inspiration. Subjects breathed spontaneously for a baseline period of -4 min, during which ratings of respiratory discomfort were made. Thereafter, FI,cO2 was increased to achieve a PET,c 2 level similar to that which had been associated with ratings of moderate in Experiment 1. As ventilation increased, FI c1 was constantly adjusted such that the was maintained at this elevated level for -4 min. PET,C02

4 808 H. R. Harlty and others J Physiol Following each of the sessions, subjects were debriefed using a standard questionnaire to further evaluate their subjective experiences. Breath-holding After concluding the studies with hypercapnia, subjects breathed air and were seated, they were then asked to hold their breath at the end of a normal expiration for as long as possible. The start of the breath-holding was signalled and subjects were asked to scale the degree of respiratory discomfort using the rating scale described previously but now used in a continuous fashion (i.e. indicating moment-to-moment changes in respiratory discomfort; Harty & Adams, 1994). Ratings were continued during both breath-holding and once breathing resumed. This was performed at least twice and oxygen saturation was monitored throughout. Data recording techniques and analyses All data were recorded on a chart-recorder (TA 4000; Gould Instrument Systems Ltd, Essex, UK). In addition, PETCO2, airflow, airway pressure and respiratory sensation were recorded onto FM instrumentation tape (Teac R-71; Teac Corp, Herts, UK). The recorded voltages were subsequently digitized at 50 Hz using a data acquisition and analysis system (Superscope II software and AMacadios analogue-to-digital converter; GW Instruments, Somerville, AIA, USA). The digitized airflow signal was integrated to give inspiratory and expiratory volumes for each breath. Periods of ten breaths were identified towards the end of the baseline and test periods in each run and mean values for VT, VE and PET,Co, were calculated using a computerized analysis routine set up specifically for this purpose (Superscope II software). Statistical analysis For Experiments 1 and 2, the changes in PETCO,2 VE and air hunger ratings were compared between the HLT and control groups using the AIann-Whitney U test. Statisical significance was set at P< Insufficient data, resulting from failure to achieve steady-state ventilation in some individuals (due to extreme ratings of air hunger) were available to perform this comparison on the results obtained in Experiment 3. RESULTS Subjects' comments All of the subjects were confident that they could rate their sensations of respiratory discomfort and could distinguish them from other sensations such as awareness of physical discomfort or sensations associated with distress or anxiety. When asked to choose the preferred description of their respiratory discomfort from a list of ten (Banzett et al. 1990), three HLT subjects selected 'urge to breathe', one Experiment 1 Experiment 2 Experiment ET,CO2 (mmhg) an VE 20 (I min-') 10., 0' Subject ----no. -01 ** o & s--- 5 Figure 1. Changes in air hunger ratings obtained from five control subjects in response to hypercapnia during Experiments 1, 2 and 3 In each figure, individual control subjects have been assigned the same symbol in all three panels; these symbols also correspond to their age- and sex-matched HLT partners in subsequent figures. denotes low CO2, denotes high CO2, denotes low ventilation and HV denotes high ventilation. Air hunger rating id - HV HV

5 J Physiol Respiratory sensation and pulmonary receptors 809 selected 'air hunger' and one selected 'changed size of breaths'. For control subjects, three selected 'urge to breathe', one selected 'air hunger' and one selected 'starved for air'. For consistency with previous studies (Banzett et al. 1990) in presenting these results, the term 'air hunger' will be used to identify the sensation of respiratory discomfort rated by subjects. In general, the descriptions of respiratory sensations offered by the subjects following sessions 1 and 2, did not differ between the HLT and control subjects. Moreover, identification of non-respiratory symptoms associated with hypercapnia were similar between the two groups with reports of 'warmness', 'dizziness' and 'irritability' being the most common. Most subjects felt that session 1 (hypercapnia with fixed ventilation) was worse than session 2 (consisting predominately of hypercapnia with elevated ventilation) and in addition to more severe ratings of air hunger, comments such as 'panic', 'claustrophobia' and 'anxious' were reported following session 1. In general, subjects in both groups reported a subjective feeling of a reduction iii tidal volume associated with an increased urge to breathe occurring with increasing hypercapnia at a constant tidal volume. Resting PET,CO2 Individual and mean values for resting PET,C02 are shown in Table 1. No significant differences were observed between the groups. Values for the HLT subjects ranged from 34 to 40 mmhg and for control subjects from 34 to 39 mmhg. Air hunger during hypercapnia and mechanical ventilation The changes in air hunger ratings in individual subjects in response to hypercapnia and changes in the level of positive-pressure ventilation (Experiments 1, 2, and 3) are shown in Figs 1 (control subjects) and 2 (HLT subjects). Experiment 1. Change in steady-state PET co2 at fixed ventilation In control subjects (Fig. 1, left panel), addition of C02 to the inspired air raised PET,C02 by between 7 and 12 mmhg. Ventilator settings were held constant, but VE varied slightly (-2-3 to min-') due to leakage around the mouthpiece. Each subject reported either zero or zero+ air hunger at low PETCO2 with ratings increasing to either moderate or moderate+ at high PET,CO2- In HLT subjects (Fig. 2, left panel), increases in PET,CO2 of between 7 and Experiment 1 Experiment 2 Experiment 3 0~~ Figure 2. Changes in air hunger ratings for individual HLT subjects in response to hypercapnia during Experiments 1, 2 and 3 Note: Experiment 2 shows data obtained from all five transplant subjects. Subject 5 failed to complete Experiment 1 and Subjects 2 and 3 failed to complete Experiment 3. PET,CO2 40 (mmhg) VE (I min-') 35 30, /... S/7 -'~' Subject no *o U a s O -i ~~~ E -... Air hunger rating M-. AL /JI -I~~~~~~~~~~~~~~v- M / r HV HV

6 .~~~~~~~~~~~~~~~ H. R. Harty and others Table 2. Mean values for respiratory parameters obtained for each individual following a rest period (Baseline) and following a 4 min period of elevated C02 (Hypercapnia) Baseline Hypercapnia Subject no. PET,C02 VT fr AH PET.CO2 VT fr AH (breaths (breaths (mmhg) (1) min-') (mmhg) (1) min-') A. Heart-lung transplant patients Z+ 48 1P M Z S Z 44 1P M P Z M 5 _ Mean P S.D B. Control subjects P Z Z Z '3 Z Z S Z+ 46 1P S Z 43 1P z Mean S.D O Results obtained from spontaneously breathing subjects during Experiment 4. AH, air hunger rating. Data missing for HLT Subject 5. 1 min mmhg (with slight variations in VE of between 2-4 and increases in PET,Co2 and the increases in air hunger ratings min-1) resulted in increases in air hunger ratings across individual subjects in either group. Statistical from zero to between slight+ and moderate+. There was no analysis, comparing four HLT with five control subjects, obvious relationship between the magnitudes of the showed that there was no significant difference between PET,CO, (mmhg) J Physiol Inspiratory f low (I s-') yy0yy y ~ y y VT (I) IO] 20 Airway pressure (cmh2o) 0] Figure 3. Typical record obtained from an lilt subject (no. 1) during Experiment 3 With PET co, held at 42 mmhg and at an initial elevated ventilation of 25 1 min-, tidal volume was steadily reduced over a period of 2-5 min until ventilation had fallen to 15 1 min-'. Concomitant with the fall in ventilation, the subject reported increases in air hunger from slight to moderate+. Air hunger - rating

7 J Physiol Respiratory sensation and pulmonary receptors 81 HLT subjects Control subjects PET.CO2 (mmhg) 40 /...? A~~~~~ Figure 4. Changes in air hunger ratings and the spontaneous ventilation level in response to steady-state hypercapnia (Experiment 4) Individual results are shown for the HLT subjects (left panel) and the control subjects (right panel). Note: for technical reasons, HLT Subject 5 failed to complete this experiment. SV denotes spontaneous ventilation. VE (I min-') A }/ p ~ a Subje no. O Air hunger rating E M Xp m. : S -/ / P ~~~~ IL - sv sv sv sv these groups with respect to changes in PET,CO, (P = 047), VE (P = 0-18) or air hunger rating (P = 0-89) between the low and high CO2 conditions. Experiment 2. Change in steady-state PET,CO2 with concomitant increase in ventilation In control subjects (Fig. 1, centre panel), addition of CO2 to the inspired air raised PET,CO2 to a similar level to that achieved in Experiment 1 (PET,Co2 differing by less than 1 mmhg in all subjects). This was accompanied by increases in mechanical ventilation of between 6-7 and min-'. Three control subjects reported no increase in air hunger, while the remaining two reported minimal increases. In HLT subjects (Fig. 2, centre panel) increases in PET,CO2 comparable with those of Experiment 1 were achieved in three of the four subjects (PET,co, differing by less than 1 mmhg in each subject); in HLT Subject 4, PET,C02 was 3 mmhg higher in Experiment 2. Associated increases in mechanical ventilation were between 7-3 and min-'. All subjects reported increases in air hunger ratings. Statistical analysis showed that there was no difference between HLT and control subjects with respect to changes in PET,CO2 (P = 0-45) and VE (P = 0-92) between the low and high CO2 conditions but increases in air hunger ratings were significantly greater in the HLT group (P = 0-02). Experiment 3. Change in ventilation at fixed elevated PET,CO2 In four control subjects (Fig. 1, right panel) PET,CO, was held constant (to within 1 mmhg) at a hypercapnic level, while mechanical ventilation was reduced by between 7 and 16 1 min-'. All subjects reported substantial increases in air hunger. In three HLT subjects, VE (Fig. 2, right panel) was reduced by between 6 and 8 1 min-' at a constant PET,CO2 (to within 1 mmhg). All subjects reported increases in air hunger similar in magnitude to those seen in the control group. This is exemplified in Fig. 3, which shows an original record from one HLT subject (no. 1) undergoing this experiment. Experiment 4. Spontaneous ventilation during hypercapnia The changes in ventilation and air hunger ratings in response to steady-state hypercapnia are shown for individuals of both groups in Fig. 4. Overall, the levels of

8 812 H. R. Harty and others J Phy8iol Table 3. Individual and mean results of the duration of breath-holding for the HLT and control subjects Subject Time to Time to 1st fall no. break point in air hunger (s) (s) A. Heart-lung transplant subjects PG P0 00 Mean 43-5 S.D B. Control subjects P Mean 38-0 S.D. 11i1 PG ' '2 1 6 Time to slight air hunger (s) 3.0 3' % Time to zero air hunger (s) '0 15'5 11P The time course of the reduction in air hunger following breath-holding is also shown for both groups. HLT Subject 1 did not participate in breath-holding. hypercapnia induced in the HLT subjects were higher than those for the control subjects, as were the corresponding ratings of air hunger. There was little difference in the levels of ventilation induced by hypercapnia in the two groups. Similarly, few differences can be seen in the pattern of the ventilatory response adopted in response to C02 in both groups. Individual values for VT, fr and PET,CO2' together with a rating of air hunger, are shown in Table 2 during the rest condition and following the 4 min of spontaneous ventilation at the elevated PET,CO.* One of the HLT subjects (no. 2) showed a paradoxical fall in fr as PET,CO2 increased. Comparison of air hunger during hypercapnia between spontaneous breathing and mechanical ventilation All five control subjects reported less air hunger during spontaneous breathing than during fixed mechanical ventilation at similar levels of PET,CO, (see Fig. 4, right panel and Fig. 1, left panel). In HLT subjects there was no consistent difference in air hunger rating between spontaneous and fixed mechanical ventilation (see Fig. 4, left panel and Fig. 2, left panel); however, in this group PET,CO2 was not well matched across conditions. During spontaneous breathing all control subjects reported similar ratings of air hunger to those obtained during increased mechanical ventilation despite the fact that PET,C02 tended to be higher and VE lower in the former (see Fig. 4, right panel and Fig. 1, centre panel). Three of the four HLT subjects reported greater air hunger with spontaneous breathing compared with increased mechanical ventilation (see Fig. 4, left panel and Fig. 2, centre panel). In this group, VE during spontaneous breathing was generally lower than that during increased mechanical ventilation; there was no consistent difference in PET,C02* Breath-holding Table 3 summarizes the results of the duration of breathholding and the time course of the reduction in air hunger following breath-holding in the HLT subjects and control subjects. The mean duration of breath-holding at endexpiratory lung volume was not significantly different between the HLT and the control subjects, neither was there any significant difference in the mean time course of relief of respiratory discomfort after the break point. DISCUSSION The principal finding of the present study is that lung denervation does not abolish the relief of hypercapniainduced air hunger associated with increased tidal expansion of the respiratory system. This suggests that mechanoreceptive information from the lungs is not obligatory for such relief. Our interpretation does depend on the assumption that there has been no afferent reinnervation of the transplanted lungs following surgery and, although we did not test this formally, there is substantial functional evidence from other studies in similar patients that such reinnervation does not occur (Higenbottam, Jackson, Woolman, Lowry & Wallwork, 1989; Sanders et al. 1989; Hathaway, Higenbottam, Lowry

9 J Physiol Respiratory sensation and pulmonary receptors 813 & Wallwork, 1991). We also acknowledge that an important limitation of the present study relates to the small number of HLT recipients that we were able to recruit. The main reason for this was that, of the patient population available for us to study, relatively few had normal lung function, a criterion we considered essential. Even though tidal volume-related relief of air hunger was evident in both groups, the magnitude of the relief appears to be less in HLT subjects. Firstly, although hypercapnia induced similar degrees of air hunger in both groups under conditions of fixed ventilation, the reduction in air hunger associated with increased mechanical ventilation (Figs 1 and 2) was significantly greater in the control subjects (P = 0 02). Secondly, during maintained hypercapnia, a reduction in tidal volume tended to induce greater air hunger in control compared with HLT subjects (Experiment 3; Figs 1 and 2). Thirdly, during spontaneous breathing, HLT subjects reported greater increases in air hunger during hypercapnia in the face of similar increases in ventilation (Fig. 4). However, these apparent differences must be interpreted with caution since the group sizes were small and there was overlap in the responses of individuals. The changes in PET,co, and ventilation were not precisely matched between groups, although detailed examination of Figs 1 and 2 does not indicate that this imperfect matching would explain the fact that HLT subjects appear to obtain less volume-related relief of air hunger. The present study shows clearly that a ventilationdependent interaction exists between the degree of air hunger and the level of Pco2* However, because we recorded air hunger at only two levels of ventilation, we are unable to establish the extent to which air hunger is linearly (and inversely) related to ventilation (at constant Pco,) as opposed to there being a threshold level of ventilation below which air hunger is independent of respiratory movements. Further work would be required to enable this distinction to be made, thereby increasing the understanding of the underlying mechanisms. As a group, HLT subjects would appear to behave no differently from matched control subjects in ability to hold their breath or in the time course of improvement in air hunger following the end of breath-holding; however, two of the four HLT subjects reported full relief only after a delay longer than that reported by all five control subjects. It is known that resumption of breathing at the end of breath-holding is accompanied by rapid relief of discomfort even when any improvement in blood gas status is prevented (Hill & Flack, 1908; Fowler, 1954); this has led to the view that afferent feedback from mechanoreceptors within the respiratory system provides the neural basis for such relief. All HLT subjects studied reported some relief of respiratory discomfort within 2 s of breath-hold break point (i.e. less than the circulation time from the lungs to carotid bodies, where improvements in blood gas levels would first be detected). Thus, based on the assumption that afferent feedback from pulmonary receptors is absent in our HLT subjects, such mechanoreceptive activity could not have accounted for the rapid amelioration of air hunger reported by these individuals following breath-holding. A recent study by Flume et at. (1993) recorded significantly shorter durations of breath-holding in subjects following bilateral lung transplantation compared with normal controls. In the present study the mean duration of breathholding for both of our groups (HLT, 44 s; control, 38 s) was close to that reported by Flume et al. (1993) in their normal subjects (37 s). However, a mean duration of breathholding of 22 s which they obtained from their patient group is less than that found in any of our four HLT subjects and indicates a clear difference between the subjects with lung denervation in the two studies. More recently, Flume, Mattison & Eldridge (1995) have observed that heart transplant recipients have a reduced period of breath-holding, similar to that seen in bilateral lung transplant recipients. However, the relief of respiratory distress associated with breathing movements in the heart transplant group was, unlike the lung transplant group, immediate and similar to that seen in normal subjects. In the present study, we selected only the most healthy of subjects and this might explain the discrepancy between our findings and those of Flume et al. (1993, 1995). In addition to studies on breath-holding, other observations suggest that respiratory movements act to diminish sensations of respiratory discomfort arising as a result of respiratory stimulation. Remmers et al. (1968) found that normal subjects tolerated greater hypercapnia when voluntarily targeted ventilation was greater. More recent studies have confirmed that for a given degree of hypercapnia, normal subjects report more respiratory discomfort when breathing is constrained below spontaneous levels either volitionally (Chonan et al. 1987; Schwartzstein et al. 1989) or during positive-pressure mechanical ventilation (Opie et al. 1959; Banzett, Lansing, Evans & Shea, 1995). Similarly, during mild exercise, with the level of CO2 maintained slightly above the resting isocapnic level, greater intensities of respiratory discomfort are present when breathing is constrained below the level that would occur spontaneously (Oku, Kump, Cherniack & Altose, 1993). The fact that patients with high cervical spinal cord lesions report less air hunger during hypercapnia when being ventilated at a higher tidal volume (Manning et al. 1992) suggests that afferent feedback from receptors within the chest wall (ribeage, abdomen and diaphragm) are not obligatory for such volume-related relief and that vagal afferents are able to subserve this function. The present study was designed in a similar fashion to that of Manning et at. (1992) to enable comparisons between subjects who lack pulmonary afferent information (HLT subjects), subjects who lack chest wall afferent information (C1-C3 quadriplegics) and subjects in whom both pathways should be functioning (normal subjects). The group size, age

10 814 H. R. Harty and others J. Physiol and sex distribution of our subjects was similar to those studied by Manning et al. (1992), as was the experimental protocol and the subjective rating scale used. On the other hand, there were differences in Pco, levels at which the studies were done and the direction of imposed changes in tidal volume. However, taken together, these findings suggest that volume-related relief of air hunger can be effected by lung or chest-wall receptors, and that either pathway alone is nearly as effective as both together. There is, however, an important caveat: these transplant patients retain their own trachea, which may contain a sufficient number of stretch receptors to provide relief. It is also conceivable that relief was afforded by extrathoracic airway receptors stimulated by differences in upper airway pressure or in airflow (although not via cooling since we used humidified and heated air). An alternative explanation is that volume-related relief of air hunger depends on a mechanism not related to mechanoreceptive feedback from respiratory structures. A possible criticism of the present study was the relatively short time allowed between a change in inspired CO2 concentration and data collection (i.e. a minimum of 4 min). Since cerebral ph could still be falling at this time, it is possible that central chemoreceptor drive would not have been stable. However, for practical considerations it was necessary to limit the time over which mechanical ventilation was used. Our justification for the period chosen was based on previous studies which showed stabilization of the ventilatory response within 4 min following CO2 administration using a constant flow method analogous to that used in the present study (Saunders, Partridge & Watson, 1980; Jacobi, Iyawe, Patil, Cummin & Saunders, 1987). Further support is provided by data recently obtained by our group which shows that, under conditions of constant mechanical ventilation, a step change in Pco, results in changes in air hunger which are essentially complete within 2 min (R. B. Banzett, unpublished observations). In the present study we elected to use mechanical ventilation because we felt it was the best way in which to establish a constant ventilation (and respiratory pattern) and achieve 'steady-state' hypercapnia at precisely controlled levels. However, some subjects were unable to tolerate mechanical ventilation and had to be excluded from the study. An alternative approach would have been to ask subjects to volitionally control their level of ventilation at fixed levels of hypercapnia, although the mental distraction associated with this would have introduced a potentially confounding factor. A further concern is our use of healthy subjects as controls for our HLT patients. Patients who had undergone heart transplant operations would have been more closely matched to our HLT group in terms of their clinical, psychological and pharmacological profile. It has been suggested that perception of respiratory discomfort can be influenced by previous experience, and indeed all of the HLT subjects who participated in this study had experienced chronic shortness of breath prior to their transplant. Banner, Lloyd, Hamilton, Innes, Guz & Yacoub (1989) showed that there was no significant difference in dyspnoea scores or the maximum ventilation reached at peak exercise between normal subjects, heart-lung recipients and heart transplant subjects; these results would therefore suggest that the effects of chronic illness have not modified the subjects' perception of respiratory sensation. There is also some evidence to suggest that following heart-lung transplantation subjects may have a blunted or reduced ventilatory response to CO2 (Sanders et al. 1989), which might suggest some abnormality of respiratory control mechanisms and hence respiratory sensations in this group. However, on close examination it would appear that this phenomenon is due to subjects having poor lung function and that if subjects with normal lung function are selected, normal ventilatory responses are observed (Duncan, Kagawa, Starnes & Theodore, 1991). In the present study, we were careful to select only those patients with respiratory function within the normal range, although we did not measure ventilatory sensitivity to CO2. None of the subjects were hypoxaemic at rest and previous pulmonary function testing had shown no evidence of ventilation-perfusion inequalities. The fact that we were unable to demonstrate any difference in response compared with normal healthy subjects makes it unlikely that the use of heart transplant subjects as controls could have influenced the interpretation of our findings. In summary, increased tidal volume relieved-air hunger resulting from hypercapnia in HLT patients, as it did in control subjects, suggesting that afferent information from mechanoreceptors in the lungs is not the only mechanism by which the act of breathing ameliorates the sensation of an urge to breathe. The magnitude of the volume-related relief was less in HLT subjects but the small number of individuals studied makes it difficult to assess the physiological significance of this difference. BANNER, N. R., LLOYD, M. H., HAMILTON, R. D., INNES, J. A., Guz, A. & YACOUB, M. H. (1989). Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation. British Heart Journal 61, BANZETT, R. B., LANSING, R. W., BROWN, R., TOPULOS, G. P., YAGER, D., STEELE, S., LONDONO, B., LORING, S. H., REID, M. B., ADAMS, L. & NATIONS, C. S. (1990). 'Air hunger' from increased Pco, persists after complete neuromuscular block in humans. Respiration Physiology 81, BANZETT, R. B., LANSING, R. W., EVANS, K. C. & SHEA, S. A. (1995). Stimulus response characteristics of CO2-induced air hunger in normal subjects. Respiration Physiology (in the Press). CHONAN, T., MULLHOLLAND, M. B., CHERNIACK, N. S. & ALTOSE, M.D. (1987). Effects of voluntary constraining of thoracic displacement during hypercapnia. Journal of Applied Physiology 63,

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