to hypercapnia and hypoxia in patients chronic obstructive pulmonary disease

Transcription

1 Thorax 1997;52: Effects of fenoterol on ventilatory response to hypercapnia and hypoxia in patients with chronic obstructive pulmonary disease Shunsuke Suzuki, Yuuji Watanuki, Yasuhiro Yoshiike, Takao Okubo Abstract adrenergic agonists potentiate chemosensitivity Background It has previously been whilst another study did not. 7 The ventilatory shown that fenoterol, a β 2 adrenergic agon- response to hypercapnia or hypoxia in patients ist, increases the ventilatory response to with chronic obstructive pulmonary disease hypoxia (HVR) and hypercapnia (HCVR) (COPD) continues to be debated. Patients with in normal subjects. The effects of β 2 adrenergic carbon dioxide retention were found to have a agonists on chemoreceptors in decreased response to carbon dioxide while patients with chronic obstructive pulmonary non-hypercapnic patients had a normal disease (COPD) remain con- response. 89 In another study there was no troversial. This study was designed to difference in the response to carbon dioxide examine whether fenoterol increases the between hypercapnic and non-hypercapnic HVR and HCVR in patients with COPD. patients. 1 In some studies hypoxaemic patients Methods The HCVR was tested in 2 with COPD have been reported to have a patients using a rebreathing method and decreased response to hypoxia, while in one the HVR was examined using a progressive study they had an increased response. 13 The isocapnic hypoxic method. The HCVR and effects of β agonists on ventilation and its chem- HVR were assessed by calculating the ical control may therefore be important when slopes of plots of occlusion pressure (P.1 ) β agonists are used to treat obstructive airway and ventilation (V E) against end tidal car- diseases. We have recently shown that fenoterol bon dioxide pressure (PETCO 2 ) and arterial increases the ventilatory responses to both oxygen saturation (SaO 2 ), respectively. hypercapnia and hypoxia in normal subjects. 6 Spirometric values, lung volumes, and The purpose of this study was to investigate respiratory muscle strength were also the effects of fenoterol on the ventilatory responses measured. The HCVR and HVR were examined to hypercapnia and hypoxia in patients after the oral administration of with COPD. fenoterol (15 mg/day) or placebo for seven days. Results Fenoterol treatment increased Methods the forced expiratory volume in one second Twenty patients (19 men) with COPD of mean (FEV 1 ) and inspiratory muscle strength. (SD) age 67.2 (7.8) years (range 5 8) par- In the HCVR the slope of P.1 versus PETCO 2 ticipated in the study. The patients were diagwas increased by fenoterol from.35 (.23) nosed as having COPD according to the to.43 (.24) (p<.1). Moreover, the P.1 definition of the American Thoracic Society. 14 at PETCO 2 of 8 kpa was higher on fenoterol All patients were clinically stable and had given than on placebo (p<.5) and the V E was informed consent to participate. The study was also greater (p<.1). In the HVR fenoterol approved by the Committee on Investigation treatment increased the P.1 at 8% SaO 2 in Humans of our hospital. from.9 (.72) to.97 (.55) kpa (p<.5) Spirometric tests were performed using a dry while the slopes of the response of P.1 and seal spirometer (OST-8, Chest Co, Tokyo) V E were not changed. and lung volumes were measured using a body Conclusions Fenoterol increases the plethysmograph (Autobox 28, Gould, USA). The First Department ventilatory response to hypercapnia in of Internal Medicine, The vital capacity (VC), forced expiratory vol- patients with COPD, presumably by Yokohama City ume in one second (FEV 1 ), airway resistance University School of stimulation of the central chemoreceptor. (Raw), specific airway conductance (sgaw), Medicine, 3 9 Fukura, The hypoxic ventilatory response is only Kanazawa-ku, and functional residual capacity (FRC) were slightly affected by fenoterol. Yokohama, Kanagawa obtained. Arterial blood was sampled by punc- 236, Japan (Thorax 1997;52: ) ture of the radial artery with the subjects sitting, S Suzuki Keywords: fenoterol, β two hours after drug administration, and gas Y Watanuki 2 adrenergic agonist, hypercapnic Y Yoshiike ventilatory response, hypoxic ventilatory response, tensions and ph were analysed with ap- T Okubo chronic obstructive pulmonary disease (COPD). propriate electrodes (IL BGM-1312, Instrumentation Laboratory, Milan, Italy). Correspondence to: Dr S Suzuki. Chemical control of breathing was assessed Received 21 November 1995 Previous studies have shown that isoprenaline, by measuring minute ventilation (V E) and oc- Returned to authors a potent β adrenergic agonist, induces hyper- clusion pressure (P.1 ) during hypercapnia and 9 April 1996 Revised version received pnoea 1 4 and its major effect on respiration hypoxia, as in our previous study. 6 The re- 16 September 1996 Accepted for publication is thought to be due to an action on the carotid sponse to hypercapnia was measured by a modi- 18 September 1996 body. 2 4 Some studies 56 have found that β 2 fication of the Read technique. 15 The circuit Thorax: first published as /thx on 1 February Downloaded from on 31 October 218 by guest. Protected by copyright.

2 126 Suzuki, Watanuki, Yoshiike, Okubo Table 1 Mean (SD) pulmonary function data of patients with chronic obstructive pulmonary disease %VC FEV 1 /VC %FEV 1 FRC %FRC sgaw PImax %PImax PaO 2 PaCO 2 (%) (%) (%) (l) (%) (kpa 1 s 1 ) (kpa) (%) (kpa) (kpa) Placebo 9(2) 5(14) 63(25) 4.29(.95) 131(28).71(.57) 8.7(3.6) 52(21) 1.8(1.8) 5.3(.6) Fenoterol 93(19) 51(18) 67(3) 4.22(.97) 129(29).71(.53) 1.1(4.) 58(21) 1.7(1.6) 5.1(.5) Difference NS p<.5 p<.5 NS NS NS p<.5 p<.5 NS NS VC=vital capacity; FEV 1 =forced expiratory volume in one second; FRC=functional residual capacity; sgaw=specific airway conductance; PImax=maximum inspiratory mouth pressure at FRC; PaO 2,PaCO 2 =arterial oxygen and carbon dioxide tensions; NS=not significant. %VC, %FEV 1, and %FRC were calculated from the predicted values. 19 used was similar to that of Whitelaw and co- max and PEmax were repeated until three measurements workers. 16 Volume was obtained from electrical varying by <5% and sustained for integration of the flow signal which was meas- one second or longer were recorded. The highest ured at the mouthpiece. The P.1 was obtained value thus obtained was reported. from a mouth pressure measured 1 ms after Placebo or fenoterol (15 mg) was administered the onset of inspiration, as defined by the appearance as three divided doses in a double of a negative mouth pressure. The blind crossover design for a week and then expiratory side was sampled continuously using changed to the alternative for a week with no a mass spectrometer (WSMR-14; Westron, washout period. The ventilatory response tests Chiba, Japan). The subjects breathed air until (HCVR and HVR) and the pulmonary function they became accustomed to the circuit by by- tests were examined at the same time on the passing the rebreathing bag to room air. They seventh day of each treatment. Subjects were then rebreathed a gas mixture of 7% carbon asked to refrain from other drugs such as other dioxide and 93% oxygen from a six litre rebreathing β adrenergic agonists, theophylline, sedatives, bag. During rebreathing the in- caffeine-containing beverages, and alcohol for spiratory side of the circuit was occluded 24 hours before the test day. On each test day randomly every 4 6 breaths. Rebreathing was the tests were performed two hours after taking usually terminated within 3 4 minutes. The the placebo or fenoterol. The baseline meas- V E was obtained as the average for the two urements of the lung function tests, respiratory breaths that preceded the breath from which muscle strength, heart rate, and blood pressure the P.1 was measured. Simultaneously, the end were measured at rest and then the ventilatory tidal partial pressure of carbon dioxide responses to hypercapnia and hypoxia were (PETCO 2 ) was measured. The ventilatory re- assessed. The order of the ventilatory tests sponse to hypercapnia was assessed from the was randomised with at least 1 minutes rest slope of the linear regression between V E and between each test. PETCO 2, and between P.1 and PETCO 2 (ΔV E/ All values are expressed as mean (SD) unless ΔPETCO 2 and ΔP.1 /ΔPETCO 2, respectively). otherwise specified. Statistical analysis was performed The ventilatory response to hypoxia was using the Wilcoxon signed rank test. measured by the progressive isocapnic hypoxia A p value of less than.5 was considered method of Rebuck. 17 The subjects used the significant. A prestudy power calculation in- same rebreathing circuit as for the ventilatory dicated that, with 21 subjects, this study had response to hypercapnia, except that a rebreathing an 8% chance of detecting a true change in bag containing eight litres of gas HCVR or HVR of more than 19%, which was mixture (3.5% carbon dioxide, 23% oxygen, calculated from data in our previous study. 6 and 73.5% nitrogen) and a bypass carbon di- The STATISTICA statistical software package oxide absorber were used. During the test the (StatSoft, Tulsa, USA) was used. arterial oxygen saturation (SaO 2 ) was monitored with a pulse oximeter (Biox IIA, Biox Technology, Boulder, USA). During re- Results breathing the PETCO 2 was kept constant at the The patients had severe airway obstruction with resting level of each subject during room air a mean FEV 1 /VC of 5 (14)% and increased breathing by removing carbon dioxide from the lung volumes as shown in table 1. Hypoxaemia circuit with a variable AC motor fan connected (PaO 2 <1 kpa) was observed in six of 2 to a bypass carbon dioxide absorber. Rebreathing patients and hypercapnia (PaCO 2 >6 kpa) in was continued until SaO 2 decreased only one. Fenoterol treatment for one week to 75 8%. The ventilatory response to hypoxia increased the mean FEV 1 from 1.66 (.7) l was calculated from the slope of the linear to 1.79 (.89) l (p<.5) with no significant regression of plots of V E versus SaO 2 and P.1 change in sgaw or FRC. The mean PImax at versus SaO 2 (ΔV E/ΔSaO 2 and ΔP.1 /ΔSaO 2, re- FRC was 52 (21)% of our normal value (see spectively). Appendix) and was increased by a mean of Respiratory muscle strength was assessed by 16% following fenoterol treatment (p<.2), measuring mouth pressures during maximal whereas the PEmax was 58 (21)% of normal static inspiratory (PImax) and expiratory (PE- and did not change following fenoterol. The max) efforts against a closed valve with a small heart rate was increased by 7% from 74.5 (1.5) air leak to prevent glottic closure. 18 PImax was to 79.8 (9.1) beats/min (p<.1) following fenoterol measured at FRC and residual volume, and but there was no significant change in PEmax at FRC and total lung capacity with a PaCO 2,PaO 2, or blood pressure. differential pressure transducer (Validyne MP- The minute ventilation showed a trend to 45±25 mm Hg). The determinations of PI- increase with fenoterol from a mean (SD) of Thorax: first published as /thx on 1 February Downloaded from on 31 October 218 by guest. Protected by copyright.

3 Effects of fenoterol on HCVR in COPD 127 P.1 (kpa) A Fenoterol PETCO 2 (kpa) Placebo 9. P.1 (kpa) B Placebo 8 9 Fenoterol (2.8) l/min with placebo to 14.2 (3.4) l/ min after fenoterol (p=.6), although neither the VT, breathing frequency, nor PETCO 2 showed any significant change. The P.1 during air breathing did not differ between the two treatments at.2 (.9) versus.23 (.9) kpa, whereas the VT/TI of.57 (.12) l/min on fenoterol was significantly higher than the.52 (.12) l/min when on placebo (p<.2). Our patients showed a wide range of ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR). Fenoterol increased the slope of P.1 versus PETCO 2 (ΔP.1 /ΔPETCO 2 ) by 23%, from a mean (SD) of.35 (.23) kpa/kpa with placebo to.43 (.24) kpa/kpa (p<.1; fig 1). The slope of V E versus PETCO 2 (ΔV E/ΔPETCO 2 ) showed a trend to increase with fenoterol from a mean (SD) of 9.2 (3.4) with placebo to 1.5 SaO 2 (%) (4.9) l/min/kpa after fenoterol (p=.8; fig 2). Figure 1 Mean occlusion pressure (P.1 ) responses to (A) the hypercapnic ventilatory The P.1 at PETCO 2 of 8 kpa increased by 13% response (HCVR) and (B) the hypoxic ventilatory response (HVR). Fenoterol treatment from.82 (.57) kpa on placebo to.93 (.45) (dashed lines) increased HCVR (p<.1) and the position of the mean P.1 at 8% SaO 2 (p<.5) compared with placebo (solid lines). Mean response curves were calculated from kpa on fenoterol (p<.5), and the V E at individual slopes of P.1 in both HCVR and HVR. The mean responses and one standard PETCO 2 of 8 kpa was also increased from 32.6 error are represented by thick and thin lines, respectively. (13.8) on placebo to 34.9 (15.) l/min on fenoterol (p<.1). The slopes of the response VE/ PETCO 2 (l/min/kpa) VE P.1 P.1 / PETCO 2 (kpa/kpa) curves to hypoxia (ΔP.1 /ΔSaO 2 and V E/ΔSaO 2 ) were greater than for the normal subjects in our previous study 6 (both p<.2). Fenoterol did not change the slope of either V E or P.1 versus SaO 2, as shown in fig 3, but from fig 1 it can be seen that the P.1 at an SaO 2 value of 8% was significantly increased from a mean of.9 (.72) to.97 (.55) kpa following fenoterol treatment (p<.5) whereas V E was unchanged at 8% oxygen saturation. 5.2 Discussion We have shown that fenoterol significantly increased the ventilatory response to hypercapnia in patients with COPD but caused a nonsignificant trend to increase their response to hypoxia. Fenoterol did significantly increase Figure 2 Hypercapnic ventilatory response (HCVR). Left: slope of V E versus PETCO 2 the FEV 1 and inspiratory muscle strength but curve (ΔV E/ΔPETCO 2 ) of placebo and fenoterol groups. Right: slope of P.1 versus PETCO 2 these changes did not affect the resting ventcurve (ΔP.1 /ΔPETCO 2 ) of placebo and fenoterol groups. Open boxes and bars represent the 95% confidence interval and mean value, respectively. Note that fenoterol increased the slopes of the response curve of P.1 by 23% (p<.1) but did not affect the V E. VE/ SaO 2 (l/min/%) VE P.1.2 P.1 / SaO 2 (kpa/%) ilation and P.1. These results suggest that, in patients with COPD, fenoterol may stimulate the central chemoreceptor with a lesser effect on the peripheral chemoreceptor. To be certain that these findings are true it is necessary to consider whether our experimental method or protocol could have influenced the result. Ventilatory responses were measured two hours after the last oral dose of fenoterol because plasma levels reach a maximum at this time 2 and, with a half life of only 6 7 hours, there was no need for a prolonged washout period. We therefore believe that the results truly reflect the effects of the drug and placebo. Blood levels were not checked but we had no reason to suspect that our subjects were not complying with the dose regimen. The rebreathing techniques used for HCVR and HVR were first designed for normal subjects based on the assumption that a relation between V E and PETCO 2 or between V E and SaO 2 is linear. One concern when using the V E Figure 3 Hypoxic ventilatory response (HVR). Left: slope of V E versus SaO 2 curve response in patients with airway obstruction is (ΔV E/ΔSaO 2 ) with placebo and fenoterol. Right: slope of P.1 versus SaO 2 curve (ΔP.1 / that the response may no longer be linear. In ΔSaO 2 ) with placebo and fenoterol. Open boxes and bars represent the 95% confidence interval and mean value, respectively. Note that neither of the slopes changed. our patients the correlation coefficient for V E Thorax: first published as /thx on 1 February Downloaded from on 31 October 218 by guest. Protected by copyright.

4 128 Suzuki, Watanuki, Yoshiike, Okubo with PETCO 2 when taking placebo was.97 and parable with those of the normal subjects in for V E with SaO our previous study. 6 2 it was.93, indicating a close linear relationship in the range of PETCO 2 The HVR in COPD has been less well stud- and SaO 2 in our experiment. This close rebeen ied than HCVR and a range of HVR values have lationship was not affected by fenoterol and so reported for patients with COPD we believe that the rebreathing techniques of Those patients who were hypoxaemic were Read and Rebuck were valid tests for our subatory found by some authors to have a reduced ventiljects. Because of the concern that V E may be response to hypoxia, whereas others affected by the presence of airflow limitation, have found these patients to have an increased we also used P.1 as a measure of respiratory HVR. 13 The HVR in our patients was greater output. P.1 may be influenced by changes in than that of the normal subjects in our previous muscle strength or lung volume 21 and in our study 6 (ΔV E/SaO 2.22 (.6) for normal sub- subjects fenoterol increased PImax by 16% but jects versus.87 (.49) l/min/% for patients did not alter FRC. However, we found that with COPD, p<.1). In our study only the P.1 when breathing air was not changed by most hypoxaemic patient (PaO 2 =6.3 kpa) had fenoterol and so we believe that this change in a decreased HVR; PaO 2 in the remaining muscle strength was not affecting P.1 in our patients was more than 8.3 kpa. In our previous tests. We also found that fenoterol increased study in normal subjects we found a reduced FEV 1 but had no effect on sgaw, and others response to hypoxia compared with the results have found that bronchodilation with atropine from some studies but our finding was sim- did not affect P ilar to that of others, 13.1 whereas resistive unloading and it is accepted that with helium/oxygen reduced it. 22 It therefore there is a wide range of HVR responses in seems that fenoterol is unlikely to influence P normal subjects. In those studies in which a.1 by its effects on airway mechanics. For a given reduced HVR response was found in patients P with COPD most of the patients were hyp-.1 the mean inspiratory flow will increase if flow resistance decreases, and we found that the oxaemic and so the different finding in our VT/TI whilst breathing air increased following study may be due to the fact that our patients fenoterol while the P were essentially normoxic..1 did not change. It has been reported in patients with COPD that the Fenoterol increased the slopes of both P.1 effective inspiratory impedance decreased after and V E during the HCVR, but that of V E did fenoterol only in those patients who had an not reach significance. The position of the P.1 increase in their FEV and V E response curves at PETCO 2 of 8 kpa was We found no difference moved to a higher value by fenoterol treatment. in the effective impedance between our placebo The increase in the P.1 response by fenoterol and fenoterol groups, and so the recorded inwas similar to that found in normal subjects crease in FEV 6 1 after fenoterol in our subjects and the smaller change in V E compared with may have been too small to change the effective P.1 may be due to the effect of airflow limimpedance. itation. The effect of fenoterol on HVR is weak Patients with COPD are characterised by and so its action on the peripheral chemoincreased neuromuscular inspiratory drive and receptors seems limited. The increased reincreased effective inspiratory impedance. 24 In sponse to carbon dioxide with fenoterol could our patients with COPD the P.1 and VT/TI be due to an action on central chemoreceptors were comparable with that found in our normal but this putative action remains controversial. subjects. 6 The effective inspiratory impedance, Some, but not all, studies have shown that P.1 /(VT/TI), during air breathing did not differ β 2 adrenergic agonists potentiate ventilatory from that of the normal subjects (.4 (.14) chemosensitivity 5 7 and those studies underversus.38 (.22) kpa/l/min) and this similarity taken on humans, 56 together with the current suggests that our patients had no increased study, have shown that β 2 adrenergic agonists neuromuscular drive and that their airflow lim- stimulate HCVR which suggests an effect on itation was not sufficiently severe to increase the central chemoreceptor. the effective inspiratory impedance. The position of the P.1 response curve at The abnormalities of control of breathing 8% SaO 2 in the HVR was augmented by fenin patients with COPD remain controversial. oterol treatment, although the slope of the Hypercapnic patients have a diminished response curve was not changed. The effect of HCVR, while the HCVR in non-hypercapnic fenoterol on the HVR may be weak in patients patients is normal. 89 It has also been reported with COPD. In our previous study fenoterol that the HCVR in patients with COPD is lower increased both the slope and the position of than in normal subjects, although there is no P.1 at 8% SaO 2 of HVR in normal subjects. 6 difference in the HCVR between hypercapnic The PaCO 2 did not differ between placebo and and non-hypercapnic patients. 1 On the con- fenoterol, suggesting that the level of carbon trary, patients with COPD are reported to have dioxide may not affect the HVR. Little is known a normal or increased response to hypercapnia about the effects of β 2 adrenergic agonists on the when measured with diaphragmatic electro- ventilatory response to hypoxia. Isoprenaline myography, although the P.1 response slope stimulates the carotid body through a β adis decreased. 25 In the present study hypercapnia renergic mechanism 34 and fenoterol has weak was observed in only one patient but the in- β 1 activity in spite of being a relatively selective crease in PaCO 2 was slight (6.4 kpa). His ΔP.1 / β 2 adrenergic agonist. 27 It is therefore possible ΔPETCO 2 was normal but he had a low ΔV E/ that fenoterol increases the response of the ΔPETCO 2. The average values of ΔP.1 /ΔPETCO 2 carotid body to hypoxia through β 1 activity. and ΔV E/ΔPETCO 2 in our patients were com- The plasma potassium level is a putative po- Thorax: first published as /thx on 1 February Downloaded from on 31 October 218 by guest. Protected by copyright.

5 Effects of fenoterol on HCVR in COPD Eldridge FL, Gill-Kumar P. Mechanisms of hyperpnea intentiator of carotid body response. 28 Salduced by isoproterenol. Respir Physiol 198;4: butamol can induce hypokalaemia and its 4 Lahiri S, Pokorski M, Davies RO. Augmentation of carotid body chemoreceptor responses by isoproterenol in the cat. stimulant action on ventilation may be effected Respir Physiol 1981;44: by a potassium shift from the extracellular to the 5 Leitch AG, Clancy LJ, Costello JE, Flenley DC. Effect of intravenous infusion of salbutamol on ventilatory response intracellular space. 5 Fenoterol can also affect to carbon dioxide and hypoxia and on heart rate and plasma potassium levels 29 and so its effect on plasma potassium in normal men. BMJ 1976;1: Yoshiike Y, Suzuki S, Watanuki Y, Okubo T. Effects of the ventilatory response could be due to this fenoterol on ventilatory responses to hypoxia and hypercapnia in normal subjects. Thorax 1995;5: mechanism. We did not measure plasma potas- 7 Folgering H. Central β-adrenergic effects on the control of sium levels in our patients and so cannot supply ventilation in cats. Respiration 198;39: direct evidence to support this possibility. 8 Altose MD, McCauley WC, Kelsen SG, Cherniack NS. Effects of hypercapnia and inspiratory flow-resistive load- Beta adrenergic agonists can lead to an in- ing on respiratory activity in chronic airways obstruction. crease in metabolic activity 3 and the raised J Clin Invest 1977;59: Zackon H, Despas PJ, Anthonisen NR. Occlusion pressure metabolic rate associated with exercise or feed- responses in asthma and chronic obstructive pulmonary ing may stimulate peripheral and/or central disease. Am Rev Respir Dis 1976;114: Lourenco RV, Miranda JM. Drive and performance of the chemoreceptors In the current study we ventilatory apparatus in chronic obstructive lung disease. did not measure oxygen consumption but in N Engl J Med 1968;279: Bradley CA, Fleetham JA, Anthonisen NR. Ventilatory conour previous study we found fenoterol in- trol in patients with hypoxemia due to obstructive lung creased resting V E without any changes in disease. Am Rev Respir Dis 1979;12: Flenley DC, Franklin DH, Millar JS. The hypoxic drive to PETCO 2 or P.1, suggesting the possibility that breathing in chronic bronchitis and emphysema. Clin Sci fenoterol increased the metabolic activity. If 197;38: Erbland ML, Ebert RV, Snow SL. Interaction of hypoxia this was true then this may be a possible mech- and hypercapnia on respiratory drive in patients with anism to explain the effect of fenoterol on COPD. Chest 199;97: American Thoracic Society. Standards for the diagnosis and the ventilatory responses to hypercapnia and care of patients with chronic obstructive pulmonary disease hypoxia. Another possible mechanism could (COPD) and asthma. Am Rev Respir Dis 1987;136: Read DJC. A clinical method for assessing the ventilatory relate to changes in cardiac output. Iso- response to carbon dioxide. Australas Ann Med 1967;16: prenaline stimulates ventilation and this was Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure initially thought to be secondary to the con- as a measure of respiratory centre output in conscious sequent increase in cardiac output, 33 but a man. Respir Physiol 1975;23: Rebuck AS, Campbell EJM. A clinical method for assessing direct action on the carotid body has sub- the ventilatory response to hypoxia. Am Rev Respir Dis sequently been proposed. 2 Fenoterol stimulates 1974;19: Black LF, Hyatt RE. Maximal respiratory pressures: normal cardiac function 27 but we found only a 7% values and relationship to age and sex. Am Rev Respir Dis 1969;99: increase in heart rate, much less than that found 19 The Pulmonary Physiology Committee of Japan Society of with isoprenaline, 33 and P.1 was not changed Chest Diseases. Normal standards of pulmonary function tests for healthy Japanese adults. Jpn J Thorac Dis 1993; by fenoterol when breathing air. Thus, a mech- 31(Suppl):1 25. anism for the ventilatory action of fenoterol 2 Rominger KL, Pollmann W. Comparative pharmacokinetic studies on fenoterol-hydrobromide in rat, dog and man. through changes in cardiac output seems un- Arzneim Forsch 1972;22: likely. 21 Eldridge FL, Vaughn KZ. Relationship of thoracic volume and airway occlusion pressure: muscular effects. J Appl In conclusion, we have shown that fenoterol Physiol 1977;43: stimulates the ventilatory responses to hyperto resistive unloading: helium vs. bronchodilatation. J 22 DeWeese EL, Sullivan TY, Yu PL. Neuromuscular response capnia and hypoxia in patients with COPD Appl Physiol 1984;56: but the exact mechanism is unclear. Patients 23 Appendini L, Molina G, Senis L, Garbagni L. Control of breathing in chronic obstructive pulmonary disease with COPD whose disease progresses tend to patients at rest and after beta-2 agonist inhalation. Respiration 1991;58:42 8. become hypoxic and hypercapnic. Whilst fen- 24 Sorli J, Grassino A, Lorange G, Milic-Emili J. Control of oterol may benefit these patients by its broncho- breathing in patients with chronic obstructive lung disease. dilator action, it is possible that its effect on Clin Sci Mol Med 1978;54: Scano G, Duranti R, Spenelli A, Gorini M, Conte CL, ventilatory responses may also be of benefit Gigliottie F. Control of breathing in normal subjects and and this deserves further study. in patients with chronic airflow obstruction. Bull Eur Physiopathol Respir 1987;23: Light RW, Mahutte CK, Stansbury DW, Fischer CE, Brown SE. Relationship between improvement in exercise performance with supplemental oxygen and hypoxic ventilatory drive in patients with chronic airflow obstruction. Appendix Chest 1989;95: Mean (SD) normal values of respiratory muscle 27 Giles RE, Williams JC, Finkel MP. The bronchodilator and cardiac stimulant effects of Th1165a, salbutamol and strength: isoproterenol. J Pharmacol Exp Ther 1973;186: PImax at FRC; 16.6 (4.3) kpa (men), Linton RAF, Band DM. The effect of potassium on carotid chemoreceptor activity and ventilation in the cat. Respir (3.1) kpa (women) Physiol 1985;59:65 7. PImax at RV; 18.4 (4.1) kpa (men), Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic (3.1) kpa (women) effects of fenoterol, salbutamol, and terbutaline in asthma. PEmax at TLC; 25.1 (6.2) kpa (men), 14.7 Lancet 199;336: Amoroso P, Wilson SR, Moxham J, Ponte J. Acute effects (4.1) kpa (women) of inhaled salbutamol on the metabolic rate of normal PImax at FRC; 2.9 (5.8) kpa (men), 11.7 subjects. Thorax 1993;48: Zwillich CW, Sahn SA, Weil JV. Effects of hypermetabolism (3.34) kpa (women) on ventilation and chemosensitivity. J Clin Invest 1977; 6: Weil JV, Byrne-Quinn E, Sodal IE, Kline JS, McCullough 1 Heistad DD, Wheeler RC, Mark AL, Schmid PG, Abboud RE, Filley GF. Augmentation of chemosensitivity during FM. Effects of adrenergic stimulation on ventilation in mild exercise in normal man. J Appl Physiol 1972;66: man. J Clin Invest 1972;51: Wasserman K, Mitchell RA, Berger AJ, Casaburi R, Davis 33 Wasserman K, Whipp BJ, Castagna J. Cardiodynamic hyper- JA. Mechanism of isoproterenol hyperpnea in the cat. pnea: hyperpnea secondary to cardiac output increase. 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