- Email: [email protected]
The effects of high-frequency inflation and high-frequency deflation on respiration in rabbits
Neuroscience Letters, 60 (1985) 307-311
307
Elsevier Scientific Publishers Ireland Ltd.
NSL 03551
THE EFFECTS OF HIGH-FREQUENCY INFLATION AND HIGH-FREQUENCY DEFLATION ON R E S P I R A T I O N IN RABBITS
IKUO HOMMA*, HIROSHI ONIMARU, MICHIKO OOUCHI and SANTA ICHIKAWA
Department of Physiology, Showa University School of Medicine, 1-5 Hatanodai, Shinagawa-ku, Tokyo 142 (Japan) (Received M arch 20th, 1985; Revised version received June 14th, 1985; Accepted June 28th, 1985)
Key words: high-frequency inflation - high-frequency deflation - pulmonary stretch receptor - irritant receptor - expiratory time - inspiratory time - rabbit
High-frequency inflating and deflating triangular pulses of pressure were applied to air in the trachea of urethane--chloralose-anesthetized rabbits. Expiratory time was increased by high-frequency inflation (HFI) and decreased by high-frequency deflation (HFD). Both had little effect on inspiratory time or tidal phrenic nerve activity. HFD provoked more tonic type phrenic activity, with discharges being evident during the expiratory phase. It was demonstrated that HFI, which probably stimulates pulmonary stretch receptors, inhibits the initiation of inspiration and HFD, which probably stimulates irritant receptors, facilitates inspiration.
Respiratory reflexes may be produced by activation of pulmonary or respiratory tract receptors [9, 17, 23]. These receptors respond to mechanical or chemical stimuli. The receptors that respond to mechanical stimulation have been classified as slowly adapting and rapidly adapting. The slowly adapting receptor, which is known as the pulmonary stretch receptor (PSR), is effectively stimulated by lung inflation. The reflex elicited by stimulation of these receptors is the well-known Hering-Breuer inflation reflex. Inflation applied during the inspiratory phase inhibits inspiration, and during the expiratory phase it prolongs the expiratory time. In contrast, activation of the rapidly adapting receptor, which is known as an irritant or deflation receptor, decreases expiratory time. In the past, steady or brief applications of inflation or deflation have been used to examine reflexes elicited from both types of receptors [6, 13, 14]. Recently, highfrequency ventilation (HFV) has been used for this purpose [2, 4, 21]. HFV, at frequencies between 1 and 50 Hz and producing tidal volume less than the dead space, has been investigated as a possible replacement for positive pressure ventilation in some clinical situations [3, 4, 16, 19, 20]. HFV is also under consideration as a possible method of artificial ventilation, but it has been reported to inhibit inspiration [5]. We have recently demonstrated that the effects of 100 Hz HFV, which prolonged expiratory time, are opposite to those of histamine, which reduces expiratory time *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
308
[l 1]. The H F V used until now was restricted to sine waves, which were usually produced by piston pumps with no consideration as to whether the stimulation was inflation or deflation. In this experiment we used triangular electrical pulses to drive a sealed moving-coil transducer and produce either an inflating or deflating pressure change. High-frequency mechanical stimulation produced by repetitive triangular inflations is referred to as high-frequency inflation ( H F I ) and that produced by repetitive triangular deflations is called high-frequency deflation (H FD). Experiments were performed on 7 rabbits, weighing 2.5-4.0 kg, anesthetized with urethane-chloralose (initial dose: 450 mg urethane + 4 5 mg chloralose/kg i.v.). The right C5 phrenic nerve was dissected free, cut distally, desheathed and prepared for recording. Phrenic efferent activity was picked up through bipolar electrodes, amplified and stored in a data recorder (SONY RF-3500). The p u m p consisted of a diaphragm attached to a moving-coil transducer in a sealed box and driven by a triangular-wave generator. Time-to-peak of each triangular pulse was 3 ms. This p u m p was coupled to the tracheal cannula, lntratracheal pressure wa measured with a transducer (Stathem P37) connected to a side arm of the cannula. A third arm was free to the open air. The peak intratracheal pressure of the H F I and H F D was measured at 7.28_+0.76 cm H20, positive for H F I or negative for H F D . H F I and H F D were applied for 10-15 s. Phrenic nerve activity from the data recorder was lead through a computer (Nihon Elec. Co.: 8001mklI) and spikes were counted for each 100 ms. Either direct or pulse density of the phrenic nerve activity during the stimulation was compared with the activity before and after stimulation.
A y.~v,~%tt-~2;'.'t-~'-L7~
(B)
_AA
.. £ % . ' _ . _ . ' ~
A :_
-
"-'~ ~ ' " " ; . ' _ ' " ~ Y t
T
A
A
K£:..-%'-"A';__''..t'r'._.''2
/k it"
A
" %;..±:t2N-
;~71
A_, I
Fig. 1. Effects of 100 Hz on phrenic nerve activity. Top: phrenic nerve activity. Middle: sequential pulse density (counts/100 ms). Bottom: intratracheal pressure. A: before application of HFI. B: during application of HF1. Abscissa: time, 1 s calibration: ordinate: upper, 20 impulses; lower, pressure, 5 cm H20 calibration.
309
Phrenic nerve discharges during quiet breathing and during HFI and H F D are shown in Figs. l and 2, respectively. HFI applied to the airway prolonged the expiratory time (TE), but had little effect on tidal phrenic nerve activity or inspiratory time (T~). The clear elongation of the TE caused a definite reduction of the respiratory rate (Fig. 1). Critical frequencies to induce prolongation of the T~ were between 50 and 100 Hz. Below 40 Hz HFI had little effect on the TE o r decreased the TE when stimulation strength was increased. I n contrast to HFI, H F D decreased the T E and the critical frequencies were between l0 and 50 Hz. H F D had little effect on T~ or tidal phrenic nerve activity. However, H F D did provoke more tonic type phrenic nerve activity in 4 out of 7 rabbits with discharges being evident during the expiratory phase. When H F D was stopped, the tonic activity disappeared (Fig. 2). HFI and H F D did not induce reflexes after bilateral vagotomy. HFI and HFD are repetitive triangular inflation and deflation pressure pulses with time-to-peak of 3 ms. These differ from single brief pulses of inflation or deflation which have durations exceeding 100 ms [8, 14]. Therefore, afferent receptors activated by HFI or H F D may fire repetitively rather than transiently and continue to do so until the HFI or H F D are stopped. HFI and H F D must stimulate lung or respiratory tract receptors since the effects were not observed after bilateral vagotomy. HFI, which prolongs TE, may stimulate pulmonary stretch r,.,eptors as indicated by the reports of lung inflation or HFV [1, 7, 12, 15, 22]. The reflex caused by activation of the PSR is the well-known Hering-Breuer inflation reflex. One characteristic of
(A)
(B) .
.
.
.
.
.
!1111riT]~IITIiI!JI~I11IJ lllllMi111IJTTIIIMIIIlllll J!It111!JI lITI111II 1111J111~11 ItTllliMII11111111111111J ilJIIII IIIij11111J TIll111111 lit111111 Jllll
Fig. 2. Effects of 20 Hz HFD on phrenic nerve activity. Top, middle and lower as described in Fig. 1. A: before application of HFD. B: during application of HFD. Time, impulse number, pressure calibration as in Fig. I.
310
this reflex is early termination of inspiration, thus tidal inspiratory activity and the T~ decreased when inflation was given during the inspiratory phase, and inflation applied during the expiratory phase prolonged the Tt~. HFI prolonged the TE but had little effect on tidal inspiratory activity or Tj. This effect is confirmed by the HFV report by Banzett et al. [2]. Afferent activity produced by HFI might be subthreshold for terminating inspiration but be sufficient to inhibit the initiation of the following inspiration. This would agree with pulse inflation reports by Clark and von Euler [6] and Knox [13]. They showed that the afferent activity was below threshold to switch off inspiration, but once activated, this switch mechanism might continue to mediate inhibition of later inspiration so that even small lung inflation can modulate the TE. HFD may stimulate irritant receptors to shorten the TE. This is confirmed by reports of steady pulse deflation [13, 14]. However, HFD not only shortened the Tw, but also facilitated inspiratory activity. The outstanding effect of HFD was the rise of tonic phrenic nerve activity between phrenic bursts that was observed in 4 rabbits. Tonic facilitation of the inspiratory activity was observed when histamine was inhaled into the airway or when thyrotropin-releasing hormone (TRH) was injected into the fourth ventricle in rabbits [10, 11]. lnspiratory tonic activity has also been seen in the hypoxic-hypercapnic stage when bulbospinal respiratory neurons were not regulating respiratory rhythm [18]. However, as shown in this work, inspiratory tonic activity can be provoked by HFD which probably stimulates irritant receptors. We demonstrated that high-frequency airway inflation (HFI), which probably stimulates pulmonary stretch receptors, inhibits inspiration and high-frequency airway deflation (HFD), which probably stimulates irritant receptors, facilitates inspiration. 1 Adrian, E.D., Afferent impulses in the vagus and their effect on respiration, J. Physiol. (Lond.), 79 (1933) 332-358. 2 Banzett, R., Lehr, J. and Geffroy, B., High frequency ventilation lengthens expiration in the anesthetized dog, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 55 (1983) 329-334. 3 Bohn, D.J., Miyasaka, K., Marchak, B.E., Thompson, W.K., Froese, A.B. and Byran, A.C., Ventilation by high-frequency oscillation, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 48 (1980) 710-716. 4 Butler, W.J., Bohn, D.J., Bryan, A.C. and Froese, A.B., Ventilation by high-frequency oscillation in humans, Anesth. Analg., 59 (1980) 577-584. 5 Chang, H.K. and Haft, A., High-frequency ventilation: a review, Respir. Physiol., 57 (1984) 135-152. 6 Clark, F.J. and Euler, C., von, On the regulation of depth and rate of breathing, J. Physiol. (Lond.), 222 (1972) 267-295. 7 Davies, A., Dixon, M., Callannan, D., Husczuk, A., Widdicombe, J.G. and Wise, J.C.M., Lung reflexes in rabbits during pulmonary stretch receptor block by sulfur dioxide, Respir. Physiol., 34 (1978) 83-101. 8 Davies, A. and Roumy, M., The effect of transient stimulation of lung irritant receptors on the pattern of breathing in rabbits, J. Physiol. (Lond.), 324 (1982) 389-401. 9 Euler, C. von, The contribution of sensory inputs to the pattern generation of breathing, Can. J. Physiol. Pharmacol., 59 (1981) 700-706. 10 Homma, I., Oouchi, M. and Ichikawa, S., Facilitation of inspiration by intracerebroventricular injection of thyrotropin-releasing hormone in rabbits, Neurosci. Lett., 44 (1984) 265-269. 11 Homma, I., Onimaru, H. and Oouchi, M., Effects of histamine inhalation and airway vibration on phrenic nerve activity in rabbits, Neurosci. Lett., 48 (1984) 93-96. 12 Knowlton, G.C. and Larrabee, M.G., A unitary analysis of pulmonary volume receptors, Am. J. Physiol., 147 (1946) 100-114.
311 13 Knox, C.K., Characteristics of inflation and deflation reflexes during expiration in the cat, J. Neurophysiol., 36 (1973) 284-295. 14 Knox, C.K., Reflex and central mechanisms controlling expiratory duration. In C. von Euler and H. Lagercrantz (Eds.), Central Nervous Control Mechanisms in Breathing, Pergamon Press, Oxford, 1979, pp. 203-216. 15 Man, G.C.W., Man, S.F.P. and Kappagod, C.T., Effects of high frequency oscillatory ventilation on vagal and phrenic nerve activities, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 54 (1983) 502-507. 16 Roumy, M. and Leitner, L.M. Localization of stretch and deflation receptors in the airways of the rabbit, J. Physiol. (Paris), 76 (1980) 67-70. 17 Sant'Ambrogio, G., Information arising from the tracheobronchial tree of mammals, Physiol. Rev., 62 (1982) 531-569. 18 Sears, T.A., Berger, A.J. and Phillipson, E.A., Reciprocal tonic activation of inspiratory and expiratory motoneurones by chemical drives, Nature (Lond.), 299 (1982) 728-730. 19 Sjostrand, U.H. and Eriksson, I.A., High rates and low volumes in mechanical ventilation - not just a matter of ventilatory frequency, Anesth. Analg., 59 (1980) 567-576. 20 Sluttsky, A.S., Kamm, R.D., Rossing, T.H., Loring, S.H., Lehr, J., Shapiro, R.H., Ingrain, Jr. and Drazen, J.M., Effects of frequency, tidal volume and lung volume on CO2 elimination in dogs by high frequency, low tidal volume ventilation, J. Clin. Invest., 68 (1981) 1475-1484. 21 Thompson, W.K., Marchak, B.E., Bryan, A.C. and Froese, A.B., Vagotomy reverses apnea induced by high-frequency oscillatory ventilation, J. Appl. Physiol.: Respirat. Environ. Exercise Physicol., 51 (1981) 1484-1487. 22 Widdicombe, J.G., Respiratory reflexes from the trachea and bronchi of the cat, J. Physiol. (Lond.), 123 (1954) 55-70. 23 Widdicombe, J.G., Pulmonary and respiratory tract receptors, J. Exp. Biol., 100 (1982) 41-57.
307
Elsevier Scientific Publishers Ireland Ltd.
NSL 03551
THE EFFECTS OF HIGH-FREQUENCY INFLATION AND HIGH-FREQUENCY DEFLATION ON R E S P I R A T I O N IN RABBITS
IKUO HOMMA*, HIROSHI ONIMARU, MICHIKO OOUCHI and SANTA ICHIKAWA
Department of Physiology, Showa University School of Medicine, 1-5 Hatanodai, Shinagawa-ku, Tokyo 142 (Japan) (Received M arch 20th, 1985; Revised version received June 14th, 1985; Accepted June 28th, 1985)
Key words: high-frequency inflation - high-frequency deflation - pulmonary stretch receptor - irritant receptor - expiratory time - inspiratory time - rabbit
High-frequency inflating and deflating triangular pulses of pressure were applied to air in the trachea of urethane--chloralose-anesthetized rabbits. Expiratory time was increased by high-frequency inflation (HFI) and decreased by high-frequency deflation (HFD). Both had little effect on inspiratory time or tidal phrenic nerve activity. HFD provoked more tonic type phrenic activity, with discharges being evident during the expiratory phase. It was demonstrated that HFI, which probably stimulates pulmonary stretch receptors, inhibits the initiation of inspiration and HFD, which probably stimulates irritant receptors, facilitates inspiration.
Respiratory reflexes may be produced by activation of pulmonary or respiratory tract receptors [9, 17, 23]. These receptors respond to mechanical or chemical stimuli. The receptors that respond to mechanical stimulation have been classified as slowly adapting and rapidly adapting. The slowly adapting receptor, which is known as the pulmonary stretch receptor (PSR), is effectively stimulated by lung inflation. The reflex elicited by stimulation of these receptors is the well-known Hering-Breuer inflation reflex. Inflation applied during the inspiratory phase inhibits inspiration, and during the expiratory phase it prolongs the expiratory time. In contrast, activation of the rapidly adapting receptor, which is known as an irritant or deflation receptor, decreases expiratory time. In the past, steady or brief applications of inflation or deflation have been used to examine reflexes elicited from both types of receptors [6, 13, 14]. Recently, highfrequency ventilation (HFV) has been used for this purpose [2, 4, 21]. HFV, at frequencies between 1 and 50 Hz and producing tidal volume less than the dead space, has been investigated as a possible replacement for positive pressure ventilation in some clinical situations [3, 4, 16, 19, 20]. HFV is also under consideration as a possible method of artificial ventilation, but it has been reported to inhibit inspiration [5]. We have recently demonstrated that the effects of 100 Hz HFV, which prolonged expiratory time, are opposite to those of histamine, which reduces expiratory time *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
308
[l 1]. The H F V used until now was restricted to sine waves, which were usually produced by piston pumps with no consideration as to whether the stimulation was inflation or deflation. In this experiment we used triangular electrical pulses to drive a sealed moving-coil transducer and produce either an inflating or deflating pressure change. High-frequency mechanical stimulation produced by repetitive triangular inflations is referred to as high-frequency inflation ( H F I ) and that produced by repetitive triangular deflations is called high-frequency deflation (H FD). Experiments were performed on 7 rabbits, weighing 2.5-4.0 kg, anesthetized with urethane-chloralose (initial dose: 450 mg urethane + 4 5 mg chloralose/kg i.v.). The right C5 phrenic nerve was dissected free, cut distally, desheathed and prepared for recording. Phrenic efferent activity was picked up through bipolar electrodes, amplified and stored in a data recorder (SONY RF-3500). The p u m p consisted of a diaphragm attached to a moving-coil transducer in a sealed box and driven by a triangular-wave generator. Time-to-peak of each triangular pulse was 3 ms. This p u m p was coupled to the tracheal cannula, lntratracheal pressure wa measured with a transducer (Stathem P37) connected to a side arm of the cannula. A third arm was free to the open air. The peak intratracheal pressure of the H F I and H F D was measured at 7.28_+0.76 cm H20, positive for H F I or negative for H F D . H F I and H F D were applied for 10-15 s. Phrenic nerve activity from the data recorder was lead through a computer (Nihon Elec. Co.: 8001mklI) and spikes were counted for each 100 ms. Either direct or pulse density of the phrenic nerve activity during the stimulation was compared with the activity before and after stimulation.
A y.~v,~%tt-~2;'.'t-~'-L7~
(B)
_AA
.. £ % . ' _ . _ . ' ~
A :_
-
"-'~ ~ ' " " ; . ' _ ' " ~ Y t
T
A
A
K£:..-%'-"A';__''..t'r'._.''2
/k it"
A
" %;..±:t2N-
;~71
A_, I
Fig. 1. Effects of 100 Hz on phrenic nerve activity. Top: phrenic nerve activity. Middle: sequential pulse density (counts/100 ms). Bottom: intratracheal pressure. A: before application of HFI. B: during application of HF1. Abscissa: time, 1 s calibration: ordinate: upper, 20 impulses; lower, pressure, 5 cm H20 calibration.
309
Phrenic nerve discharges during quiet breathing and during HFI and H F D are shown in Figs. l and 2, respectively. HFI applied to the airway prolonged the expiratory time (TE), but had little effect on tidal phrenic nerve activity or inspiratory time (T~). The clear elongation of the TE caused a definite reduction of the respiratory rate (Fig. 1). Critical frequencies to induce prolongation of the T~ were between 50 and 100 Hz. Below 40 Hz HFI had little effect on the TE o r decreased the TE when stimulation strength was increased. I n contrast to HFI, H F D decreased the T E and the critical frequencies were between l0 and 50 Hz. H F D had little effect on T~ or tidal phrenic nerve activity. However, H F D did provoke more tonic type phrenic nerve activity in 4 out of 7 rabbits with discharges being evident during the expiratory phase. When H F D was stopped, the tonic activity disappeared (Fig. 2). HFI and H F D did not induce reflexes after bilateral vagotomy. HFI and HFD are repetitive triangular inflation and deflation pressure pulses with time-to-peak of 3 ms. These differ from single brief pulses of inflation or deflation which have durations exceeding 100 ms [8, 14]. Therefore, afferent receptors activated by HFI or H F D may fire repetitively rather than transiently and continue to do so until the HFI or H F D are stopped. HFI and H F D must stimulate lung or respiratory tract receptors since the effects were not observed after bilateral vagotomy. HFI, which prolongs TE, may stimulate pulmonary stretch r,.,eptors as indicated by the reports of lung inflation or HFV [1, 7, 12, 15, 22]. The reflex caused by activation of the PSR is the well-known Hering-Breuer inflation reflex. One characteristic of
(A)
(B) .
.
.
.
.
.
!1111riT]~IITIiI!JI~I11IJ lllllMi111IJTTIIIMIIIlllll J!It111!JI lITI111II 1111J111~11 ItTllliMII11111111111111J ilJIIII IIIij11111J TIll111111 lit111111 Jllll
Fig. 2. Effects of 20 Hz HFD on phrenic nerve activity. Top, middle and lower as described in Fig. 1. A: before application of HFD. B: during application of HFD. Time, impulse number, pressure calibration as in Fig. I.
310
this reflex is early termination of inspiration, thus tidal inspiratory activity and the T~ decreased when inflation was given during the inspiratory phase, and inflation applied during the expiratory phase prolonged the Tt~. HFI prolonged the TE but had little effect on tidal inspiratory activity or Tj. This effect is confirmed by the HFV report by Banzett et al. [2]. Afferent activity produced by HFI might be subthreshold for terminating inspiration but be sufficient to inhibit the initiation of the following inspiration. This would agree with pulse inflation reports by Clark and von Euler [6] and Knox [13]. They showed that the afferent activity was below threshold to switch off inspiration, but once activated, this switch mechanism might continue to mediate inhibition of later inspiration so that even small lung inflation can modulate the TE. HFD may stimulate irritant receptors to shorten the TE. This is confirmed by reports of steady pulse deflation [13, 14]. However, HFD not only shortened the Tw, but also facilitated inspiratory activity. The outstanding effect of HFD was the rise of tonic phrenic nerve activity between phrenic bursts that was observed in 4 rabbits. Tonic facilitation of the inspiratory activity was observed when histamine was inhaled into the airway or when thyrotropin-releasing hormone (TRH) was injected into the fourth ventricle in rabbits [10, 11]. lnspiratory tonic activity has also been seen in the hypoxic-hypercapnic stage when bulbospinal respiratory neurons were not regulating respiratory rhythm [18]. However, as shown in this work, inspiratory tonic activity can be provoked by HFD which probably stimulates irritant receptors. We demonstrated that high-frequency airway inflation (HFI), which probably stimulates pulmonary stretch receptors, inhibits inspiration and high-frequency airway deflation (HFD), which probably stimulates irritant receptors, facilitates inspiration. 1 Adrian, E.D., Afferent impulses in the vagus and their effect on respiration, J. Physiol. (Lond.), 79 (1933) 332-358. 2 Banzett, R., Lehr, J. and Geffroy, B., High frequency ventilation lengthens expiration in the anesthetized dog, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 55 (1983) 329-334. 3 Bohn, D.J., Miyasaka, K., Marchak, B.E., Thompson, W.K., Froese, A.B. and Byran, A.C., Ventilation by high-frequency oscillation, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 48 (1980) 710-716. 4 Butler, W.J., Bohn, D.J., Bryan, A.C. and Froese, A.B., Ventilation by high-frequency oscillation in humans, Anesth. Analg., 59 (1980) 577-584. 5 Chang, H.K. and Haft, A., High-frequency ventilation: a review, Respir. Physiol., 57 (1984) 135-152. 6 Clark, F.J. and Euler, C., von, On the regulation of depth and rate of breathing, J. Physiol. (Lond.), 222 (1972) 267-295. 7 Davies, A., Dixon, M., Callannan, D., Husczuk, A., Widdicombe, J.G. and Wise, J.C.M., Lung reflexes in rabbits during pulmonary stretch receptor block by sulfur dioxide, Respir. Physiol., 34 (1978) 83-101. 8 Davies, A. and Roumy, M., The effect of transient stimulation of lung irritant receptors on the pattern of breathing in rabbits, J. Physiol. (Lond.), 324 (1982) 389-401. 9 Euler, C. von, The contribution of sensory inputs to the pattern generation of breathing, Can. J. Physiol. Pharmacol., 59 (1981) 700-706. 10 Homma, I., Oouchi, M. and Ichikawa, S., Facilitation of inspiration by intracerebroventricular injection of thyrotropin-releasing hormone in rabbits, Neurosci. Lett., 44 (1984) 265-269. 11 Homma, I., Onimaru, H. and Oouchi, M., Effects of histamine inhalation and airway vibration on phrenic nerve activity in rabbits, Neurosci. Lett., 48 (1984) 93-96. 12 Knowlton, G.C. and Larrabee, M.G., A unitary analysis of pulmonary volume receptors, Am. J. Physiol., 147 (1946) 100-114.
311 13 Knox, C.K., Characteristics of inflation and deflation reflexes during expiration in the cat, J. Neurophysiol., 36 (1973) 284-295. 14 Knox, C.K., Reflex and central mechanisms controlling expiratory duration. In C. von Euler and H. Lagercrantz (Eds.), Central Nervous Control Mechanisms in Breathing, Pergamon Press, Oxford, 1979, pp. 203-216. 15 Man, G.C.W., Man, S.F.P. and Kappagod, C.T., Effects of high frequency oscillatory ventilation on vagal and phrenic nerve activities, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol., 54 (1983) 502-507. 16 Roumy, M. and Leitner, L.M. Localization of stretch and deflation receptors in the airways of the rabbit, J. Physiol. (Paris), 76 (1980) 67-70. 17 Sant'Ambrogio, G., Information arising from the tracheobronchial tree of mammals, Physiol. Rev., 62 (1982) 531-569. 18 Sears, T.A., Berger, A.J. and Phillipson, E.A., Reciprocal tonic activation of inspiratory and expiratory motoneurones by chemical drives, Nature (Lond.), 299 (1982) 728-730. 19 Sjostrand, U.H. and Eriksson, I.A., High rates and low volumes in mechanical ventilation - not just a matter of ventilatory frequency, Anesth. Analg., 59 (1980) 567-576. 20 Sluttsky, A.S., Kamm, R.D., Rossing, T.H., Loring, S.H., Lehr, J., Shapiro, R.H., Ingrain, Jr. and Drazen, J.M., Effects of frequency, tidal volume and lung volume on CO2 elimination in dogs by high frequency, low tidal volume ventilation, J. Clin. Invest., 68 (1981) 1475-1484. 21 Thompson, W.K., Marchak, B.E., Bryan, A.C. and Froese, A.B., Vagotomy reverses apnea induced by high-frequency oscillatory ventilation, J. Appl. Physiol.: Respirat. Environ. Exercise Physicol., 51 (1981) 1484-1487. 22 Widdicombe, J.G., Respiratory reflexes from the trachea and bronchi of the cat, J. Physiol. (Lond.), 123 (1954) 55-70. 23 Widdicombe, J.G., Pulmonary and respiratory tract receptors, J. Exp. Biol., 100 (1982) 41-57.