Inhibition of inspiratory motor output by high‐frequency low‐pressure oscillations in the upper airway of sleeping dogs
1999; Wiley; Volume: 517; Issue: 1 Linguagem: Inglês
10.1111/j.1469-7793.1999.0259z.x
ISSN1469-7793
AutoresPeter R. Eastwood, Makoto Satoh, Aidan K. Curran, Maria T. Zayas, Curtis A. Smith, Jerome A. Dempsey,
Tópico(s)Obstructive Sleep Apnea Research
ResumoThe Journal of PhysiologyVolume 517, Issue 1 p. 259-271 Free Access Inhibition of inspiratory motor output by high-frequency low-pressure oscillations in the upper airway of sleeping dogs Peter R. Eastwood, Peter R. Eastwood John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorMakoto Satoh, Makoto Satoh John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorAidan K. Curran, Aidan K. Curran John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorMaria T. Zayas, Maria T. Zayas John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorCurtis A. Smith, Curtis A. Smith John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorJerome A. Dempsey, Jerome A. Dempsey John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this author Peter R. Eastwood, Peter R. Eastwood John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorMakoto Satoh, Makoto Satoh John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorAidan K. Curran, Aidan K. Curran John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorMaria T. Zayas, Maria T. Zayas John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorCurtis A. Smith, Curtis A. Smith John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this authorJerome A. Dempsey, Jerome A. Dempsey John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, WI 53705, USASearch for more papers by this author First published: 08 September 2004 https://doi.org/10.1111/j.1469-7793.1999.0259z.xCitations: 12 Corresponding author P. R. Eastwood: Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009, Australia. 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Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract 1 We utilized a chronically tracheostomized, unanaesthetized dog model to study the reflex effects on inspiratory motor output of low-amplitude, high-frequency pressure oscillations (HFPOs) applied to the isolated upper airway (UA) during stable non-rapid eye movement (NREM) sleep. 2 HFPOs (30 Hz and ±2 to ±4 cmH2O) were applied via a piston pump during eupnoea, inspiratory resistive loading and tracheal occlusion. 3 When applied to the patent UA during expiration, and especially during late expiration, HFPOs prolonged expiratory time (TE) and tonically activated the genioglossus muscle EMG. When applied to the patent UA during inspiration, HFPOs caused tonic activation of the genioglossus muscle EMG and inhibition of inspiratory motor output by either: (a) a shortening of inspiratory time (TI), as inspiration was terminated coincident with the onset of HFPOs; or (b) a prolonged TI accompanied by a decreased rate of rise of diaphragm EMG and rate of fall of tracheal pressure. These effects of HFPOs were observed during eupnoea and inspiratory resistive loading, but were maximal during tracheal occlusion where the additional inhibitory effects of lung inflation reflexes were minimized. 4 During eupnoea, topical anaesthesia of the UA abolished the HFPO-induced prolongation of TE, suggesting that the response was mediated primarily by mechanoreceptors close to the mucosal surface; whereas the TE-prolonging effects of a sustained square wave of negative pressure (range, -4·0 to -14·9 cmH2O) sufficient to close the airway were preserved following anaesthesia. 5 These results demonstrate that high-frequency, low-amplitude oscillatory pressure waves in the UA, similar to those found in snoring, produce reflex inhibition of inspiratory motor output. This reflex may help maintain UA patency by decreasing the collapsing pressure generated by the inspiratory pump muscles and transmitted to the UA. Snoring is characterized by high-frequency oscillations of the soft palate, pharyngeal walls, epiglottis and tongue (Liistro et al. 1991). Previous investigators, applying high-frequency pressure oscillations to the upper airway (UA) at a similar frequency (30 Hz) as seen during snoring (Robin, 1968; Liistro et al. 1991), have demonstrated reflex activation of muscles in the UA in anaesthetized, waking and sleeping dogs, and in sleeping humans with and without obstructive sleep apnoea (Plowman et al. 1990b; Henke & Sullivan, 1993; Brancatisano et al. 1996). The results from these studies have led to the hypothesis that snorers may be able to resist complete UA obstruction, despite the generation of substantial negative pressures in the UA, because the pressure oscillations trigger reflex activation of dilator muscles in the UA which serve to stiffen it (Plowman et al. 1990b; Henke & Sullivan, 1993; Brancatisano et al. 1996). Low-amplitude, high-frequency pressure oscillations (HFPOs) in the UA have also been shown to elicit reflex changes in breathing pattern and in the magnitude of respiratory motor output; however, the results are variable. HFPOs applied to the UA of normal sleeping subjects and patients with obstructive sleep apnoea during a single inspiration cause increased diaphragm EMG activity, implying a reflex excitation of inspiratory motor output (Henke & Sullivan, 1993). However, when applied to the UA over successive inspirations in sleeping dogs, HFPOs cause a decreased minute-averaged inspiratory time (TI), implying an inhibitory effect on inspiratory motor output (Plowman et al. 1990b). When applied during expiration HFPOs result in a prolonged, shortened or unchanged expiratory time (TE) (Plowman et al. 1990b; Henke & Sullivan, 1993). Therefore the purpose of this study was to investigate the reflex effects of HFPOs on timing, drive and UA muscle EMG activity in the sleeping dog when HFPOs were applied during inspiration and expiration, together or separately, on backgrounds of eupnoea, increased resistance and airway occlusion. We also used mucosal blockade to examine the role of surface receptors in mediating the reflex responses. METHODS General Studies were performed on each of three unanaesthetized female mixed-breed dogs (20-25 kg) during non-rapid eye movement (NREM) sleep. The dogs were trained to sleep in an air-conditioned sound-attenuated chamber. Throughout all experiments the dogs' behaviour was monitored by an investigator seated within the chamber, and also by closed-circuit television. The protocol for this study was approved by the Animal Care and Use Committee of the University of Wisconsin. Animal preparation Sterile surgical techniques were used to create a permanent tracheostomy, and to implant electrodes for recording of inspiratory and UA muscle activities, and permit staging of sleep state. The dogs were premedicated with acepromazine (0.5 mg kg−1s.c.), induced with sodium thiopental (20 mg kg−1i.v.) and maintained on a mechanical ventilator with 1 % halothane in oxygen. A mid-line cervical incision and removal of the ventral aspect of four to five cartilagenous rings was used to create the chronic tracheostomy. Bipolar Teflon-coated multistrand stainless steel wire electrodes were sewn into the crural diaphragm and genioglossus muscles for measurement of EMG activity. The raw EMGs were filtered (30-1000 Hz), amplified, rectified and moving-time averaged with a time constant of 100 ms. Five wire electrodes were implanted subcutaneously, consisting of an EEG, two electro-oculograms (EOGs), a common reference and a ground electrode. The EEG and EOGs were amplified (BMA-831, CWE Inc., PA, USA) and filtered at 1-50 Hz. These methods have been described in detail previously (Chow et al. 1994). All electrodes were tunnelled subcutaneously to the cephalad portion of the dog's back, where they were exteriorized. Analgesics (butorphanol, 0.3 mg kg−1s.c.) and antibiotics (enrofloxacin, 2.2 mg kg−1per os (p.o.) or trimethoprim sulfa, 24 mg kg−1 p.o.) were administered postoperatively as required. At least 2 months were allowed for recovery from surgery before any experiments were performed. At the end of these experiments, each dog was killed with methods consistent with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association. Experimental set-up and measurements The dogs breathed via a cuffed tracheostomy tube (o.d. 12.0 mm) inserted into the permanent tracheostomy. A heated (37°C) pneumotachograph system (model 3700, Hans Rudolph, Kansas City, MO, USA; model MP-45-14-871, Validyne, Northbridge, CA, USA) connected to the tracheostomy tube was used to measure airflow and was calibrated prior to each study with five known flows. A low-resistance two-way valve (model 1400, Hans Rudolph) was attached to the pneumotachograph. The inspiratory port of the two-way valve was connected to a circuit which, by inflating or deflating different combinations of balloon-valves, could allow inspiration to proceed without external load, apply an inspiratory flow-resistive load (80 cmH2O l−1 s−1 at 0.2 l s−1), or occlude inspiration (Eastwood et al. 1998). The dead space of this system was approximately 40 ml. The UA was isolated by sealing both around a snout mask and below the larynx (Fig. 1). A light-weight polyethylene mask with polymer gel inserts (Silipos, Niagara Falls, NY, USA) was placed over the dog's snout to form an airtight seal around the mouth and nose. An additional cuffed endotracheal tube (o.d. 6.0 mm) was inserted rostrally into the tracheostomy above the tracheostomy tube to lie just caudal to the larynx. Inflation of this cuff produced an isolated UA. Figure 1Open in figure viewerPowerPoint Schematic representation of the isolated upper airway (UA) preparation The preparation allowed high-frequency pressure oscillations (HFPOs) to be applied to the isolated UA via the mask or sub-laryngeal catheters. During application of HFPOs continuous measurements were made of mask pressure (PM), sub-laryngeal pressure (PSl) and tracheal pressure (PTr). Sleep state was assessed from electro-oculograms (EOG), EEG and genioglossus EMG (EMGGg). Airway pressure changes were simultaneously measured at three sites: mask pressure (PM) was measured with a catheter passed through the mask near the nares; sub-laryngeal pressure (PSl) was measured via the laryngeal endotracheal tube; tracheal pressure (PTr) was measured from a catheter passed into the tracheostomy tube. Each catheter was connected to a pressure transducer (model MP-45-14-871, Validyne) and was calibrated prior to each study by applying eight known pressures. Oscillating pressure waves of 30 Hz and between ±2 and ±4 cmH2O were generated from a mechanical piston pump (Metrex Instruments, Toronto, Canada) and applied to the dog's isolated UA via the snout mask or the laryngeal endotracheal tube. All signals were collected on a 12-channel polygraph (Gould ES 2000, Rolling Meadows, IL, USA), and were passed via an analog-to-digital converter and stored on the hard disk of a microcomputer for subsequent analysis. Experimental protocol Over separate days, multiple trials were performed on each dog in stable NREM sleep. Trials consisted of the application of HFPOs to the isolated UA for a single respiratory effort, during inspiration or expiration, while the tracheostomy tube remained unloaded, during inspiratory resistive loading or during occlusion. Time of application (inspiratory or expiratory) and mode of breathing (unloaded or loaded) were randomized. Any trials in which there was EEG evidence of arousal were discarded. Application of HFPOs during expiration and inspiration. At various times during expiration HFPOs were initiated and then maintained throughout the following inspiration, which was either unloaded (eupnoea), or against a resistance or occlusion. HFPOs were terminated at the beginning of the subsequent expiration. Application of HFPOs during inspiration alone. At various times during unloaded inspiration (eupnoea) or during inspiratory efforts against a resistance or occlusion, HFPOs were initiated and then maintained until the beginning of the subsequent expiration. Upper airway anaesthesia. To anaesthetize the surface mucosa of the UA, lidocaine aerosol (4 %) was introduced into the UA of dogs 2 and 3 using a high-output extended aerosol nebulizer (B&B Medical Technologies Inc., Orangevale, CA, USA) which delivered high density particles (2-3 μm) at approximately 50 ml h−1. The aerosol was delivered via the laryngeal endotracheal tube and vented through the dog's unmasked nose and mouth. Before and immediately after 1 h of anaesthetic application the awake dog's responses to probing the larynx with small polyethylene tubing and to ammonium hydroxide passed near the nares were tested. Once the UA was anaesthetized the mask was immediately positioned on the dog and multiple HFPO trials and square-wave negative pressure trials (see Results, 'Responses to square-wave negative pressures') were performed during eupnoea in NREM sleep. Generally, the dogs required less than 5 min to attain stable NREM sleep following repositioning of the snout mask. Data were collected for approximately 30 min, immediately following which the dog was woken and the UA retested to confirm the maintenance of anaesthesia. Data selection and statistical analyses For any given trial, occluded or resistive-loaded efforts with or without HFPOs and eupnoeic trials with HFPOs, were compared with control values, which were obtained by averaging the values for the preceding three breaths. Inspiratory effects of HFPOs were compared for each of the three conditions (eupnoea, resistance or occlusion). Expiratory effects of HFPOs were analysed using the combined data from all trials, regardless of the condition, because the subsequent inspiration had no effect on the preceding expiratory responses. During eupnoea, paired t tests were used to compare control breaths and HFPO breaths, and unpaired t tests to compare the responses when HFPOs were applied during inspiration alone or maintained during inspiration and expiration. During efforts against an inspiratory resistance and inspiratory occlusion, ANOVA was used to compare the responses when HFPOs were not applied, applied during inspiration only, or applied during both inspiration and expiration. While the data in Tables 1-4 are presented as a percentage change from eupnoeic control values, statistical analyses for each dog were performed on the raw data. A Student- Newman-Keuls post hoc test was applied to correct for multiple comparisons. Statistical significance was inferred when P < 0.05. RESULTS Representative polygraph examples of the responses to HFPOs during single efforts against an inspiratory resistance are shown in Fig. 2A-D. The mean changes in timing, volume, pressure and EMG activity for each of the three conditions (eupnoea, inspiratory resistance and inspiratory occlusion) are shown for each dog in Tables 1-3. Figure 2Open in figure viewerPowerPoint Polygraph examples of the effects of HFPOs applied to the isolated UA Each panel shows the changes in EEG, integrated and raw diaphragm EMG (EMGDi), raw genioglossus muscle activity (EMGGg), respired flow and volume, and mask, sub-laryngeal and tracheal pressure changes (PM, PSl, PTr) during NREM sleep. In each example two unloaded control breaths are followed by a single inspiratory effort against an inspiratory resistance (80 cmH2O l−1 s−1) without (A) and with (B, C and D) application of HFPOs to the isolated UA. Application of HFPOs during expiration (B) resulted in aprolongation of expiratory time (eTE) and, in this example, activation of genioglossus muscle EMG activity. Application of HFPOs during inspiration resulted in a prolongation of inspiratory time and depression of EMGDi activity, particularly at the onset of HFPOs (C), or early termination of inspiration coincident with the onset of HFPOs (D). It was notable that the UA remained patent throughout all trials, as similar changes were observed in PM and PSl. Route of application of HFPOs To assess the potential effect of the route of application of HFPOs, in dogs 1 and 2 the responses to HFPOs applied from the mask and sub-laryngeal catheters were compared. We found no significant differences between TI, TE, tidal volume (VT), diaphragm EMG activity (EMGDi) or PTr changes in response to HFPOs between the two routes of application. Because of this lack of effect, measurements in dog 3 were obtained from the mask only, and mask and sub-laryngeal data were pooled in each of dogs 1 and 2. Effects of HFPOs applied during expiration on expiratory time During all trials in which HFPOs were applied during expiration, expiratory time was identified by eTE, in order to distinguish these changes from the expiratory time following an inspiration, which was identified by TE. Application of HFPOs during expiration caused eTE to beprolonged by 151 ± 55, 129 ± 26 and 128 ± 18 % (means ±s.d.) of control values in each of dogs 1, 2 and 3, respectively (Tables 1-3, Fig. 2B). Linear regression analyses of these data demonstrated a significant positive correlation between the time of application of HFPOs and the magnitude of eTE prolongation for each dog: regression coefficient 0.485, 0.705 and 0.556, respectively (P < 0.05); slope of the regression line 1.015, 0.636 and 0.427, respectively (P < 0.05). Thus the magnitude of eTE prolongation was dependent on when during expiration HFPOs were applied, such that the greatest prolongation was observed when HFPOs were initiated during late expiration (Fig. 3). Figure 3Open in figure viewerPowerPoint The effect of time of application of HFPOs on expiratory time (eTE) In each of the three dogs, during NREM sleep, the magnitude of eTE prolongation depended on when during expiration HFPOs were initiated, with the greatest prolongation seen when HFPOs were initiated during late expiration (•). Topical anaesthesia of the upper airway (○) abolished the prolongation of eTE. Effects of HFPOs on inspiratory timing and motor output Application of HFPOs during expiration and continuing through the subsequent inspiration invariably prolonged that inspiration. Application of HFPOs during inspiration alone resulted in two distinct responses, represented by either (i) a prolonged TI or, (ii) a shortened TI as a consequence of the termination of inspiratory effort coincident with the onset of HFPOs. Trials in which TI was prolonged During eupnoea. Relative to eupnoeic control values, initiation of HFPOs during inspiration increased TI (by 14 ± 7 %, significant in 2 dogs only), decreased the rate of rise of EMGDi (by 14 ± 6 %), and decreased the rate of fall of PTr (by 22 ± 14 %) (means ±s.d. from the 3 dogs, Table 1). Similar changes were observed when HFPOs were initiated in expiration and maintained throughout the subsequent inspiration. That is, relative to eupnoeic control values TI increased (by 32 ± 15 %), VT increased (by 13 ± 6 %), rate of rise of EMGDi decreased (by 19 ± 11 %) and rate of fall of PTr decreased (by 29 ± 12 %) (means ±s.d. from 3 dogs, Table 1). Table 1. Effects of HFPOs during eupnoea Dog 1 Dog 2 Dog 3 Absolute values during eupnoea No. of trials 94 36 45 TI (s) 1.6 ± 0.3 1.4 ± 0.1 1.7 ± 0.1 TE (s) 3.0 ± 0.8 2.7 ± 0.4 3.9 ± 0.3 VT (ml) 380 ± 64 274 ± 32 349 ± 35 PTr/TI (cmH2O s−1) −0.9 ± 0.4 −0.5 ± 0.3 −0.5 ± 0.1 HFPOs applied during inspiration only No. of trials 23 7 6 TI (%) 114 ± 16* 107 ± 9 121 ± 13 * TE (%) 112 ± 46 122 ± 26 98 ± 5 VT (%) 106 ± 14 100 ± 7 103 ± 11 P/Tr/TI (%) 81 ± 19* 90 ± 12 62 ± 24* EMGDi/TI (%) 91 ± 17* 88 ± 12* 79 ± 13* HFPOs applied during expiration and inspiration No. of trials 71 29 39 TI (%) 133 ± 23 *† 116 ± 14 * 147 ± 20 *† TE (%) 148 ± 59* 133 ± 27* 128 ± 18* VT (%) 120 ± 22 *† 110 ± 17 * 110 ± 19 * PTr/TI (%) 70 ± 24* 84 ± 18* 60 ± 21* EMGDi/TI (%) 83 ± 23* 91 ± 15* 70 ± 10*† Values are means ± S.D. of multiple trials on each dog, expressed as absolute values or as a percentage of eupnoeic control values. TI, inspiratory time (from the inspiratory period); TE, expiratory time (from the expiratory period following this inspiratory period); eTE, expiratory time (from the expiratory period prior to the inspiratory period); VT, tidal volume; PT/TI, rate of fall of tracheal pressure; EMGDi/TI, rate of rise of diaphragm EMG. *Raw values significantly different from eupnoeic control breaths, P < 0.05. † Raw values significantly different from HFPOs applied during inspiration only, P < 0.05. In 2 of the 3 dogs the magnitude of increase of TI was significantly greater when HFPOs were initiated in expiration than inspiration, while the changes in VT, rate of rise of EMGDi and rate of fall of PTr were generally similar whether HFPOs were initiated in expiration or inspiration. During efforts against an inspiratory resistance. Relative to eupnoeic control values, application of an inspiratory resistance increased TI (127 ± 10 %), decreased VT (50 ± 6 %), decreased the rate of rise of EMGDi (88 ± 2 %) and increased the rate of fall of PTr (732 ± 171 %) (means ±s.d. from 3 dogs, P < 0.05 for each dog; Table 2 and Fig. 2A). Table 2. Effects of HFPOs during efforts against an inspiratory resistance Dog 1 Dog 2 Dog 3 Without HFPOs No. of trials 12 27 27 TI (%) 120 ± 11 138 ± 16 123 ± 13 TE (%) 106 ± 27 111 ± 18 106 ± 16 VT (%) 47 ± 7 57 ± 7 45 ± 8 PTr/TI (%) 574 ± 95 710 ± 146 914 ± 244 EMGDi/TI (%) 87 ± 12 87 ± 16 90 ± 16 HFPOs applied during inspiration only No. of trials — 24 10 TI (%) — 165 ± 30* 155 ± 12* TE (%) — 103 ± 11 109 ± 13 VT (%) — 67 ± 7 * 55 ± 10 * PTr/TI (%0 — 564 ± 181 * 621 ± 129 * EMGDi/TI (%) — 70 ± 18 * 72 ± 8 * HFPOs applied during expiration and inspiration No. of trials 18 13 14 TI (%) 158 ± 32* 156 ± 24* 157 ± 16* eTE (%) 158 ± 32* 121 ± 19 129 ± 19* VT (%) 58 ± 13* 71 ± 19* 59 ± 8* PTr/TI (%) 426 ± 152 * 728 ± 252 † 778 ± 116 * EMGDi/TI (%) 73 ± 21* 87 ± 24† 81 ± 12 Values are means ± S.D. of multiple trials on each dog, expressed as a percentage of eupnoeic control values. TI, inspiratory time (from the inspiratory period); TE, expiratory time (from the expiratory period following this inspiratory period); eT<E, expiratory time (from the expiratory period prior to the inspiratory period); VT, tidal volume; PTr/TI, rate of fall of tracheal pressure;EMGDi/TI, rate of rise of diaphragm EMG. For dog 1, HFPOs applied during inspiration only caused termination of inspiratory efforts (see Results). *Raw values significantly different from efforts without HPFOs, P < 0.05. † Raw values significantly different from HFPOs applied during inspiration only, P < 0.05. Initiation of HFPOs during inspiration caused termination of inspiration in all trials performed in dog 1 (see below, 'Trials in which TI was shortened'). In dogs 2 and 3, relative to the control responses against a resistance (without HFPOs), initiation of HFPOs during inspiration increased TI (by 25 ± 11 %), increased VT (by 31 ± 4 %), decreased the rate of rise of EMGDi (19 ± 1 %) and decreased the rate of fall of PTr (by 24 ± 13 %) (means ±s.d. from 2 dogs, Table 2 and Fig. 2C). It was possible to obtain data from all dogs when HFPOs were initiated in expiration. Relative to the control responses against a resistance, HFPOs increased TI (24 ± 14 %), increased VT (by 32 ± 7 %), decreased the rate of rise of EMGDi (8 ± 8 %, significant in dog 1 only) and decreased the rate of fall of PTr (by 14 ± 18 %, significant in dogs 1 and 3) (means ±s.d. from 3 dogs; Table 2 and Fig. 2B). Generally, the magnitudes of increase of TI and VT and decrease of rate of rise of EMGDi and rate of fall of PTr were similar whether HFPOs were applied in expiration or inspiration. During efforts against an inspiratory occlusion. Relative to eupnoeic control values, inspiratory occlusion increased TI (133 ± 15 %), decreased the rate of rise of EMGDi (90 ± 10 %, significant in 2 dogs only) and increased the rate of fall of PTr (1398 ± 465 %) (means ±s.d. of 3 dogs, P < 0.05 for each dog; Table 3). Table 3. Effects of HFPOs during efforts against an inspiratory occlusion Dog 1 Dog 2 Dog 3 Without HFPOs No. of trials 15 14 32 TI (%) 124 ± 11 150 ± 12 124 ± 12 TE (%) 99 ± 35 121 ± 16 100 ± 22 PTr/TI (%) 965 ± 174 1339 ± 324 1890 ± 437 EMGDi/TI (%) 86 ± 17 83 ± 11 102 ± 18 HFPOs applied during inspiration only No. of trials — 11 3 TI (%) — 204 ± 22* 213 ± 18* TE (%) — 99 ± 13 * 76 ± 16 PTr/TI (%) − 1053 ± 284 * 1110 ± 247 * EMGDi/TI (%) — 64 ± 15 * 48 ± 3 * HFPOs applied during expiration and inspiration No. of trials 13 13 7 TI (%) 186 ± 27* 211 ± 38* 186 ± 18*† eTE (%) 174 ± 40* 132 ± 32 127 ± 12* PTr/TI (%) 628 ± 131 * 1052 ± 325 * 1167 ± 625 * EMGDi/TI (%) 73 ± 21* 75 ± 30* 66 ± 12* Values are means ± S.D. of multiple trials on each dog, expressed as a percentage of eupnoeic control values. TI, inspiratory time (from the inspiratory period); TE, expiratory time (from the expiratory period following this inspiratory period); eTE, expiratory time (from the expiratory period prior to the inspiratory period); VT, tidal volume; PTr/TI, rate of fall of tracheal pressure; EMGDi/TI, rate of rise of diaphragm EMG. For dog 1, HFPOs appplied during inspiration only caused arousal in all trials (see Results). *Raw values significantly different from efforts without HPFOs, P < 0.05. †Raw values significantly different from HFPOs applied during inspiration only, P < 0.05. Initiation of HFPOs during inspiration caused arousal in dog 1, and these data were discarded. In dogs 2 and 3, relative to the control values against an occluded airway (without HFPOs), initiation of HFPOs during inspiration increased TI (by 62 ± 37 %), decreased the rate of rise of EMGDi (by 38 ± 21 %) and decreased the rate of fall of PTr (28 ± 14 %) (means ±s.d. from 2 dogs, Table 3). Data could be obtained from all dogs when HFPOs were initiated in expiration. Relative to control responses against an occlusion, HFPOs increased TI (by 40 ± 7 %), decreased the rate of rise of EMGDi (by 20 ± 10 %) and decreased the rate of fall of PTr (by 24 ± 12 %) (means ±s.d. from 3 dogs, Table 3). Generally, the magnitudes of increase of TI and VT and decrease of rate of rise of EMGDi and rate of fall of PTr were similar whether HFPOs were applied in expiration or inspiration. Therefore, relative to their respective controls, HFPOs increased TI during eupnoea, resistance and occlusion trials. Analysis of the group data showed that the magnitude of the increase in TI with HFPOs was greater during inspiratory efforts against occlusion than during resistive loading and eupnoea, which were similar (P < 0.05, n= 3, 2-way ANOVA). Trials in which TI was shortened Figure 2D shows an example of a trial in which HFPOs initiated during inspiration caused early termination of inspiration, coincident with the onset of HFPOs. This was observed in 50 ± 24 % of trials in eupnoea (means ±s.d. from 3 dogs), 57 ± 44 % of trials during resistive loading (3 dogs) and 63 ± 26 % of trials during occlusion (2 dogs), otherwise TI was prolonged (see above). During eupnoea and breaths against a resistance and occlusion, TI was decreased to 69 ± 5, 70 ± 13 and 83 ± 6 % of eupnoeic control values, respectively. The time of application of HFPOs during inspiration ranged between 42 and 99 % of TI, and bore no relationship to whether TI was terminated or prolonged. Shortening of TI was never seen and TI prolongation was always observed when HFPOs were initiated in expiration and maintained throughout the subsequent inspiration. We found that the time of application of HFPOs was an important determinant of the duration of the apnoea, such that the greatest magnitude of TE prolongation occurred when HFPOs were initiated in late expiration. A similar phase dependency has been reported in sleeping dogs by Harms et al. (1996), who described TE prolongation when brief negative pressur
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