Negative Upper Airway Pressure Research Articles

Differential effects of positive and negative upper airway pressure application on atrial electrophysiology: implications for CPAP-therapy in OSA-patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo nordisk foundation Background Obstructive sleep apnea (OSA) is closely associated with atrial fibrillation (AF) and OSA-treatment by continuous positive airway pressure (CPAP) is believed to reduce the AF burden in OSA-patients. While negative upper airway pressure during obstructive respiratory events have been shown to increase AF susceptibility, atrial electrophysiological effects of positive upper airway pressure during CPAP-therapy are unknown. Purpose In pigs, we investigated differential atrial electrophysiological effects of increasing levels of CPAP-applications compared to obstructive respiratory events. Methods In sedated and spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds with a 10 minute resting period in-between. After four INAP-applications, during which atrial electrophysiological responses to INAP were recorded, continuous positive airway pressure was applied in increasing pressure stages for a duration of 20 minutes for each pressure level (4, 8, 12 and 16 mbar). Atrial effective refractory periods (AERP) were recorded at the free wall of the right atrium (RA) and in the distal area of the coronary sinus (CS) before (Pre-INAP), during (INAP) and after (Post-) INAP and every 10 minutes throughout the stepwise increase of CPAP. Results AERP shortened due to INAP application in the RA (Pre-INAP 134±7ms vs. INAP 95±7ms; p=0.008, Fig.1.), but not in the CS (Pre-INAP 132±8ms vs. INAP 110±9ms; p=0.144, Fig.2). Stepwise increases of CPAP-application up until 12 mbar did neither result in changes of RA- nor CS-AERP. Only CPAP-application at 16 mbar (CPAP16) resulted in transiently shortened CS-AERP (CPAP-baseline 140±6ms versus CPAP16 115±10ms; p=0.0081, Fig.2.), but not RA-AERPs (p=0.31, Fig.1.). Conclusion While simulation of obstructive respiratory events by INAP were reproducibly associated with a predominantly right atrial shortening of refractoriness, high-pressure CPAP-application of 16 mbar was associated with an isolated moderate shortening of left atrial refractoriness. These findings may have important implications for CPAP treatment in patients with AF, which should be considered in the design of future clinical studies.

Obstructive respiratory events transiently impair electromechanical coupling and increase premature ventricular contraction rate in a drug-induced Long-QT-2 pig model

Abstract Background Obstructive sleep apnea (OSA) is characterized by intermittent negative thoracic pressure fluctuations and intermittent hypoxemic events. Recent findings associate OSA with impaired ventricular repolarization during sleep and increased risk of sudden cardiac death, which may have special implications for Long-QT-2-syndrome patients. Therefore, we elucidated changes in ventricular repolarization and electromechanical coupling (electromechanical window; EMW) during either obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) or hypoxemic events simulated by intermittent hypoxia (IH) in vehicle (VEH) and dofetilide (DOF) treated pigs, as a simulation of drug induced Long-QT-2 syndrome. Methods In sedated spontaneously breathing pigs, either VEH or DOF (50 μg/kg) was perfused and INAP was applied by a negative pressure device connected to the intubation tube. For IH-application the device was connected and left turned off. INAP or IH was maintained for 75 seconds followed by a ten-minute resting period. In order to evaluate the electromechanical window, the time difference between electrical (QT-duration) and mechanical systole (Q-wave to the end of left ventricular pressure signal, QLVPend) was measured before (pre-INAP/-IH), during and 60 seconds after INAP/IH (post-INAP/-IH). Incidence rates of premature ventricular contractions (PVC) and ventricular tachycardia were compared pre- to post-INAP/-IH. Results In VEH-pigs, EMW shortened throughout INAP and post-INAP periods steadily (VEH: pre-INAP: 81.69±2.31ms; INAP: 55.65±6.13ms; post-INAP: 38±8.89ms. p=0.008). EMW shortening during post-INAP was associated with an increase in PVCs (VEH: pre-INAP 5.41±1.87 vs. post-INAP 26.5±8.15; p=0.04). In DOF-pigs, INAP-associated EMW-shortening was further potentiated (DOF: pre-INAP: 61.16±7.18ms; INAP: 38.09±9.84ms; post-INAP: 14.93±9.24ms. p=0.016), which was associated with an increase in PVCs (DOF: pre-INAP 4.75±2.36 vs. post-INAP 36.58±10.92; p=0.017). Administration of Atenolol could prevent post-INAP shortening of the EMW and decrease counts of premature ventricular contractions. While desaturations were comparable in INAP and IH, IH did not result in EMW-shortening or increased arrhythmia risk. Conclusion Transient dissociation of the ventricular electromechanical coupling during a simulated obstructive apnea, but not during IH, creates a dynamic and sympathetically driven arrhythmogenic substrate. Apnea associated ventricular electromechanical uncoupling was aggravated in a drug-induced Long-QT-2 simulation. Whether OSA represents a modifiable arrhythmogenic risk factor in Long-QT-2-patients warrants further studies. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Novo nordisk fonden

741Pharmacological inhibition of the acetylcholine-regulated potassium channel (IK,ACh) prevents atrial arrhythmogenic changes in a rat model for obstructive sleep apnea

Abstract Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone, resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP), inducible atrial fibrillation (AF)-durations and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results During single INAP applications atrial activation times prolonged transiently in both groups (Control: INAP vs. pre-INAP p = 0.034; XAF-1407: INAP vs. pre-INAP p = 0.039). In control-rats, seventy minutes of repetitive INAP prolonged P-wave duration (+10.8 ± 2.7% vs. baseline, p = 0.008) and decreased AERP by 14.6 ± 3.1% (vs. baseline p = 0.001). AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r= -0.773; p= 0.025). XAF-1407 could prevent P-wave prolongation and AERP shortening. Inducible AF-durations (CTR 0.94 ± 0.34s vs. XAF-1407 0.1 ± 0.09s p = 0.049) were shorter in XAF-1407 treated rats. Drops in oxygen saturation or applied INAP were comparable in control and XAF-1407 rats. Conclusion Short-term simulated OSA is associated with AF-related arrhythmogenic changes, which could be prevented by pharmacological IK,ACh inhibition. Moreover, the cumulative negative airway pressure applied determined aERP shortening and may represent a target for OSA treatment. These findings have important implications for the antiarrhythmic management of AF patients with OSA.

P2561Withdrawal of simulated obstructive sleep apnea partially reverses atrial arrhythmogenic substrate in rats

Abstract Background Obstructive sleep apnea (OSA) is associated with structural alterations of the left atria (LA) and increased occurrence of atrial fibrillation (AF). Obstructive respiratory events lead to intermittent hypoxia (IH) and ineffective inspiration against the occluded upper airways, which result in intrathoracic and cardiac transmural pressure changes. Data on reversibility of LA-structural remodeling processes after withdrawal of OSA are still missing. Objectives Aim of the study was to develop a novel AF animal model mimicking intrathoracic pressure changes in addition to IH and to analyze the effect of OSA-withdrawal on atrial remodeling reversibility. Method In sedated rats (2% isoflurane), IH (n=9) was applied by intermittent increase in the respiratory dead volume. Standardized obstructive respiratory events were induced by defined intermittent negative upper airway pressure (INAP = inverse CPAP) applied via a customized mask connected to a negative pressure device (n=9). One minute of IH or INAP was followed by a rest period of nine minutes for four hours every second day. Rats with comparable anesthesia were used as controls (CTR). After three weeks, the animals were sacrificed. To analyze atrial structural remodeling reversibility, additional INAP-rats (n=5) were sacrificed after INAP-withdrawal of three weeks and compared to respective CTR (n=7). Result Blood pressure was not affected by IH or INAP. Intermittent desaturation and post-apneic hyperventilation were comparable in INAP- and IH-rats, but INAP-rats showed significantly higher breathing efforts during apneas compared to IH-rats. LA connexin43 (Cx43) protein expression assessed by quantitative immunofluorescence was reduced in both groups compared to CTR (0.77±0.07% in CTR vs. 0.45±0.06% in IH, p=0.02; CTR vs. 0.39±0.06% in INAP, p=0.005). However, LA interstitial fibrosis content (7.03±0.58% vs. CTR, p=0.01) and LA myocyte diameters (13.23±0.34μm vs. CTR, p=0.03) were increased in INAP-rats, but not in IH-rats. This was associated with longer inducible AF-durations in INAP-rats (11.65±4.43s vs. 0.72±0.33s in CTR, p=0.03) but not in IH-rats (1.28±0.33s vs. CTR, p=0.31). Three weeks of INAP-withdrawal (INAP-W) normalized interstitial fibrosis content (INAP-W vs. CTR, p=0.50) and LA-myocyte diameter (INAP-W vs. CTR, p=0.31). However, LA Cx43 protein expression remained low after three weeks of INAP withdrawal and inducible AF-episodes were still prolonged compared to respective CTR. Conclusion Application of INAP in rats mimics important components of OSA beyond IH and allows the study of an arrhythmogenic substrate in the atrium independent of the development of risk factors. In our model, withdrawal of INAP resulted in partial reversibility of structural LA remodeling but was not sufficient to abolish inducible AF-episodes completely. Future clinical studies are warranted to determine the anti-arrhythmic effect of isolated sleep apnea treatment in AF-patients. Acknowledgement/Funding Else Kröner-Fresenius-Stiftung, SFB-TRR219-M02/S-02

Diagnosis of Obstructive Sleep Apnea during Wakefulness Using Upper Airway Negative Pressure and Machine Learning.

Background and Rational: Obstructive Sleep Apnea (OSA) is a common disorder, affecting almost 10% of adults, but very underdiagnosed. This is largely due to limited access to overnight sleep testing using polysomnography (PSG). Our goal was to distinguish OSA from healthy individual using a simple maneuver during wakefulness in combination with machine learning methods. Methods: Participants have undergone an overnight PSG to determine their ground truth OSA severity. Separately, they were asked to breathe through a nasal mask or a mouth piece through which negative pressure (NP) was applied, during wakefulness. Airflow waveforms were acquired and several features were extracted and used to train various classifiers to predict OSA. Results and Discussion: The performance of each classifier and experimental setup was calculated. The best results were obtained using Random Forest classifier for distinguishing OSA from healthy individuals with a very good area under the curve of 0.80. To the best of our knowledge, this is the first study to deploy machine learning and NP with promising path to diagnose OSA during wakefulness.

P798Application of intermittent negative upper airway pressure as a novel rat model for obstructive sleep apnea and atrial fibrillation

P798Application of intermittent negative upper airway pressure as a novel rat model for obstructive sleep apnea and atrial fibrillation

Long‐term facilitation of upper airway muscle activity induced by episodic upper airway negative pressure and hypoxia in spontaneously breathing anaesthetized rats

Obstruction of the upper airway (UA) is associated with episodes of hypoxia and upper airway negative pressure (UANP). In the companion paper it is shown that episodic hypoxia elicits long-term facilitation (LTF) of tongue protrudor, retractor and respiratory pump muscle activity. However, whether repeated exposure to UANP also induces LTF is unknown. We hypothesized that repetitive exposure to UANP would induce LTF of UA and respiratory pump muscle activity and when coupled with hypoxia, as occurs when the UA obstructs, would lead to an even greater facilitation of muscle activity and the response to UANP. Experiments were performed in 24 anaesthetized, spontaneously breathing rats with intact vagi. To induce LTF, UANP stimuli (-10 cmH(2)O) of 5 s duration were delivered every 30 s for 3 min (+/- hypoxia). This was repeated eight times over 1 h, each 3 min episode separated by 5 min of normoxia. Genioglossus (GG), hyoglossus (HG) and diaphragm (Dia) muscle activity was recorded before, during and for 1 h following the last exposure to episodic UANP alone (n = 8), UANP and hypoxia together (n = 8) or normoxia alone (n = 8). During the final hour, single pulses of UANP were applied at 1 min and every 10 min thereafter to determine whether LTF of the response to UANP had been induced. Our results show that LTF of GG muscle activity and its response to UANP was induced following exposure to episodic UANP stimuli alone and UANP applied during hypoxia. However, there was no significant difference between these responses. Episodic UANP alone also induced LTF of HG muscle activity but this effect did not manifest until 40 min following the last episode of repeated UANP stimulation. In the presence of hypoxia, no LTF of HG muscle response to UANP was found. In conclusion, episodic UANP stimulation induces LTF of UA dilator and retractor tongue muscles, but no further facilitation occurs when coupled with hypoxia. This response may serve as an important protective mechanism of respiratory homeostasis during sleep, particularly in patients who suffer from obstructive sleep apnoea.

Upper airway muscle paralysis reduces reflex upper airway motor response to negative transmural pressure in rat.

The reflex upper airway (UA) motor response to UA negative pressure (UANP) is attenuated by neuromuscular blockade. We hypothesized that this is due to a reduction in the sensitivity of laryngeal mechanoreceptors to changes in UA pressure. We examined the effect of neuromuscular blockade on hypoglossal motor responses to UANP and to asphyxia in 15 anesthetized, thoracotomized, artificially ventilated rats. The activity of laryngeal mechanoreceptors is influenced by contractions of laryngeal and tongue muscles, so we studied the effect of selective denervation of these muscle groups on the UA motor response to UANP and to asphyxia, recording from the pharyngeal branch of the glossopharyngeal nerve (n = 11). We also examined the effect of tongue and laryngeal muscle denervation on superior laryngeal nerve (SLN) afferent activity at different airway transmural pressures (n = 6). Neuromuscular blockade and denervation of laryngeal and tongue muscles significantly reduced baseline UA motor nerve activity (P < 0.05), caused a small but significant attenuation of the motor response to asphyxia, and markedly attenuated the response to UANP. Motor denervation of tongue and laryngeal muscles significantly decreased SLN afferent activity and altered the response to UANP. We conclude that skeletal muscle relaxation reduces the reflex UA motor response to UANP, and this may be due to a reduction in the excitability of UA motor systems as well as a decrease of the response of SLN afferents to UANP.

Reflex respiratory response to changes in upper airway pressure in the anaesthetized rat.

1. We examined the upper airway (UA) motor response to upper airway negative pressure (UANP) in the rat. We hypothesized that this response is mediated by superior laryngeal nerve (SLN) afferents and is not confined to airway dilator muscles but also involves an increase in motor drive to tongue retractor and pharyngeal constrictor muscles, reflecting a role for these muscles in stabilizing the UA. 2. Experiments were performed in 49 chloralose-anaesthetized, tracheostomized rats. Subatmospheric pressure in the range 0 to -30 cmH(2)O was applied to the isolated UA. Motor activity was recorded in separate experiments from the main trunk of the hypoglossal nerve (XII, n = 8), the pharyngeal branch of the glossopharyngeal nerve (n = 8), the medial and lateral branches of the XII (n = 8) and the pharyngeal branch of the vagus (n = 8). Afferent activity was recorded from the whole SLN in six experiments. 3. All UA motor outflows exhibited phasic inspiratory activity and this was significantly (P < 0.05) increased by UANP. Tonic end-expiratory activity increased significantly in response to pressures more negative than -20 cmH(2)O. Bilateral section of the SLN also increased (P < 0.05) motor activity and abolished the responses to UANP. Electrical stimulation of the SLN inhibited inspiratory XII activity. SLN afferents were tonically active and inhibited by UANP. 4. We conclude that UANP causes a reflex increase in motor drive to pharyngeal dilator, tongue retractor and pharyngeal constrictor muscles via afferent fibres in the SLN. Tonic activity in SLN afferent fibres at zero transmural pressure exerts a marked inhibitory effect on UA motor outflow.

The influence of a transmucosal cholinergic agonist on pharyngeal muscle activity.

To assess the effect of high local oral nicotine administration on the upper airway (UA) of normal males during wakefulness. Nonrandomized study. Brigham & Women's Hospital General Clinical Research Center. Two groups of 13 and 12 normal male subjects were evaluated. A "Fast acting" or "Intermediate acting" 2 mg transmucosal nicotine patch was attached to an upper molar tooth of study participants during wakefulness. All data were collected prior to, and at several time points after, patch placement. Data measured included serum nicotine levels, genioglossal EMG, and pharyngeal resistance during basal breathing as well as the UA muscle response and UA collapsibility during negative UA pressure pulses. None of the variables measured showed a statistically significant change with either nicotine patch despite a significant rise (p<0.05) in nicotine serum levels post patch placement in both groups. In several subjects, muscle activity and responsiveness to negative pressure increased after application of both patches and returned to near baseline levels at the last time point measured, a response consistent with the time course of nicotine release in both patches. Oral nicotine administration failed to consistently increase GG muscle activation which may be a problem of local bioavailability of nicotine in the muscle.

Effect of upper airway negative pressure on proprioceptive afferents from the tongue.

We examined whether receptors in the tongue muscle respond to negative upper airway pressure (NUAP). In six cats, one hypoglossal nerve was cut and its distal end was prepared for single-fiber recording. Twelve afferent fibers were selected for study on the basis of their sensitivity to passive stretch (PS) of the tongue. Fiber discharge frequency was measured during PS of the tongue and after the rapid onset of constant NUAP. During PS of 1-3 cm, firing frequency increased from 17 +/- 7 to 40 +/- 11 (SE) Hz (P < 0.01). In addition, 8 of the 12 fibers responded to NUAP (-10 to -30 cmH2O), with firing frequency increasing from 23 +/- 9 to 41 +/- 9 Hz (P < 0.001). In two fibers tested, the increase in firing frequency in response to NUAP was not altered by topical anesthesia (10% lignocaine) applied liberally to the entire upper airway mucosa. Our results demonstrate that afferent discharges from the hypoglossal nerve are elicited by 1) stretching of the tongue and 2) NUAP before and after upper airway anesthesia. We speculate that activation of proprioceptive mechanoreceptors in the cat's tongue provides an additional pathway for the reflex activation of upper airway dilator muscles in response to NUAP, independent of superficially located mucosal mechanoreceptors.

Soft palate muscle responses to negative upper airway pressure.

The afferent pathways and upper airway receptor locations involved in negative upper airway pressure (NUAP) augmentation of soft palate muscle activity have not been defined. We studied the electromyographic (EMG) response to NUAP for the palatinus, tensor veli palatini, and levator veli palatini muscles in 11 adult, supine, tracheostomized, anesthetized dogs. NUAP was applied to the nasal or laryngeal end of the isolated upper airway in six dogs and to four to six serial upper airway sites from the nasal cavity to the subglottis in five dogs. When NUAP was applied at the larynx, peak inspiratory EMG activity for the palatinus and tensor increased significantly (P < 0.05) and plateaued at a NUAP of -10 cmH2O. Laryngeal NUAP failed to increase levator activity consistently. Nasal NUAP did not increase EMG activity for any muscle. Consistent NUAP reflex recruitment of soft palate muscle activity only occurred when the larynx was exposed to the stimulus and, furthermore, was abolished by bilateral section of the internal branches of the superior laryngeal nerves. We conclude that soft palate muscle activity may be selectively modulated by afferent activity originating in the laryngeal and hypopharyngeal airway.

Upper airway reflexes.

It is usually assumed that upper airway pressure receptors mediate the reflexes involved in sleep apneas, but many other receptors may be involved, including those responding to chemical stimuli. The reflexes to upper airway negative pressure have been further studied, and the timing of their inputs shown to be important. Their effects on the cardiovascular system, including cerebral blood flow, have been emphasized. The central nervous pathways for the upper airway reflexes and their relationship to the neuronal circuits of the respiratory rhythm generator are being analyzed, but no clear pattern has emerged. Many neurotransmitters have been identified, usually on the motor pathways, which points to possible therapeutic approaches. The central nervous pharmacology and the neuronal pattern for the cough reflex have been described, and a similar approach to other upper airway reflexes, especially those involved in sleep apneas, would be valuable.

Superior laryngeal nerve section alters responses to upper airway distortion in sleeping dogs.

We investigated the effect of superior laryngeal nerve (SLN) section on expiratory time (TE) and genioglossus electromyogram (EMGgg) responses to upper airway (UA) negative pressure (UANP) in sleeping dogs. The same dogs used in a similar intact study (C. A. Harms, C. A., Y.-J. Zeng, C. A. Smith, E. H. Vidruk, and J. A. Dempsey. J. Appl. Physiol. 80: 1528-1539, 1996) were bilaterally SLN sectioned. After recovery, the UA was isolated while the animal breathed through a tracheostomy. Square waves of negative pressure were applied to the UA from below the larynx or from the mask (nares) at end expiration and held until the next inspiratory effort. Section of the SLN increased eupneic respiratory frequency and minute ventilation. Relative to the same dogs before SLN section, sublaryngeal UANP caused less TE prolongation while activation of the genioglossus required less negative pressures. Mask UANP had no effect on TE or EMGgg activity. We conclude that the SLN 1) is not obligatory for the reflex prolongation of TE and activation of EMGgg activity produced by UANP and 2) plays an important role in the maintenance of UA stability and the pattern of breathing in sleeping dogs.

Influence of preload and afterload on genioglossus muscle length in awake goats.

The genioglossus is an upper airway dilator muscle, the length of which is directly related to patency in the oropharyngeal region. We hypothesized that genioglossal length (Lgg) is dynamically influenced by the afterload exerted by negative upper airway pressure during inspiration and by the intrinsic length-tension characteristics of the muscle (preload). Seven awake goats were chronically instrumented with electrodes for EMGgg and sonomicrometry for Lgg. We examined the Lgg-EMGgg relationship during hypercapnia and inspiratory resistive loading (18 cm H2O/L/s). The goats breathed through the upper airway (TC) or airflow was diverted through a tracheostomy (TO). We found that: (1) passive inspiratory lengthening was observed with negative upper airway pressure (UAP) but not when UAP = 0 (TO breathing), (2) Lgg shortening for a given EMGgg was significantly decreased with negative inspiratory UAP, and (3) phasic Lgg shortening per unit EMGgg was greatest when Lgg was near optimal length (Lo). We conclude that genioglossal length is substantially influenced by afterload exerted by negative UAP and that genioglossal active shortening may be limited if the muscle operates at a length significantly greater or less than the optimal length.

A Longitudinal Study of the Upper Airway Negative Pressure Reflex in Newborn Lambs. 1498

It has been previously shown that the activity of the neonatal Genioglossus(GG) muscle reflexly increases only in response to large amounts of upper airway negative pressure (UANP) in lambs (Duara, Ped Res: 4:331A,1994), in comparison to the small amounts needed to activate the GG in adults. In order to evaluate maturation of the UANP reflex in lambs, we hypothesized that onset of the adult pattern would coincide with the onset of another developmental marker, namely rumination, at 3-4 weeks of age. Because hypoxia increases respiratory muscles activity, we also hypothesized that hypoxia would potentiate the UANP reflex. Therefore, we studied seven chronically instrumented lambs shortly after birth (study 1: mean±SD age 10.6±0.48 days & weight 5.47±0.43 kg) and again at approximately 1 month of age (study 2: mean±SD age 25.1 ± 0.7 days & weight 8.14 ± 0.43 kg). During surgery, EMG wires were placed in the diaphragm and GG and a mid-cervical tracheal stoma was created. The animals were allowed to recover for 24-48 hours prior to study 1. Isolated upper airways (UA) were evaluated while awake lambs were allowed to breathe through tracheostomies. End-expiratory NP of different magnitudes (-5, -10,-20, -40 cm H2O) were randomly applied to the isolated UA for 3 breaths, or 3 seconds if apnea was induced, in room air (RA) and hypoxia (10% O2 through the tracheostomy for 7-10 min). EMG activity of the GG was quantified as average activity (AvAc, area under the curve/duration) derived from the moving time average of phasic EMG output. Results revealed that there was a significant increase in the GG response in relationship to increasing magnitudes of UANP in both study 1 and study 2 (p<0.05). Hypoxia induced a significant increase in GG activity in both studies (<0.05). However, there was no significant increase in GG activity with small amounts of NP (-5 cm H2O) in either study, and hypoxia did not potentiate augmentation of GG at this level of NP. We conclude that the UANP reflex remains relatively immature in ruminating lambs, and that the adult response to low magnitude NP must occur later in development. Hypoxia augmented GG muscle activity above basal values in both studies, but did not potentiate its response to low magnitude NP. We speculate that the immature UANP reflex in neonates contributes to impaired oropharyngeal airway reopening in the event of its closure, and the failure to augment reflex activation with hypoxia may be a contributory factor in certain instances of SIDS.

Control of epiglottic position in dogs: role of negative upper airway pressure

We investigated the influence of negative upper airway pressure (NUAP) on hyoepiglotticus and genioglossus muscle electromyographic (EMG) activity in anaesthetised (sodium pentobarbitone/chloralose) dogs breathing via a tracheostomy. Changes in pressure were not transmitted through the entire upper airway, thus confirming airway occlusion during NUAP. When NUAP was applied at the larynx, peak inspiratory and tonic EMG activity of the genioglossus and HE both increased significantly ( p < 0.05) and reached a plateau at NUAP of −10 to −20 cmH 2O. Nasal NUAP at any level failed to influence either genioglossus or HE EMG activity. Following bilateral section of the internal branches of the superior laryngeal nerves (SLNin), resting levels of HE and genioglossus EMG activity decreased to virtually zero. Moreover, NUAP applied at the larynx now failed to recruit EMG activity for either muscle. These findings suggest active control of epiglottic position in dogs during NUAP.

Central and reflex neural control of genioglossus in subjects who underwent laryngectomy

Inspiratory activation of the genioglossus (GG) may occur by central drive or as a reflex to negative airway pressure. To distinguish between these, we studied seven laryngectomy patients who breathe via tracheal stomas. Negative pressure stimuli (-15 and -25 cmH2O for 500 ms) were applied 1) at functional residual capacity and 2) during early inspiration via (i) the upper airway (UA) and (ii) the tracheal stoma. Intraoral surface GG electromyogram was quantified, as described previously (R. L. Horner, J. A. Innes, K. Murphy, and A. Guz, J. Physiol. Lond. 436: 15-29, 1991). Phasic GG activity was also measured from an integrated electromyogram during spontaneous and inspiratory loaded breathing. Reflex GG activation occurred with negative UA pressure both at functional residual capacity and during inspiration (P < 0.001), but pressure stimuli at the stoma caused no significant activation (P = 0.07). Phasic inspiratory activation occurred in four patients at rest and in all seven patients during inspiratory loading (P < 0.02). These patients demonstrate 1) reflex activation of the GG by negative UA pressure without airflow or respiratory effort and 2) central inspiratory GG activation that is not mediated by negative airway pressure.

Mechano- and chemoreceptor modulation of respiratory muscles in response to upper airway negative pressure.

To investigate the influence of phasic pulmonary stretch receptors (n = 6) and chemoreceptors (n = 7) on the reflex response of the genioglossus (GG) muscle and diaphragm (DIA) to upper airway (UAW) negative pressure, we measured the response of the GG and DIA electromyogram (EMG) to three challenges: 1) negative pressure applied to the UAW during normoxia and hypercapnia, 2) end-expiratory tracheal occlusion, and 3) application of UAW negative pressure simultaneous with tracheal occlusion in spontaneously breathing tracheotomized anesthetized cats. Peak GG EMG was greatest when UAW negative pressure and end-expiratory tracheal occlusion were combined. No GG EMG activity was seen when UAW negative pressure was applied alone unless the animal was vagotomized or hypercapnic. DIA EMG increased in response to UAW negative pressure combined with occlusion. However, the increase in peak GG EMG was significantly greater than for the DIA with the same challenge. DIA EMG amplitude increased in response to occlusion alone but did not change when UAW negative pressure was applied alone. In the cat, phasic feedback from phasic pulmonary stretch receptors is a potent inhibitor of reflex activation of the GG in response to negative pressure applied to the UAW, which can be overridden by an increase in chemoreceptor drive.

Respiratory-related activity of soft palate muscles: augmentation by negative upper airway pressure.

We studied respiratory-related activity of the soft palate muscles in 10 anesthetized tracheostomized supine dogs. Moving time average (MTA) electromyographic (EMG) activity was measured in the palatinus (PAL), levator veli palatini (LP), and tensor veli palatini (TP) with bipolar fine-wire electrodes and in the diaphragm with bipolar hook electrodes. Measurements were made during tracheostomy breathing and nasal breathing with the mouth sealed (NB). During tracheostomy breathing, all soft palate muscles displayed respiratory-related phasic inspiratory and expiratory as well as tonic EMG activity. During NB, peak inspiratory EMG activity increased in PAL, LP, and TP because of an increase in both phasic inspiratory and tonic MTA activity. In contrast, phasic expiratory activity did not change. A constant negative pressure equal to peak inspiratory tracheal pressure during NB was applied to the caudal end of the isolated upper airway with the nose occluded. This was associated with soft palate muscle responses qualitatively similar to the responses during NB but accounted for only 39, 25, and 32% of the magnitude of the peak inspiratory MTA EMG responses to NB in PAL, LP, and TP, respectively. Our results demonstrate that the soft palate muscles exhibit respiratory-related activity in common with other upper airway muscles. Furthermore, such activity is augmented in each soft palate muscle during NB, and negative upper airway pressure makes a substantial contribution to the recruitment of soft palate muscle activity.