Hemodynamic effects of pressures applied to the upper airway during sleep.

The increase in systemic blood pressure after an obstructive apnea is due, in part, to sympathetically mediated vasoconstriction. We questioned whether upper airway (UA) receptors could contribute reflexly to this vasoconstriction. Four unanesthetized dogs were studied during wakefulness and non-rapid-eye-movement (NREM) sleep. The dogs breathed via a fenestrated tracheostomy tube sealed around the tracheal stoma. The snout was sealed with an airtight mask, thereby isolating the UA when the fenestration was closed and exposing the UA to negative inspiratory intrathoracic pressure when it was open. The blood pressure response to three UA perturbations was studied: 1) square-wave negative pressures sufficient to cause UA collapse with the fenestration closed during a mechanical hyperventilation-induced central apnea; 2) tracheal occlusion with the fenestration open vs. closed; and 3) high-frequency pressure oscillations (HFPO) with the fenestration closed. During NREM sleep, 1) blood pressure response to tracheal occlusion was similar with the fenestration open or closed; 2) collapsing the UA with negative pressures failed to alter blood pressure during a central apnea; and 3) application of HFPO to the UA during eupnea and resistive-loaded breaths increased heart rate and blood pressure. However, these changes were likely to be secondary to the effects of HFPO-induced reflex changes on prolonging expiratory time. These findings suggest that activation of UA pressure-sensitive receptors does not contribute directly to the pressor response associated with sleep-disordered breathing events.     

Neuromechanical control of upper airway patency during sleep.

Obstructive sleep apnea is caused by pharyngeal occlusion due to alterations in upper airway mechanical properties and/or disturbances in neuromuscular control. The objective of the study was to determine the relative contribution of mechanical loads and dynamic neuromuscular responses to pharyngeal collapse during sleep. Sixteen obstructive sleep apnea patients and sixteen normal subjects were matched on age, sex, and body mass index. Pharyngeal collapsibility, defined by the critical pressure, was measured during sleep. The critical pressure was partitioned between its passive mechanical properties (passive critical pressure) and active dynamic responses to upper airway obstruction (active critical pressure). Compared with normal subjects, sleep apnea patients demonstrated elevated mechanical loads as demonstrated by higher passive critical pressures [-0.05 (SD 2.4) vs. -4.5 cmH2O (SD 3.0), P = 0.0003]. Dynamic responses were depressed in sleep apnea patients, as suggested by failure to lower their active critical pressures [-1.6 (SD 3.5) vs. -11.1 cmH2O (SD 5.3), P < 0.0001] in response to upper airway obstruction. Moreover, elevated mechanical loads placed some normal individuals at risk for sleep apnea. In this subset, dynamic responses to upper airway obstruction compensated for mechanical loads and maintained airway patency by lowering the active critical pressure. The present study suggests that increased mechanical loads and blunted neuromuscular responses are both required for the development of obstructive sleep apnea.     

Characteristics of the upper airway pressure-flow relationship during sleep

In examining the mechanical properties of the respiratory system during sleep in healthy humans, we observed that the inspiratory pressure-flow relationship of the upper airway was often flow limited and too curvilinear to be predicted by the Rohrer equation. The purposes of this study were 1) to describe a mathematical model that would better define the inspiratory pressure-flow relationship of the upper airway during sleep and 2) to identify the segment of airway responsible for the sleep-related flow limitation. We measured nasal and total supralaryngeal pressure and flow during wakefulness and stage 2 sleep in five healthy male subjects lying supine. A right rectangular hyperbolic equation, V = (alpha P)/(beta + P), where V is flow, P is pressure, alpha is an asymptote for peak flow, and beta is pressure at a flow of alpha/2, was used in its linear form, P/V = (beta/alpha) + (P/alpha). The goodness of fit of the new equation was compared with that for the linearized Rohrer equation P/V = K1 + K2V. During wakefulness the fit of the hyperbolic equation to the actual pressure-flow data was equivalent to or significantly better than that for the Rohrer equation. During sleep the fit of the hyperbolic equation was superior to that for the Rohrer equation. For the whole supralaryngeal airway during sleep, the correlation coefficient for the hyperbolic equation was 0.90 +/- 0.50, and for the Rohrer equation it was 0.49 +/- 0.25. The flow-limiting segment was located within the pharyngeal airway, not in the nose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Collapsibility of the human upper airway during normal sleep

Upper airway resistance (UAR) increases in normal subjects during the transition from wakefulness to sleep. To examine the influence of sleep on upper airway collapsibility, inspiratory UAR (epiglottis to nares) and genioglossus electromyogram (EMG) were measured in six healthy men before and during inspiratory resistive loading. UAR increased significantly (P less than 0.05) from wakefulness to non-rapid-eye-movement (NREM) sleep [3.1 +/- 0.4 to 11.7 +/- 3.5 (SE) cmH2O.1-1.s]. Resistive load application during wakefulness produced small increments in UAR. However, during NREM sleep, UAR increased dramatically with loading in four subjects although two subjects demonstrated little change. This increment in UAR from wakefulness to sleep correlated closely with the rise in UAR during loading while asleep (e.g., load 12: r = 0.90, P less than 0.05), indicating consistent upper airway behavior during sleep. On the other hand, no measurement of upper airway behavior during wakefulness was predictive of events during sleep. Although the influence of sleep on the EMG was difficult to assess, peak inspiratory genioglossus EMG clearly increased (P less than 0.05) after load application during NREM sleep. Finally, minute ventilation fell significantly from wakefulness values during NREM sleep, with the largest decrement in sleeping minute ventilation occurring in those subjects having the greatest awake-to-sleep increment in UAR (r = -0.88, P less than 0.05). We conclude that there is marked variability among normal men in upper airway collapsibility during sleep.     

Relationship between surface tension of upper airway lining liquid and upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome.

Lowering surface tension (gamma) of upper airway lining liquid (UAL) reduces upper airway opening (anesthetized humans) and closing (anesthetized rabbits) pressures. We now hypothesize that in sleeping obstructive sleep apnea hypopnea syndrome (OSAHS) patients lowering gamma of UAL will enhance upper airway stability and decrease the severity of sleep-disordered breathing. Nine OSAHS patients [respiratory disturbance index (RDI): 49 +/- 8 (SE) events/h, diagnostic night] participated in a two-part, one-night, polysomnography study. In the first part, upper airway closing pressures (during non-rapid eye movement sleep, Pcrit) were measured and samples of UAL (awake) were obtained before and after 2.5 ml of surfactant (Exosurf, Glaxo Smith Kline) was instilled into the posterior pharynx. The gamma of UAL was determined with the use of the "pull-off" force technique. In the second part, subjects received a second application of 2.5 ml of surfactant and then slept the remainder of the night (205 +/- 30 min). Instillation of surfactant decreased the gamma of UAL from 60.9 +/- 3.1 mN/m (control) to 45.2 +/- 2.5 mN/m (surfactant group) (n = 9, P < 0.001). Pcrit decreased from 1.19 +/- 1.14 cmH2O (control) to -0.56 +/- 1.15 cmH2O (surfactant group) (n = 7, P < 0.02). Compared with the second half of diagnostic night, surfactant decreased RDI from 51 +/- 8 to 35 +/- 8 events/h (n = 9, P < 0.03). The fall in RDI (deltaRDI) correlated with the fall in gamma of UAL (deltagamma) (deltaRDI = 1.8 x deltagamma, r = 0.68, P = 0.04). Hypopneas decreased approximately 50% from 42 +/- 8 to 20 +/- 5 events/h (n = 9, P < 0.03, paired t-test). The gamma of UAL measured the next morning remained low at 49.5 +/- 2.7 mN/m (n = 9, P < 0.001, ANOVA, compared with control). In conclusion, instillation of surfactant reduced the gamma of UAL in OSAHS patients and decreased Pcrit and the occurrence of hypopneas. Therapeutic manipulation of gamma of UAL may be beneficial in reducing the severity of sleep-disordered breathing in OSAHS patients.     

Influence of age and gender on upper airway resistance in NREM and REM sleep.

The prevalence of irregular breathing during sleep is age and gender dependent, but the reason for this is unknown. This study tested the hypothesis that older men have a greater sleep-related increase in respiratory resistance. In 48 healthy subjects, 12 in each of four groups of younger and older men and women, airway resistance was measured during wakefulness and sleep using a mask, pneumotachograph, and catheter-mounted pressure sensors. Total respiratory resistance and total "low-flow," and "high-flow" oropharyngeal resistance were analyzed from 170,000 breaths, high flow being at rates above 50% maximal inspiratory flow. High-flow oropharyngeal and total respiratory resistance increased during non-rapid eye movement (NREM) sleep in all groups but not low-flow resistance. Total respiratory resistance increased from 12 +/- 1.2 cmH(2)O. l(-1). s(-1) awake to 16.2 +/- 2.4 in NREM sleep in young men, from 22.8 +/- 3.6 to 33.6 +/- 5.4 in young women, from 18 +/- 3 to 34.8 +/- 4.8 in older men, and from 26.6. +/- 4.2 to 34.2 +/- 6 in older women. The percentage of change in total respiratory resistance from awake to NREM sleep was not different between age groups or genders. We conclude that there are no major age or gender differences in the changes in airway resistance with sleep in normal subjects.     

Adjustment of the human respiratory system to increased upper airway resistance during sleep

A cardiorespiratory model incorporating control of the human upper airway during sleep is described. Most previous models have not considered the possibility that the upper airway could be a limiting factor for gas exchange. Our model was developed to also predict certain pathophysiological phenomena in the cardiorespiratory system that characterize heavy snoring or sleep apnea. We started by adapting our collapsible upper airway model to include the impact of nasal passage and larynx, and extended the model with equations for gas exchange in the lungs. A feedback loop both to the respiratory pump and the upper airway dilator muscles was included. The model enabled successful breath-by-breath simulations of obstructive events of the upper airway. Although the model incorporates several physiologically relevant components of the system, the simulation results suggest that only few parameters suffice to predict the key adjustments that the cardiorespiratory system is known to make in patients with heavy snoring.     

Contribution of upper airway geometry to convective mixing

We investigated the axial dispersive effect of the upper airway structure (comprising mouth cavity, oropharynx, and trachea) on a traversing aerosol bolus. This was done by means of aerosol bolus experiments on a hollow cast of a realistic upper airway model (UAM) and three-dimensional computational fluid dynamics (CFD) simulations in the same UAM geometry. The experiments showed that 50-ml boluses injected into the UAM dispersed to boluses with a half-width ranging from 80 to 90 ml at the UAM exit, across both flow rates (250, 500 ml/s) and both flow directions (inspiration, expiration). These experimental results imply that the net half-width induced by the UAM typically was 69 ml. Comparison of experimental bolus traces with a one-dimensional Gaussian-derived analytical solution resulted in an axial dispersion coefficient of 200-250 cm(2)/s, depending on whether the bolus peak and its half-width or the bolus tail needed to be fully accounted for. CFD simulations agreed well with experimental results for inspiratory boluses and were compatible with an axial dispersion of 200 cm(2)/s. However, for expiratory boluses the CFD simulations showed a very tight bolus peak followed by an elongated tail, in sharp contrast to the expiratory bolus experiments. This indicates that CFD methods that are widely used to predict the fate of aerosols in the human upper airway, where flow is transitional, need to be critically assessed, possibly via aerosol bolus simulations. We conclude that, with all its geometric complexity, the upper airway introduces a relatively mild dispersion on a traversing aerosol bolus for normal breathing flow rates in inspiratory and expiratory flow directions.     

Upper airway muscle activity and upper airway resistance in young adults during sleep

Henke, Kathe G. Upper airway muscle activity and upperairway resistance in young adults during sleep. J. Appl. Physiol. 84(2): 486-491, 1998.To determinethe relationship between upper airway muscle activity and upper airwayresistance in nonsnoring and snoring young adults, 17 subjects werestudied during sleep. Genioglossus and alae nasi electromyogramactivity were recorded. Inspiratory and expiratory supraglotticresistance (Rinsp and Rexp, respectively) were measured at peak flow,and the coefficients of resistance(K_insp andK_exp,respectively) were calculated. Data were recorded during control,with continuous positive airway pressure (CPAP), and on the breathimmediately after termination of CPAP. Rinsp during control averaged 7 ± 1 and 10 ± 2 cmH₂O · l¹ · sand K_inspaveraged 26 ± 5 and 80 ± 27 cmH₂O · l¹ · s²in the nonsnorers and snorers, respectively(P = not significant). Onthe breath immediately after CPAP,K_insp did notincrease over control in snorers (80 ± 27 for control vs. 46 ± 6 cmH₂O · l¹ · s²for the breath after CPAP) or nonsnorers (26 ± 5 vs. 29 ± 6 cmH₂O · l¹ · s²).These findings held true for Rinsp.K_exp did notincrease in either group on the breath immediately after termination ofCPAP. Therefore, 1) increases inupper airway resistance do not occur, despite reductions inelectromyogram activity in young snorers and nonsnorers, and2) increases in Rexp and expiratoryflow limitation are not observed in young snorers.

     

Effect of age on sleep onset-related changes in respiratory pump and upper airway muscle function.

In normal young men, there is an abrupt fall in ventilation (VE), a rise in upper airway resistance (UAR), and falls in the activities of the diaphragm (Di), intercostals (IC), genioglossus (GG), and tensor palatini (TP) at sleep onset. On waking, there is an abrupt increase in VE and fall in UAR and an increase in the activities of Di, IC, GG, and TP. The aim of this study was to determine whether these changes are age dependent. Nine men aged 20 to 25 yr were compared with nine men aged 42 to 67 yr. Airflow, UAR, Di, and IC surface electromyograms (EMGs) and the intramuscular EMGs of GG and TP were recorded. It was found that the falls in IC, GG, and TP at the transition from alpha to theta electroencephalogram (EEG) activity were significantly greater in the older than in the younger men (P < 0.05) and that the fall in Di was also greater, although this was only marginally significant (P = 0.15). The rise in GG at theta-to-alpha transitions was also greater in the older than in the younger men, and there was a trend for TP to be higher.     

Activity of respiratory pump and upper airway muscles during sleep onset

Ventilationdecreases at sleep onset. This change is initiated abruptly at -electroencephalographic transitions. The aim of this study was todetermine the contributions of reduced activity in respiratory pumpmuscles and upper airway dilator muscles to this change. Surfaceelectromyograms over the diaphragm (Di) and intercostal muscles andfine-wire intramuscular electrodes in genioglossus (GG) and tensorpalatini (TP) muscles were recorded in nine healthy young men. It wasshown that phasic Di and both phasic and tonic TP activities were lowerduring  than during  activity. Breath-by-breath analysis of thechanges at - transitions during the sleep-onset period showed anumber of changes. At - transitions, phasic activity of Di,intercostal, and GG muscles fell and rose again, and phasic and tonicactivities of TP fell and remained at low levels during . With astate transition from  to , the phasic and tonic activities ofthe Di, GG, and TP increased dramatically. It is now clear that thefall in ventilation that occurs with sleep is related to a fall inactivities of both upper airway dilator muscles and respiratory pumpmuscles.

     

Effects of upper airway anesthesia on pharyngeal patency during sleep

Pharyngeal patency depends, in part, on the tone and inspiratory activation of pharyngeal dilator muscles. To evaluate the influence of upper airway sensory feedback on pharyngeal muscle tone and thus pharyngeal patency, we measured pharyngeal airflow resistance and breathing pattern in 15 normal, supine subjects before and after topical lidocaine anesthesia of the pharynx and glottis. Studies were conducted during sleep and during quiet, relaxed wakefulness before sleep onset. Maximal flow-volume loops were also measured before and after anesthesia. During sleep, pharyngeal resistance at peak inspiratory flow increased by 63% after topical anesthesia (P less than 0.01). Resistance during expiration increased by 40% (P less than 0.01). Similar changes were observed during quiet wakefulness. However, upper airway anesthesia did not affect breathing pattern during sleep and did not alter awake flow-volume loops. These results indicate that pharyngeal patency during sleep is compromised when the upper airway is anesthetized and suggest that upper airway reflexes, which promote pharyngeal patency, exist in humans.     

Effect of upper airway negative pressure on inspiratory drive during sleep

To determine the effect of upper airway(UA) negative pressure and collapse during inspiration on regulation ofbreathing, we studied four unanesthetized female dogs duringwakefulness and sleep while they breathed via a fenestratedtracheostomy tube, which was sealed around the permanent trachealstoma. The snout was sealed with an airtight mask, thereby isolatingthe UA when the fenestration (Fen) was closed and exposing the UA tointrathoracic pressure changes, but not to flow changes, when Fen wasopen. During tracheal occlusion with Fen closed, inspiratory time(TI) increased duringwakefulness, non-rapid-eye-movement (NREM) sleep and rapid-eye-movement(REM) sleep (155 ± 8, 164 ± 11, and 161 ± 32%,respectively), reflecting the removal of inhibitory lung inflationreflexes. During tracheal occlusion with Fen open (vs. Fen closed):1) the UA remained patent;2)TI further increased duringwakefulness and NREM (215 ± 52 and 197 ± 28%, respectively) but nonsignificantly during REM sleep (196 ± 42%);3) mean rate of rise of diaphragmEMG (EMGdi/TI) and rate offall of tracheal pressure(Ptr/TI) were decreased,reflecting an additional inhibitory input from UA receptors; and4) bothEMGdi/TI andPtr/TI were decreasedproportionately more as inspiration proceeded, suggesting greaterreflex inhibition later in the effort. Similar inhibitory effects ofexposing the UA to negative pressure (via an open tracheal Fen) wereseen when an inspiratory resistive load was applied over severalbreaths during wakefulness and sleep. These inhibitory effectspersisted even in the face of rising chemical stimuli. This inhibitionof inspiratory motor output is alinear within an inspiration andreflects the activation of UA pressure-sensitive receptors by UAdistortion, with greater distortion possibly occurring later in theeffort.

     

Effect of hypoxia-induced periodic breathing on upper airway obstruction during sleep

We studied the effect of hypoxia-induced unstable and periodic breathing on the incidence of obstructed breaths in nine subjects who varied widely in their increase in total pulmonary resistance (RL) during non-rapid-eye-movement (NREM) sleep. During normoxic NREM sleep, all subjects showed hypoventilation, augmented diaphragmatic electromyogram (EMGdi), and increased RL. This response varied: two subjects doubled their mean RL (range 6-9 cmH2O X l-1 X s); four moderate snorers increased RL four- to eightfold (RL = 16-48 cmH2O X l-1 X s); three heavy snorers showed high RL (31-89 cmH2O X l-1 X s) plus cyclical obstructive hypopnea as their predominant breathing pattern. In seven of nine subjects, hypoxia and coincident hypocapnia initially caused an irregular cyclical breathing pattern with obstructed breaths (RL greater than 50 cmH2O X l-1 X s). The incidence of obstructed breaths induced by unstable breathing was closely correlated with the level of RL experienced in the control condition of normoxic sleep (r = 0.91). The obstructed breaths had relatively high O2 saturation (90-96%) and markedly reduced EMGdi activity and peak flow rate (less than 0.2 l/s) compared with breaths immediately after the obstructed breaths, which showed lower O2 saturation (81-93%) and markedly augmented EMGdi and flow rates. After 3-6 cycles of obstructive hypopnea, periodic breathing occurred in most subjects. During periodic breathing in six of seven subjects, the incidence of obstructed or high-resistance breaths was decreased or eliminated since each central apneic period was followed by breath clusters characterized by very high EMGdi, very low RL, and high flow rates. The remaining subject showed a high incidence of obstructed breaths during all phases of normoxic and hypoxic sleep. These data show that hypoxia-induced instability in breathing pattern can cause obstructed breaths during sleep coincident with reduced motor output to inspiratory muscles. However, this obstruction is only manifested in subjects susceptible to upper airway atonicity and narrowing (such as snorers) and can be prevented in most cases if respiratory drive is permitted to reach sufficiently high levels (as during central apnea).     

Dynamic modulation of upper airway function during sleep: a novel single-breath method.

To examine the dynamic modulation of upper airway (UA) function during sleep, we devised a novel approach to measuring the critical pressure (Pcrit) within a single breath in tracheostomized sleep apnea patients. We hypothesized that the UA continuously modulates airflow dynamics during transtracheal insufflation. In this study, we examine tidal pressure-flow relationships throughout the respiratory cycle to compare phasic differences in UA collapsibility between closure and reopening. Five apneic subjects (with tracheostomy) were recruited (2 men, 3 women; 18-50 yr; 20-35 kg/m2; apnea-hypopnea index >20) for this polysomnographic study. Outgoing airflow through the UA (face mask pneumotachograph) and tracheal pressure were recorded during brief transtracheal administration of insufflated airflow via a catheter. Pressure-flow relationships were generated from deflation (approaching Pcrit) and inflation (after Pcrit) of the UA during non-rapid eye movement sleep. During each breath, UA function was described by a pressure-flow relationship that defined the collapsibility (Pcrit) and upstream resistance (Rus). UA characteristics were examined in the presence and absence of complete UA occlusion. We demonstrated that Pcrit and Rus changed dynamically throughout the respiratory cycle. The UA closing pressure (4.4 +/- 2.0 cm H2O) was significantly lower than the opening pressure (10.8 +/- 2.4 cm H2O). Rus was higher for deflation (18.1 +/- 2.4 cm H2O x l(-1) x s) than during inflation (7.5 +/- 1.9 cm H2O x l(-1) x s) of the UA. Preventing occlusion decreases UA pressure-flow loop hysteresis by approximately 4 cm H2O. These findings indicate that UA collapsibility varies dynamically throughout the respiratory cycle and that both local mechanical and neuromuscular factors may be responsible for this dynamic modulation of UA function during sleep.     

Effect of episodic hypoxia on upper airway mechanics in humans during NREM sleep.

We hypothesized that long-term facilitation (LTF) is due to decreased upper airway resistance (Rua). We studied 11 normal subjects during stable non-rapid eye movement sleep. We induced brief isocapnic hypoxia (inspired O(2) fraction = 8%) (3 min) followed by 5 min of room air. This sequence was repeated 10 times. Measurements were obtained during control, hypoxia, and at 20 min of recovery (R(20)) for ventilation, timing, and Rua. In addition, nine subjects were studied in a sham study with no hypoxic exposure. During the episodic hypoxia study, inspiratory minute ventilation (VI) increased from 7.1 +/- 1.8 l/min during the control period to 8.3 +/- 1.8 l/min at R(20) (117% of control; P < 0.05). Conversely, there was no change in diaphragmatic electromyogram (EMG(dia)) between control (16.1 +/- 6.9 arbitrary units) and R(20) (15.3 +/- 4.9 arbitrary units) (95% of control; P > 0.05). In contrast, increased VI was associated with decreased Rua from 10.7 +/- 7.5 cmH(2)O. l(-1). s during control to 8.2 +/- 4.4 cmH(2)O. l(-1). s at R(20) (77% of control; P < 0.05). No change was noted in VI, Rua, or EMG(dia) during the recovery period relative to control during the sham study. We conclude the following: 1) increased VI in the recovery period is indicative of LTF, 2) the lack of increased EMG(dia) suggests lack of LTF to the diaphragm, 3) reduced Rua suggests LTF of upper airway dilators, and 4) increased VI in the recovery period is due to "unloading" of the upper airway by LTF of upper airway dilators.