Jason P. Kirkness

Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep

Male sex, obesity, and age are risk factors for obstructive sleep apnea, although the mechanisms by which these factors increase sleep apnea susceptibility are not entirely understood. This study examined the interrelationships between sleep apnea risk factors, upper airway mechanics, and sleep apnea susceptibility. In 164 (86 men, 78 women) participants with and without sleep apnea, upper airway pressure-flow relationships were characterized to determine their mechanical properties [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] during non-rapid eye movement sleep. In multiple linear regression analyses, the effects of body mass index and age on passive Pcrit were determined in each sex. A subset of men and women matched by body mass index, age, and disease severity was used to determine the sex effect on passive Pcrit. The passive Pcrit was 1.9 cmH(2)O [95% confidence interval (CI): 0.1-3.6 cmH(2)O] lower in women than men after matching for body mass index, age, and disease severity. The relationship between passive Pcrit and sleep apnea status and severity was examined. Sleep apnea was largely absent in those individuals with a passive Pcrit less than -5 cmH(2)O and increased markedly in severity when passive Pcrit rose above -5 cmH(2)O. Passive Pcrit had a predictive power of 0.73 (95% CI: 0.65-0.82) in predicting sleep apnea status. Upper airway mechanics are differentially controlled by sex, obesity, and age, and partly mediate the relationship between these sleep apnea risk factors and obstructive sleep apnea.

Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea

Obstructive sleep apnea is the result of repeated episodes of upper airway obstruction during sleep. Recent evidence indicates that alterations in upper airway anatomy and disturbances in neuromuscular control both play a role in the pathogenesis of obstructive sleep apnea. We hypothesized that subjects without sleep apnea are more capable of mounting vigorous neuromuscular responses to upper airway obstruction than subjects with sleep apnea. To address this hypothesis we lowered nasal pressure to induce upper airway obstruction to the verge of periodic obstructive hypopneas (cycling threshold). Ten patients with obstructive sleep apnea and nine weight-, age-, and sex-matched controls were studied during sleep. Responses in genioglossal electromyography (EMG(GG)) activity (tonic, peak phasic, and phasic EMG(GG)), maximal inspiratory airflow (V(I)max), and pharyngeal transmural pressure (P(TM)) were assessed during similar degrees of sustained conditions of upper airway obstruction and compared with those obtained at a similar nasal pressure under transient conditions. Control compared with sleep apnea subjects demonstrated greater EMG(GG), V(I)max, and P(TM) responses at comparable levels of mechanical and ventilatory stimuli at the cycling threshold, during sustained compared with transient periods of upper airway obstruction. Furthermore, the increases in EMG(GG) activity in control compared with sleep apnea subjects were observed in the tonic but not the phasic component of the EMG response. We conclude that sustained periods of upper airway obstruction induce greater increases in tonic EMG(GG), V(I)max, and P(TM) in control subjects. Our findings suggest that neuromuscular responses protect individuals without sleep apnea from developing upper airway obstruction during sleep.

Evolution of changes in upper airway collapsibility during slow induction of anesthesia with propofol.

Background:Upper airway collapsibility is known to increase under anesthesia. This study assessed how this increase in collapsibility evolves during slow Propofol induction and how it relates to anesthesia-induced changes in upper airway muscle activity and conscious state. Methods:Nine healthy volunteers were studied. Anesthesia was induced with Propofol in a step-wise manner (effect-site concentration steps of 0.5 &mgr;g · ml−1 from 0 to 3 &mgr;g · ml−1 and thereafter to 4 &mgr;g · ml−1 and 6 &mgr;g · ml−1 [target-controlled infusion]). Airway patency was maintained with continuous positive airway pressure. Pharyngeal collapsibility was assessed at each concentration by measuring critical pressure. Intramuscular genioglossus electromyogram and anesthetic depth (bispectral index score) were monitored throughout. Loss of consciousness was defined as failure to respond to loud verbal command. Results:Loss of consciousness occurred at varying Propofol effect-site concentrations between 1.5 and 4.0 &mgr;g · ml−1. Initially genioglossus electromyographic activity was sustained with increases in Propofol concentration, increasing in some individuals. At or approaching loss of consciousness, it decreased, often abruptly, to minimal values with an accompanying increase in critical pressure. In most subjects, bispectral index score decreased alinearly with increasing Propofol concentration with greatest rate of change coinciding with loss of consciousness. Conclusions:Slow stepwise induction of Propofol anesthesia is associated with an alinear increase in upper airway collapsibility. Disproportionate decreases in genioglossus electromyogram activity and increases in pharyngeal critical closing pressure were observed proximate to loss of consciousness, suggesting that particular vulnerability exists after transition from conscious to unconscious sedation. Such changes may have parallels with upper airway behavior at sleep onset.

Obesity and upper airway control during sleep

Mechanisms linking obesity with upper airway dysfunction in obstructive sleep apnea are reviewed. Obstructive sleep apnea is due to alterations in upper airway anatomy and neuromuscular control. Upper airway structural alterations in obesity are related to adipose deposition around the pharynx, which can increase its collapsibility or critical pressure (P(crit)). In addition, obesity and, particularly, central adiposity lead to reductions in resting lung volume, resulting in loss of caudal traction on upper airway structures and parallel increases in pharyngeal collapsibility. Metabolic and humoral factors that promote central adiposity may contribute to these alterations in upper airway mechanical function and increase sleep apnea susceptibility. In contrast, neural responses to upper airway obstruction can mitigate these mechanical loads and restore pharyngeal patency during sleep. Current evidence suggests that these responses can improve with weight loss. Improvements in these neural responses with weight loss may be related to a decline in systemic and local pharyngeal concentrations of specific inflammatory mediators with somnogenic effects.

Effect of end-expiratory lung volume on upper airway collapsibility in sleeping men and women

The relationship between changes in absolute end-expiratory lung volume (EELV) and collapsibility has not been rigorously quantified. We hypothesized that pharyngeal collapsibility varies inversely with absolute lung volume in sleeping humans during 1) conventional and 2) isovolume measurements of passive critical pressure (Pcrit). Eighteen healthy subjects (11 male, 7 female) slept in a negative pressure ventilator for measurements of pharyngeal collapsibility (Pcrit) during non-rapid eye movement sleep. EELV was 1) allowed to vary with changes in nasal pressure for conventional Pcrit measurements and 2) controlled by maintaining a fixed pressure difference across the respiratory system (P(RS)) from the nose to the body surface for isovolume Pcrit measurements at elevated EELV (P(RS) = +10 cmH(2)O), reduced EELV (P(RS) = -5 cmH(2)O), and functional residual capacity (FRC; P(RS) = 0 cmH(2)O). In each condition, the absolute EELV was determined and the corresponding Pcrit was derived from upper airway pressure-flow relationships. In the entire group, Pcrit varied inversely with EELV (P < 0.001). Pcrit decreased as EELV increased from the conventional to the FRC isovolume condition by -3.5 ± 1.0 cmH(2)O/l (P < 0.003). Subjects with a conventional Pcrit below -2 cmH(2)O exhibited greater reductions in EELV and correspondingly greater decreases in the FRC isovolume compared with the conventional Pcrit (P < 0.001). The overall response, ΔPcrit/ΔEELV, was -2.0 ± 0.2 cmH(2)O/l (P < 0.001) and did not differ between men and women (P = 0.16). Nevertheless, men and women differed significantly in FRC (2.63 ± 0.16 vs. 1.88 ± 0.13 liters, P <0.05) and FRC isovolume Pcrit (-2.3 ± 0.8 vs. -7.2 ± 1.2 cmH(2)O, P < 0.05), implying that the men had larger lungs and more collapsible airways than the women. The ΔPcrit/ΔEELV response was independent of sex, conventional Pcrit, body mass index, and neck, waist, and hip circumferences. We conclude that Pcrit varies inversely with absolute EELV, which may lead to 1) an underestimation of the magnitude of quantitative differences in Pcrit across the spectrum from health (negative Pcrit) to disease (positive Pcrit) and 2) increases in sleep apnea susceptibility in obesity.

Decreased surface tension of upper airway mucosal lining liquid increases upper airway patency in anaesthetised rabbits.

The obstructive sleep apnoea syndrome (OSA) is a disorder characterised by repetitive closure and re‐opening of the upper airway during sleep. Upper airway luminal patency is influenced by a number of factors including: intraluminal air pressure, upper airway dilator muscle activity, surrounding extraluminal tissue pressure, and also surface forces which can potentially act within the liquid layer lining the upper airway. The aim of the present study was to examine the role of upper airway mucosal lining liquid (UAL) surface tension (γ) in the control of upper airway patency. Upper airway opening (PO) and closing pressures (PC) were measured in 25 adult male, supine, tracheostomised, mechanically ventilated, anaesthetised (sodium pentabarbitone), New Zealand White rabbits before (control) and after instillation of 0.5 ml of either 0.9 % saline (n= 9) or an exogenous surfactant (n= 16; Exosurf Neonatal) into the pharyngeal airway. The γ of UAL (0.2 μl) was quantified using the ‘pull‐off’ force technique in which γ is measured as the force required to separate two curved silica discs bridged by the liquid sample. The γ of UAL decreased after instillation of surfactant from 54.1 ± 1.7 mN m−1 (control; mean ±s.e.m.) to 49.2 ± 2.1 mN m−1 (surfactant; P < 0.04). Compared with control, PO increased significantly (P < 0.04; paired t test, n= 9) from 6.2 ± 0.9 to 9.6 ± 1.2 cmH2O with saline, and decreased significantly (P < 0.05, n= 16) from 6.6 ± 0.4 to 5.5 ± 0.6 cmH2O with surfactant instillation. Findings tended to be similar for PC. Change in both PO and PC showed a strong positive correlation with the change in γ of UAL (both r > 0.70, P < 0.001). In conclusion, the patency of the upper airway in rabbits is partially influenced by the γ of UAL. These findings suggest a role for UAL surface properties in the pathophysiology of OSA.

Effects of leptin and obesity on the upper airway function

Obesity is associated with alterations in upper airway collapsibility during sleep. Obese, leptin-deficient mice demonstrate blunted ventilatory control, leading us to hypothesize that (1) obesity and leptin deficiency would predispose to worsening neuromechanical upper airway function and that (2) leptin replacement would acutely reverse neuromuscular defects in the absence of weight loss. In age-matched, anesthetized, spontaneously breathing C57BL/6J (BL6) and ob(-)/ob(-) mice, we characterized upper airway pressure-flow dynamics during ramp decreases in nasal pressure (P(N)) to determine the passive expiratory critical pressure (P(CRIT)) and active responses to reductions in P(N), including the percentage of ramps showing inspiratory flow limitation (IFL; frequency), the P(N) threshold at which IFL developed, maximum inspiratory airflow (Vi(max)), and genioglossus electromyographic (EMG(GG)) activity. Elevations in body weight were associated with progressive elevations in P(CRIT) (0.1 ± 0.02 cmH(2)O/g), independent of mouse strain. P(CRIT) was also elevated in ob(-)/ob(-) compared with BL6 mice (1.6 ± 0.1 cmH(2)O), independent of weight. Both obesity and leptin deficiency were associated with significantly higher IFL frequency and P(N) threshold and lower VI(max). Very obese ob(-)/ob(-) mice treated with leptin compared with nontreated mice showed a decrease in IFL frequency (from 63.5 ± 2.9 to 30.0 ± 8.6%) and P(N) threshold (from -0.8 ± 1.1 to -5.6 ± 0.8 cmH(2)O) and increase in VI(max) (from 354.1 ± 25.3 to 659.0 ± 71.8 μl/s). Nevertheless, passive P(CRIT) in leptin-treated mice did not differ significantly from that seen in nontreated ob(-)/ob(-) mice. The findings suggest that weight and leptin deficiency produced defects in upper airway neuromechanical control and that leptin reversed defects in active neuromuscular responses acutely without reducing mechanical loads.

The compensatory responses to upper airway obstruction in normal subjects under propofol anesthesia

Upper airway obstruction during sleep can trigger compensatory neuromuscular responses and/or prolong inspiration in order to maintain adequate minute ventilation. The aim of this study was to investigate the strength of these compensatory responses during upper airway obstruction during propofol anesthesia. We assessed respiratory timing and upper airway responses to decreases in nasal pressure in nine propofol anesthetized normal subjects under condition of decreased (passive) and increased (active) neuromuscular activity. Critical closing pressure (PCRIT) and upstream resistance (RUS) were derived from pressure-flow relationships generated from each condition. The inspiratory duty cycle (IDC), maximum inspiratory flow (V1max) and respiratory rate (f) were determined at two levels of mean inspiratory airflow (VI; mild airflow limitation with VI > or = 150 ml s-1; severe airflow limitation with VI < 150 ml s-1). Compared to the passive condition, PCRIT decreased significantly (5.3 +/- 3.8 cm H2O, p < 0.05) and RUS increased (7.4 cm H2O ml-1 s, p < 0.05) in the active condition. The IDC increased progressively and comparably as decreased in both the passive and active conditions (p < 0.05). These findings imply that distinct compensatory mechanisms govern the modulation of respiratory pattern and pharyngeal patency during periods of airway obstruction under propofol anesthesia.

Effects of Nasal Insufflation on Arterial Gas Exchange and Breathing Pattern in Patients with Chronic Obstructive Pulmonary Disease and Hypercapnic Respiratory Failure

High flow nasal insufflations (NI) can improve gas exchange and alleviate dyspnea in patients with acute respiratory failure. In the present study we investigated the effects of high flow nasal insufflations in COPD patients with chronic hypercapnic respiratory failure (HRF). Seventeen patients with severe COPD and HRF were recruited. We delivered a mixture of 20 L/min room air and 2 L/min O(2) through a nasal cannula either into both nostrils (NI) or into one nostril (Partial NI). Respiratory pattern and PaCO(2) responses under NI were compared with low flow oxygen of 2 L/min. High flow nasal insufflations led to a systematic reduction in respiratory rate from 19.8 ± 4.2 at baseline to 18.0 ± 4.7 during NI (p < 0.008) and 18.1 ± 5.2 breaths/min during Partial NI (P < 0.03). The mean group inspiratory duty cycle (T(I)/T(T)) and mean group PaCO(2) remained constant between all experimental conditions. Individual responses to NI were heterogeneous: six patients demonstrated marked reductions in respiratory rate (>20% fall from baseline), another group (n = 6) demonstrated no change in respiratory rate but marked reductions in arterial carbon dioxide of more than 8 mmHg. In conclusion, high flow (20 L/min) nasal insufflations of warm and humidified air during wakefulness for 45 min reduced respiratory rate without deterioration of hypercapnia. Our data indicate that high flow NI improved efficiency of breathing and may be used as an adjunct to low flow oxygen for preventing hypercapnic respiratory failure in severely ill COPD patients.

Leptin and the control of pharyngeal patency during sleep in severe obesity

RATIONALE Obesity imposes mechanical loads on the upper airway, resulting in flow limitation and obstructive sleep apnea (OSA). In previous animal models, leptin has been considered to serve as a stimulant of ventilation and may prevent respiratory depression during sleep. We hypothesized that variations in leptin concentration among similarly obese individuals will predict differences in compensatory responses to upper airway obstruction during sleep. METHODS An observational study was conducted in 23 obese women [body mass index (BMI): 46 ± 3 kg/m(2), age: 41 ± 12 yr] and 3 obese men (BMI: 46 ± 3 kg/m(2), age: 43 ± 4 yr). Subjects who were candidates for bariatric surgery were recruited to determine upper airway collapsibility under hypotonic conditions [pharyngeal critical pressure (passive PCRIT)], active neuromuscular responses to upper airway obstruction during sleep, and overnight fasting serum leptin levels. Compensatory responses were defined as the differences in peak inspiratory airflow (ΔVImax), inspired minute ventilation (ΔVI), and pharyngeal critical pressure (ΔPCRIT) between the active and passive conditions. RESULTS Leptin concentration was not associated with sleep disordered breathing severity, passive PCRIT, or baseline ventilation. In the women, increases in serum leptin concentrations were significantly associated with increases in ΔVImax (r(2) = 0.44, P < 0.001), ΔVI (r(2) = 0.40, P < 0.001), and ΔPCRIT (r(2) = 0.19, P < 0.04). These responses were independent of BMI, waist-to-hip ratio, neck circumference, or sagittal girth. CONCLUSION Leptin may augment neural compensatory mechanisms in response to upper airway obstruction, minimizing upper airway collapse, and/or mitigating potential OSA severity. Variability in leptin concentration among similarly obese individuals may contribute to differences in OSA susceptibility.