Prof Danny Eckert

PUBLICATIONS

Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea.

Carter SG, Berger MS, Carberry JC, Bilston LE, Butler JE, Tong BK, Martins RT, Fisher LP, McKenzie DK, Grunstein RR, Eckert DJ

To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others.

Mechanisms contributing to the response of upper-airway muscles to changes in airway pressure.

Carberry JC, Hensen H, Fisher LP, Saboisky JP, Butler JE, Gandevia SC, Eckert DJ

This study assessed the effects of inhaled lignocaine to reduce upper airway surface mechanoreceptor activity on 1) basal genioglossus and tensor palatini EMG, 2) genioglossus reflex responses to large pulses (∼10 cmH2O) of negative airway pressure, and 3) upper airway collapsibility in 15 awake individuals. Genioglossus and tensor palatini muscle EMG and airway pressures were recorded during quiet nasal breathing and during brief pulses (250 ms) of negative upper-airway pressure. Lignocaine reduced peak inspiratory (5.6 ± 1.5 vs. 3.8 ± 1.1% maximum; mean ± SE, P < 0.01) and tonic (2.8 ± 0.8 vs. 2.1 ± 0.7% maximum; P < 0.05) genioglossus EMG during quiet breathing but had no effect on tensor palatini EMG (5.0 ± 0.8 vs. 5.0 ± 0.5% maximum; P = 0.97). Genioglossus reflex excitation to negative pressure pulses decreased after anesthesia (60.9 ± 20.7 vs. 23.6 ± 5.2 μV; P < 0.05), but not when expressed as a percentage of the immediate prestimulus baseline. Reflex excitation was closely related to the change in baseline EMG following lignocaine (r(2) = 0.98). A short-latency genioglossus reflex to rapid increases from negative to atmospheric pressure was also observed. The upper airway collapsibility index (%difference) between nadir choanal and epiglottic pressure increased after lignocaine (17.8 ± 3.7 vs. 28.8 ± 7.5%; P < 0.05). These findings indicate that surface receptors modulate genioglossus but not tensor palatini activity during quiet breathing. However, removal of input from surface mechanoreceptors has minimal effect on genioglossus reflex responses to large (∼10 cmH2O), sudden changes in airway pressure. Changes in pressure rather than negative pressure per se can elicit genioglossus reflex responses. These findings challenge previous views and have important implications for upper airway muscle control.

Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets.

Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A

To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA. This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.

Functional role of neural injury in obstructive sleep apnea.

Saboisky JP, Butler JE, Gandevia SC, Eckert DJ

The causes of obstructive sleep apnea (OSA) are multifactorial. Neural injury affecting the upper airway muscles due to repetitive exposure to intermittent hypoxia and/or mechanical strain resulting from snoring and recurrent upper airway closure have been proposed to contribute to OSA disease progression. Multiple studies have demonstrated altered sensory and motor function in patients with OSA using a variety of neurophysiological and histological approaches. However, the extent to which the alterations contribute to impairments in upper airway muscle function, and thus OSA disease progression, remains uncertain. This brief review, primarily focused on data in humans, summarizes: (1) the evidence for upper airway sensorimotor injury in OSA and (2) current understanding of how these changes affect upper airway function and their potential to change OSA progression. Some unresolved questions including possible treatment targets are noted.

Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment.

Eckert DJ, Younes MK

Historically, brief awakenings from sleep (cortical arousals) have been assumed to be vitally important in restoring airflow and blood-gas disturbances at the end of obstructive sleep apnea (OSA) breathing events. Indeed, in patients with blunted chemical drive (e.g., obesity hypoventilation syndrome) and in instances when other defensive mechanisms fail, cortical arousal likely serves an important protective role. However, recent insight into the pathogenesis of OSA indicates that a substantial proportion of respiratory events do not terminate with a cortical arousal from sleep. In many cases, cortical arousals may actually perpetuate blood-gas disturbances, breathing instability, and subsequent upper airway closure during sleep. This brief review summarizes the current understanding of the mechanisms mediating respiratory-induced cortical arousal, the physiological factors that influence the propensity for cortical arousal, and the potential dual roles that cortical arousal may play in OSA pathogenesis. Finally, the extent to which existing sedative agents decrease the propensity for cortical arousal and their potential to be therapeutically beneficial for certain OSA patients are highlighted.

Sensorimotor function of the upper-airway muscles and respiratory sensory processing in untreated obstructive sleep apnea.

Eckert DJ, Lo YL, Saboisky JP, Jordan AS, White DP, Malhotra A

Numerous studies have demonstrated upper-airway neuromuscular abnormalities during wakefulness in snorers and obstructive sleep apnea (OSA) patients. However, the functional role of sensorimotor impairment in OSA pathogenesis/disease progression and its potential effects on protective upper-airway reflexes, measures of respiratory sensory processing, and force characteristics remain unclear. This study aimed to gain physiological insight into the potential role of sensorimotor impairment in OSA pathogenesis/disease progression by comparing sensory processing properties (respiratory-related evoked potentials; RREP), functionally important protective reflexes (genioglossus and tensor palatini) across a range of negative pressures (brief pulses and entrained iron lung ventilation), and tongue force and time to task failure characteristics between 12 untreated OSA patients and 13 controls. We hypothesized that abnormalities in these measures would be present in OSA patients. Upper-airway reflexes (e.g., genioglossus onset latency, 20 ± 1 vs. 19 ± 2 ms, P = 0.82), early RREP components (e.g., P1 latency 25 ± 2 vs. 25 ± 1 ms, P = 0.78), and the slope of epiglottic pressure vs. genioglossus activity during iron lung ventilation (-0.68 ± 1.0 vs. -0.80 ± 2.0 cmH(2)O/%max, P = 0.59) were not different between patients and controls. Maximal tongue protrusion force was greater in OSA patients vs. controls (35 ± 2 vs. 27 ± 2 N, P < 0.01), but task failure occurred more rapidly (149 ± 24 vs. 254 ± 23 s, P < 0.01). Upper-airway protective reflexes across a range of negative pressures as measured by electromyography and the early P1 component of the RREP are preserved in OSA patients during wakefulness. Consistent with an adaptive training effect, tongue protrusion force is increased, not decreased, in untreated OSA patients. However, OSA patients may be vulnerable to fatigue of upper-airway dilator muscles, which could contribute to disease progression.

Drug effects on ventilatory control and upper airway physiology related to sleep apnea.

Wang D, Eckert DJ, Grunstein RR

Understanding the inter-relationship between pharmacological agents, ventilatory control, upper airway physiology and their consequent effects on sleep-disordered breathing may provide new directions for targeted drug therapy. Where available, this review focuses on human studies that contain both drug effects on sleep-disordered breathing and measures of ventilatory control or upper airway physiology. Many of the existing studies are limited in sample size or comprehensive methodology. At times, the presence of paradoxical findings highlights the complexity of drug therapy for OSA. The existing studies also highlight the importance of considering inter-individual pharmacokinetics and underlying causes of sleep apnea in interpreting drug effects on sleep-disordered breathing. Practical ways to assess an individual's ventilatory control and how it interacts with upper airway physiology is required for future targeted pharmacotherapy in sleep apnea.

Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold.

Eckert DJ, Malhotra A, Wellman A, White DP

The effect of common sedatives on upper airway physiology and breathing during sleep in obstructive sleep apnea (OSA) has been minimally studied. Conceptually, certain sedatives may worsen OSA in some patients. However, sleep and breathing could improve with certain sedatives in patients with OSA with a low respiratory arousal threshold. This study aimed to test the hypothesis that trazodone increases the respiratory arousal threshold in patients with OSA and a low arousal threshold. Secondary aims were to examine the effects of trazodone on upper airway dilator muscle activity, upper airway collapsibility, and breathing during sleep. Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold without major impairment in dilator muscle activity or upper airway collapsibility. However, the magnitude of change in arousal threshold was insufficient to overcome the compromised upper airway anatomy in these patients.

Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway.

Genta PR, Owens RL, Edwards BA, Sands SA, Eckert DJ, Butler JP, Loring SH, Malhotra A, Jackson AC, White DP, Wellman A

The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50±10 years with a BMI of 35±6 kg/m(2) and severe OSA (apnea-hypopnea index=52±28 events/h) were studied. NED and phasic genioglossus muscle activity (EMG(GG)) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMG(GG) activity (p<0.001), but NED worsened only by 3.6±5.8% (p=0.056). In conclusion, phasic EMG(GG) had little effect on NED. This finding suggests that individual differences in phasic EMG(GG) activation do not likely explain the variability in NED found among OSA patients.

Obstructive sleep apnea in older adults is a distinctly different physiological phenotype.

Edwards BA, Wellman A, Sands SA, Owens RL, Eckert DJ, White DP, Malhotra A

Current evidence suggests that the pathological mechanisms underlying obstructive sleep apnea (OSA) are altered with age. However, previous studies examining individual physiological traits known to contribute to OSA pathogenesis have been assessed in isolation, primarily in healthy individuals. Our data suggest that airway anatomy/collapsibility plays a relatively greater pathogenic role in older adults, whereas a sensitive ventilatory control system is a more prominent trait in younger adults with obstructive sleep apnea.

Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea.

Sands SA, Eckert DJ, Jordan AS, Edwards BA, Owens RL, Butler JP, Schwab RJ, Loring SH, Malhotra A, White DP, Wellman A

To determine the key physiologic traits (upper-airway anatomy/collapsibility, upper-airway muscle responsiveness, chemoreflex control of ventilation, arousability from sleep) responsible for the absence of OSA in overweight/obese individuals. Overweight/obese individuals without apnea have a moderately compromised upper-airway structure that is mitigated by highly responsive upper-airway dilator muscles to avoid OSA. Elucidating the mechanisms underlying enhanced muscle responses in this population may provide clues for novel OSA interventions.

Upper airway collapsibility is associated with obesity and hyoid position.

Genta PR, Schorr F, Eckert DJ, Gebrim E, Kayamori F, Moriya HT, Malhotra A, Lorenzi-Filho G

Upper airway anatomy plays a major role in obstructive sleep apnea (OSA) pathogenesis. An inferiorly displaced hyoid as measured by the mandibular plane to hyoid distance (MPH) has been consistently associated with OSA. The hyoid is also a common landmark for pharyngeal length, upper airway volume, and tongue base. Tongue dimensions, pharyngeal length, and obesity are associated with OSA severity, although the link between these anatomical variables and pharyngeal collapsibility is less well known. We hypothesized that obesity as measured by body mass index (BMI), neck and waist circumferences, and variables associated with hyoid position (pharyngeal length, upper airway volume, and tongue dimensions) would be associated with passive pharyngeal critical closing pressure (Pcrit). Pharyngeal critical closing pressure is associated with obesity and hyoid position. Tongue dimensions, pharyngeal length, and the mandibular plane to hyoid distance are associated with obesity variables. These findings provide novel insight into the potential factors mediating upper airway collapse in obstructive sleep apnea.

Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.

Terrill PI, Edwards BA, Nemati S, Butler JP, Owens RL, Eckert DJ, White DP, Malhotra A, Wellman A, Sands SA

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean±sem change in loop gain (ΔLG) -0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG -0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control.

Arousal from sleep does not lead to reduced dilator muscle activity or elevated upper airway resistance on return to sleep in healthy individuals.

Jordan AS, Cori JM, Dawson A, Nicholas CL, O'Donoghue FJ, Catcheside PG, Eckert DJ, McEvoy RD, Trinder J

To compare changes in end-tidal CO2, genioglossus muscle activity and upper airway resistance following tone-induced arousal and the return to sleep in healthy individuals with small and large ventilatory responses to arousal. Regardless of the magnitude of the ventilatory response to arousal from sleep and subsequent reduction in PETCO2, healthy individuals did not develop reduced dilator muscle activity nor increased upper airway resistance, indicative of partial airway collapse, on the return to sleep. These findings challenge the commonly stated notion that arousals predispose to upper airway obstruction.

An Integrative Model of Physiological Traits Can be Used to Predict Obstructive Sleep Apnea and Response to Non Positive Airway Pressure Therapy.

Owens RL, Edwards BA, Eckert DJ, Jordan AS, Sands SA, Malhotra A, White DP, Loring SH, Butler JP, Wellman A

Both anatomical and nonanatomical traits are important in obstructive sleep apnea (OSA) pathogenesis. We have previously described a model combining these traits, but have not determined its diagnostic accuracy to predict OSA. A valid model, and knowledge of the published effect sizes of trait manipulation, would also allow us to predict the number of patients with OSA who might be effectively treated without using positive airway pressure (PAP). An integrative model of physiological traits can be used to predict population-wide and individual responses to non-PAP therapy. Many patients with OSA would be expected to be treated based on known trait manipulations, making a strong case for the importance of non-anatomical traits in OSA pathogenesis and the effectiveness of non-PAP therapies.

Effects of low-dose morphine on perceived sleep quality in patients with refractory breathlessness: A hypothesis generating study.

Martins RT, Currow DC, Abernethy AP, Johnson MJ, Toson B, Eckert DJ

The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality.

Upper Airway Collapsibility (Pcrit) and Pharyngeal Dilator Muscle Activity are Sleep Stage Dependent.

Carberry JC, Jordan AS, White DP, Wellman A, Eckert DJ

An anatomically narrow/highly collapsible upper airway is the main cause of obstructive sleep apnea (OSA). Upper airway muscle activity contributes to airway patency and, like apnea severity, can be sleep stage dependent. Conversely, existing data derived from a small number of participants suggest that upper airway collapsibility, measured by the passive pharyngeal critical closing pressure (Pcrit) technique, is not sleep stage dependent. This study aimed to determine the effect of sleep stage on Pcrit and upper airway muscle activity in a larger cohort than previously tested. Upper airway collapsibility measured via the Pcrit technique and genioglossus muscle activity vary with sleep stage. These findings should be taken into account when performing and interpreting "passive" Pcrit measurements.

Mild Airflow Limitation during N2 Sleep Increases K-complex Frequency and Slows Electroencephalographic Activity.

Nguyen CD, Wellman A, Jordan AS, Eckert DJ

To determine the effects of mild airflow limitation on K-complex frequency and morphology and electroencephalogram (EEG) spectral power. Mild airflow limitation increases K-complex frequency, N550 amplitude, and spectral power of delta and theta bands. In addition to providing mechanistic insight into the role of mild airflow limitation on K-complex characteristics and EEG activity, these findings may have important implications for respiratory conditions in which airflow limitation during sleep is common (e.g., snoring and OSA).

Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility During Non-REM Sleep in Healthy Subjects.

Taranto-Montemurro L, Edwards BA, Sands SA, Marques M, Eckert DJ, White DP, Wellman A

We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility. Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for OSA. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02428478.