Bradley A. Edwards

A method for measuring and modeling the physiological traits causing obstructive sleep apnea

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individuals set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patients physiology and guide therapy based on the traits.

The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVES We sought to provide an updated systematic review and meta-analysis of studies investigating the effect of positive airway pressure (PAP) treatment for obstructive sleep apnea (OSA) on systolic and diastolic blood pressure (SBP, DBP). METHODS Two independent investigators undertook a systematic search of the PubMed database (1980-2012) to identify randomized controlled trials comparing therapeutic PAP to sham-PAP, pill placebo, or standard care over at least one week in adult OSA patients without major comorbidities. The mean, variance, and sample size for diurnal and nocturnal SBP and DBP data were also extracted independently from each study. Random effects meta-analyses were conducted, followed by pre-specified subgroup and meta-regression analyses. RESULTS 32 studies were identified, with data available from 28 studies representing n = 1,948 patients. The weighted mean difference in diurnal SBP (-2.58 mm Hg, 95% CI -3.57 to -1.59 mm Hg) and DBP (-2.01 mm Hg, 95% CI -2.84 to -1.18 mm Hg) both significantly favored PAP treatment over control arms, with similar results seen in nocturnal readings. Statistically significant reductions in BP were seen in studies whose patients were younger, sleepier, had more severe OSA, and exhibited greater PAP adherence. Meta-regression indicated that the reductions in DBP with PAP were predicted by mean baseline BP (β = -0.22, p = 0.02) and Epworth Sleepiness Scale scores (β = -0.27, p = 0.04). CONCLUSIONS PAP treatment for OSA is associated with modest but significant reductions in diurnal and nocturnal SBP and DBP. Future research should be directed towards identifying subgroups likely to reap greater treatment benefits as well as other therapeutic benefits provided by PAP therapy.

Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea

•  Obstructive sleep apnoea (OSA) probably results from the interaction of key pathophysiological traits including compromised pharyngeal anatomy, inadequate upper‐airway muscle function, high ventilatory response to a change in ventilation (high loop gain), and a low arousal threshold. •  Because the standard therapy with positive airway pressure is often poorly tolerated, alternative options have long been sought which have included various pharmacological interventions. •  Acetazolamide may be a useful therapeutic tool, yet there have been few studies examining how it affects the traits causing OSA. •  Our study demonstrates that acetazolamide reduces loop gain by approximately 40% in individuals with OSA, but has little impact on the remaining OSA traits. •  The marked reduction in loop gain with acetazolamide suggests that acetazolamide may be of therapeutic benefit when used alone or in combination with other therapies to treat individuals whose loop gain is known to contribute to OSA.

A simplified method for determining phenotypic traits in patients with obstructive sleep apnea

We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure = 0 cmH(2)O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from -0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apnea-hypopnea index (r = 0.9, P < 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy.

Loop Gain As a Means to Predict a Positive Airway Pressure Suppression of Cheyne-Stokes Respiration in Patients with Heart Failure

RATIONALE Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2π/(2πDR - sin2πDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy.

Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea.

RATIONALE A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

Aging and Sleep: Physiology and Pathophysiology

Aging effects on sleep are important to consider for the practicing pulmonologist due to the increase in prevalence of major respiratory disorders as well as the normal changes that occur in sleep patterns with aging. Typically, aging is associated with decreases in the amount of slow wave sleep and increases in stage 1 and 2 non-rapid eye movement sleep, often attributed to an increased number of spontaneous arousals that occur in the elderly. Elderly individuals tend to go to sleep earlier in the evening and wake earlier due to a phase advance in their normal circadian sleep cycle. Furthermore the development of sleep-related respiratory disorders such as obstructive sleep apnea (OSA) and central sleep apnea or Cheyne-Stokes respiration (CSA-CSR) associated with congestive heart failure (CHF) occur with increasing prevalence in the elderly. The development of such disorders is often of major concern because they are associated with systemic hypertension and cardiovascular disease, metabolic disorders such as diabetes, and impaired neurocognition. The present review reflects the current understanding of the normal changes in sleep patterns and sleep needs with advancing age, in addition to the effect that aging has on the predisposition to and consequences of OSA and CSA-CSR associated with CHF.

Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.

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. Ventilatory instability can be measured by clinical polysomnography to guide nonanatomical sleep apnoea therapy http://ow.ly/AyXT3

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

STUDY OBJECTIVES 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). DESIGN, PARTICIPANTS AND INTERVENTION Fifty-seven subjects with and without OSA underwent standard clinical and research sleep studies to measure OSA severity and the physiological traits important for OSA pathogenesis, respectively. The traits were incorporated into a physiological model to predict OSA. The model validity was determined by comparing the model prediction of OSA to the clinical diagnosis of OSA. The effect of various trait manipulations was then simulated to predict the proportion of patients treated by each intervention. MEASUREMENTS AND RESULTS The model had good sensitivity (80%) and specificity (100%) for predicting OSA. A single intervention on one trait would be predicted to treat OSA in approximately one quarter of all patients. Combination therapy with two interventions was predicted to treat OSA in ∼50% of patients. CONCLUSIONS 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.

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

STUDY OBJECTIVES 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. DESIGN We assessed the four physiological traits responsible for OSA in a group of young and old patients with OSA. SETTING Sleep research laboratory. PARTICIPANTS Ten young (20-40 y) and old (60 y and older) patients with OSA matched by body mass index and sex. MEASUREMENTS AND RESULTS Pharyngeal anatomy/collapsibility, loop gain (LG), upper airway muscle responsiveness/gain (UAG) and the respiratory arousal threshold were determined using multiple 2- to 3-min decreases or drops in continuous positive airway pressure (CPAP). Passive pharyngeal anatomy/collapsibility was quantified as the ventilation at CPAP = 0 cmH2O immediately after the CPAP drop. LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. UAG was taken as the ratio of the increase in ventilation to the increase in ventilatory drive across the pressure drop. Arousal threshold was estimated as the ventilatory drive that caused arousal. Veupnea was quantified as the mean ventilation prior to the pressure drop. In comparison with younger patients with OSA, older patients had a more collapsible airway (ventilation at 0 cmH2O = 3.4 ± 0.9 versus 1.5 ± 0.7 L/min; P = 0.05) but lower Veupnea (8.2 ± 0.5 versus 6.1 ± 0.4 L/min; P < 0.01) and a lower LG (5.0 ± 0.7 versus 2.9 ± 0.5; P < 0.05). The remaining traits were similar between groups. CONCLUSIONS 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. CITATION Edwards BA, Wellman A, Sands SA, Owens RL, Eckert DJ, White DP, Malhotra A. Obstructive sleep apnea in older adults is a distinctly different physiological phenotype.