Follow-up assessment of sleep-related symptoms in patients after treatment for cancer: responses to continuous positive airway pressure treatment for co-morbid obstructive sleep apnoea.

PURPOSE: To assess changes in sleep-related symptoms in patients with breast cancer, endometrial cancer and melanoma previously examined for sleep-related symptoms and the presence of PSG (polysomnography)-determined OSA, ≥ 3 years post-treatment; and to evaluate how CPAP treatment affects sleep-related symptoms in patients previously diagnosed with OSA. METHODS: Patients initially recruited from breast cancer, endometrial cancer, and melanoma follow-up clinics at Westmead Hospital (Sydney, Australia) participated in this questionnaire-based study. Demographic and change in cancer status data were collected at follow-up. Patients completed the Pittsburgh Sleep Quality Index [poor sleep quality, PSQITOTAL ≥ 5au], Insomnia Severity Index, Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire; with ΔPSQITOTAL ≥ 3au indicating a clinically meaningful change in sleep quality over follow-up. PSG-determined OSA was confirmed using the apnoea-hypopnoea index. CPAP compliance was determined via self-report (CPAP compliant, CPAP; not compliant, non-CPAP). Logistic regression models determined if changes in cancer status, AHI, cancer subgroup or CPAP treatment was predictive of ΔPSQITOTAL ≥ 3 au and p < 0.05 indicated statistical significance. RESULTS: The 60 patients recruited had breast cancer (n = 22), endometrial cancer (n = 15), and melanoma (n = 23). Cancer subgroups were similarly aged, and all had median follow-up PSQITOTAL scores ≥ 5au; breast cancer patients scoring the highest (p < 0.05). The CPAP group had significantly reduced PSQITOTAL scores (p = 0.02) at follow-up, unlike the non-CPAP group. Cancer subgroups had similar median ISITOTAL, ESSTOTAL and FOSQ-10TOTAL scores at follow-up, regardless of CPAP treatment. There were no significant predictors of ΔPSQITOTAL ≥ 3 au at follow-up. CONCLUSION: Sleep-related symptoms persist in patients with cancer ≥ 3 years after treatment, although these symptoms improve with CPAP. Future studies should evaluate how CPAP affects survival outcomes in cancer patients with comorbid OSA.

Increased intrapulmonary shunt and alveolar dead space post-COVID-19.

Increased intrapulmonary shunt (QS/Qt) and alveolar dead space (VD/VT) are present in early recovery from 2019 Novel Coronavirus (COVID-19). We hypothesized patients recovering from severe critical acute illness (NIH category 3-5) would have greater and longer lasting increased QS/Qt and VD/VT than patients with mild-moderate acute illness (NIH 1-2). Fifty-nine unvaccinated patients (33 males, aged 52 [38-61] yr, body mass index [BMI] 28.8 [25.3-33.6] kg/m2; median [IQR], 44 previous mild-moderate COVID-19, and 15 severe-critical disease) were studied 15-403 days postacute severe acute respiratory syndrome coronavirus infection. Breathing ambient air, steady-state mean alveolar Pco2, and Po2 were recorded simultaneously with arterial Po2/Pco2 yielding aAPco2, AaPo2, and from these, QS/Qt%, VD/VT%, and relative alveolar ventilation (40 mmHg/[Formula: see text], VArel) were calculated. Median [Formula: see text] was 39.4 [35.6-41.1] mmHg, [Formula: see text] 92.3 [87.1-98.2] mmHg; [Formula: see text] 32.8 [28.6-35.3] mmHg, [Formula: see text] 112.9 [109.4-117.0] mmHg, AaPo2 18.8 [12.6-26.8] mmHg, aAPco2 5.9 [4.3-8.0] mmHg, QS/Qt 4.3 [2.1-5.9] %, and VD/VT16.6 [12.6-24.4]%. Only 14% of patients had normal QS/Qt and VD/VT; 1% increased QS/Qt but normal VD/VT; 49% normal QS/Qt and elevated VD/VT; 36% both abnormal QS/Qt and VD/VT. Previous severe critical COVID-19 predicted increased QS/Qt (2.69 [0.82-4.57]% per category severity [95% CI], P < 0.01), but not VD/VT. Increasing age weakly predicted increased VD/VT (1.6 [0.1-3.2]% per decade, P < 0.04). Time since infection, BMI, and comorbidities were not predictors (all P > 0.11). VArel was increased in most patients. In our population, recovery from COVID-19 was associated with increased QS/Qt in 37% of patients, increased VD/VT in 86%, and increased alveolar ventilation up to ∼13 mo postinfection. NIH severity predicted QS/Qt but not elevated VD/VT. Increased VD/VT suggests pulmonary microvascular pathology persists post-COVID-19 in most patients.NEW & NOTEWORTHY Using novel methodology quantifying intrapulmonary shunt and alveolar dead space in COVID-19 patients up to 403 days after acute illness, 37% had increased intrapulmonary shunt and 86% had elevated alveolar dead space likely due to independent pathology. Elevated shunt was partially related to severe acute illness, and increased alveolar dead space was weakly related to increasing age. Ventilation was increased in the majority of patients regardless of previous disease severity. These results demonstrate persisting gas exchange abnormalities after recovery.

Sleep disordered breathing has minimal association with retinal microvascular diameters in a non-diabetic sleep clinic cohort.

INTRODUCTION: Obstructive sleep apnea (OSA) may increase stroke risk; retinal arteriolar (central retinal arteriolar equivalent, CRAE) diameter narrowing and/or retinal venular (central retinal venule equivalent, CRVE) widening may predict stroke. We examined relationships between sleep disordered breathing (SDB) and CRAE and CRVE and in a diabetes-free sleep clinic cohort. METHODS: Patients for SDB assessment were recruited (Main Group, n = 264, age: 58.5 ± 8.9 yrs [mean ± SD]; males: 141) for in-laboratory polysomnography (standard metrics, eg apnea hypopnea index, AHI) and retinal photographs (evening and morning). A more severe SDB sub-group (n = 85) entered a 12-month cardiovascular risk factor minimisation (hypertension/hypercholesterolemia control; RFM) and continuous positive airway pressure (CPAP) intervention (RFM/CPAP Sub-Group); successfully completed by n = 66 (AHI = 32.4 [22.1-45.3] events/hour, median[IQR]). Univariate (Spearman's correlation, t-test) and multiple linear regression models examined non-SDB and SDB associations with CRAE and CRVE measures. RESULTS: Main Group: Evening CRAE predictors were: systolic blood pressure (0.18µm decrease per mmHg, p = 0.001), age (2.47µm decrease per decade, p = 0.012), Caucasian ethnicity (4.45 µm versus non-Caucasian, p = 0.011), height (0.24 µm decrease per cm increase, p = 0.005) and smoking history (3.08 µm increase, p = 0.052). Evening CRVE predictors were: Caucasian ethnicity (11.52 µm decrease versus non-Caucasian, p>0.001), diastolic blood pressure (0.34 µm increase in CRVE per mmHg, p = 0.001), hypertension history (6.5 µm decrease, p = 0.005), and smoking history (4.6 µm increase, p = 0.034). No SDB metric (all p>0.08) predicted CRAE or CRVE measures. RFM/CPAP Sub-Group: A one-unit increase in ln(AHI+1) was associated with a 0.046µm increase in CRAE (n = 85; p = 0.029). Mean evening CRAE and CRVE values did not change across the intervention (n = 66), but evening CRVE decreased ~6.0 µm for individuals with AHI >30 events/hr. CONCLUSION: No major SDB associations with CRAE or CRVE were identified, although the RFM/CPAP intervention reduced evening CRVE for severe OSA patients. Implications for cerebro-vascular disease risk remain uncertain. TRIAL REGISTRATION: The protocol was registered with the Australian New Zealand Clinical Trials Registry (Trial Id: ACTRN12620000694910).

Screening for obstructive sleep apnoea in post-treatment cancer patients.

BACKGROUND AND AIMS: For cancer patients, comorbid obstructive sleep apnea (OSA) poses additional risk to their surgical/anaesthetic outcomes, quality of life, and survival. However, OSA screening is not well-established in oncology settings. We tested two screening tools (STOP-Bang questionnaire [SBQ] and the at-home monitoring device, ApneaLink™Air), for predicting polysomnography (PSG) confirmed OSA in post-treatment cancer patients. METHODS: Breast (n = 56), endometrial (n = 37) and melanoma patients (n = 50) were recruited from follow-up clinics at Westmead Hospital (Sydney, Australia). All underwent overnight PSG, 137 completed SBQ, and 99 completed ApneaLink™Air. Positive (PPV) and negative (NPV) predictive values for PSG-determined moderate-to-severe OSA and severe OSA, were calculated using an SBQ threshold ≥3 au and ApneaLink™Air apnoea-hypopnea index thresholds of ≥10, ≥15 and ≥30 events/h. RESULTS: Both SBQ and ApneaLink™Air had high NPVs (92.7% and 85.2%-95.6% respectively) for severe OSA, but NPVs were lower for moderate-to-severe OSA (69.1% and 59.1%-75.5%, respectively). PPV for both tools were relatively low (all <73%). Combining both tools did not improve screening performance. CONCLUSIONS: These screening tools may help identify cancer patients without severe OSA, but both are limited in identifying those with moderate-to-severe or severe OSA. PSG remains optimal for adequately identifying and managing comorbid OSA in cancer patients.

Retinal abnormalities, although relatively common in sleep clinic patients referred for polysomnography, are largely unrelated to sleep-disordered breathing.

STUDY OBJECTIVES: There has been long-standing interest in potential links between obstructive sleep apnea (OSA) and eye disease. This study used retinal photography to identify undiagnosed retinal abnormalities in a cohort of sleep clinic patients referred for polysomnography (PSG) and then determined associations with PSG-quantified sleep-disordered breathing (SDB) severity. METHODS: Retinal photographs (n = 396 patients) were taken of each eye prior to polysomnography and graded according to validated, standardized, grading scales. SDB was quantified via in-laboratory polysomnography (PSG; n = 385) using standard metrics. A questionnaire (n = 259) documented patient-identified pre-existing eye disease. Within-group prevalence rates were calculated on a per patient basis. Data were analyzed using multivariate logistic regression models to determine independent predictors for retinal abnormalities. P < 0.05 was considered significant. RESULTS: Main findings were (1) 76% of patients reported no pre-existing "eye problems"; (2) however, 93% of patients had at least one undiagnosed retinal photograph-identified abnormality; (3) most common abnormalities were drusen (72%) and peripapillary atrophy (PPA; 47%); (4) age was the most common risk factor; (5) diabetes history was an expected risk factor for retinopathy; (6) patients with very severe levels of SDB (apnea hypopnea index ≥ 50 events/h) were nearly three times more likely to have PPA. CONCLUSION: Retinal photography in sleep clinic settings will likely detect a range of undiagnosed retinal abnormalities, most related to patient demographics and comorbidities and, except for PPA, not associated with SDB. PPA may be indicative of glaucoma, and any association with severe SDB should be confirmed in larger prospective studies.

Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery.

BACKGROUND: Pathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery. METHODS: We studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed. RESULTS: For acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4% (0-6.1%) and alveolar dead space was 8.5% (0-22.4%) (both p<0.05 versus acute). Shunt was marginally elevated for two patients; however, five patients (30%) had elevated alveolar dead space. CONCLUSIONS: We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks; however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.

Cancer sleep symptom-related phenotypic clustering differs across three cancer specific patient cohorts.

Specific sleep disorders have been linked to disease progression in different cancers. We hypothesised sleep symptom clusters would differ between cancer types. The aim of this study was to compare sleep symptom clusters in post-treatment melanoma, breast and endometrial cancer patients. Data were collected from 124 breast cancer patients (1 male, 60 ± 15 years, 28.1 ± 6.6 kg/m2 ), 82 endometrial cancer patients (64.0 ± 12.5 years, 33.5 ± 10.4 kg/m2 ) and 112 melanoma patients (59 male, 65.0 ± 18.0 years, 29.1 ± 6.6 kg/m2 ). All patients completed validated questionnaires to assess sleep symptoms, including the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10). Snoring, tiredness, observed apneas, age, BMI, and gender data were also collected. Binary values (PSQI, ISI, FOSQ), or continuous variables for sleepiness (ESS) and perceived sleep quality (PSQI), were created and sleep symptom clusters were identified and compared across cancer cohorts. Four distinct sleep symptom clusters were identified: minimally symptomatic (n = 152, 47.7%); insomnia-predominant (n = 87, 24.9%); very sleepy with upper airway symptoms (n = 51, 16.3%), and severely symptomatic with severe dysfunction (n = 34, 11.1%). Breast cancer patients were significantly more likely to be in the insomnia predominant or severely symptomatic with severe dysfunction clusters, whereas melanoma patients were more likely to be minimally symptomatic or sleepy with upper airway symptoms (p <0.0001). Endometrial cancer patients were equally distributed across symptom clusters. Sleep symptom clusters vary across cancer patients. A more personalised approach to the management of sleep-related symptoms in these patients may improve the long term quality of life and survival.

Irregular Sleep/Wake Patterns Are Associated With Reduced Quality of Life in Post-treatment Cancer Patients: A Study Across Three Cancer Cohorts.

Background: Cancer patients often describe poor sleep quality and sleep disruption as contributors to poor quality of life (QoL). In a cross-sectional study of post-treatment breast, endometrial, and melanoma cancer patients, we used actigraphy to quantify sleep regularity using the sleep regularity index (SRI), and examined relationships with reported sleep symptoms and QoL. Methods: Participants were recruited post-primary treatment (35 diagnosed with breast cancer, 24 endometrial cancer, and 29 melanoma) and wore an actigraphy device for up to 2 weeks and SRI was calculated. Self-report questionnaires for cancer-related QoL [European Organization for Research and Treatment of Cancer EORTC (QLQ-C30)] were completed. Data were compared using analysis of variance (ANOVA) or Chi-Square tests. Multivariate linear regression analysis was used to determine independent variable predictors for questionnaire-derived data. Results: Age distribution was similar between cohorts. Endometrial and breast cancer cohorts were predominantly female, as expected, and body mass index (BMI) was higher in the endometrial cancer cohort, followed by breast and melanoma. There were no differences between tumor groups in: total sleep time, sleep onset latency, bedtime, and SRI (breast 80.9 ± 8.0, endometrial 80.3 ± 12.2, and melanoma 81.4 ± 7.0) (all p > 0.05). A higher SRI was associated with both better functional and symptom scores, including increased global QoL, better physical functioning, less sleepiness and fatigue, better sleep quality, and associated with less nausea/vomiting, dyspnea, and diarrhea (all p < 0.05). Conclusion: In cancer patients post-treatment, greater sleep regularity is associated with increased global QoL, as well as better physical functioning and fewer cancer related symptoms. Improving sleep regularity may improve QoL for cancer patients.

Predictors for carotid and femoral artery intima-media thickness in a non-diabetic sleep clinic cohort.

INTRODUCTION: The impact of sleep disordered breathing (SDB) on arterial intima-media thickness (IMT), a surrogate measure for cardiovascular disease, remains uncertain, in part because of the potential for non-SDB vascular risk factor interactions. In the present study, we determined predictors for common carotid (CCA) and femoral (CFA) artery IMT in an adult, sleep clinic cohort where non-SDB vascular risk factors (particularly diabetes) were eliminated or controlled. METHODS: We recruited 296 participants for polysomnography (standard SDB severity metrics) and CCA/CFA ultrasound examinations, followed by a 12 month vascular risk factor minimisation (RFM) and continuous positive pressure (CPAP) intervention for participants with a range of SDB severity (RFM Sub-Group, n = 157; apnea hyponea index [AHI]: 14.7 (7.2-33.2), median [IQR]). Univariable and multivariable linear regression models determined independent predictors for IMT. Linear mixed effects modelling determined independent predictors for IMT change across the intervention study. P<0.05 was considered significant. RESULTS: Age, systolic blood pressure and waist:hip ratio were identified as non-SDB predictive factors for CCA IMT and age, weight and total cholesterol:HDL ratio for CFA IMT. No SDB severity metric emerged as an independent predictor for either CCA or CFA IMT, except in the RFM Sub-Group, where a 2-fold increase in AHI predicted a 2.4% increase in CFA IMT. Across the intervention study, CCA IMT decreased in those who lost weight, but there was no CPAP use interaction. CFA IMT, however, decreased by 12.9% (95%CI 6.8, 18.7%, p = 0.001) in those participants who both lost weight and used CPAP > = 4hours/night. CONCLUSION: We conclude that SDB severity has little impact on CCA IMT values when non-SDB vascular risk factors are minimised or not present. This is the first study, however, to suggest a potential linkage between SDB severity and CFA IMT values. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12611000250932 and ACTRN12620000694910.

Increased prevalence of obstructive sleep apnea in women diagnosed with endometrial or breast cancer.

BACKGROUND: Epidemiological studies demonstrate associations between obstructive sleep apnea (OSA) and cancer incidence and mortality. The aim of this study was to measure OSA in women with breast (BC) or endometrial cancer (EC) and associations with clinico-pathological tumor variables. METHODS AND FINDINGS: In a cross sectional study, women with BC (12 months) or EC (3 months) post-diagnosis were recruited from cancer clinics. We collected demographic, anthropometric data, cancer stage, grade, histopathology and history of cancer treatment and all subjects had in-laboratory polysomnography. Sleepiness was assessed with the Epworth Sleepiness Scale (ESS). We compared anthropometric and polysomnographic data between cancer groups (unpaired t-tests), and assessed relationships between cancer characteristics and OSA variables (Fishers exact test). There were no significant differences between average age (BC:59.6±8.7 years(n = 50); EC:60.3±7.7 years(n = 37)), or ESS score (BC:6.4±4.4; EC 6.8±4.7; mean±SD; all p>0.2), however, BMI was higher in EC (BC: 29.7±7.9kgm-2; EC: 34.2±8.0 kgm-2; p<0.05). BC had longer sleep latency (BC:31.8±32minutes; EC:19.3±17.9 minutes), less Stage 3 sleep (BC:20.0±5.2%; EC:23.6±8.2%) and more REM sleep (BC:21.1±6.9%; EC: 16.6±5.7%), all p<0.05. EC had lower average awake and asleep oxygen saturation levels (BC: 95.6±1.3%; EC: 94.6±1.9% [awake]: BC: 94.8±2.1%; EC: 93.3±2.4% [asleep]; both p<0.05). Apnea-Hypopnea Index (AHI) (BC: 21.2(7.3-36.9) events/hr; EC: 15.7 (10-33.5) events/hour (median (interquartile range)) was not different p = 0.7), however, 58% and 57% of women with BC and EC respectively, had an AHI>15 events/hour. In this small sample size group, no significant associations (all p>0.1) were detected between OSA metrics and clinico-pathological tumor variables. CONCLUSION: In postmenopausal women with breast or endometrial cancer there is high prevalence of OSA, with no association with specific tumor characteristics detected. Recognition of the high prevalence of OSA in women with cancer is important to recognise as it may impact on surgical risk and quality of life.

Correction to: Objective and Subjective Effects of a Prototype Nasal Dilator Strip on Sleep in Subjects with Chronic Nocturnal Nasal Congestion.

The article "Objective and Subjective Effects of a Prototype Nasal Dilator Strip on Sleep in Subjects with Chronic Nocturnal Nasal Congestion", written by John R. Wheatley, Terence C. Amis, Sharon A. Lee, Renee Ciesla, Gilbert Shanga was originally published electronically on the publisher's internet portal (currently SpringerLink) on May, 22, 2019 without Open Access. The article has now been made Open Access.

Objective and Subjective Effects of a Prototype Nasal Dilator Strip on Sleep in Subjects with Chronic Nocturnal Nasal Congestion.

INTRODUCTION: This exploratory study characterized the performance of a nasal dilator strip with improved spring forces in lowering nasal resistance during sleep and reducing sleep-disordered breathing in subjects with difficulty sleeping due to chronic nocturnal nasal congestion. METHODS: Subjects applied the strip at bedtime for 28 days (active phase; n = 70). Objective assessments included snoring variables, breathing route during sleep, and polysomnography measures compared with baseline. Nasal breathing, congestion, and sleep were measured subjectively using rating scales and questionnaires. During a crossover nasal resistance phase (n = 55), nasal resistance was measured using posterior rhinomanometry with the strip applied on one of two nights. RESULTS: In the active phase, breathing and sleep were perceived to improve, with less daytime sleepiness (P < 0.04) and increased ease of breathing, sleep quality, staying asleep, and feeling refreshed in the morning (all P < 0.0001). However, while objective polysomnography metrics were generally similar with and without the strip, median wake after sleep onset time was numerically reduced by ~ 11 min, and the spontaneous arousal rate fell by ~ 37%. In the nasal resistance phase (n = 55), median resistance (at 0.2-0.25 l/s) while asleep was 39.1% lower with (n = 37) versus without (n = 36) the strip (1.34 vs. 2.20 cmH2O/l/s; P = 0.048). CONCLUSIONS: This exploratory study supports a role for the improved spring force nasal dilator strip in alleviating sleep-related symptoms in subjects with chronic nasal congestion, potentially via lowering nasal resistance and reducing nocturnal awakenings. A larger study is indicated to confirm these preliminary data. CLINICALTRIALS. GOV IDENTIFIER: NCT03105297. FUNDING: GlaxoSmithKline Consumer Healthcare. Plain language summary available for this article.

Modelling mucosal surface roughness in the human velopharynx: a computational fluid dynamics study of healthy and obstructive sleep apnea airways.

We previously published a unique methodology for quantifying human velopharyngeal mucosal surface topography and found increased mucosal surface roughness in patients with obstructive sleep apnea (OSA). In fluid mechanics, surface roughness is associated with increased frictional pressure losses and resistance. This study used computational fluid dynamics (CFD) to analyze the mechanistic effect of different levels of mucosal surface roughness on velopharyngeal airflow. Reconstructed velopharyngeal models from OSA and control subjects were modified, giving each model three levels of roughness, quantified by the curvature-based surface roughness index (CBSRI0.6) (range 24.8-68.6 mm-1). CFD using the k-ω shear stress transport turbulence model was performed (unidirectional, inspiratory, steady-state, 15l/min volumetric flow rate), and the effects of roughness on flow velocity, intraluminal pressure, wall shear stress, and velopharyngeal resistance (Rv) were examined. Across all models, increasing roughness increased maximum flow velocity, wall shear stress, and flow disruption while decreasing intraluminal pressures. Linear mixed effects modeling demonstrated a log-linear relationship between CBSRI0.6 and Rv, with a common slope (log(Rv)/CBSRI0.6) of 0.0079 [95% confidence interval (CI) 0.0015-0.0143; P = 0.019] for all subjects, equating to a 1.9-fold increase in Rv when roughness increased from control to OSA levels. At any fixed CBSRI0.6, the estimated difference in log(Rv) between OSA and control models was 0.9382 (95% CI 0.0032-1.8732; P = 0.049), equating to an 8.7-fold increase in Rv. This study supports the hypothesis that increasing mucosal surface roughness increases velopharyngeal airway resistance, particularly for anatomically narrower OSA airways, and may thus contribute to increased vulnerability to upper airway collapse in patients with OSA.NEW & NOTEWORTHY Increased mucosal surface roughness in the velopharynx of patients with obstructive sleep apnea (OSA) has recently been identified, but its role in OSA pathogenesis is unknown. This is the first study to model the impact of increased roughness on airflow mechanics in the velopharynx. We report that increasing roughness significantly affects airflow, increasing velopharyngeal resistance and potentially increasing the vulnerability to upper airway collapse, particularly in those patients with an already compromised anatomy.

Pupil Dilation May Affect Retinal Vessel Caliber Measures.

PURPOSE: To assess the effect of pupil dilation on measures of retinal vessel caliber. DESIGN: Observational study with self-comparisons Methods: Retinal photographs were taken for both eyes of 25 subjects before and after pupil dilation. Three photographic graders, masked to pupil dilation status, measured the same set of images using a computer-assisted, semi-automatic method. We compared means (standard deviations) of retinal arteriolar caliber equivalent (CRAE) and retinal venular caliber equivalent (CRVE) of the same eyes between pre- and post-dilation images. We assessed concordance correlation coefficients (CC), Bland Altman limits-of-agreements, and used linear mixed models to assess CRAE and CRVE measures associated with pupil dilation (influencing image quality), graders (observers) and right-left eye variation. RESULTS: We found high CCs for CRAE (0.82-0.94) and CRVE (0.87-0.94) between pre- and post-dilation images of the same eyes across the graders. Bland Altman plots showed that mean differences ranged from 0.55-3.42µm for CRAE and 1.56-2.29µm for CRVE. After adjusting for right-left eye random variation, a significant fixed effect of dilation was evident in mean CRAE in two of the three graders. There was no significant fixed effect of dilation in mean CRVE across all graders. In models including data of both eyes' measures from pre- and post-dilation images by three graders, the fixed effect for dilation status contributed significantly to CRAE and CRVE variances whereas random effects for graders and dilation status contributed minimally. CONCLUSIONS: Contrary to our hypothesis, we found a systematic effect of pupil dilation on retinal vessel caliber measures.

Feedback modulation of surrounding pressure determines the onset of negative effort dependence in a collapsible tube bench model of the pharyngeal airway.

Negative effort dependence (NED), decreased airflow despite increased driving pressure, has been proposed as a specific obstructive sleep apnea (OSA) phenotypic characteristic. We examined conditions under which NED occurs in a collapsible tube, pharyngeal airway bench model with the chamber enclosed, focusing on relationships with surrounding pressure levels and longitudinal strain. Using a vacuum source, graded airflows (V̇; 0-5 l/s) were generated through a thin-walled latex tube enclosed within a rigid, cylindrical chamber, sealed with initial chamber pressures (Pci) of 0-5 cmH2O (separate runs), or opened to the atmosphere. Upstream minus downstream pressure (Pu - Pd), maximum airflow (V̇max), and chamber pressure (Pc) were measured at 0-50% longitudinal strain. NED occurred across the range of Pci and strains studied but was most pronounced for the chamber open condition. With a sealed chamber, V̇ increased and Pc decreased with increasing Pu - Pd until the onset of NED at V̇max and a Pc value that was designated as critical (Pcc). Pcc was lowest (-17 cmH20) and V̇max was highest (~5 l/s) with chamber sealed: Pci = 0 cmH2O and 12.5 to 25% strain. We conclude that for our collapsible tube model, the achievable V̇max before the onset of NED depends on both the initial conditions (Pci and strain) and the dynamics of feedback between driving pressure and chamber pressure (chamber sealed vs. open). NED-based phenotypic analyses for OSA may need to focus on potential feedback control mechanisms (eg lung volume change, muscle activity) that may link peripharyngeal tissue pressure levels to driving pressures for airflow.NEW & NOTEWORTHY A collapsible tube, pharyngeal airway bench model was used to study the role of surrounding pressure and longitudinal wall strain at the onset of negative effort dependence (NED). NED occurred to varying degrees across all conditions tested, but maximum airflow was achieved with 1) low initial surrounding pressure, 2) a feedback mechanism between surrounding pressure and driving pressure; and 3) a moderate amount of strain applied. Potential impacts on OSA phenotypic analyses are discussed.

Velopharyngeal mucosal surface topography in healthy subjects and subjects with obstructive sleep apnea.

Macroscopic pharyngeal anatomical abnormalities are thought to contribute to the pathogenesis of upper airway (UA) obstruction in obstructive sleep apnea (OSA). Microscopic changes in the UA mucosal lining of OSA subjects are reported; however, the impact of these changes on UA mucosal surface topography is unknown. This study aimed to 1) develop methodology to measure UA mucosal surface topography, and 2) compare findings from healthy and OSA subjects. Ten healthy and eleven OSA subjects were studied. Awake, gated (end expiration), head and neck position controlled magnetic resonance images (MRIs) of the velopharynx (VP) were obtained. VP mucosal surfaces were segmented from axial images, and three-dimensional VP mucosal surface models were constructed. Curvature analysis of the models was used to study the VP mucosal surface topography. Principal, mean, and Gaussian curvatures were used to define surface shape composition and surface roughness of the VP mucosal surface models. Significant differences were found in the surface shape composition, with more saddle/spherical and less flat/cylindrical shapes in OSA than healthy VP mucosal surface models (P < 0.01). OSA VP mucosal surface models were also found to have more mucosal surface roughness (P < 0.0001) than healthy VP mucosal surface models. Our novel methodology was utilized to model the VP mucosal surface of OSA and healthy subjects. OSA subjects were found to have different VP mucosal surface topography, composed of increased irregular shapes and increased roughness. We speculate increased irregularity in VP mucosal surface may increase pharyngeal collapsibility as a consequence of friction-related pressure loss.NEW & NOTEWORTHY A new methodology was used to model the upper airway mucosal surface topography from magnetic resonance images of patients with obstructive sleep apnea and healthy adults. Curvature analysis was used to analyze the topography of the models, and a new metric was derived to describe the mucosal surface roughness. Increased roughness was found in the obstructive sleep apnea vs. healthy group, but further research is required to determine the functional effects of the measured difference on upper airway airflow mechanics.

Development and validation of a computational finite element model of the rabbit upper airway: simulations of mandibular advancement and tracheal displacement.

The mechanisms leading to upper airway (UA) collapse during sleep are complex and poorly understood. We previously developed an anesthetized rabbit model for studying UA physiology. On the basis of this body of physiological data, we aimed to develop and validate a two-dimensional (2D) computational finite element model (FEM) of the passive rabbit UA and peripharyngeal tissues. Model geometry was reconstructed from a midsagittal computed tomographic image of a representative New Zealand White rabbit, which included major soft (tongue, soft palate, constrictor muscles), cartilaginous (epiglottis, thyroid cartilage), and bony pharyngeal tissues (mandible, hard palate, hyoid bone). Other UA muscles were modeled as linear elastic connections. Initial boundary and contact definitions were defined from anatomy and material properties derived from the literature. Model parameters were optimized to physiological data sets associated with mandibular advancement (MA) and caudal tracheal displacement (TD), including hyoid displacement, which featured with both applied loads. The model was then validated against independent data sets involving combined MA and TD. Model outputs included UA lumen geometry, peripharyngeal tissue displacement, and stress and strain distributions. Simulated MA and TD resulted in UA enlargement and nonuniform increases in tissue displacement, and stress and strain. Model predictions closely agreed with experimental data for individually applied MA, TD, and their combination. We have developed and validated an FEM of the rabbit UA that predicts UA geometry and peripharyngeal tissue mechanical changes associated with interventions known to improve UA patency. The model has the potential to advance our understanding of UA physiology and peripharyngeal tissue mechanics.

Pharyngeal mucosal wall folds in subjects with obstructive sleep apnea.

Mechanical processes underlying pharyngeal closure have not been examined. We hypothesized that the pharyngeal mucosal surface would fold during closure, and lowering the upper airway lining liquid surface tension would unfold areas of mucosal apposition, i.e., folds. We compared baseline pharyngeal fold numbers and response to reduction in upper airway liquid surface tension in healthy and obstructive sleep apnea (OSA) subjects. Awake, gated magnetic resonance pharyngeal airway images of 10 healthy and 11 OSA subjects were acquired before and after exogenous surfactant administration (beractant). Upper airway liquid surface tension was measured at the beginning and end of image acquisition and averaged. Velopharyngeal and oropharyngeal images were segmented and analyzed separately for average cross-sectional area, circumference, and fold number. Compared with healthy subjects, at baseline, velopharynx for OSA subjects had a smaller cross-sectional area (98.3 ± 32.5 mm(2) healthy, 52.3 ± 23.6 mm(2) OSA) and circumference (46.5 ± 8.1 mm healthy, 30.8 ± 6.1 mm OSA; both P < 0.05, unpaired t-test), and fewer folds (4.9 ± 1.6 healthy, 3.1 ± 1.8 OSA, P < 0.03). There were no differences in oropharynx for cross-sectional area, circumference, or folds. Reduction in upper airway liquid surface tension from 61.3 ± 1.2 to 55.3 ± 1.5 mN/m (P < 0.0001) did not change cross-sectional area or circumference for velopharynx or oropharynx in either group; however, in OSA subjects, oropharyngeal folds fell from 6.8 ± 3.1 to 4.7 ± 1.2 (n = 8, P < 0.05), and velopharyngeal folds from 3.3 ± 1.9 to 2.3 ± 1.2 (P = 0.08), and were unchanged in healthy subjects. Subjects with OSA have fewer velopharyngeal wall folds, which decrease further when surface tension falls. We speculate that reduced pharyngeal wall folds contribute to an increase in pharyngeal collapsibility.