Relationships between MRI fat distributions and sleep apnea and obesity hypoventilation syndrome in very obese patients.

PURPOSE: Obesity is associated with both obstructive sleep apnea (OSA) and obesity hypoventilation. Differences in adipose tissue distribution are thought to underlie the development of both OSA and hypoventilation. We explored the relationships between the distribution of upper airway, neck, chest, abdominal and muscle fat in very obese individuals. METHODS: We conducted a cross-sectional cohort study of individuals presenting to a tertiary sleep clinic or for assessment for bariatric surgery. Individuals underwent magnetic resonance (MR) imaging of their upper airway, neck, chest, abdomen and thighs; respiratory polygraphy; 1 week of autotitrating CPAP; and morning arterial blood gas to determine carbon dioxide partial pressure and base excess. RESULTS: Fifty-three individuals were included, with mean age of 51.6 ± 8.4 years and mean BMI of 44.3 ± 7.9 kg/m2; there were 27 males (51%). Soft palate, tongue and lateral wall volumes were significantly associated with the AHI in univariable analyses (p < 0.001). Gender was a significant confounder in these associations. No significant associations were found between MRI measures of adiposity and hypoventilation. CONCLUSIONS: In very obese individuals, our results indicate that increased volumes of upper airway structures are associated with increased severity of OSA, as previously reported in less obese individuals. Increasingly large upper airway structures that reduce pharyngeal lumen size are likely to lead to OSA by increasing the collapsibility of the upper airway. However, we did not show any significant association between regional fat distribution and propensity for hypoventilation, in this population.

Adhesion molecule increases in sleep apnea: beneficial effect of positive airway pressure and moderation by obesity.

BACKGROUND: Elevated levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) may contribute to cardiovascular disease and are associated with obstructive sleep apnea (OSA) and obesity. The relationship between OSA and obesity in determining ICAM-1 and VCAM-1 levels, and the effect of treatment, is unclear. OBJECTIVE: Our aim was to study whether positive airway pressure (PAP) usage resulted in changes in ICAM-1 and VCAM-1 after 2 years within 309 OSA patients from the Icelandic Sleep Apnea Cohort, and determine how obesity affected such changes. SUBJECTS/METHODS: The mean body mass index (BMI) was 32.4±5.1 kg m(-2); subjects had moderate-to-severe OSA (apnea-hypopnea index=45.0±20.2) and 79% were male. There were 177 full PAP users (⩾4 h per night and ⩾20 of last 28 nights), 44 partial (<4 h per night or <20 nights) and 88 nonusers. RESULTS: ICAM-1 (P<0.001) and VCAM-1 (P=0.012) change was significantly different among the PAP groups. The largest ICAM-1 differences were among the most obese subjects (P<0.001). At follow-up, nonusers had increased ICAM-1 compared with decreased levels in full users. All groups had increased VCAM-1, but nonusers had a significantly larger increase than full users. CONCLUSIONS: Within moderate-to-severe OSA patients, PAP usage prevents increases in adhesion molecules observed in nonusers after 2 years. For ICAM-1, the largest effect is in the most obese subjects. As OSA and obesity commonly coexist, the usage of PAP to limit increases in adhesion molecules may decrease the rate of progression of OSA-related cardiovascular disease.

Hormone variations associated with quantitative fat measures in the menopausal transition.

OBJECTIVE: Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat. METHODS: Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm(3)) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status. RESULTS: In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures. CONCLUSIONS: Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition.

The role of obesity, different fat compartments and sleep apnea severity in circulating leptin levels: the Icelandic Sleep Apnea Cohort study.

OBJECTIVES: To assess whether sleep apnea severity has an independent relationship with leptin levels in blood after adjusting for different measures of obesity and whether the relationship between obstructive sleep apnea (OSA) severity and leptin levels differs depending on obesity level. METHODS: Cross-sectional study of 452 untreated OSA patients (377 males and 75 females), in the Icelandic Sleep Apnea Cohort (ISAC), age 54.3±10.6 (mean±s.d.), body mass index (BMI) 32.7±5.3 kg m(-2) and apnea-hypopnea index 40.2±16.1 events per h. A sleep study and magnetic resonance imaging of abdominal visceral and subcutaneous fat volume were performed, as well as fasting serum morning leptin levels were measured. RESULTS: Leptin levels were more highly correlated with BMI, total abdominal and subcutaneous fat volume than visceral fat volume per se. No relationship was found between sleep apnea severity and leptin levels, assessed within three BMI groups (BMI <30, BMI 30-35 and BMI > or =35 kg m(-2)). In a multiple linear regression model, adjusted for gender, BMI explained 38.7% of the variance in leptin levels, gender explained 21.2% but OSA severity did not have a significant role and no interaction was found between OSA severity and BMI on leptin levels. However, hypertension had a significant effect on the interaction between OSA severity and obesity (P=0.04). In post-hoc analysis for nonhypertensive OSA subjects (n=249), the association between leptin levels and OSA severity explained a minor but significant variance (3.2%) in leptin levels. This relationship was greatest for nonobese nonhypertensive subjects (significant interaction with obesity level). No relationship of OSA severity and leptin levels was found for hypertensive subjects (n=199). CONCLUSION: Obesity and gender are the dominant determinants of leptin levels. OSA severity is not related to leptin levels except to a minor degree in nonhypertensive nonobese OSA subjects.

Identification of craniofacial risk factors for obstructive sleep apnoea using three-dimensional MRI.

The alteration of craniofacial structures has been associated with obstructive sleep apnoea (OSA). We hypothesised that: 1) a smaller mandible is a risk factor for OSA; and 2) the previously observed inferiorly positioned hyoid bone in apnoeics is associated with enlarged tongue volume. This is a case-control study using three-dimensional magnetic resonance imaging cephalometry. 55 apneics and 55 controls were matched for age, sex and race. The analysis was stratified by sex and controlled for age, race, height, neck visceral fat, skeletal type and tongue volume. We found that a 1-sd increase in mandibular length and depth were associated with decreased risk of sleep apnoea (OR 0.52, 95% CI 0.28-0.99 and OR 0.46, 95% CI 0.23-0.91, respectively) in males but not in females. Greater hyoid-to-nasion (OR 2.64, 95% CI 1.19-5.89 in males and OR 5.01, 95% CI 2.00-12.52 in females) and supramentale-to-hyoid (OR 2.39, 95% CI 1.12-5.14) in males and OR 3.38, 95% CI 1.49-7.68 in females) distances were associated with increased risk of OSA. The difference for hyoid position between apnoeics and controls was lost after controlling for tongue volume. Enlargement of tongue is likely to be the pathogenic factor for inferior-posterior positioning of hyoid. A small and shallow mandible is an independent risk factor for OSA in males but not in females.

Pharmacokinetics and safety of multiple doses of daptomycin 6 mg/kg in noninfected adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis.

AIMS: The purpose of this study was to characterize the pharmacokinetics and tolerability of daptomycin in subjects undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). METHOD: 16 noninfected adults on stable dialysis regimens were enrolled. Daptomycin 6 mg/kg was administered after HD during a 48 h - 48 h - 72 h dialysis week or before a CAPD dwell time over a 48 h - 48 h - 48 h dialysis week. Pharmacokinetic parameters were described, and adverse events were monitored. RESULTS: Daptomycin had mean half-lives in HD subjects of 28.0 and 35.9 h on Days 1 and 5, with corresponding values of 25.8 and 26.7 h in CAPD subjects. Steady state was reached by Day 5 in both groups. At steady state, HD subjects had a mean peak plasma concentration (Cmax) of 81.6 µg/ml and a mean trough concentration of 15.3 µg/ml (on Day 8). In CAPD subjects, Cmax was 93.9 µg/ml and the trough was 20.7 µg/ml (on Day 7). Adverse events were experienced by 71.4% and 66.7% of HD and CAPD subjects, respectively. Most of these were mild or moderate in intensity; however, 2 subjects experienced muscle spasms and mild creatine phosphokinase elevations although neither event was considered to be related to study drug. CONCLUSIONS: The pharmacokinetics of daptomycin 6 mg/kg support a dosing regimen of every 48 h in CAPD and thrice-weekly dosing in HD.

Properties of tissues surrounding the upper airway.

The pathogenesis of obstructive sleep apnea (OSA) remains unknown. However, we are beginning to understand the mechanisms leading to sleep apnea by evaluating the structure and function of the upper airway (UA) and the surrounding soft-tissue structures using sophisticated magnetic-resonance-imaging techniques. Knowledge of the morphology and mechanical behavior of the soft-tissue structures is essential for a complete understanding of the physiology of the UA. Although the tongue and soft palate have been considered the most important UA soft-tissue structures, our data have highlighted the importance of the lateral pharyngeal walls in the mediating UA caliber. We have demonstrated that: (1) during wakefulness, the predominant anatomic abnormality underlying UA narrowing in patients with OSA is thickening of the lateral pharyngeal walls; (2) during respiration, there are significant changes in lateral airway dimensions as well as in the thickness of the lateral walls; and (3) incremental levels of continuous positive airway pressure (CPAP) result in progressive thinning of the lateral pharyngeal walls. The dynamic biomechanical behavior of the lateral pharyngeal walls during wakefulness, sleep, and during apneas needs to be investigated.

Quantitative magnetic resonance imaging demonstrates alterations of the lingual musculature in obstructive sleep apnea.

Upper airway musculature is important in the pathogenesis of obstructive sleep apnea. Electromyographic studies of patients with obstructive sleep apnea demonstrate increased activity of upper airway dilator muscles. Biopsy studies of these muscles show both adaptation and muscle injury. In this study we utilized quantitative magnetic resonance imaging to characterize changes in the upper airway musculature of patients with obstructive sleep apnea. This technique provides measurements of the T2 relaxation times of upper airway muscles (genioglossus, geniohyoid, sternohyoid/sternothyroid) spatially localized to submillimeter resolution. Our results demonstrate that the mean T2 values of genioglossus (p = 0.04) and geniohyoid (p = 0.06) differ between the apneic and control groups, while the values for the sternohyoid/sternothyroid muscles (p = 0.6) are similar between groups. In both apneics and normals respectively the T2 values for the genioglossus (p = 0.0003, 0.0001) and geniohyoid (p = 0.0054, 0.001) were significantly greater than for the sternohyoid/sternothyroid muscles. The changes observed are compatible with the hypothesis that there is increased edema and possibly increased fat content of the tongue muscles in patients with obstructive sleep apnea.

A survey screen for prediction of apnea.

Questionnaire data from patients presenting at three sleep disorders centers were used to develop and assess a screening tool for sleep apnea based on the reporting of the frequency of various symptoms of sleep apnea and other sleep disorders plus age, body mass index (BMI) and gender. Patients were not specifically referred for suspicion of sleep apnea. Separate factor analyses of survey responses from 658, 193 and 77 respondents from the first, second and third sites, respectively, each yielded four orthogonal factors, one of which accounted for all the questions concerned with the frequency of disordered breathing during sleep. The survey was shown to be reliable in a subset of patients from one of the sites (test-retest correlation = 0.92). Survey data were then compared to a clinical measure of sleep apnea (respiratory disturbance index) obtained from polysomnography. A multivariable apnea risk index including survey responses, age, gender and BMI was estimated using multiple logistic regression in a total sample of 427 respondents from two of the sites. Predictive ability was assessed using receiver operating characteristic (ROC) curves. The area under the ROC curve was 0.79 (p < 0.0001). For BMI alone, it was 0.73, and for an index measuring the self-report of the frequency of apnea symptoms, it was 0.70. The multivariable apnea risk index has potential utility in clinical settings.

Ventilator autocycling due to an endotracheal tube cuff leak.

Ventilator autocycling can occur with any ventilator if the sensitivity is improperly set or if a gas leak exists in the respiratory system which creates a negative change in proximal airway pressure. We report a case of ventilator autocycling in a paralyzed patient secondary to an endotracheal cuff leak which was misconstrued as assisted ventilation. We believe this is the first report of autocycling due to a cuff leak.

Tension pneumothorax secondary to a gastropleural fistula in a traumatic diaphragmatic hernia.

We report a case of tension pneumothorax due to a gastropleural fistula resulting from perforation of the stomach in a traumatic diaphragmatic hernia. Awareness of perforation of strangulated stomach or bowel in a diaphragmatic hernia as a cause of pneumothorax, with or without tension physiology, in a patient with a history of trauma is important so that surgical repair can be undertaken without delay.

Dynamic imaging of the upper airway during respiration in normal subjects.

The present study was conducted to determine the effects of quiet respiration on upper airway caliber in 15 normal subjects by using cine computed tomography. The cine computed tomography (Imatron) scanner was programmed to obtain 8-mm-thick axial slices every 0.4 s during inspiration and expiration at four anatomic levels, from the nasopharynx to the retroglossal region. Airflow (pneumotachograph) was measured, and tidal volume was obtained by integration. Upper airway area, determined by an objective edge detection algorithm, was plotted as a function of tidal volume to generate a loop describing upper airway area changes at each level during a respiratory cycle. The results demonstrate a 17% change in airway size across all anatomic levels during respiration. The maximum upper airway cross-sectional area at all four anatomic levels was significantly greater during expiration than during inspiration. Other major findings include 1) upper airway cross-sectional area decreases slightly during early inspiration, enlarges toward end inspiration, and is larger at end inspiration than at the beginning of inspiration; 2) upper airway cross-sectional area enlarges from end inspiration to the first point in expiration; the airway enlarges further, reaching its maximum early in expiration, and then narrows toward end expiration; and 3) the changes in upper airway dimensions during resting tidal breathing are greater in the lateral than in the anteroposterior direction. The data suggest that during inspiration, the action of negative intraluminal pressure may be largely balanced by the action of the upper airway dilator muscles, whereas during expiration, positive intraluminal pressure produces expansion of the upper airway.

Upper airway imaging.

Upper airway imaging is a powerful technique to study the mechanisms underlying the pathogenesis, biomechanics, and efficacy of treatment options in patients with obstructive sleep apnea. Imaging studies have provided significant insight into the static and dynamic structure, and function of the upper airway and surrounding soft-tissue structure during wakefulness and sleep. Upper airway imaging modalities primarily include nasopharyngoscopy, cephalometrics, computed tomography (CT), and magnetic resonance (MR) scanning. These imaging modalities have been used to study the effect of respiration, weight loss, dental appliances, and upper airway surgery on the upper airway. MR imaging and CT have allowed quantification of the airway and surrounding soft-tissue structures in three dimensions. Clinical indications for upper airway imaging are evolving for patients being treated with dental appliances and upper airway surgery.

Quantitative evaluation of the upper airway during nasopharyngoscopy with the Müller maneuver.

OBJECTIVE: To quantitatively examine changes in the upper airway caliber of normal subjects at graded negative inspiratory pressures generated during nasopharyngoscopy with a Müller maneuver. STUDY DESIGN: Eighteen normal subjects prospectively underwent nasopharyngoscopy with Müller maneuvers. Subjects performed graded and maximal effort Müller maneuvers while sitting upright, and maximal-effort Müller maneuvers in the supine position. Two regions of the upper airway--the retropalatal and retroglossal--were examined. METHODS: Images from the endoscopic examination were objectively analyzed by adjusting manually traced airway contours using full-width, half-maximum edge detection algorithm software. The adjusted tracings' area and dimensions through the airway centroid were measured. RESULTS: Müller maneuvers performed at -40 cm H2O resulted in a 64%+/-17% (P = .0001) reduction in upper airway area that consisted of a 51%+/-20% (P = .0001) reduction in the lateral dimension and a 21%+/-24% (P = .0026) reduction in antero-posterior dimension. Müller maneuvers in the retroglossal region did not significantly reduce airway area (P = .575), but demonstrated an altered airway conformation that consisted of lateral narrowing and an increase in antero-posterior dimension. Changes in body position did not result in significant differences in either airway caliber or airway dimension. CONCLUSIONS: Airway caliber during forced inspiration is mediated primarily through changes in the lateral pharyngeal walls. This study has also shown that antero-posterior and lateral airway structures are largely independent in their response to Müller maneuvers. Similarly, the retropalatal and retroglossal regions of the upper airway respond differently to forced negative intraluminal pressure.

Disturbances of sleep in the intensive care unit.

Sleep can be extremely difficult to achieve in ICUs. Sleep deprivation is a major problem in the ICU and physicians should be aware of the effects of sleep deprivation on physiologic and immune function. Sleep deprivation has been associated with the ICU syndrome. Multiple factors interfere with sleep in the ICU; the single most significant cause of sleep disruption in the ICU is noise. Effective means of controlling noise and sensory overload in ICU patients must be developed. Nonpharmacologic options to enhance sleep should be considered in all ICUs. Sleep should never be considered a luxury in the ICU; it is an essential physiologic need.

Identifying the patient with sleep apnea: upper airway assessment and physical examination.

Since the final common pathway for obstructive sleep apnea is obstruction of the upper airway during nocturnal respiration, examination and assessment of the anatomy of the upper airway plays a central role in patient evaluation. Since the upper airway begins at the nose and lips and ends at the larynx, a complete assessment of the upper airway evaluates this entire length of this anatomic region including the bony framework and soft tissue. Though office assessment of these structures does not necessarily mimic the appearance of behavior of these structures during physiologic sleep, the office examination can give important information as to the site of obstruction during sleep that can help direct therapy.

Upper airway assessment: radiographic and other imaging techniques.

Upper airway imaging is a powerful technique to study the mechanisms underlying the pathogenesis and biomechanics of sleep apnea and the mechanisms underlying the efficacy of therapeutic interventions in patients with sleep disordered breathing. The primary upper airway imaging modalities include nasopharyngoscopy, cephalometrics, CT scanning, and MR imaging. Imaging studies using these modalities have provided important insights into the static and dynamic structure and function of the upper airway and surrounding soft-tissue structures during wakefulness and sleep. Such imaging studies have highlighted the importance of the lateral pharyngeal walls in mediating upper airway caliber. These imaging modalities have also been used to study the effect of respiration, weight loss, mandibular repositioning devices, and upper airway surgery on the upper airway. Three-dimensional reconstruction of the airway and surrounding soft-tissue structures can be performed with MR imaging and CT scanning. Clinical indications for upper airway imaging are evolving such that imaging studies should be considered in patients with sleep apnea who are being treated with dental appliances or upper airway surgery.

Imaging for the snoring and sleep apnea patient.

Upper airway imaging techniques have significantly advanced the understanding of the pathogenesis of obstructive sleep apnea and the biomechanical mechanisms by which therapeutic interventions for this disorder exert their effects. Both static and dynamic imaging studies have been used to examine the structure and function of the upper airway during wakefulness and sleep. These studies have highlighted the importance of the lateral pharyngeal walls in addition to the tongue and soft palate in modulating changes in upper airway caliber. Upper airway imaging has also been used to understand the changes in upper airway anatomy associated with weight loss, mandibular repositioning devices, and upper airway surgery. At present, upper airway imaging should be considered in patients undergoing upper airway surgery and possibly in patients being evaluated for oral appliances. MR imaging and nasopharyngoscopy are the imaging modalities of choice in patients undergoing a UPPP. Cephalometrics should be considered in patients being treated with mandibular repositioning devices. Upper airway imaging has provided an important framework to examine the pathogenesis of airway closure, and these investigations may, in time, lead to more effective treatment options for patients with sleep apnea.

Patient perception of sleep quality and etiology of sleep disruption in the intensive care unit.

The etiology of sleep disruption in patients in intensive care units (ICUs) is poorly understood, but is thought to be related to environmental stimuli, especially noise. We sampled 203 patients (121 males and 82 females) from different ICUs (cardiac [CCU], cardiac stepdown [CICU], medical [MICU], and surgical [SICU]) by questionnaire on the day of their discharge from the unit, to determine the perceived effect of environmental stimuli on sleep disturbances in the ICU. Perceived ICU sleep quality was significantly poorer than baseline sleep at home (p = 0.0001). Perceived sleep quality and daytime sleepiness did not change over the course of the patients' stays in the ICU, nor were there any significant differences (p > 0.05) in these parameters among respective units. Disruption from human interventions and diagnostic testing were perceived to be as disruptive to sleep as was environmental noise. In general, patients in the MICU appeared to be more susceptible to sleep disruptions from environmental factors than patients in the other ICUs. Our data show that: (1) poor sleep quality and daytime sleepiness are problems common to all types of ICUs, and affect a broad spectrum of patients; and (2) the environmental etiologies of sleep disruption in the ICU are multifactorial.

Physical findings and the risk for obstructive sleep apnea. The importance of oropharyngeal structures.

In this study, we hypothesized that anatomic abnormalities of the oropharynx, particularly narrowing of the airway by the lateral pharyngeal walls, tonsils, and tongue, would be associated with an increased likelihood for obstructive apnea among patients presenting to a sleep disorders center. To test this hypothesis, we used data from a cohort of 420 patients presenting to the Penn Center for Sleep Disorders. Associations between individual variables in the clinical evaluation model and sleep apnea as defined by a respiratory disturbance index greater than or equal to 15 events per hour were characterized by odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable logistic regression was used to simultaneously estimate ORs for multiple variables and to control for other relevant patient characteristics. Results showed that narrowing of the airway by the lateral pharyngeal walls (OR = 2.5; 95% CI, 1.6-3.9) had the highest association with obstructive sleep apnea (OSA) followed by tonsillar enlargement (OR = 2.0; 95% CI, 1.0-3.8), enlargement of the uvula (OR = 1.9; 95% CI, 1.2-2.9), and tongue enlargement (OR = 1.8; 95% CI, 1.0-3.1). Low-lying palate, retrognathia, and overjet were not found to be significantly associated with OSA. Controlling for BMI and neck circumference, only lateral narrowing and enlargement of the tonsils maintained their significant (OR = 2.0 and 2.6, respectively). A subgroup analysis examining differences between male and female subjects showed that no oropharyngeal risk factor achieved significance in women while lateral narrowing was the sole independent risk factor in men. These findings suggest that enlargement of the oropharyngeal soft tissue structures, particularly the lateral pharyngeal walls, is associated with an increased likelihood of OSA among patients presenting to sleep disorders centers.