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.

Markers of inflammation: data from the MOSAIC randomised trial of CPAP for minimally symptomatic OSA.

UNLABELLED: The Multi-centre Obstructive Sleep Apnoea Interventional Cardiovascular (MOSAIC) trial compared 6 months of CPAP therapy, versus no CPAP, in 391 patients with minimally symptomatic obstructive sleep apnoea (OSA). We now report some exploratory outcomes, markers of systemic inflammation (interleukin 6 (IL-6), IL-10, C reactive protein, tumour necrosis factor). We found no consistent changes (all p values >0.13). TRIAL REGISTRATION NUMBER: ISRCTN 34164388.

The prevalence of retinopathy in men with Type 2 diabetes and obstructive sleep apnoea.

AIMS: To clarify the relationship between obstructive sleep apnoea (OSA) and diabetic retinopathy. RESEARCH DESIGN AND METHODS: A cohort of 240 men from primary and secondary care previously participated in a study on the prevalence of OSA in Type 2 diabetes and provided anthropometric information, details of their diabetes, had glycated haemoglobin (HbA1c) measured and overnight oximetry performed. They were re-contacted for permission to review their routine screening clinical retinal photographs, which were then scored by a trained grader, providing detailed retinopathy, maculopathy and photocoagulation scores. RESULTS: One hundred and eighteen men both consented and had retinal photographs available to review. Of these, 24% had OSA, with mean+/-sd 4% oxygen saturation (SaO2) dips/h of 20.9+/-16.6 vs. 2.8+/-2.1 in the non-OSA group. As expected, the OSA group had a significantly higher mean body mass index of 31.9+/-5.2 vs. 28.5+/-5.1 kg/m2 and neck size 44.5+/-3.6 vs. 41.9+/-2.5 cm, but the two groups did not differ significantly in age, diabetes duration, diabetes treatment, HbA1c, smoking history or proportion with known hypertension. Retinopathy and maculopathy scores were significantly worse in the OSA group (P<0.0001). Multiple regression analysis showed only OSA (R2=0.19, P<0.0001) and HbA1c (R2=0.04, P=0.03) to be significant independent predictors of retinopathy. OSA was the only independent significant predictor of the total microaneurysm score (R2=0.21, P=0.004), a detailed retinopathy subclassification. OSA was the only independent significant predictor of maculopathy (R2=0.3, P<0.001). CONCLUSION: In men with Type 2 diabetes, there is a strong association between retinopathy and OSA, independent of conventional retinopathy risk factors.

The prevalence of obstructive sleep apnoea and its association with aortic dilatation in Marfan's syndrome.

BACKGROUND: Craniofacial abnormalities and increased pharyngeal collapsibility due to abnormal connective tissue suggest the possibility of an increased prevalence of obstructive sleep apnoea (OSA) in patients with Marfan's syndrome but the actual prevalence is uncertain. Aortic dilatation and dissection are life threatening manifestations of Marfan's syndrome and case reports have suggested a possible association with OSA but data from cohort studies are not available. METHODS: A sleep study was performed in 61 patients with Ghent criteria positive Marfan's syndrome (mean age 38.3 (SD 12.9) years; 37 females) and in 26 control subjects matched for age, gender, height and weight. OSA was defined using two conventional levels of apnoea-hypopnoea index (AHI), >5 and >15/h. In patients with Marfan's syndrome, aortic root diameter was measured by echocardiography. RESULTS: More patients with Marfan's syndrome than controls had OSA (AHI >5, 32.8% compared with 11.5%, mean difference +21.3%, 95% CI 4.2% to 38.3%, p = 0.04; AHI >15, 18.0% compared with 0%, mean difference +18.0%, 95% CI 8.4% to 27.7%, p = 0.02). AHI was correlated with aortic root diameter (r = 0.50, 95% CI 0.26 to 0.69, p = 0.0003), and mean aortic root diameter was significantly greater in patients with OSA (4.5 (SD 0.6) cm) compared with those without OSA (3.7 (0.6) cm) (mean difference 0.8 cm, 95% CI 0.4 to 1.2 cm, p<0.0001). CONCLUSIONS: In patients with Marfan's syndrome, the prevalence of OSA is considerably higher than in matched control subjects. OSA may be a risk factor for aortic root dilatation in Marfan's syndrome.

Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. METHODS: 100 men with moderate-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon gamma (IFNgamma) and anti-inflammatory adiponectin. RESULTS: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes -0.24 mg/l (95% CI -0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNgamma did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and -0.07 pg/ml (95% CI -0.72 to +1.94 and -0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI -0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNgamma and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. CONCLUSIONS: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate-severe obstructive sleep apnoea.

Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea.

Moderate-severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk. In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry. In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566-3,964) microL(-1) versus 1,206 (474-2,501) microL(-1), respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102-3,592) microL(-1) and 20 (14-31) microL(-1), respectively) compared with control subjects (925 (328-2,068) microL(-1) and 15 (5-23) microL(-1), respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8-25) microL(-1) versus 11 (6-17) microL(-1)). In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.

Cost-effectiveness of using continuous positive airway pressure in the treatment of severe obstructive sleep apnoea/hypopnoea syndrome in the UK.

OBJECTIVE: A study was undertaken to estimate the cost-effectiveness of using continuous positive airway pressure (CPAP) in the management of patients with severe obstructive sleep apnoea/hypopnoea syndrome (OSAHS) compared with no treatment from the perspective of the UK's National Health Service (NHS). METHODS: A Markov model was constructed to assess the cost-effectiveness of CPAP compared with no treatment. The model depicted the management of a 55-year-old patient with severe OSAHS as defined by an apnoea-hypopnoea index (AHI) >30 and daytime sleepiness (Epworth Sleepiness Scale score >or=12). The model spans a period of 14 years. RESULTS: According to the model, 57% of untreated patients are expected to be alive at the end of 14 years compared with 72% of patients treated with CPAP. Untreated patients are expected to cost the NHS pound10 645 (95% CI pound7988 to pound14,098) per patient over 14 years compared with pound9672 (95% CI pound8057 to pound12,860) per CPAP-treated patient. Treatment with CPAP for a period of 1 year was found not to be a cost-effective option since the cost per quality-adjusted life year (QALY) gained is expected to be > pound20,000, but after 2 years of treatment the cost per QALY gained is expected to be pound10,000 or less and, after 13 years of treatment, CPAP becomes a dominant treatment (ie, more effective than no treatment for less cost). CONCLUSION: Within the limitations of the model, CPAP was found to be clinically more effective than no treatment and, from the perspective of the UK's NHS, a cost-effective strategy after a minimum of 2 years of treatment.

Predictors of blood pressure fall with continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea (OSA).

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Randomised controlled trials have shown that, on average, treatment of OSA with continuous positive airway pressure (CPAP) reduces blood pressure (BP) by 3-5 mm Hg, although with considerable variation between individuals. No predictors of the change in BP with CPAP have been convincingly identified. This prospective study aimed to determine predictors of BP change, which might provide an insight into the aetiology of the raised BP seen in untreated OSA. METHODS: Eighty-six patients with daytime hypersomnolence warranting treatment with CPAP were recruited. 24 h mean BP (24 hMBP), subjective sleepiness, fasting venous blood samples and anthropometric measurements were assessed at baseline and after 6 months of CPAP treatment. RESULTS: The mean (SD) 24 hMBP fell at 6 months from 101.0 (10.3) mm Hg to 96.1 (9.1) mm Hg (change -4.92 mm Hg (95% CI -2.8 to -7.1)). The Epworth Sleepiness Score (ESS) fell from a median of 16 (IQR 12-18) to 4 (2-7) with a mean fall of 9.7 (95% CI 8.6 to 10.8). Several factors correlated with the fall in 24 hMBP but, after allowing for the baseline 24 hMBP, only the fall in ESS and the body mass index (BMI) remained significant independent predictors (p = 0.006 and 0.007, respectively). There was also a correlation between the fall in 24 hMBP and the fall in pulse rate (r = 0.44, p<0.001). Baseline severity of OSA, overnight hypoxia, caffeine intake or being on antihypertensive drugs were not independent predictors of a fall in 24 hMBP. CONCLUSION: Improvement in hypersomnolence and the BMI are independent correlates of the fall in 24 hMBP following CPAP therapy. Markers of initial OSA severity did not predict the fall in 24 hMBP. This suggests that sleep fragmentation and its effects may be more important than hypoxia in the pathogenesis of the hypertension associated with human sleep apnoea.

CPAP and measures of cardiovascular risk in males with OSAS.

Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.

Is it necessary to record sleep?

The severe limitations of conventional sleep staging during sleep apnea are now understood. Microarousals are likely to be the dominant cause of symptoms in sleep apnea, but it has been extremely difficult to quantify them in a way that will predict daytime sleepiness or poor vigilance any better than respiratory indices. It is clear that not all apneas are equal on sleep, differences in the degree of arousal required to end an apnea and open the pharynx may help to explain why some individuals with apnea-plus-hypopnea indices (AHIs) of 15 may be symptomless, whereas others are severely disabled. Use of newer techniques to measure arousals, both cortical and autonomic, may produce a better understanding of how to measure sleep.

Is more NCPAP better?

STUDY OBJECTIVES: To assess the benefit of NCPAP in OSA and its relation to the degree of use of NCPAP. DESIGN: Randomised parallel controlled one month study comparing NCPAP set at therapeutic levels of pressure, with NCPAP set at sub-therapeutic pressure levels. SETTING: Teaching hospital sleep clinic and laboratory SUBJECTS: 101 men referred for investigation of possible OSA who were sleepy (Epworth Sleepiness Score > or = 10) and had > or = 10/hr of >4% dips in SaO2 due to OSA. OUTCOME MEASURES: Baseline and one month measures of Epworth Sleepiness Score (ESS), Maintenance of Wakefulness Test (MWT), and the Energy/Vitality dimension of the SF-36 (health status questionnaire). Correlation of these outcome measures with NCPAP usage. RESULTS: All outcome measures improved significantly more in the therapeutic, compared to the sub-therapeutic, group (e.g. ESS 15.0 to 13.0 on sub-therapeutic, and 15.5 to 7.0 on therapeutic, p<1x10(-6)). The degree of improvement correlated significantly with NCPAP usage in the therapeutic group (ESS, r=-0.60; MWT, r=0.55) but insignificantly in the sub-therapeutic group (ESS, r=-0.15; MWT, r=-0.06). Sub-therapeutic NCPAP did not improve OSA severity and acted as a control. CONCLUSIONS: NCPAP is clearly effective in relieving the sleepiness of OSA compared to a control group identical in every way, except for receiving a nasal pressure inadequate to control the OSA.

New approaches to monitoring sleep-related breathing disorders.

Conventional approaches to the analysis of sleep and sleep apnea do not describe all of the critical events that result from upper airway narrowing during sleep. The hypersomnolence that drives treatment is mainly due to microarousals, but these are poorly documented with conventional epoch-based sleep staging. The counting of apneas and hypopneas also fails to document other equally important events, such as the arousals due to increased respiratory effort in response to partial upper airway narrowing that may not cause significant hypopnea, hypoxemia, or even snoring. Modifications of conventional polysomnography, such as microarousal detection and analysis of the ribcage/abdominal paradox, may be an improvement. However, no system has been shown to be better than any other at identifying the critical events that produce symptoms of sleep-related breathing disorders, and thus be likely to respond to effective treatment. The time is right to explore innovative ways to characterize sleep-related breathing disorders, such as those derived from the cardiovascular change related to upper airway obstruction and arousal, without the shackles of conventional polysomnography. New monitoring techniques need to identify patients with events that will respond to treatment, not mimic the flawed gold standard of polysomnography.

Periodic movements of the legs during sleep associated with rises in systemic blood pressure.

We report the relationship between periodic leg movements during sleep and recurrent rises in systemic blood pressure in a patient with narcolepsy. The mean increase in systolic blood pressure following leg movements was 23%, which is of the same order as the rises seen in patients with obstructive sleep apnea. Following treatment with temazepam, the swings in blood pressure were unchanged despite considerably less electroencephalographic evidence of cortical arousal.

Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects.

STUDY OBJECTIVES: To assess whether MRI detectable evidence of silent cerebrovascular disease is more prevalent in patients with obstructive sleep apnea (OSA) when compared to carefully matched control subjects. DESIGN AND SETTING: Case-control study of patients with OSA attending a specialist sleep clinic and matched control subjects drawn from the normal community. PARTICIPANTS: Forty-five sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness, matched to 45 control subjects without excessive sleepiness or evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension, and ischaemic heart disease. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent 24-hour ambulatory blood pressure recordings (before treatment in OSA patients) and sagittal T1, axial T2, and coronal dual echo cerebral MRI imaging to detect clinically silent abnormalities related to hypertensive cerebrovascular disease; areas of high signal foci in deep white matter (DWM), lacunae, and periventricular hyperintensity. Lacunae/high signal foci in DWM and/or periventricular hyperintensity were present in 15 (33%) OSA subjects and 16 (35%) controls, despite significant increases in mean daytime diastolic blood pressure (4.6mmHg, p<0.05), and both nighttime diastolic (7.2mmHg, p<0.001) and systolic blood pressures (9.2mmHg, p<0.05) in OSA subjects. These data exclude more than a 17% excess prevalence of MRI detected minor cerebrovascular disease in the OSA patients, with 95% confidence. CONCLUSIONS: Sub-clinical cerebrovascular disease is prevalent in both clinic patients with OSA and their matched control subjects. Despite the increased arterial blood pressures, there is, however, no apparent excess of MRI-evident subclinical cerebrovascular disease in patients with OSA compared to appropriately matched control subjects.

What is an arousal and how should it be quantified?

Pathologically severe daytime sleepiness is one of the main symptoms seen in a respiratory sleep clinic and is due to repeated arousal from sleep. Which types of arousal are most important in causing this is uncertain and most studies have only found loose relationships between indices of arousal frequency and the severity of the ensuing daytime sleepiness. Recent attempts to improve these disappointing correlations have concentrated on detecting more minor arousal events through the use of novel EEG signal analysis techniques and non-EEG based signals such as blood pressure and heart rate. To date there are no good data sets which allow the relative merits of these various techniques to be compared and it is unclear whether these efforts to increase the sensitivity of arousal detection will lead to improvements in the clinical usefulness of sleep fragmentation scoring. Studies which relate both the traditional indices of sleep fragmentation and the newer methodologies to clinically relevant reference standards (such as measured excessive daytime sleepiness) are needed to clarify these issues.

An artifact induced by negative pressure ventilation.

This report draws attention to an artifact that influences the qualitative information gained from respiratory inductance plethysmography during negative pressure ventilation with a cuirass. This artifact may prevent identification of upper airway obstruction, a manageable complication of this mode of ventilation.

Ear involvement in the yellow nail syndrome.

Recognized features of the yellow nail syndrome include yellow nails, lymphedema, and pleural effusions. We report a patient with the additional feature of keratosis obturans, which may be a manifestation of this syndrome in the external ear.

Should ipratropium bromide be added to beta-agonists in treatment of acute severe asthma?

In a double-blind randomized trial, 40 patients with acute severe asthma were given either nebulized salbutamol, 5 mg, or salbutamol, 5 mg mixed with ipratropium bromide 500 micrograms, on admission to hospital and again two hours later. There was no significant difference between the mean peak flows of the two treatment groups at any time. However, two hours after each treatment, there were fewer subjects in the ipratropium and salbutamol group whose peak flow rates had fallen back toward baseline levels than in the salbutamol only treatment group. Thus, although ipratropium did not improve the overall maximal bronchodilator response, it may have prolonged the duration of the response, which would be a clinically useful effect.

The acute effects of continuous positive airway pressure and oxygen administration on blood pressure during obstructive sleep apnea.

We have measured blood pressure continuously with a digital artery blood pressure monitor in eight patients with severe obstructive sleep apnea (OSA) during 30 min each of wakefulness, OSA, OSA with added oxygen to keep saturation above 96 percent at all times (OSA+O2), and nasal continuous positive airway pressure (CPAP) therapy. Mean blood pressures were not different between wakefulness, OSA, OSA+O2, and CPAP, although the variability in blood pressure was significantly greater during OSA and OSA+O2 than during wakefulness and CPAP. The addition of oxygen did not attenuate the variability in blood pressure. Using multiple linear regression modeling to further dissect out the principal variables determining the postapneic blood pressure rise, we found that only apnea length (r2 = 0.28, p less than 0.0001) and pulse rate changes (r2 = 0.15, p less than 0.0001) remained significantly related to SBPmax, while hypoxemia did not. We found the same trends in the other variables SBPten, DBPmax, and DBPten. Hypoxemia made a small contribution to the size of DBPmax, although this was small by comparison with apnea length. We conclude that CPAP treatment of OSA does not lower mean blood pressure acutely, although it significantly reduces the large oscillations in blood pressure seen in patients with untreated OSA. The rise in blood pressure following each apnea is not primarily due to arterial desaturation but is related to apnea length and may be caused by increased sympathetic activity secondary to arousal.