Utility of respiratory ward-based NIV in acidotic hypercapnic respiratory failure.

BACKGROUND AND OBJECTIVE: We sought to elicit predictors of in-hospital mortality for first and subsequent admissions with acidotic hypercapnic respiratory failure (AHRF) in a cohort of chronic obstructive pulmonary disease patients who have undergone ward-based non-invasive ventilation (NIV), and identify features associated with long-term survival. METHODS: Analysis of prospectively collected data at a single centre on patients undergoing NIV for AHRF between 2004 and 2009. Predictors of in-hospital mortality and intubation were sought by logistic regression and predictors of long-term survival by Cox regression. RESULTS: Initial pH exhibited a threshold effect for in-hospital mortality at pH 7.15. This relationship remained in patients undergoing their first episode of AHRF. In both first and subsequent admissions, a pH threshold of 7.25 at 4 h was associated with better prognosis (P = 0.02 and P = 0.04 respectively). In second or subsequent episodes of AHRF, mortality was lower and predicted only by age (P = 0.002) on multivariate analysis. CONCLUSIONS: NIV could be used on medical wards for patients with pH 7.16 or greater on their first admission, although more conservative values should continue to be used for those with a second or subsequent episodes of AHRF.

The impact of hypoxemia on nephropathy in extremely obese patients with type 2 diabetes mellitus.

STUDY OBJECTIVES: Diabetes mellitus (DM) is associated with obstructive sleep apnea (OSA) and nephropathy. The hypoxemia associated with OSA may exacerbate renal deterioration in DM nephropathy. We examined the role of hypoxemia in the development of DM nephropathy in severely obese patients. METHODS: This cross-sectional study examined anonymized data from 90 DM patients with extreme obesity attending a weight management service. All patients underwent a routine overnight sleep study. Respiratory parameters measured included apnea-hypopnea index (AHI), mean and minimum oxygen (O2) saturations, and time spent under 90% O2 saturation (%TST < 90%). Chronic kidney disease (CKD+) was defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m(2). RESULTS: Twenty (22%) patients were CKD+. These patients were 7 years older (mean age ± SD 57 ± 11 years, p = 0.003) and had greater adiposity (mean body mass index [BMI] ± SD 50.6 ± 8.7 kg/m(2), p = 0.012). No significant differences were found for median AHI and minimum O2 saturation. %TST < 90% was 4 times greater in CKD+ group (p = 0.046). Multivariate regression analysis showed that AHI (ß = -0.17, 95% CI: -0.316 to -0.024) and %TST < 90% (ß = -0.215, 95% CI: -0.406 to -0.023) were negatively correlated with eGFR after adjustment for age, gender, BMI, comorbidities, insulin treatment, and drugs affecting the renin-angiotensin system. No associations were found between mean and minimum O2 saturations, and eGFR. CONCLUSION: Apnea and hypopnea events as well as duration of nocturnal hypoxemia were inversely associated with renal function after adjusting for potential confounders. Given the significant burden of renal disease in diabetes, greater vigilance is required in identifying OSA in DM patients with extreme obesity.

Hypoxemia and glycemic control in type 2 diabetes mellitus with extreme obesity.

CONTEXT: Obstructive sleep apnea (OSA) has been shown to be associated with type 2 diabetes mellitus (DM). Studies on healthy individuals found that OSA is associated with lower insulin sensitivity. We hypothesized that nocturnal hypoxemia from OSA is associated with poorer glycemia in severely obese DM individuals. DESIGN AND SETTING: This was a retrospective observational study of 122 non-DM, 126 non-insulin-treated DM, and 35 insulin-treated DM patients. Data were collected on demographic characteristics, body mass index, and comorbidities. An overnight sleep study was performed in all patients, and OSA was defined as an apnea-hypopnea index of ≥5 events/h. RESULTS: There were more males (P = .003) and a lower proportion of white Europeans (P = .010) among DM patients. The prevalence of OSA was 80.1% in DM and 63.1% in non-DM individuals (P = .001). DM individuals also had lower oxygen saturation (O2) (P = .0106), greater percentage of time spent under 90% oxygen saturation (%TST<90%) (P = .0067), and higher apnea-hypopnea index (P = .0085). Regression analysis showed that %TST<90% and minimum O2 saturations were associated with worse hemoglobin A1c results among DM individuals. Every 10% reduction in minimum O2 was associated with a 0.3% increase in HbA1c, whereas a 10% increase in %TST<90% was associated with a 0.2% increase in hemoglobin A1c after adjusting for a range of potential confounders. CONCLUSION: The high OSA prevalence in DM individuals and a positive relationship between nocturnal hypoxemia and glycemia supports the need to assess correction of hypoxemia as a management strategy for glycemic control.

Novel insights into metabolic sequelae of obstructive sleep apnoea: a link between hypoxic stress and chronic diabetes complications.

An increasing body of evidence suggests that obstructive sleep apnoea (OSA) is independently associated with an increased risk of cardiovascular disease, glucose intolerance, and deteriorations in glycaemic control. Despite the knowledge of a multifactorial pathogenesis of long-term diabetes complications, there is a paucity of information on impact of comorbidities associated with chronic intermittent hypoxemia on development and progression of chronic diabetes complications. This review explores the clinical and scientific overlap of OSA and type 2 diabetes mellitus (T2DM) and its possible impact on the development and progression of diabetes macrovascular and microvascular complications. Multiple prospective observational cohort studies have demonstrated that OSA significantly increases the risk of cardiovascular disease independent of potential confounding risk factors. The current evidence further suggests that OSA with concurrent T2DM is associated with an increased risk of oxidative stress-induced damage of vulnerable endothelial and mesangial cells and peripheral nerves. Further studies are needed to validate the impact of OSA treatment on diabetes micro- and macrovascular complications. Since it is presently still unknown whether OSA treatment may provide a diabetes-modifying intervention that could delay or halt the progression of chronic diabetes complications, the emphasis is on early diagnosis and satisfactory treatment of both OSA and T2DM.

The potential association between obstructive sleep apnea and diabetic retinopathy in severe obesity-the role of hypoxemia.

BACKGROUND: Obstructive sleep apnea (OSA) is common in obese patients with type 2 diabetes mellitus (DM) and may contribute to diabetic microvascular complications. METHODS: To investigate the association between OSA, hypoxemia during sleep, and diabetic retinal complications in severe obesity. This was a prospective observational study of 93 obese patients mean (SD) age: 52(10) years; mean (SD) body mass index (BMI): 47.3(8.3) kg/m(2)) with DM undergoing retinal screening and respiratory monitoring during sleep. OSA was defined as apnea-hypopnea index (AHI) of ≥15 events/hour, resulting in two groups (OSA+ vs. OSA-). RESULTS: Forty-six patients were OSA+: median (95% CI) AHI = 37(23-74)/hour and 47 were OSA-ve (AHI = 7(4-11)/hour). Both groups were similar for ethnicity, BMI, cardiovascular co-morbidities, diabetes duration, HbA1c, and insulin treatment (p>0.05). The OSA+ group was significantly more hypoxemic. There was no significant difference between OSA+ and OSA- groups for the presence of retinopathy (39% vs. 38%). More OSA+ subjects had maculopathy (22% vs. 13%), but this did not reach statistical significance. Logistic regression analyses showed that AHI was not significantly associated with the presence of retinopathy or maculopathy (p>0.05). Whilst minimum oxygen saturation was not significantly associated with retinopathy, it was an independent predictor for the presence of maculopathy OR = 0.79 (95% CI: 0.65-0.95; p<0.05), after adjustment. CONCLUSIONS: The presence of OSA, as determined by AHI, was not associated with diabetic retinal complications. In contrast, severity of hypoxemia during sleep (minimum oxygen saturations) may be an important factor. The importance of hypoxia in the development of retinal complications in patients with OSA remains unclear and further studies assessing the pathogenesis of hypoxemia in patients with OSA and diabetic retinal disease are warranted.

Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder associated with several adverse health outcomes. Given the close association between OSA and obesity, lifestyle and dietary interventions are commonly recommended to patients, but the evidence for their impact on OSA has not been systematically examined. OBJECTIVES: To conduct a systematic review and meta-analysis to assess the impact of weight loss through diet and physical activity on measures of OSA: apnea-hypopnea index (AHI) and oxygen desaturation index of 4% (ODI4). METHODS: A systematic search was performed to identify publications using Medline (1948-2011 week 40), EMBASE (from 1988-2011 week 40), and CINAHL (from 1982-2011 week 40). The inverse variance method was used to weight studies and the random effects model was used to analyze data. RESULTS: Seven randomized controlled trials (519 participants) showed that weight reduction programs were associated with a decrease in AHI (-6.04 events/h [95% confidence interval -11.18, -0.90]) with substantial heterogeneity between studies (I(2) = 86%). Nine uncontrolled before-after studies (250 participants) showed a significant decrease in AHI (-12.26 events/h [95% confidence interval -18.51, -6.02]). Four uncontrolled before-after studies (97 participants) with ODI4 as outcome also showed a significant decrease in ODI4 (-18.91 episodes/h [95% confidence interval -23.40, -14.43]). CONCLUSIONS: Published evidence suggests that weight loss through lifestyle and dietary interventions results in improvements in obstructive sleep apnea parameters, but is insufficient to normalize them. The changes in obstructive sleep apnea parameters could, however, be clinically relevant in some patients by reducing obstructive sleep apnea severity. These promising preliminary results need confirmation through larger randomized studies including more intensive weight loss approaches.

The prevalence and severity of obstructive sleep apnea in severe obesity: the impact of ethnicity.

STUDY OBJECTIVES: The South Asian population is at increased risk of cardiovascular disease. We compared the prevalence and severity of obstructive sleep apnea (OSA) in South Asians and white Europeans with severe obesity. METHODS: Data from consecutive patients attending a specialist weight management service were analyzed. Self-reported age, gender, and ethnicity were recorded. Objective measurements of blood pressure, body mass index (BMI), and apneahypopnea index (AHI) were also acquired. RESULTS: A total of 308 patients (72.7% women; 13% South Asian) were included, with mean age and BMI of 46 ± 12 y and 49 ± 8 kg/m2, respectively. South Asians had significantly increased prevalence of OSA compared to white Europeans (85% vs. 66% [p = 0.017]) and were more likely to have severe OSA (42.5% vs. 21.6% [p = 0.015]). South Asians had significantly higher median AHI (24 events/h: interquartile range [IQR] 9.3-57.6 vs. 9 events/h: IQR 3.4-26.6; p < 0.01), significantly lower minimum oxygen saturation (76%: IQR 64% to 84% vs. 83%: IQR 77% to 87%; p < 0.01), and spent a significantly greater amount of time < 90% oxygen saturation (8.4%: IQR 1.0% to 24.3% vs. 2.4%: IQR 0.2% to 16.0%; p = 0.03). South Asian ethnicity, independent of demographics, BMI, and comorbidities, was associated with ß = 1.84 (95% CI: 1.27-2.65) increase in AHI+1 compared to white Europeans. Furthermore, we confirmed other independent OSA risk factors including increasing age, BMI, and male gender (all p < 0.001). CONCLUSIONS: Severely obese South Asians had significantly greater prevalence and severity of OSA than white Europeans. OSA may contribute to increased cardiovascular risk in South Asians compared to white Europeans with severe obesity. Mechanisms mediating the observed associations between these ethnicities require further investigation.

Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea.

BACKGROUND: Although obstructive sleep apnea (OSA) is strongly linked with obesity, both conditions have been associated with increased cardiovascular risk including glucose intolerance, dyslipidemia, and hypertension independent of one another. Weight loss is known to improve both cardiovascular risk and OSA severity. The aim of this study was to evaluate cardiovascular and metabolic changes, including compartment-specific fat loss in obese OSA subjects undergoing a weight loss program. DESIGN: Observational study. PARTICIPANTS: 93 men with moderate-severe OSA. INTERVENTIONS: 6-month open-label weight loss trial combining sibutramine (a serotonin and noradrenaline reuptake inhibitor) with a 600-kcal deficit diet and exercise. MEASUREMENTS AND RESULTS: At baseline and following 6 months of weight loss, OSA was assessed together with CT-quantified intraabdominal and liver fat and markers of metabolic and cardiovascular function. At 6 months, weight loss and improvements in OSA were accompanied by improved insulin resistance (HOMA), increased HDL cholesterol, and reduced total cholesterol/HDL ratio. There were also reductions in measures of visceral and subcutaneous abdominal fat and liver fat. Reductions in liver fat and sleep time spent below 90% oxyhemoglobin saturation partly explained the improvement in HOMA (R2 = 0.18). In contrast, arterial stiffness (aortic augmentation index), heart rate, blood pressure, and total cholesterol did not change. CONCLUSIONS: Weight loss with sibutramine was associated with improvements in metabolic and body composition risk factors but not blood pressure or arterial stiffness. Improved insulin resistance was partly associated with reductions in liver fat and hypoxemia associated with sleep apnea.

Obesity hypoventilation syndrome: hypoxemia during continuous positive airway pressure.

BACKGROUND: Polysomnography findings between matched groups with obstructive sleep apnea (OSA) and OSA plus obesity-hypoventilation syndrome (OHS) before and after continuous positive airway pressure (CPAP), particularly in the extremely severe obese (body mass index [BMI] >or= 50 kg/m2), are unclear. DESIGN: Prospective study of subjects (BMI >or= 50 kg/m2) undergoing diagnostic polysomnography. Subjects with an apnea-hypopnea index (AHI) >or= 15/h underwent a second polysomnography with CPAP. The effect of 1 night of CPAP on sleep architecture, AHI, arousal indexes, and nocturnal oxygenation was assessed. OHS was defined as those subjects with obesity, PaCo2 > 45 mm Hg, and PaO2 < 70 mm Hg in the absence of lung disease. RESULTS: Twenty-three subjects with moderate-to-severe OSA and 23 subjects with moderate-to-severe OSA plus OHS underwent a 1-night trial of CPAP. Both groups were matched for spirometry, BMI, and AHI, but oxygen desaturation was worse in the OSA-plus-OHS group. CPAP significantly improved rapid eye movement (REM) duration (p < 0.005), AHI (p < 0.005), arousal indexes (p < 0.005), and percentage of total sleep time (TST) with oxygen saturation (SpO2) < 90% (p < 0.005) in both groups. In subjects with OSA plus OHS, 43% continued to spend > 20% of TST with SpO2 < 90%, compared to 9% of the OSA group, despite the adequate relief of upper airway obstruction. CONCLUSIONS: Extremely severe obese subjects (BMI >or= 50 kg/m2) with moderate-to-severe OSA plus OHS exhibit severe oxygen desaturation but similar severities of AHI, arousal indexes, and sleep architecture abnormalities when compared to matched subjects without OHS. CPAP significantly improves AHI, REM duration, arousal indexes, and nocturnal oxygen desaturation. Some subjects with OHS continued to have nocturnal desaturation despite the control of upper airway obstruction; other mechanisms may contribute. Further long-term studies assessing the comparative role of CPAP and bilevel ventilatory support in such subjects with OHS is warranted.

The case of "Judge Nodd" and other sleeping judges--media, society, and judicial sleepiness.

STUDY OBJECTIVES: Review cases of judicial sleepiness and subsequent outcomes, including media and community attitudes. DESIGN: Index case report and Internet search in English language at 2 recent time points. PARTICIPANTS: Index case and 14 other cases of judicial sleepiness reported on the Internet. MEASUREMENTS: Qualitative review of media and Internet reports. RESULTS: The index and other cases highlighted the role of the media seeking a punitive approach to occupational sleepiness, similar to that observed within the transport sector. In the index case, the judge's driver's license was withdrawn, despite official acknowledgement of effective treatment of sleep apnea. In 10 cases, judicial sleepiness resulted in a retrial and, in up to 5 cases, resulted in dismissal or retirement of the judge. In most cases, the cause of sleepiness was not determinable. CONCLUSION: Judicial sleepiness is not uncommon and is viewed negatively by the media, community, and judicial system. Active monitoring of the judiciary for sleepiness and sleep disorders is suggested.

Assessment of sleep and breathing in adults with prader-willi syndrome: a case control series.

OBJECTIVES: Prader-Willi syndrome (PWS) is a genetic disorder (linked to chromosome 15q11-13) characterized by hypotonia and developmental delay, hyperphagia and obesity, hypersomnia and abnormal sleep, and behavioral problems. Such patients may also be at increased risk of obstructive sleep apnea (OSA), although whether this risk is explained by known risk factors has not previously been directly tested. Our aim was to compare sleep and breathing in an older group of patients with Prader-Willi syndrome with a control group-matched on the basis of age, sex, and body mass index (BMI)-in order to determine which specific features are not explained by these known confounders. METHODS: Consecutive patients with PWS attending the PWS clinic at Royal Prince Alfred Hospital Sydney, Australia, were recruited. Age-, sex-, and BMI-matched controls were selected from the Sleep Investigation Unit at Royal Prince Alfred Hospital, and polysomnography-derived sleep and other parameters were compared across the groups. RESULTS: Nineteen subjects with PWS (14 males) were included in the study. Eighteen (95%) had a total respiratory disturbance index (TRDI) of greater than 5 events per hour, with 4 (21%) having severe obstructive sleep apnea (TRDI > or = 30 events/hour) and 9 (47%) having evidence of obesity hypoventilation syndrome. Patients with PWS, as compared with the control group, had evidence of more nocturnal hypoxemia, with lower oxyhemoglobin saturations and percentages of sleep time at less than 80% oxyhemoglobin saturation (all p values < 0.05). There were no significant differences in sleep architecture; however, there was a reduction in rapid eye movement latency seen in the PWS group (p < 0.05). Serum leptin was higher than the reference range in the PWS group but was not measured in the control group. CONCLUSION: Patients with PWS drawn from an adult and adolescent PWS clinic have a high rate of sleep-disordered breathing. There is evidence that patients with PWS may have more nocturnal hypoventilation than a well-matched control group. These data suggest that the chromosome region 15q11-13 may be involved in some aspects of the regulation of breathing, although whether putative molecular mechanisms act directly or indirectly will require further investigation.

Treatment of obesity hypoventilation syndrome and serum leptin.

BACKGROUND: Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels. OBJECTIVES: The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations. METHOD: We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study. RESULTS: The average age of the subjects was (mean +/- SE) 62 +/- 13 years, BMI 40.9 +/- 2.2 kg/m(2), PaCO(2) 6.7 +/- 0.2 kPa, PaO(2 )8.9 +/- 0.4 kPa and total respiratory disturbance index 44 +/- 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6-3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred. CONCLUSION: Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.

Pharmacotherapy for excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) has recognized detrimental consequences such as road traffic accidents, impaired psychological functioning and reduced work performance. EDS can result from multiple causes such as sleep deprivation, sleep fragmentation, neurological, psychiatric and circadian rhythm disorders. Treating the underlying cause of EDS remains the mainstay of therapy but in those who continue to be excessively sleepy, further treatment may be warranted. Traditionally, the amphetamine derivatives, methylphenidate and pemoline (collectively sympathomimetic) psychostimulants were the commonest form of therapy for EDS, particularly in conditions such as narcolepsy. More recently, the advent of modafinil has broadened the range of therapeutic options. Modafinil has a safer side-effect profile and as a result, interest in this drug for the management of EDS in other disorders, as well as narcolepsy, has increased considerably. There is a growing school of thought that modafinil may have a role to play in other indications such as obstructive sleep apnea/hypopnea syndrome already treated by nasal continuous positive airway pressure but persisting EDS, shift work sleep disorders, neurological causes of sleepiness, and healthy adults performing sustained operations, particularly those in the military. However, until adequately powered randomised-controlled trials confirm long-term efficacy and safety, the recommendation of wakefulness promoters in healthy adults cannot be justified.

The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial.

INTRODUCTION: COPD is characterized by bronchial neutrophilic inflammation. Clarithromycin is a macrolide antibiotic that has antibacterial and anti-inflammatory properties. Macrolide antibiotics have been shown to improve airway inflammation in diffuse pan-bronchiolitis but their role in COPD is undetermined. The aim of the study was to determine if 3 months of therapy with modified-release oral clarithromycin (Klaricid XL) 500 mg/day reduced bronchial airway inflammation in patients with moderate-to-severe stable COPD compared with placebo. METHODS: A prospective, double-blind controlled trial randomized patients with moderate-to-severe stable COPD to 3 months' therapy with oral modified-release clarithromycin 500 mg/day or placebo. Patients underwent saline sputum induction before and after treatment with clarithromycin. The effects of clarithromycin on sputum total cell and neutrophil counts, supernatant interleukin-8 (IL-8), leukotriene B(4) (LTB(4)), tumor necrosis factor (TNF)-alpha, neutrophil elastase (NE), and neutrophil chemotaxis were assessed in comparison with placebo. RESULTS: Of a total of 67 patients included in the trial, 31 were treated with clarithromycin and 36 with placebo. The groups were similar in age, body mass index, history of smoking, and spirometry. Of 60 evaluable patients, 26 and 34 completed 3 months' therapy with clarithromycin and placebo, respectively. Clarithromycin had no significant effect on sputum total cell count, neutrophil count, IL-8, LTB(4), TNFalpha levels or neutrophil elastase. However, clarithromycin did cause a small reduction in the neutrophil differential (p = 0.04 relative to placebo) and neutrophil chemotaxis (p = 0.058 relative to placebo). CONCLUSIONS: Oral clarithromycin 500 mg/day administered for 3 months had no significant effect on sputum neutrophil numbers or cytokine levels in patients with moderate-to-severe stable COPD. However, clarithromycin did cause a small reduction in the neutrophil differential and neutrophil chemotaxis. Further studies may be warranted to determine the clinical significance of these findings.