Update in Sleep Medicine 2011AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 185 2012
Thomas B. Rice1, Patrick J. Strollo, Jr.1, and Mary J. Morrell2
1Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 2Academic Unit of Sleep and Breathing, Royal Brompton Hospital, National Heart and Lung Institute, ImperialCollege London, United Kingdom
In 2011, the Journal published a number of original articles that have advanced our understanding of the pathogenesis, sequelae, and management of sleep disorders, particularly as related to disordered breathing during sleep.
PATHOGENESIS OF ADULT OBSTRUCTIVE SLEEP APNEA
Although it is unclear why all respiratory events in obstructive sleep apnea (OSA) are not terminated with a recognizable cortical arousal, it has been hypothesized that events terminated without arousal may lead to more stable breathing. Jordanand colleagues attempted to deﬁne the physiologic parameters immediately related to stable breathing, including airﬂow, genioglossus and tensor palatini muscle activity, and airway resistance, after respiratory events terminated with or withoutcortical arousal (1). They hypothesized that respiratory events terminated without cortical arousal would produce less hyperventilation and less secondary events due to higher pharyngeal dilator activity compared with events with arousal.
Sixteen patients with mild to severe OSA already treated with continuous positive airway pressure (CPAP) were studied. Using a sudden drop in CPAP pressure to subtherapeutic levels, they found that respiratory events terminated withoutarousal led to less hyperventilation and less secondary events (primarily hypopneas) compared with events terminated with arousal. This reduction in inspired minute ventilation and subsequent events was not accounted for by differences inresidual pharyngeal dilator activity. Speciﬁcally, secondary events were marked by less ﬂow limitation and greater pharyngeal dilator activity relative to the initial event whether cortical arousal was present or not. These ﬁndings question thenotion of arousal predisposing patients to further obstructive events.
PATHOGENESIS OF PEDIATRIC OSA
Although adenotonsillar hypertrophy has never fully accounted for OSA in the pediatric population, the relative contributions of adiposity and airway lymphoid tissue in the emerging epidemic of obese pediatric OSA patients are unclear. Tobegin to address these unknowns, Arens and colleagues performed magnetic resonance imaging of the upper airway and abdomen in 22 obese children with OSA and 22 obese children without OSA matched for age and body mass index (BMI) (2).Conﬁrming their hypothesis, they found greater adenoid and tonsil tissue volumes in those with OSA, leading to a 28% reduction in the oropharyngeal volume. They also identiﬁed retropharyngeal lymph node hypertrophy as an importantcontributor to airway restriction. Individual lymphoid tissue sizes were highly correlated with OSA severity, whereas BMI was not, suggesting that lymphoid tissue hypertrophy is due to local or systemic inﬂammation in children with OSA and not obesity itself. With regard to excess adiposity, two important ﬁndings emerged that could further promote airway collapse in those with OSA: greater parapharyngeal fat pad size and greatervisceral abdominal fat. Although OSA and visceral fat have a highly confounded relationship, the negative effects of parapharyngeal fat pads on the upper airway caliber were similar to obese adults with OSA.
SEQUELAE OF SLEEP PATHOLOGY
Basic Science Insights into Cardiovascular Sequelae of OSA
Focusing on the pathophysiologic perturbation of intermittent hypoxia, two investigations using mouse models looked to identify molecular pathways leading to cardiovascular disease (CVD). Arnaud and colleagues identiﬁed regulated uponactivation, normal T-cell expressed, and secreted (RANTES)/CC chemokine ligand 5 (CCL5) as a mechanism of early inﬂammatory arterial remodeling that could lead to atherosclerosis (3). In these experiments, they ﬁrst demonstrated that micesubjected to 14 days of intermittent hypoxia (21 to 5% FIO2, 60-s cycle) developed splenocyte activation with increased chemokine expression (notably RANTES/CCL5) compared with controls, as a result of systemic inﬂammation. They thendemonstrated that leukocyte recruitment was enhanced in the microcirculation with up-regulation of intercellular adhesion molecule 1 (ICAM-1), evidence for increased leukocyte– endothelium interactions in the mice subjected to intermittenthypoxia. Next, they identiﬁed structural remodeling of large arteries with enlargement of intima media thickness under intermittent hypoxia conditions. Finally, they showed that this pre-atherosclerotic remodeling was inﬂammatory in nature withbiochemical (greater nuclear factor [NF]-kB expression) and histologic (peripheral aorta T-cell inﬁltration) evidence. Neutralizing RANTES/CCL5 with a monoclonal antibody attenuated the structural arterial changes and the inﬂammatoryinﬁltrates. The authors suggest that the inﬂammatory response of OSA may be a target for future interventions.
Examining an alternate pathway to atherogenesis, Li and colleagues posited that leukotriene B4 (LTB4), acting through its high-afﬁnity G protein–coupled receptor leukotriene B4 receptor 1 (BLT1), mediated inﬂammation due to intermittenthypoxia (4). LTB4 is linked with the chronic inﬂammation that leads to atherosclerosis, and its role in intermittent hypoxia–induced atherogenesis was tested using in vitro and in vivo studies. Using cell lines, the authors ﬁrst demonstrated thatconditions of intermittent hypoxia led to a large increase in LTB4 levels associated with up-regulation of messenger RNA expression of its key synthetic enzymes, 5lipoxygenase and leukotriene A hydrolase, via NF-kB and mitogenactivatedprotein kinase–dependent pathways. In further cell culture work, BLT1 and -2 were found to potentiate the expression of 5-lipoxygenase and leukotriene A hydrolase. Shifting to a chronic 10-week animal model of intermittent hypoxia,apolipoprotein E–deﬁcient mice (ApoE2/2) were fed a high-cholesterol atherogenic Western diet, resulting in marked atherosclerotic lesions of the aorta compared with room air controls on the same diet. After conﬁrming that intermittent hypoxiainduced atherogenesis in the model, the experiments were repeated with a BLT12/2 strain and a double knock-out ApoE2/2 BLT2/2 strain. In the same chronic intermittent hypoxia model, aortic atherosclerotic burden was reducedinboththe BLT12/2and double knock-out mice, compared with the ApoE2/2, suggesting protection from atherogenesis in the absence of BLT1. The authors concluded that LTB4 may play an important role in intermittent hypoxia–dependent atherogenesis, whichcould be amenable to pharmacologic intervention.
Basic Science Insights into Neurocognitive Sequelae of OSA
Besides intermittent hypoxia, another prominent consequence of OSA is sleep fragmentation. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity has recently been identiﬁed as a source of reactive oxygen species generation.Having previously shown that NADPH oxidase activity mediates deleterious responses to intermittent hypoxia, Nair and colleagues turned their attention to its role in sleep fragmentation–induced neurobehavioral function in mice with transgenicmice null for NADPH oxidase (gp91phox2/Y) (5). After 2 weeks of sleep fragmentation, both the gp91phox2/Y mice and their wild-type littermates showed an increase in the number of wake episodes and a decrease in slow-wave sleep latency,despite no change in total wake time, slow-wave sleep, REM sleep, or delta power. Neurobehavioral testing revealed that wild-type C57B6 mice who underwent sleep fragmentation performed worse than their normal sleep controls and worsethan either gp91phox2/Y sleep fragmentation or sleep controls in well-deﬁned tests of spatial learning and memory retention, implying protection from neurocognitive consequences of sleep fragmentation in the null gp91phox2/Y mice. Harvestedfrontal cortex and hippocampal tissues revealed evidence for excess lipid peroxidation and oxidative DNA damage after 2 weeks of sleep fragmentation in the wild-type mice. The gp91phox2/Y null NADPH oxidase mice were protected from thistissue damage. Nair and colleagues concluded that NADPH plays a role in the neurocognitive sequelae of sleep fragmentation and therefore may be a target for intervention.
Clinical and Epidemiologic Evidence for Cardiovascular Consequences of OSA
Complementing the work of Arnaud and colleagues and Li and colleagues above on mediators of the atherogenic pathway in OSA, Mason and colleagues provide clinical evidence for an association of OSA with abdominal aortic aneurysm (AAA)(6). In a cohort of 127 patients (91% men) undergoing active surveillance for AAA expansion, home sleep apnea tests were performed to measure the apnea–hypopnea index (AHI) and oxygen desaturation index (ODI) using automated scoringsoftware. AAA expansion was then retrospectively calculated from that time point back to their baseline measures to determine a rate of expansion per year (range, 2–113 mo). Despite a relatively low mean BMI of 28 kg/m2, the authors found aprevalence of an AHI and ODI greater than or equal to 10 in 40% of the population. In multivariable models fully adjusted for traditional CVD risk factors, those with severe OSA deﬁned by either an AHI or an ODI greater than or equal to 30had signiﬁcantly higher rates of AAA expansion compared with those with no or mild OSA. Two important conclusions can be drawn from the results of Mason and coworkers. First, there is a high prevalence of OSA in this cohort of patientswith AAA, and clinicians that care for these patients should be vigilant to diagnose and treat OSA. Second, the strong association of severe OSA with AAA expansion suggests that future longitudinal and intervention studies are needed to fullyimplicate OSA in the development and progression of AAA.
Cano-Pumarega and colleagues have added to the debate about the development of hypertension (HTN) in individuals with OSA (7). Clinical cohorts have demonstrated evidence implicating OSA’s role in incident HTN, particularly whereCPAP treatment has been shown to reduce blood pressure. However, although the Wisconsin Sleep Cohort Study found a signiﬁcantly increased risk of developing HTN in those with severe OSA, the Sleep Heart Health Study found that severeOSA was not signiﬁcantly associated with incident HTN after adjustment for BMI. Addressing this issue, Cano-Pumarega and colleagues now report the association of incident HTN in 1,180 individuals with untreated OSA over 7.5 years ofstudy follow-up. Although those in the highest quartile of the respiratory disturbance index (RDI > 14) had an odds ratio of 2.61 for incident HTN in univariate analyses compared with the lowest quartile, when models were simply adjusted forage the effect was attenuated and was no longer statistically signiﬁcant. This longitudinal population study questions the putative role of OSA in the development of HTN. It should be further noted, however, that the results of this study arehard to directly compare with Wisconsin Sleep Cohort Study and Sleep Heart Health Study due to differences in study population, baseline rates of HTN, method of measuring sleep apnea, referent control groups for analysis, and durations ofstudy follow-up.”
Clinical and Epidemiologic Evidence for Neurocognitive Consequences of OSA
In human studies complementary to the work of Nair and colleagues above, Canessa and colleagues investigated the cognitive deﬁcits and corresponding brain morphology changes in 17 treatment-naive men with severe OSA (8). Compared with15 age-and education-matched controls, those with OSA had impairments in multiple cognitive domains, mood, and sleepiness. Moreover, the impairments corresponded with reductions in focal gray matter volume of the left hippocampus andright superior frontal gyrus. After 3 months of CPAP treatment, there were signiﬁcant increases in gray matter volume in these areas, paralleled by improvements in memory, attention, and executive functioning. This study suggests that earlydiagnosis and treatment of OSA may not only improve neurocognitive function but also preserve vital gray matter, particularly when the ﬁndings are considered in conjunction with those of Yaffe and coworkers (9).
Yaffe and colleagues attempted to implicate OSA as a possible cause of cognitive impairment. Drawing on participants from the Study of Osteoporotic Fractures, the authors followed 298 older women (>65 yr, mean age 82.3 yr) withoutdementia at baseline that underwent nocturnal PSG for a median of 4.7 years. Utilizing an ODI greater than or equal to 15 to deﬁne OSA, the authors found a fully adjusted odds ratio of 1.85 (95% conﬁdence 1.11– 3.08) greater risk of developingmild cognitive impairment or dementia compared with those without OSA. Hypoxic parameters were particularly associated with cognitive decline, but sleep fragmentation, as measured by the arousal index and wake after sleep onset, was notassociated with incident cognitive dysfunction. In conjunction with the work of Canessa and coworkers suggesting brain morphometry changes with CPAP therapy, the data of Yaffe and colleagues support the notion that early diagnosis andtreatment of OSA might improve neurocognitive outcomes. We should perform larger intervention studies to substantiate hypotheses that OSA improves reversible cognitive impairment associated with radiographic brain tissue changes.
Evidence for Sequelae of Short Sleep Duration
Pulmonary sleep physicians spend the majority of their time addressing sleep apnea, but are often faced with other sleep-related issues, especially insufﬁcient sleep duration. To examine diet and lifestyle factors that predict long-term weight gainin adults, Mozaffarian and colleagues examined over 120,000 adults who were healthy and not obese (10). They were followed between 12 and 20 years at 4-year intervals, and predictors of weight gain were assessed. In congruence with themounting evidence about sleep duration, a U-shaped relationship was seen, whereby sleeping less than 6 or more than 8 hours nightly was associated with excess weight gain compared with sleeping between 6 and 8 hours nightly. This studyhighlights the importance of adequate sleep duration in long-term health. The signiﬁcance of excess weight gain in those with more than 8 hours of sleep is unclear, because unlike in other cohorts in which adverse risk in those with long sleepduration is often ascribed to comorbidities, it would be hard to implicate comorbidities in this healthy cohort.
DIAGNOSIS AND TREATMENT OF OSA
The diagnosis of OSA has received considerable attention in 2011. Across the globe, the obesity-related increase in the prevalence of OSA, linked with reduced resources, has led clinical scientists to evaluate alternative pathways for the diagnosisof OSA. Both Masa and colleagues (11) and Kuna and colleagues (12) have conducted multicenter studies to investigate the utility of home monitoring in the diagnosis of OSA. Masa and coworkers (11), from the Spanish Sleep Group, studied348 OSA patients; half were assigned to home respiratory polygraphy and half to in-laboratory nocturnal polysomnography (NPSG). The accuracy of the treatment decisions were evaluated, and it was found that there was a moderate (79%)level of agreement using data from the home respiratory polygraphy studies, compared with in-laboratory NPSG. In patients with severe OSA (AHI.30 events/h), the agreement rose to more than 90%, and the authors concluded that homemonitoring using respiratory measurements was of value in the diagnosis of patients with severe OSA, but was of limited value in patients with mild to moderate OSA.
In the study by Kuna and colleagues (12), 296 patients were studied using either an in-laboratory or in-home diagnostic and therapeutic pathway. The patients who completed the in-laboratory protocol underwent a two-night diagnostic andtherapeutic NPSG study, or a split-night treatment study if clinically indicated. The patients following the in-home protocol had a home respiratory polygraphy study followed by an auto-titrating CPAP titration to determine ﬁxed CPAPsettings, unless otherwise indicated. Using a 1-point reduction on the Functional Outcome of Sleep Questionnaire as the noninferiority primary outcome at 3 months, the home respiratory polygraphy testing and treatment protocol was notinferior to in-laboratory testing and treatment. Taken together, these studies support the role of home respiratory polygraphy for the diagnosing OSA. The use of home studies is likely to be of greater value where there is a strong suspicion ofOSA. Clinically the percentage of patients with severe OSA varies across centers according to referral patterns. Notably, in the study by Kuna and coworkers, the prevalence of OSA was 88% and the patients were somewhat heavier than thosein the study of Masa and colleagues. Overall, the increasing use of home studies in different settings, such as primary care, needs to be evaluated (13).
Evidence for Metabolic Consequences of OSA and Response to CPAP Treatment
The effectiveness of CPAP treatment to reverse symptoms of sleepiness has now been established; however, the metabolic response to treatment is less clear (14). In a randomized, placebo-controlled CPAP trial performed in India, Sharma andcoworkers (15) have shown that 3 months of autotitrating CPAP treatment reduces blood pressure (BP) in line with other studies. Importantly, blood lipid levels also fell and the metabolic syndrome was reversed in 13% (n ¼ 11) of those onauto-titrating CPAP compared with just 1% (n ¼ 1) of those on sham-CPAP treatment. The study was a crossover design with 90 patients randomized (86 completed) to receive either 3 months of auto-titrating CPAP or sham-CPAP treatment,separated with a 1-month washout period. The duration of the washout period is of concern if the components of the metabolic syndrome did not return to baseline before the start of the subsequent intervention. Indeed, reanalysis of the baselinedata showed that systolic BP, high-density lipoprotein cholesterol, and abdominal circumference did not return to baseline in the patients treated with active CPAP in the ﬁrst arm of the study. However, as emphasized by the authors, anycarryover effect would be anticipated to reduce the impact of the CPAP treatment, making the ﬁndings of their study more robust. Overall, the study positively supports the use of CPAP in metabolic syndrome.
Continuing with the theme of metabolic consequences, the impact of OSA on triglycerides as a marker of CVD was evaluated in another randomized controlled trial published earlier in 2011. Phillips and colleagues (16) monitored triglycerideconcentrations during both wakefulness and sleep over 24 hours following 2 months of CPAP treatment or placebo, with a wash-out period of 1 month. The triglyceride concentrations peaked at 2:00 P.M.and 3:00 A.M., and the magnitudes of both peaks were smaller in patients on CPAP treatment (n ¼ 18)comparedwithplacebo controls (n ¼ 19). Moreover, 24-hour cholesterol was also lower in OSA patients treated CPAP, which may in turn reducecardiovascular risk. A feature of this study was the careful measurement of the triglycerides over 24 hours with controlled food intake at set mealtimes.
The sample size required to carry out a proof-of-principle (phase III) randomized, controlled trial to assess the reduction of cardiovascular risk with hard endpoints in OSA patients treated with CPAP is much larger than the proof-of-concept(phase II) studies discussed in this review. Fortunately, several researchers have taken up the challenge of carrying out these phase III trials (e.g., NCT00738179: SAVE—Sleep Apnea Cardiovascular End-points Study), and the results are eagerlyanticipated.
Others have attempted to address the difﬁculties of recruitment to large randomized, controlled trials by considering alternative approaches. Kohler and coworkers (17) have recently reported a CPAP withdrawal protocol with clearlydocumented cardiovascular endpoints. Two weeks of CPAP withdrawal produced a return of symptoms of sleepiness, an increase in BP, and urine catecholamines with impairment of endothelial function. This protocol could potentially be usedin the evaluation of new therapies for the treatment of OSA and/or its sequelae. When new treatments are developed, there is a requirement to assess their efﬁcacy in selected patient groups. An important advantage of the withdrawal protocoldescribed by Kohler and colleagues is that it allows the selection of speciﬁc patient groups from cohorts already established on CPAP.
SLEEP-DISORDERED BREATHING IN PATIENTS WITH HEART FAILURE
Understanding which patients will respond to the treatment of sleep-disordered breathing is complex. This may be even more so in heart failure patients with sleep apnea, because the classic symptom of excessive daytime sleepiness is oftenabsent. Additionally, both central and obstructive events frequently coexist in the same patient, which may affect the response to treatment. Sands and coworkers (18) have addressed the issue of predicting the response to treatment in heartfailure patients with sleep apnea by developing a model to calculate loop gain from the duty cycle of periodic breathing. In a validation study, the authors assessed the impact of CPAP treatment on sleep apnea in 14 heart failure patients. Theresponders to CPAP (n ¼ 6) had a lower loop gain with a higher duty ratio (longer ventilatory period with shorter apneas), compared with non-CPAP responders (n ¼ 8). Therefore, Sands and colleagues(18) and other researchers (19) have argued that algorithms aimed at calculating loop gain can be used to detect patients more likely to respond to treatment. Although this view is not universally held (20), the underdiagnosis of sleep apnea in thecardiology setting is an issue that needs to be addressed. The retrospective cohort study by Javaheri and colleagues (21) clearly demonstrates that sleep apnea is often overlooked as a comorbidity in newly diagnosed heart failure patients. Indeed,of the 30,719 incident heart failure cases identiﬁed from a Medicare population spanning 2003–2005, only 1,263 (4%) were clinically suspected as having sleep apnea, andonly2%weretestedand treated. Importantly, treatment improved the 2-year survival in these patients. These uncontrolled data must be interpreted with caution; however, if the outcome of ongoing phase III randomized, controlled trials of positive pressure treatment in heart failure patients with sleep apnea showbeneﬁts of positive pressure on cardiovascular risk and a reduction in hard endpoints (e.g., NCT01128816-ADVENT-HF and NCT00733343SERVE-HF), this will lead to pressure on sleep laboratory facilities and a possible need to predict andprioritize those patients who require more urgent NPSG.
Finally, Redolﬁ and colleagues put forth a proof-of-concept study for a novel treatment for disordered breathing during sleep in individuals with venous insufﬁciency, which could ultimately extend to individuals with volume overload fromheart failure (22). In 12 individuals with OSA and chronic venous insufﬁciency, 1-week treatment with compression stockings signiﬁcantly reduced overnight leg ﬂuid volume and neck circumference, which led to a 36% reduction in the AHI.Reducing rostral ﬂuid shifts overnight, by preventing lower extremity ﬂuid collection in the day, may represent a new treatment modality for certain individuals with OSA.
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- Arens R, Sin S, Nandalike K, Rieder J, Khan UI, Freeman K, Wylie-Rosett J, Lipton ML, Wootton DM, McDonough JM, et al. Upper airway structure and body fat composition in obese children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2011;183:782–787.
- Arnaud C, Beguin PC, Lantuejoul S, Pepin JL, Guillermet C, Pelli G, Burger F, Buatois V, Ribuot C, Baguet JP, et al. The inﬂammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Am J Respir Crit Care Med2011;184:724–731.
- Li RC, Haribabu B, Mathis SP, Kim J, Gozal D. Leukotriene B4 receptor-1 mediates intermittent hypoxia-induced atherogenesis. Am J Respir Crit Care Med 2011;184:124–131.
- Nair D, Zhang SX, Ramesh V, Hakim F, Kaushal N, Wang Y, Gozal D. Sleep fragmentation induces cognitive deﬁcits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Respir Crit Care Med 2011;184:1305–1312.
- Mason RH, Ruegg G, Perkins J, Hardinge M, Amann-Vesti B, Senn O, Stradling JR, Kohler M. Obstructive sleep apnea in patients with abdominal aortic aneurysms: highly prevalent and associated with aneurysm expansion. Am J Respir Crit Care Med 2011;183:668–674.
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- Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011;364:2392–2404.
- Masa JF, Corral J, Pereira R, Duran-Cantolla J, Cabello M, Hernandez-Blasco L, Monasterio C, Alonso A, Chiner E, Zamorano J, et al. Therapeutic decision-making for sleep apnea and hypopnea syndrome using home respiratory polygraphy: a large multicentric study. Am JRespir Crit Care Med 2011;184:964–971.
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- Kuna ST, Badr MS, Kimoff RJ, Kushida C, Lee-Chiong T, Levy P, McNicholas WT, Strollo PJ Jr. An ofﬁcial ATS/AASM/ACCP/ERS workshop report: research priorities in ambulatory management of adults with obstructive sleep apnea. Proc Am Thorac Soc 2011;8:1–16.
- McDaid C, Dure´e KH, Grifﬁn SC, Weatherly HL, Stradling JR, Davies RJ, Sculpher MJ, Westwood ME. A systematic review of continuous positive airway pressure for obstructive sleep apnoea-hypopnoea syndrome. Sleep Med Rev 2009;13:427–436.
- Sharma SK, Agrawal S, Damodaran D, Sreenivas V, Kadhiravan T, Lakshmy R, Jagia P, Kumar A. CPAP for the metabolic syndrome in patients with obstructive sleep apnea. N Engl J Med 2011;365:2277– 2286.
- Phillips CL, Yee BJ, Marshall NS, Liu PY, Sullivan DR, Grunstein RR. Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial. Am J Respir Crit Care Med 2011;184:355–361.
- Kohler M, Stoewhas AC, Ayers L, Senn O, Bloch KE, Russi EW, Stradling JR. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 2011;184:1192–1199.
- Sands SA, Edwards BA, Kee K, Turton A, Skuza EM, Roebuck T, O’Driscoll DM, Hamilton GS, Naughton MT, Berger PJ. Loop gain as a means to predict a positive airway pressure suppression of Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit CareMed 2011;184:1067–1075.
- Wellman A, Eckert DJ, Jordan AS, Edwards BA, Passaglia CL, Jackson AC, Gautam S, Owens RL, Malhotra A, White DP. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol 2011;110:1627–1637.
- Basner RC. Loop gain: can it help close the heart failure-periodic breathing loop? Am J Respir Crit Care Med 2011;184:996–997.
- Javaheri S, Caref EB, Chen E, Tong KB, Abraham WT. Sleep apnea testing and outcomes in a large cohort of Medicare beneﬁciaries with newly diagnosed heart failure. Am J Respir Crit Care Med 2011;183: 539–546.
- Redolﬁ S, Arnulf I, Pottier M, Lajou J, Koskas I, Bradley TD, Similowski T. Attenuation of obstructive sleep apnea by compression stockings in subjects with venous insufﬁciency. Am J Respir Crit Care Med 2011;184:1062–1066.
(Received in original form April 9, 2012; accepted in ﬁnal form April 30, 2012)
Correspondence and requests for reprints should be addressed to Thomas B. Rice, M.D., M.S., Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 5th Avenue, Suite 639, MUH, Pittsburgh, PA 15213. E-mail: firstname.lastname@example.org
Am J Respir Crit Care Med Vol 185, Iss. 12, pp 1271–1274, Jun 15, 2012 Copyright ª 2012 by the American Thoracic Society DOI: 10.1164/rccm.201204-0637UP Internet address: www.atsjournals.org