Nov 15, 2014 - aureus clones with hospital and community origin. PLoS ONE 2014;. 9:e98634. 14. Cameron DR, Howden BP, Peleg AY. The interface between ..... For example, the Howard Hughes Medical Institute (Chevy Chase,. MD) has ...
EDITORIALS antibody for prevention and treatment of Staphylococcus aureusinduced pneumonia. Antimicrob Agents Chemother 2014;58: 1108–1117. 13. Tavares A, Nielsen JB, Boye K, Rohde S, Paulo AC, Westh H, Schønning K, de Lencastre H, Miragaia M. Insights into alphahemolysin (Hla) evolution and expression among Staphylococcus aureus clones with hospital and community origin. PLoS ONE 2014; 9:e98634. 14. Cameron DR, Howden BP, Peleg AY. The interface between antibiotic resistance and virulence in Staphylococcus aureus and its impact upon clinical outcomes. Clin Infect Dis 2011;53: 576–582. 15. Rello J, Ollendorf DA, Oster G, Vera-Llonch M, Bellm L, Redman R, Kollef MH; VAP Outcomes Scientific Advisory Group. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest 2002;122:2115–2121.
16. Craven DE, Lei Y, Ruthazer R, Sarwar A, Hudcova J. Incidence and outcomes of ventilator-associated tracheobronchitis and pneumonia. Am J Med 2013;126:542–549. 17. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53–59. 18. Rello J, Molano D, Villabon M, Reina R, Rita-Quispe R, Previgliano I, Afonso E, Restrepo MI; LATINVAP and EUVAP Study Investigators. Differences in hospital- and ventilator-associated pneumonia due to Staphylococcus aureus (methicillin-susceptible and methicillinresistant) between Europe and Latin America: a comparison of the EUVAP and LATINVAP study cohorts. Med Intensiva 2013;37:241–247.
Copyright © 2014 by the American Thoracic Society
REM Sleep: A Nightmare for Patients with Obstructive Sleep Apnea? Obstructive sleep apnea (OSA) is a common condition characterized by recurrent episodes of upper airway collapse during sleep, causing intermittent hypoxemia, sleep fragmentation, and acute changes in blood pressure and heart rate (1). Despite increasing evidence suggesting OSA as a risk factor for hypertension (2), there are also data showing no or modest effect of continuous positive airway pressure treatment on blood pressure control in patients with OSA in randomized controlled trials (3). Deciding the threshold for treatment in terms of the level of OSA severity (apnea–hypopnea index [AHI] and/or daytime sleepiness) is also a common clinical dilemma because OSA represents a heterogeneous group of patients with a multifactorial etiology. Across individuals with OSA, there are various contributions attributable to anatomic and physiological factors and variable degrees of positional and state (REM vs. other) dependencies (4). Among those phenotypes, REMrelated OSA has been reported to account for 10–36% of patients with OSA in sleep clinic cohorts (5), especially in patients with mild or moderate OSA (AHI, 5.0–29.9 events/h), who represent more than 80% of individuals with OSA in the community-based samples (6, 7). Despite existing data demonstrating that obstructive apneas and hypopneas are longer and associated with more severe oxygen desaturations and greater surges in heart rate and blood pressure during REM sleep compared with during non-REM (NREM) sleep (8), to date, there has been no epidemiologic study in literature indicating an association between REM-related OSA and incident hypertension. In this issue of the Journal, Mokhlesi and colleagues (pp. 1158–1167) address the relationship between REM-related OSA and hypertension, based on reported measurements of polysomnography (4,385 sleep studies on 1,451 individuals) and blood pressure (including a subset with ambulatory blood pressure monitoring data), as well as clinical follow-up data (9), of the wellknown Wisconsin Sleep Cohort study published in 2000 (2). In fully adjusted statistical models, the current report demonstrates The author is supported by the Swedish Research Council, the Swedish Heart-Lung-Foundation, and the research fund at Skaraborg Hospital, Sweden.
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significant dose relationships between REM-AHI and prevalent hypertension (9). More interestingly, the relationship between a REM-AHI of 15 or higher and prevalent hypertension is more robust in the subgroup of patients with a NREM-AHI lower than 5, who otherwise are classified as non-OSA on the basis of the overall AHI values. The authors also report a significant dose–response relationship between REM-AHI categories and incident hypertension for the entire cohort, whereas NREM-AHI is not a significant predictor of hypertension in any of the models. Given the knowledge that REM sleep predominates in the early morning hours before typical awakening, the authors state that the cardiovascular benefits of continuous positive airway pressure therapy may not be achieved with the typical use of 3–4 hours per night, limited to the first half of the sleep period, leaving most REM sleep untreated (9). In the literature, there have been reports of a higher prevalence of REM-predominant OSA in mostly women and younger populations in the sleep clinic cohorts (10). In the current Wisconsin article (9), individuals with higher REM-AHI values are older, which is in line with the report from the Sleep Heart Health Study (11). However, sex differences in upper airway control during sleep, especially during REM state, is an important factor (12) and should be taken into consideration regarding its relationship with hypertension. The current article does not adjust for fixed variables such as sex and race/ethnicity in the models involving within-subject comparisons (changes of OSA status associated with changes in hypertension status) and, thus, leaves the question of whether or not the development of hypertension in REM-predominant OSA is sex dependent unanswered. There are other concerns that should be taken into account in the interpretation of the results from the current article. First, we should consider supine position dependencies and potential variability in signals over time, and whether REM-predominant OSA may be a marker for variability in hypertension, rather than a specific marker of incident hypertension. It is also important to consider characteristics of overnight oxygen saturation levels as a potential alternative exposure for the development of hypertension during REM sleep. As acknowledged by the authors, information
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EDITORIALS regarding the oxygen desaturation index and percentage sleep time below 90%, as well as time spent in a supine position, were available for only a small subset of the sleep studies performed before the initiation of fully digitalized data collection of the entire Wisconsin cohort. However, although the subanalyses of the position and oxygen saturation parameters were underpowered relative to those that use the AHI, the b coefficients for REM-AHI categories were essentially unchanged after adjustment for supine position (9), supporting that these findings are independent of supine body position during sleep. So, how should we define and identify REM-predominant OSA, and consequently, how and when should this entity be treated with regard to cardiovascular risks irrespective of overall AHI and/or daytime sleepiness? In the literature, there are several definitions based on (1) overall AHI > 5 and REM-AHI/NREM-AHI ratio > 2; (2) overall AHI > 5, REM-AHI/NREM-AHI ratio > 2, and NREM-AHI , 15; or (3) overall AHI > 5, REM-AHI/NREM-AHI ratio > 2, NREM-AHI , 15, and at least 10.5 minutes of REM sleep duration (5). The current report differs from these definitions and does not allow any comparisons based on the previous criteria, as only subjects with at least 30 minutes of recorded REM sleep are included in the analyses. Although the threshold value of 30 minutes is chosen for sufficient observation of REM sleep to characterize REM-predominant OSA and to reduce the possibility of exaggerating the effect of REM OSA in individuals for short REM duration (9), the strict criterion brings a potential bias, as the excluded patients are probably the ones with severe OSA (overall AHI, >30), with higher prevalence of hypertension. Thus, the significance of the comparisons between REM-AHI and NREMAHI categories with regard to hypertension may be confounded by exclusion of the individuals with severe OSA, and thus weakens the conclusion that NREM-OSA is not related with hypertension. However, as also clarified by the authors, the results do not imply that OSA severity based on overall AHI is not related to hypertension. Indeed, the adjusted odds ratios for prevalent hypertension are still significant, with increasing overall AHI category in the supplementary data. When overall AHI is replaced with NREM-AHI and REM-AHI, only REM-AHI is significant in all the models, suggesting hypertension is mainly driven by REM OSA, rather than NREM OSA, in this community-based population (9). Notwithstanding the limitations, the current report is unique in that it uses a large, community-based sample with cross-sectional and longitudinal analytic approaches demonstrating the first epidemiologic evidence of the relationship between REMpredominant OSA and hypertension. Of note, the accumulated mean REM sleep time is approximately 1 hour of total sleep time and only 1 of 24 hours of the day, which is related to the development of clinical hypertension with increasing REM-AHI severity in this community-based population that consists mainly of individuals with mild to moderate OSA. Despite the lack of longitudinal evidence of the association between REM-OSA and cardiovascular outcomes in sleep clinic cohorts, as well as in cardiac populations, who already are at high risk, it is not difficult to imagine that the consequences are more serious than those in the general population. Indeed, earlier reports with polysomnography and electrocardiographic recordings have already demonstrated that episodes of nocturnal ischemia are more common in patients with OSA with coronary artery disease (mainly during REM sleep), Editorials
during episodes of high apnea activity, and during sustained hypoxemia (13). The low frequency of REM-predominant OSA in clinical cohorts with severe OSA, as well as in patients with an already-established cardiovascular disease, in cross-sectional reports (5) may be a result of frequent sleep fragmentations. One question remains: Whether this phenomenon may also reflect the possibility that individuals with REM-predominant OSA do not survive anymore to be detected in clinical cohorts. Thus, given the emergence of new mechanical and pharmacological interventions, as summarized in a recent update in the sleep medicine research field (4), there is need to improve the “personalization” of sleep apnea therapy through more complete characterization of each patient’s pathophysiology. As concluded by the authors of the current report from the Wisconsin cohort, more focus should be given to increasing adherence to continuous positive airway pressure treatment in patients with OSA to cover the early morning hours before awakening, thus treating the whole REM sleep period. More research with larger studies considering individual risk factor profiling in refining treatment strategies in sleep apnea phenotypes is, however, still needed. n Author disclosures are available with the text of this article at www.atsjournals.org. Yuksel ¨ Peker, M.D., Ph.D. Sahlgrenska Academy University of Gothenburg Gothenburg, Sweden and Sleep Medicine Unit Skaraborg Hospital Skovde, ¨ Sweden
References 1. Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ 2009;108:246–249. 2. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. 3. Barbe´ F, Duran-Cantolla ´ J, Sanchez-de-la-Torre ´ M, Mart´ınez-Alonso M, Carmona C, Barcelo´ A, Chiner E, Masa JF, Gonzalez M, Mar´ın JM, et al.; Spanish Sleep And Breathing Network. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;307:2161–2168. 4. Peker Y, Redline S. Update in sleep medicine 2013. Am J Respir Crit Care Med 2014;189:1345–1350. 5. Conwell W, Patel B, Doeing D, Pamidi S, Knutson KL, Ghods F, Mokhlesi B. Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep Breath 2012;16:519–526. 6. Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ, Stubbs R, Hla KM. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008; 31:1071–1078. 7. Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O’Connor GT, Rapoport DM, Redline S, Resnick HE, Robbins JA, et al. Sleepdisordered breathing and mortality: a prospective cohort study. PLoS Med 2009;6:e1000132. 8. Findley LJ, Wilhoit SC, Suratt PM. Apnea duration and hypoxemia during REM sleep in patients with obstructive sleep apnea. Chest 1985;87: 432–436. 9. Mokhlesi B, Finn LA, Hagen EW, Young T, Hla KM, Van Cauter E, Peppard PE. Obstructive sleep apnea during REM sleep and
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EDITORIALS hypertension: results of the Wisconsin Sleep Cohort. Am J Respir Crit Care Med 2014;190:1158–1167. 10. Koo BB, Patel SR, Strohl K, Hoffstein V. Rapid eye movement-related sleep-disordered breathing: influence of age and gender. Chest 2008;134:1156–1161. 11. Chami HA, Baldwin CM, Silverman A, Zhang Y, Rapoport D, Punjabi NM, Gottlieb DJ. Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. Am J Respir Crit Care Med 2010;181:997–1002.
12. O’Connor C, Thornley KS, Hanly PJ. Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:1465–1472. 13. Hanly P, Sasson Z, Zuberi N, Lunn K. ST-segment depression during sleep in obstructive sleep apnea. Am J Cardiol 1993;71: 1341–1345.
Copyright © 2014 by the American Thoracic Society
Acute Respiratory Distress Syndrome: Emerging Research in China Acute respiratory distress syndrome (ARDS) was formally introduced into the medical literature by Ashbaugh and colleagues in their 1967 Lancet publication (1); however, this definition was not incorporated into the Chinese medical lexicon until the late 1980s (2). This delay was attributable to the economic realities of academic medicine in China before 1990 and also to the relative paucity of well-trained clinicians and researchers focused on respiratory medicine and pulmonary biology. Dramatic improvements in public health infrastructure have reduced preventable mortality in China to the point at which life expectancy is similar to that in the rest of the developed world. Combined with substantial investments in research, this has resulted in a steadily increasing interest in advanced training in pulmonary and critical care medicine in China and increasing research focused on the pathobiology and treatment of ARDS. In addition, many Chinese physician-scientists have been recruited back to China after training in expert laboratories worldwide. This has led to a dramatic increase in ARDS-focused research and publications originating from China (Figure 1). In the past 5 years, 922 articles indexed by the National Library of Medicine were published by Chinese institutions. In comparison, 1,765 were published in the United States. These improvements in research infrastructure have placed China in a position to work with international collaborators to develop new treatment strategies that will improve outcomes for patients with ARDS.
Support for Research in China A substantial fraction of support for ARDS research in China is provided by the National Natural Science Foundation of China (NSFC), an organization analogous to the National Institutes of Health Y.S. and F.X. contributed equally to this work. Supported by grants from the National Natural Science Foundation of China 81490533, (81170056, 81300055, 81100046, and 81370176), the Ministry of Education of China (no. NCET-12-0484), the Natural Science Foundation of Zhejiang Province (no. LR12H01003), and the Health Department of Zhejiang Province (no. 201342966). Y.S. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning and by a Key Medical grant from the Shanghai Science and Technology Committee (11411951102 and 12JC1402300). Author Contributions: Y.S. drafted and revised the manuscript; F.X., E.J.S., J.O., and X.Z. revised the provided data and the manuscript. R.S. and C.B. supervised drafting of the manuscript and outlined the structure of the manuscript.
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(NIH) in the United States. ARDS has been identified as a research priority for the NSFC, which has allocated 13–20% of its awards in pulmonary medicine for the study of acute lung injury (ALI)/ARDS (Figures 2 and 3). However, this commitment remains relatively small compared with funding in the United States and other nations. Further support comes from international organizations in the form of joint grants from the NSFC and foreign research organizations. As the quality of Chinese science improves, Chinese researchers are successfully competing for grants from foundations outside of China. For example, the Howard Hughes Medical Institute (Chevy Chase, MD) has funded seven Chinese researchers who returned to China after receiving their training in the United States.
Epidemiology A comprehensive study of the prevalence, mortality, and risk factors for ALI/ARDS in China is lacking. However, relatively small regional studies suggest that the epidemiology of ARDS in China is similar to the epidemiology of ALI/ARDS in Europe and the United States (3–5). For example, in a study conducted in Beijing in eight intensive care units (ICUs) from 1998 to 2003, ARDS was the reason for ICU admission in 4.5% of patients (6). However, the reported mortality rate attributable to ARDS in these studies is variable (22–100%), suggesting there may be considerable regional variation in the management of patients with ARDS in China. The incidence of pediatric ARDS also appears similar to rates in the West (7). For example, in a survey of 25 pediatric ICUs in China, investigators reported that ARDS was the reason for admission in 1.4% of ICU patients, with a mortality rate of 61.1% (8). If we extrapolate incidence data from the United States and Europe to the Chinese population (annual incidence of approximately 59/100,000 people), the annual incidence of ARDS in China would be about 670,000 patients per year. Many of the risk factors for ARDS reported to be common in Europe and the Americas were also noted in epidemiologic studies of ARDS in China. The most significant risk factor was infection (37.9–64.9%) (5, 6, 9) followed by trauma (10.7%); the latter may be related to the high incidence of car accidents (5, 6). In addition, Chinese researchers observed patients with ARDS secondary to unique risk factors rarely seen in Western ICUs, including scrub typhus (10), miliary tuberculosis–associated ARDS (11), in situ liver transplantation (12), and high-altitude pulmonary edema (4).
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 10 | November 15 2014
