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1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; 2 Department of Medicine, University of California, San Francisco, California; and 3 Department of Medicine, University of Michigan, Ann Arbor, Michigan
Correspondence and requests for reprints should be addressed to Lorraine B. Ware, M.D., T1218 MCN, 1161 21st Avenue S, Nashville, TN 37232-2650. E-mail: lorraine.ware{at}vanderbilt.edu
SEPSIS
Charles L. Sprung
Hadassah Hebrew University Medical Center
Jerusalem, Israel
Treatment of Septic Shock
Vasopressin has been recommended as second-line therapy after dopamine or norepinephrine for treatment of septic shock, but its effect on mortality has not been studied prospectively. Russell and colleagues (1) hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. They randomized 778 patients with septic shock receiving a minimum of 5 µg/minute of norepinephrine to receive either low-dose vasopressin (0.01–0.03 U/min) or norepinephrine (5 to 15 µg/min) in addition to open-label vasopressors. Vasopressor infusions were titrated according to protocols to maintain a target blood pressure. Consistent with previous trials, low-dose vasopressin raised plasma vasopressin levels and allowed a rapid decrease in the total norepinephrine dose while maintaining mean arterial pressure. The primary endpoint of 28-day mortality was not different between treatment arms, 35% in the vasopressin group and 39% in the norepinephrine group, P = 0.26. Similarly, there was no significant difference in 90-day mortality (43.9% and 49.6%, respectively; P = 0.11). The rates of adverse events were similar in both groups; of note, patients with acute heart disease who might have been at greater risk of adverse events from vasopressin were excluded from the study. In a prospectively defined subgroup analysis, patients with less severe septic shock (5–14 µg/min norepinephrine at baseline) demonstrated a significant reduction in mortality with vasopressin compared with norepinephrine, a finding that was not seen compared with the group with more severe septic shock (15 µg/min or more of norepinephrine), contrary to the authors' original hypothesis. This study demonstrates the comparable effectiveness of vasopressin to norepinephrine therapy in addition to other catecholamine vasopressors for treatment of septic shock. It should be noted that in this study, vasopressin was used in addition to norepinephrine and/or other vasopressor therapy for patients with relatively stable blood pressures on vasopressors. This was not a study of vasopressin as a rescue therapy for shock unresponsive to vasopressors.
Educational Programs in Severe Sepsis
Clinical trial results and evidence-based guidelines for the care of patients with severe sepsis are often not translated into clinical practice. Ferrer and colleagues (2) sought to determine whether a national educational program based on the Surviving Sepsis Campaign guidelines would improve processes of care and hospital mortality for patients with severe sepsis. In a multicenter study of 59 Spanish intensive care units (ICUs) (21% of all Spanish ICUs), they evaluated a national educational program based on the Surviving Sepsis Campaign Guidelines with a before and after design in affecting processes of care and hospital mortality. The authors enrolled 854 patients in the pre-intervention period, 1,465 patients in the post-intervention period, and 247 patients in a long term follow-up 1 year later. At baseline, compliance rates with process of care tasks in the sepsis resuscitation (5.3%) and sepsis management (10.9%) bundles were extremely low. After the intervention, compliance improved in the sepsis resuscitation and management bundles. For example, patients were more likely to receive early appropriate antibiotic therapy, adequate fluid resuscitation, and documented consideration of drotrecogin alfa and low-dose corticosteroids. Hospital mortality decreased from 44% to 40% (P = 0.04). Long-term follow-up revealed that compliance with sepsis resuscitation bundles returned to baseline but compliance with sepsis management and the improvement in mortality remained stable in relation to the post-intervention period. This study demonstrates that a national educational program apparently decreased hospital mortality in patients with severe sepsis. However, the lack of a randomized design or concurrent control subjects leaves open the possibility that temporal trends in mortality or differences in case-mix were responsible for the observed decrease in mortality. Nevertheless, this study suggests that quality improvement programs using widespread implementation of bundles of care are feasible on a large scale and could have a role in decreasing mortality in sepsis.
Risk Stratification in Sepsis
PIRO (predisposition, infection, response, organ dysfunction/failure) is a proposed system for risk stratification in sepsis that originally arose from the Fifth Toronto Sepsis Roundtable in 2000 (3). PIRO takes into account not only criteria for infection, but also the predisposition of the patient and the reaction of the organism to the injury. Despite several refinements since its original design, it remains a concept that has not been tested clinically. Using the SAPS 3 database, Moreno and colleagues (4) evaluated 2,628 patients in the ICU for greater than 48 hours to determine the usefulness of PIRO for predicting mortality in patients with infection and sepsis. Hospital mortality was 41%. The SAPS 3 PIRO score had excellent predictive value for mortality, with an area under the receiver operator curve of 0.77, and the PIRO components independently contributed to outcome prediction. This is the first study to address which factors affect the outcome of patients with sepsis in which the three levels of predisposition, injury, and response were addressed together. One difference between the PIRO system for modeling the risk of mortality from sepsis and other organ failure scores is that PIRO attributes different weights to specific organ failures rather than giving all organ failures the same weight. Although provocative, the proposed SAPS 3 PIRO scoring system requires validation in an independent cohort to fully demonstrate its clinical utility.
Severe Sepsis Compared with Severe Noninfectious SIRS
Sepsis has been defined as an infection coupled with a systemic inflammatory response (5). Since the original description of the systemic inflammatory response syndrome (SIRS) in 1992, there have been many studies of sepsis but few of noninfectious SIRS. In a substudy of the incidence of severe sepsis in 23 Australian and New Zealand ICUs study, Dulhunty and colleagues (6) conducted a secondary analysis to describe the onset, duration, and resolution of organ dysfunction, mortality rate, and causes of death in patients with severe sepsis compared with severe noninfectious SIRS. They evaluated 3,543 admissions for greater than 48 hours in 3,312 patients (some patients had more than one admission evaluated). The ICU prevalence of severe sepsis and severe noninfectious SIRS was 20% and 28%, respectively. ICU (27% versus 25%) and 28-day (33% versus 32%) mortalities were similar in both groups. Multiorgan failure was the most common case of death in severe sepsis and neurological failure in severe noninfectious SIRS. The time to peak organ dysfunction, overall duration of organ dysfunction, and ICU stay were shorter in patients with severe noninfectious SIRS. This study demonstrates that organ dysfunction is common in ICU patients with both severe sepsis and severe noninfectious SIRS although the timing and duration differ. The similarity in mortality between severe noninfectious SIRS and severe sepsis is intriguing and requires further investigation. The authors conclude that managing patients with severe noninfectious SIRS is a substantial component of ICU workloads and that the epidemiology and treatment of noninfectious SIRS should be addressed more fully in future studies.
MECHANICAL VENTILATION
Thomas E. Stewart
Mount Sinai Hospital and University Health Network, University of Toronto
Toronto, Ontario, Canada
Lung Protective Mechanical Ventilation
Avoidance of end-expiratory alveolar collapse using positive end-expiratory pressure (PEEP) may be an important component of lung protective mechanical ventilation in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the optimal method for titrating PEEP in individual patients is unknown, and prior studies applying uniformly high levels of PEEP across all patients with ALI/ARDS have not improved mortality (7–9). Talmor and colleagues (10) hypothesized that using esophageal pressure measurements to set PEEP to maintain a positive end-expiratory transpulmonary pressure would maintain oxygenation while preventing lung injury due to repeated alveolar collapse or overdistention. In this single-center study, 61 patients with ALI or ARDS were randomly assigned to have PEEP titrated according to a PEEP/FIO2 table similar to the one used in the NHLBI ARDS Network low tidal volume study (11) or to PEEP titration guided by esophageal pressure measurements to keep transpulmonary pressures positive (0–10 cm H2O). The primary outcome was improvements in oxygenation at 72 hours, while secondary outcomes were indices of lung mechanics, gas exchange, and important clinical outcomes. At 72 hours the esophageal pressure–guided group was receiving higher PEEP and accordingly had significantly better oxygenation and respiratory system compliance. There were no statistically significant differences in the secondary endpoints, although there was a trend to improved 28-day survival in the treatment group. Although this study is intriguing, there are several important limitations. First, improvement in oxygenation is not necessarily a surrogate for better clinical outcomes. Indeed, in the original NHLBI ARDS Network trial of 6 ml/kg versus 12 ml/kg predicted body weight ventilation (11), oxygenation was poorer in the 6 ml/kg arm, the arm that had significantly better mortality. Second, the improved oxygenation may simply have been related to the higher PEEP used in the treatment group and have had little to do with the transpulmonary pressure measurements. Finally, after 72 hours, esophageal balloon pressures were made available to clinicians in both arms of the study although it is not clear whether this made a major impact on treatment decisions. Larger randomized studies that are powered for important clinical outcomes are needed to address this and other novel methods for individual titration of PEEP in ALI/ARDS before widespread clinical adoption.
Acquired Weakness in Critically Ill Mechanically Ventilated Patients
Severe weakness is common in critical illness and has been termed ICU-acquired paresis (ICUAP). ICUAP may result from critical illness polyneuropathy, myopathy, and/or neuromyopathy, and contributes to prolonged mechanical ventilation and hospital stay. Traditionally, bedside testing for ICUAP has relied on neurophysiologic exam or the Medical Research Council (MRC) physical strength exam, which requires an awake and attentive patient able to participate in examination of 12 major muscle groups. In a study by Ali and co-investigators (12), it was hypothesized that handgrip strength (dynamometry) can be used as a simple surrogate test for ICUAP. They also sought to determine the independent association of ICUAP with mortality in critical illness. One hundred thirty-six critically ill patients who were mechanically ventilated for more than 5 days in five academic medical centers had global (MRC physical strength exam) and handgrip strength measured upon wakening. ICUAP (average MRC score < 4) was diagnosed in 35 (25.7%) patients and was associated with longer hospital stays and longer time on the ventilator. Handgrip strength was lower in subjects with ICUAP and had good test performance for diagnosing ICUAP. In addition, both ICUAP diagnosed by MRC examination and handgrip strength were independently associated with hospital mortality after adjustments for severity of illness. These findings suggest that handgrip strength may prove to be a simple method to diagnose ICUAP. However, the ideal timing, reproducibility, and best techniques for this test require further clarification. The extent to which the diagnosis of ICUAP assists with clinically useful decisions is still not clear; undoubtedly the utility of diagnosis will increase as methods for prevention and treatment of ICUAP such as early mobilization therapy are further investigated. The strong association between ICUAP and mortality emphasizes the need for further investigations in this important area.
Predictors of Mortality in ALI/ARDS
ALI and ARDS are common and have a high associated morbidity and mortality (13). In addition, these entities impose a large economic impact on our health care system. Observational studies have identified a variety of demographic, pulmonary-specific, and clinical variables predictive of mortality in patients with ALI/ARDS. However, in an era of lung protective mechanical ventilation and declining mortality rates, these predictive variables have not been reassessed. Seely and colleagues (14) postulated that with lung protective ventilation, pulmonary factors might be expected to have less impact on mortality. In a retrospective analysis of 149 consecutive patients with ALI/ARDS admitted to two academic ICUs, a variety of demographic and clinical factors were collected for a maximum of 7 days and analyzed for their independent association with hospital mortality. Notably, all patients were managed according to the ARDS network low pressure/volume protocol (11). In bivariate analysis, 17 variables were associated with mortality. In adjusted multivariate analysis, the only pulmonary specific variable associated with death was the oxygenation index ([MAP x FIO2 x 100] ÷ PaO2). These findings suggest that in the era of protective lung ventilation for ALI/ARDS, oxygenation index is superior to other factors (specifically PaO2/FIO2) in predicting death. This finding is not surprising, given that the oxygenation index is intuitively a more reliable/stable variable than PaO2/FIO2, because it controls for aggressiveness of mechanical ventilation. The oxygenation index has been a mainstay for pulmonary physiologic evaluation in the pediatric ICU. The current study, if validated in a larger prospective study, suggests that the oxygenation index may also have a role in adult critical care.
Prevention of Ventilator-associated Pneumonia
Ventilator-associated pneumonia is a common complication of mechanical ventilation. Selective decontamination of the digestive tract (SDD) and selective oral decontamination (SOD) have been proposed as methods to prevent ICU-acquired infections. Despite trials and meta-analyses demonstrating both reduced respiratory tract infections and improved survival, SOD and SDD have not been adopted by most intensivists due to methodologic concerns with the studies and the possibility of selective pressure favoring the emergence of resistant organisms. In an effort to address these concerns, de Smet and co-investigators (15) enrolled 5,939 mechanically ventilated patients in 13 ICUs using a cluster randomized, crossover design into a study comparing three strategies: SDD, SOD, and standard care. SDD included IV Cefotaxime plus antibiotic paste to the oropharynx and stomach. SOD included only antibiotic paste to the oropharynx. A robust 89.2% of eligible patients were enrolled. The primary outcome was adjusted 28-day mortality and secondary endpoints included colonization patterns, antibiotic use, emergence of resistant organisms, and duration of mechanical ventilation as well as ICU/hospital stay. The 28-day mortality rate of 27.5% for the standard care group was reduced (after adjustments) by roughly 3% in both the SDD and SOD groups, with an odds ratio for death at Day 28 in the SOD and SDD groups, as compared with the standard-care group, of 0.86 (95% confidence interval [CI], 0.74–0.99) and 0.83 (95% CI, 0.72–0.97), respectively. Importantly, during the study period neither SDD nor SOD was associated with the emergence of resistant organisms. This study suggests that both SDD and SOD are effective at reducing mortality in critically ill mechanically ventilated patients. SOD appears to be as effective as SDD and has lower costs (roughly one dollar/day), is less labor intensive, and intuitively is less likely to cause resistance as well as complications. Whether the aggressive oral care that is increasingly being adopted in ICUs (including things like teeth cleaning and oral washings with or without chlorhexidine) has efficacy equivalent to the SOD protocol used in this study is not known.
Routine Daily Chest Radiographs—Are They Necessary?
Routine daily chest radiographs (CXRs) are a common practice in mechanically ventilated patients. Despite studies demonstrating that a more restrictive approach to ordering CXRs increases therapeutic accuracy without adversely affecting outcomes, many clinicians still use daily CXRs. One clinical concern is whether a more restrictive approach to obtaining CXRs results in important delays in diagnoses that might negatively impact morbidity and mortality. To address this question, Clec'h and colleagues (16) randomly assigned 165 patients requiring mechanical ventilation for more than 48 hours to daily CXR interpretation compared with CXR interpretation only if an abnormality was suspected. For each CXR, a questionnaire was completed addressing the reason for the CXR, the new findings, and any subsequent therapeutic intervention. Endpoints were the rate of new findings, the rate of new findings that prompted therapeutic intervention, the rate of delayed diagnoses, the length of time in the ICU and on the ventilator, and mortality. The number of CXRs interpreted in the two groups were 885 versus 94, respectively. New findings and those that required therapeutic intervention were more prevalent in the restrictive group versus the daily group (66% versus 7.2% [P < 0.0001] and 56.4% versus 5.5% [P < 0.0001], respectively). The rate of delayed diagnoses in the restrictive prescription group was 0.7% (n = 6), none of which required a therapeutic intervention. Morbidity and mortality were similar in the two groups. In summary, in this small, single-center study, a more restrictive approach to daily CXRs increased the diagnostic yield and therapeutic efficacy of CXRs without impacting on morbidity or mortality. Although the findings are compelling, there are several limitations. The study was single-center, there was no gold standard for CXR interpretation, the study was unblinded, and there were no defined management protocols or clear definitions for suspected abnormalities and need for therapeutic interventions. Nevertheless, this study adds additional support for the need to reevaluate the common practice of daily CXRs, a practice that has associated costs, possible morbidities, and is likely of little or no clinical benefit.
OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE
Joel D. Kaufman
University of Washington
Seattle, Washington
Occupational Asthma
Workplace exposure to low- or high-molecular-weight (HMW) sensitizers can induce asthma. HMW agents are the "classical" cause of occupational asthma. The first study followed a large cohort of 629 subjects beginning with their apprenticeships into jobs that involved substantive exposure to HMW antigens (17). The workplace exposures evaluated were laboratory animals, flour, and latex. The study is an important contribution because it began following subjects at the onset of their occupational exposure and continued to follow them over time prosepectively. Approximately half of the subjects were followed for a period up to 8 years on the job. Evaluations included surveys, skin prick tests to occupational allergens, and methacholine challenge.
Among subjects who progressed from apprenticeship to a related job, there was a high incidence of incident allergic sensitization (positive skin prick test: 1.3 per 100 person-years), rhinoconjunctival symptoms (1.7 per 100 person-years), chest symptoms (0.7 per 100 person-years), and nonspecific bronchial hyperresponsiveness (2.0 per 100 person-years). The incidence of these endpoints was lower than during apprenticeship, but substantial given that persons who became symptomatic during apprenticeship had already left the occupation. Workers who developed sensitization or other study endpoints had a high rate of remission if they left the job early in their occupational history.
The importance of this study is that most sensitization and incident asthma occurs soon after the initial exposure to HMW antigens (i.e., during the apprenticeship), but that there is considerable new onset of sensitization and airway disease among workers later in their employment. Remission can occur, but the best chance is to remove the worker soon after they become sensitized. The implication is that workers in high-risk occupations require intensive surveillance early in their job tenure, but they still require some ongoing surveillance after they have been in the workforce for several years.
The study has some important limitations, including the high loss to follow-up rate, which could have introduced selection bias. Because the study focused on HMW agents, there was no information provided about low-molecular-weight agents and irritant exposure; these exposures likely have a different natural history. Despite these limitations, the study provides important insights into the natural history of occupational asthma onset and remission.
The second article is an update of the American College of Chest Physicians Consensus Statement last published in 1995 (18). A panel of experts, including allergists, pulmonologists, and occupational medicine physicians, convened to develop this Consensus Document. This Consensus Statement defined work-related asthma (WRA) to include occupational asthma, which is asthma induced by a sensitizer or irritant exposures in the workplace, and work-exacerbated asthma (WEA), which is pre-existing asthma that is worsened by exposure to workplace factors. WEA may be less familiar to clinicians; it is important conceptually because patients with pre-existing asthma may experience deterioration because of occupational exposures.
The Consensus Statement includes a systematic review and graded evidence-based recommendations for all aspects of occupational asthma, which include diagnosis, treatment, and prevention. The document also explains the diagnosis and management of WRA and measures to prevent it. In particular, WRA should be considered in any patient with new-onset asthma or established asthma that is worsening. In addition to a detailed occupational history, diagnostic tests should include serial peak flow measurement, methacholine challenge testing, and immunologic tests (RAST or skin prick testing). In specialized centers specific inhalational challenge testing can be used to establish the diagnosis. In terms of serial peak flow monitoring a pattern of decreased peak flows during the work week and improvement on weekends or vacations (or other removal from work) can be very useful in establishing the diagnosis of WRA. The Consensus Statement also reviews the limitations of immunological testing for the diagnosis of WRA related to high molecular weight agents; these tests are of limited utility for asthma related to low molecular weight agents and irritant exposure.
Chronic Beryllium Disease
Chronic beryllium disease (CBD) is a chronic granulomatous disease that primarily involves the lungs and sometimes skin. There are many clinical similarities to sarcoidosis. Typically, CBD occurs in workers who inhale beryllium dust or fumes in a variety of industries, including aerospace, ceramic manufacturing, electronics, atomic energy and defense, laboratory work, dental work, mineral extraction from ore, or metal recycling.
In addition to occupational exposure, a historical literature exists documenting that community-level exposures to beryllium can result in sensitization and CBD. The last such report in the medical literature, however, was in 1969. A new study reports a series of CBD cases that occurred among residents of a community surrounding a beryllium-manufacturing facility in Reading, Pennsylvania (19). The authors identified by medical record review 16 potential cases of CBD from which 8 cases were confirmed (5 definite, 3 probable). None of the patients had occupational exposure to beryllium. Several of the cases had been misdiagnosed as other lung diseases, including sarcoidosis. The case patients' initial year of residence began between 1943 and 1953 and continued until 1956 to 2001. In most cases CBD can occur long after exposure has ceased. Patients lived up to approximately one mile from the facility. Six of the eight cases required medical treatment and three cases died from CBD after diagnosis. This paper is important because it documents the potential for an occupational hazard to cause disease in the nearby community. When faced with chronic granulomatous lung disease, health care providers must consider not only occupational exposures but the residential history with a focus on residence near facilities using beryllium or other toxic substances (e.g., asbestos).
Ozone Air Pollution and Respiratory Disease
Air pollution has long been known to shorten the lifespan. Previous studies have shown a consistent effect of chronic exposure to fine particulate matter (PM2.5) on mortality, including death from all causes and cardiovascular disease. The effects of tropospheric ozone on mortality, however, have been less certain. In this study, data from the American Cancer Society Cancer Prevention Study II was used to evaluate the association between city-wide average of peak ozone levels between April and September during the period from 1977 to 2000 and mortality (20). The study sample size was very large (nearly 500,000 subjects residing in 96 metropolitan areas) and follow-up was long (18 years). In statistical analyses that included both PM2.5 and ozone, PM2.5 was associated with cardiovascular disease, whereas ozone was associated with death from respiratory causes. For each 10 ppb increment in ozone, the risk of death from respiratory causes was 1.040 (95% confidence interval, 1.010 to 1.067). This corresponds to a 4% increase in the risk of death per 10 ppb increment of ozone. These results were robust after statistical control for confounders. This study is important because it shows that both fine particulate pollution and ozone are related to mortality, but in different ways (cardiovascular versus respiratory causes of death). The extensive existing data linking ozone exposure to deleterious effects on the respiratory tract, such as induction of airway inflammation and pulmonary function decrement, provides biological plausibility for this association.
Occupational Exposures and COPD
As discussed above, occupational exposures have been known to cause asthma for decades. The impact of workplace exposures, however, on COPD causation has been less studied. In this study by Hart and coworkers, a large retrospective cohort (30,671) of deceased U.S. railroad workers who had jobs that did or did not expose them to diesel exhaust was evaluated (21). Workers on jobs that involved diesel exposure had an increased risk of COPD mortality compared with workers in jobs without diesel exposure. Each year of work in a diesel-exposure job was associated with a 2.5% increase in the risk of COPD mortality. Among workers who had job tenures of 15 to 20 years as an engineer, the risk of COPD mortality was 67% greater than jobs without exposure.
This work supports an accumulating literature that workplace exposures to vapors, gas, dusts, or fumes may cause COPD, even in the absence of smoking. A limitation of this study is the absence of direct smoking data, but the investigators imputed smoking based on known characteristics. Moreover, death certificates often do not accurately assign COPD as a cause of death (under and over assign), but this bias is likely nondifferential with respect to exposure and would reduce the observed association toward the null value.
SLEEP
Richard J. Schwab
University of Pennsylvania
Philadelphia, Pennsylvania
Sleep Regulation
The understanding of sleep regulation continues to evolve. In a report from Halassa and colleagues, astrocytes, nonneuronal brain cells, are described as having the ability to modulate sleep (22). Investigators used a transgenic mouse model to turn on or off the production of SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor). SNARE protein families are responsible for forming the complex between vesicles and the target membrane of a cell, thus controlling vesicular transport, including the secretion of neurotransmitters. Astrocytes require SNARE to release ATP, which can be broken down extracellularly to adenosine, a sleep promoting molecule. Without SNARE, mice had a smaller and less sustained increase in slow wave activity, a measure of sleep pressure, on EEG after sleep deprivation. Furthermore, a lack of SNARE was associated with no increase in sleep over 18 hours after 6 hours of sleep deprivation. It was hypothesized that the inability of astrocytes to release ATP lead to decreased local adenosine and thus less sleep. Thus astrocytes appear to be important in sleep regulation and could serve as a target for the development of novel therapies for sleep-disordered breathing.
Pathogenesis of Obstructive Sleep Apnea
Role of fluid shifts at night.
Fluid shifts from the legs to the neck have been previously associated with increased neck circumference and pharyngeal resistance (23). In the study by Redolfi and colleagues, fluid shifts were found to be associated with obstructive sleep apnea in nonobese men (24). Twenty-three nonobese men self-reported the amount of time spent sitting during the day before undergoing a sleep study. Bioelectrical impedance was used to assess the change in fluid volume in one leg before and after the test. Reduction in leg fluid volume overnight was associated with the self-reported amount of sitting during the previous day, apnea–hypopnea index, and increase in neck circumference. This study raises the possibility that sedentary living may be a modifiable risk factor for the prevention of obstructive sleep apnea. This study also raises potential concerns over the impact of fluid shifts in disease states such as renal and congestive heart failure where fluid retention and sedentary time are likely to be increased.
Role of obesity.
Obesity and increased tongue size are common risk factors for obstructive sleep apnea. Brennick and colleagues used genetically abnormal obese New Zealand White mice to explore the link between obesity and increased airway resistance (25). Obese mice, compared with controls, have a smaller upper airway, larger tongue, soft palate, parapharyngeal fat pads, and lateral walls compared with control mice. Interestingly, the fat was found to be infiltrated between muscle fibers within the tongue. This study sheds light on the potential link between obesity, tongue size, and obstructive sleep apnea.
Consequences of Sleep Apnea
Results from the Wisconsin Sleep Cohort further highlighted the link between obstructive sleep apnea and increased cardiovascular mortality (26). The Wisconsin Sleep Cohort was established in 1988 as a population-based study of the natural history of sleep-disordered breathing. Young and colleagues identified deceased individuals via the U.S. Social Security Death Index and cause of death from Wisconsin Vital Statistics. After adjusting for CPAP use and potential confounders (alcohol use, smoking, education, cardiovascular disease, stroke, hypertension, self-rated general health, and daytime sleepiness), severe obstructive sleep apnea (OSA, apnea–hypopnea index 
30 episodes/h) was associated with an increased risk of both all-cause (hazard ratio [HR], 3.8; 95% CI, 1.6–9.0) and cardiovascular (HR, 5.2; 95% CI, 1.4–19.2) mortality. The study was limited in that only 63 of the 1,522 subjects examined had severe OSA. Further study is required to determine if treatment of severe OSA reduces mortality.
Consequences of Snoring
A provocative study by Lee and colleagues raised the possibility of a link between snoring and carotid atherosclerosis (27). One hundred ten volunteers with mild, nonhypoxic obstructive sleep apnea were evaluated for quantity of snoring and the presence of atherosclerosis of the carotid and femoral arteries. The majority of subjects (94%) had mild (< 50%) plaque stenosis. Thus, the analysis was categorical between absent or present (presence of plaque). Snoring was quantified into mild (0–25% of night), moderate (> 25–50%) and severe (> 50%) categories. Prevalence of carotid artery plaque increased with the degree of snoring—20% in the mild snoring group, 32% in the moderate snoring group, and 64% in the severe snoring group (P < 0.04). The odds ratio for atherosclerosis in snorers after controlling for age, sex, smoking, and hypertension was 10.5 (95% CI, 2.1–51.8; P = 0.004). There was no association with snoring and femoral atherosclerosis. Although this study shows a strong association between snoring and carotid artery atherosclerosis, it represents a relatively small and select group of patients. Further study is needed to both confirm the findings in a larger, more diverse patient group and to explore for potential causal effects.
FOOTNOTES
This is the second in a series of four executive summaries of the Clinical Year in Review Sessions presented at the American Thoracic Society International Conference in May, 2009. The main topics of each talk have been abstracted by the session chair based on the annotated bibliography provided by each presenter.
Conflict of Interest Statement: L.B.W. received grant support from Luminex $1,001–$5,000, Sirius Genomics $10,001–$50,000, and the NIH $100,001 or more. M.D.E. served as a consultant for Genentech $5,001–$10,000 and as an expert witness for DLA Piper $5,001–$10,000. He received grant support from Roche $50,001–$100,000 and the NIH $100,001–more. K.F. served as a consultant for Boehringer Ingelheim $5,001–$10,000, Gilead $1,001–$5,000, Neopharm $10,001–$50,000, and served on the Board or Advisory Board for Fibrogen and Actelion $1,001–$5,000. He received lecture fees from Pfizer $1,001–$5,000, Boehringer Ingelheim $5,001–$10,000, GlaxoSmithKline $10,001–$50,000, and Ortho McNeil $1,001–$5,000. He received grant support from Intermune $100,001 or more and he receives royalties from Up to Date $10,000–$50,000.
(Received in original form July 7, 2009; accepted in final form July 14, 2009)
REFERENCES
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