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Editorials

Chest. 2006;129(1):1-3. doi:10.1378/chest.129.1.1
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The new cover or “face” of the January, 2006 issue of CHEST heralds that changes have taken place in the editorial content and format of what will be published in the pages of the Journal as we begin a new era in its 71-year history. The cover was redesigned to reflect the changes that will occur. While the new design appears fresher and more modern, it has not lost the identity of its heritage. In this regard, while it is my goal, and that of the Associate Editors and new Editorial Board members, to improve the quality of research and scholarly works and educational offerings published in CHEST, and in advancing our field, we will not attempt to do so at the expense of publishing what our readers expect and need. CHEST is above all else a clinical journal, with a very important educational mission.

Topics: chest
Chest. 2006;129(1):3-5. doi:10.1378/chest.129.1.3
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Inhaled β2-agonists have been used for > 40 years in the treatment of asthma. Until fairly recently, their regular use had been advocated as the first-line therapy for asthma treatment. This is because inhaled β2-agonists provide rapid bronchodilation as a result of their action as airway smooth muscle relaxants, and, thus, provide rapid improvement of symptoms. Also, inhaled β2-agonists protect against stimuli, such as exercise, allergen, or pollutants, that cause bronchoconstriction in asthmatic patients. For these reasons, inhaled β2-agonists are the most widely prescribed and used drug in the treatment of asthma in many (possibly most) countries, and their regular use is still regarded by many physicians as a first-line treatment option.

Chest. 2006;129(1):5-6. doi:10.1378/chest.129.1.5
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The American Thoracic Society and the European Respiratory Society have redefined COPD as a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is associated with an abnormal inflammatory response to inhaled particles or gases, primarily cigarette smoke. COPD also has important systemic consequences.1 This definition provides a shift from a narrow paradigm, centered solely on the degree and progression of airflow obstruction, to a broader one, providing a more optimistic view in which interventions can be envisioned at different levels of the pathogenetic mechanisms.

Chest. 2006;129(1):6-7. doi:10.1378/chest.129.1.6
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Published in this issue of CHEST (see page 67) is a provocative study by Senn et al1 in which the authors initiated a trial with an autotitrating continuous positive airway pressure (CPAP) device prior to a diagnostic study for sleep-disordered breathing, testing the hypothesis that those with “significant” obstructive sleep apnea (OSA) would have a positive response to CPAP therapy, thereby potentially obviating the need for polysomnography or definitive diagnostic testing. Senn et al found that 46% of their study population had both OSA, ultimately documented by polysomnography, and a “positive CPAP trial.”

Chest. 2006;129(1):7-10. doi:10.1378/chest.129.1.7
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Since the introduction of systematically developed clinical practice guidelines > 20 years ago,1 guidelines have become a broadly accepted tool to support health-care professionals in their decision-making process. The usefulness of practice guidelines has been underlined by evidence that they can initiate changes in the way doctors practice medicine and promote improvements in patient care.23

Chest. 2006;129(1):10-12. doi:10.1378/chest.129.1.10
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The American College of Chest Physicians (ACCP) has successfully provided high-quality clinical practice guidelines for over 10 years. Over the last 6 years, a concerted effort has been supervised by the ACCP Health and Science Policy Committee to ensure that these documents move as close as possible to an evidence-based platform. The reader is invited to visit the Health and Science Policy Committee Web site to learn more about the process of the ACCP in developing evidence-based guidelines.1 Some evidence-based guideline publication topics include lung cancer,2 pulmonary arterial hypertension,3 antithrombotic and thrombolytic therapy,4 aerosol therapy,5 atrial fibrillation after coronary arterial bypass grafting,6 and cough.7 A forthcoming evidence-based guideline will highlight occupational asthma.

Chest. 2006;129(1):12-13. doi:10.1378/chest.129.1.12
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The risk of developing severe acute respiratory syndrome (SARS) after exposure was conventionally determined by the prospective follow-up for symptomatic disease or the retrospective seroprevalence study of the exposed population. The average number of secondary cases resulting from a single case of SARS ranged from two to four.1 Transmission mostly resulted from contacts with patients with overt disease rather than from asymptomatic or mildly symptomatic patients. Seroprevalence appeared to be low (0%, 0.43%, and 1.2%) for healthy individuals, and about 1% for health-care workers, approximately 1% for asymptomatic family contacts under quarantine, and 0.19% for asymptomatic contacts overall.27 Systematic use of reverse transcriptase polymerase chain reaction (RT-PCR) in the early identification of patients with higher risk for developing SARS has not been reported. In this issue of CHEST (page 95), Ho et al8 report on the nasopharyngeal shedding of SARS-coronavirus (CoV) RNA from 27 of 217 frontline health-care workers (12.4%) after encountering SARS patients for 1 week. Twenty five of those health-care workers were characterized by low mean (± SD) viral loads (312 ± 204 to 386 ± 203 copies per milliliter), a lack of or paucity of symptoms, and the absence of seroconversion during follow-up. This is in contrast to the two subsequently symptomatic health-care workers with significantly higher mean viral loads (16,900 ± 7,920 copies per milliliter) and subsequent seroconversion. The authors excluded contamination with PCR amplicon carryover by using 13 nonfrontline health-care workers as negative control subjects in addition to the usual PCR-negative control subjects. Since the word colonization is used to describe the establishment of a microbial agent in the host without inducing a specific immune response or invasion, as manifested by disease or distant dissemination, the authors concluded that SARS-CoV can “colonize” a significant proportion of exposed individuals, with disease manifestation occurring in only 2 of 27 initially colonized individuals (7.4%).

New Associate Editors

Chest. 2006;129(1):14. doi:10.1378/chest.129.1.14
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Editor in Chief Richard S. Irwin has appointed two new physicians to serve 5-year terms as Associate Editors for CHEST. They join the others named in July to help Dr. Irwin in guiding the Journal.

Topics: chest

Original Research: ASTHMA

The Salmeterol Multicenter Asthma Research Trial*: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol
Chest. 2006;129(1):15-26. doi:10.1378/chest.129.1.15
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Study objective: To compare the safety of salmeterol xinafoate or placebo added to usual asthma care.

Design: A 28-week, randomized, double-blind, placebo-controlled, observational study.

Setting: Study subjects were seen once in the study physician’s office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks.

Participants: Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting β2-agonist use were excluded.

Interventions: Salmeterol, 42 μg bid via metered-dose inhaler (MDI), and placebo bid via MDI.

Measurements and results: Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo.

Conclusions: For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.

Formoterol, 24 μg bid, and Serious Asthma Exacerbations*: Similar Rates Compared With Formoterol, 12 μg bid, With and Without Extra Doses Taken on Demand, and Placebo
Chest. 2006;129(1):27-38. doi:10.1378/chest.129.1.27
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Study objectives: The primary objective was to determine whether high-dose formoterol, 24 μg bid, was associated with more asthma exacerbations compared with lower formoterol doses in patients with stable persistent asthma. Serious asthma exacerbations (life threatening or requiring hospitalization) were the primary end point. Secondary end points included significant exacerbations requiring systemic corticosteroids, all exacerbations, and changes in FEV1.

Design: In a multicenter, placebo-controlled, parallel-group study, patients were randomized to 16 weeks of treatment with formoterol, 24 μg bid; formoterol, 12 μg bid, with up to two additional 12-μg doses daily on demand for worsening symptoms (12 μg bid plus on demand); formoterol, 12 μg bid; or placebo. The formoterol 12-μg-bid plus on-demand regimen was administered open label, while the other three regimens were double blind.

Setting: Outpatient clinics.

Patients: A total of 2,085 patients aged ≥ 12 years with stable, persistent asthma were enrolled and treated; 65% (n = 1,347) received regular concomitant antiinflammatory therapy during the study.

Measurements and results: Nine patients had respiratory-related serious adverse events (SAEs) requiring hospitalization: two patients (0.4%) in the 24-μg-bid group; one patient (0.2%) in the 12-μg-bid plus on-demand group; five patients (0.9%) in the 12-μg-bid group; and one patient (0.2%) in the placebo group. All of these events were asthma related, except for two SAEs in the 12-μg-bid group that were later considered not to be asthma related by independent reviewers who were not associated with the conduct of the study. The proportions of patients with significant asthma exacerbations (requiring systemic corticosteroids) were similar in the 24-μg-bid group (6.3%, 33 of 527 patients), 12-μg-bid group (5.9%, 31 of 527 patients) and placebo group (8.8%, 45 of 514 patients) and lower in the 12-μg-bid plus on-demand group (4.4%, 23 of 517 patients; p = 0.0057 vs placebo). All treatments were well tolerated. All formoterol treatment regimens had a significant effect on FEV1 measured 2 h after dose during the study (p < 0.0001 vs placebo); and on predose trough FEV1 measured at all visits after baseline (p < 0.002 vs placebo).

Conclusions: Treatment with formoterol, 24 μg bid, was not associated with an increase in serious asthma exacerbations compared with the lower formoterol doses or placebo.

Chest. 2006;129(1):39-49. doi:10.1378/chest.129.1.39
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Background: Previous research has demonstrated that fish oil supplementation has a protective effect on exercise-induced bronchoconstriction (EIB) in elite athletes, which may be attributed to its antiinflammatory properties. Since EIB in asthma involves proinflammatory mediator release, it is feasible that fish oil supplementation may reduce the severity of EIB in asthmatic subjects.

Study objectives: To determine the efficacy of fish oil supplementation on severity of EIB in subjects with asthma.

Design: Randomized, double-blind, crossover study.

Setting: Lung function and exercise testing in a university research laboratory.

Patients and measurements: Sixteen asthmatic patients with documented EIB entered the study on their normal diet and then received either fish oil capsules containing 3.2 g of eicosapentaenoic acid and 2.0 g of docohexaenoic acid (fish oil diet, n = 8) or placebo capsules (placebo diet, n = 8) daily for 3 weeks. At the beginning of the study (normal diet) and at the end of each treatment phase, the following pre-exercise and postexercise measures were assessed: (1) pulmonary function; (2) induced sputum differential cell count percentage and proinflammatory eicosanoid metabolite (leukotriene C4 [LTC4]-leukotriene E4 [LTE4] and prostaglandin D2 [PGD2]) and cytokine (interleukin [IL]-1β and tumor necrosis factor [TNF]-α) concentrations; and (3) eicosanoid metabolites leukotriene B4 (LTB4) and leukotriene B5 (LTB5) generation from activated polymorphonuclear leukocytes (PMNLs).

Results: On the normal and placebo diet, subjects exhibited EIB. However, the fish oil diet improved pulmonary function to below the diagnostic EIB threshold, with a concurrent reduction in bronchodilator use. Induced sputum differential cell count percentage and concentrations of LTC4-LTE4, PGD2, IL-1β, and TNF-α were significantly reduced before and following exercise on the fish oil diet compared to the normal and placebo diets. There was a significant reduction in LTB4 and a significant increase in LTB5 generation from activated PMNLs on the fish oil diet compared to the normal and placebo diets.

Conclusion: Our data suggest that fish oil supplementation may represent a potentially beneficial nonpharmacologic intervention for asthmatic subjects with EIB.

Chest. 2006;129(1):50-55. doi:10.1378/chest.129.1.50
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Objective: To distinguish between differences in prevalence, asthma severity, and treatment to explain sex-related differences in hospitalized asthma patients.

Design: Medical record review.

Setting: Thirty US hospitals as part of the University HealthSystem Consortium Asthma Clinical Benchmarking Project.

Patients: A random sample of patients aged 2 to 54 years and admitted to the hospital for acute asthma from 1999 to 2000.

Measurements: Demographics, medical history, initial oxygen saturation, initial peak expiratory flow (adults), initial pulmonary index (children), emergency department course, length of hospital stay, and discharge plans.

Results: The cohort included 606 pediatric (aged 2 to 17 years) and 680 adult (aged 18 to 54 years) inpatients. The sex ratio varied significantly by age: 40% were girls 2 to 17 years of age, and 68% were women 18 to 54 years of age p < 0.001). Among children, girls did not differ from boys according to asthma history, pulmonary index scores, or hospital length of stay. Among adults, women were more likely to have a primary care provider (90% vs 73%, p < 0.001) but did not differ according to asthma history or recent medication use. Women had a higher mean initial PEF compared to men (43% of predicted vs 36% of predicted, p < 0.001) and higher median initial oxygen saturation (95% vs 93%, p = 0.002) but did not differ by hospital length of stay. No sex differences in discharge regimens were identified in children or adults.

Conclusions: Among US inpatients with acute asthma, male children are more common than female children, while women are more common in adults. The results in children are probably explained by prevalence differences, since no sex differences were seen in markers of asthma severity or treatment. In adults, increased symptoms in response to a given level of airway obstruction in women may contribute to the female predominance in asthma hospitalizations.

Original Research: COPD

Cilomilast for COPD*: Results of a 6-Month, Placebo-Controlled Study of a Potent, Selective Inhibitor of Phosphodiesterase 4
Chest. 2006;129(1):56-66. doi:10.1378/chest.129.1.56
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Background: COPD is a relentless, progressive disease. This study evaluated the efficacy of cilomilast, a selective phosphodiesterase (PDE) 4 inhibitor, in the treatment of COPD.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects with COPD. After a 4-week, single-blind, placebo run-in period, eligible subjects were randomized in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks. Subjects between 40 and 80 years of age who had received a diagnosis of COPD were eligible for the study. The primary efficacy variables were changes from baseline in trough (ie, predose) FEV1 and in total score of the St. George’s Respiratory Questionnaire (SGRQ). A key secondary end point was the incidence rate of COPD exacerbations.

Results: The average change from baseline in FEV1 over 24 weeks in the cilomilast group was an increase of 10 mL compared with a decrease of 30 mL in the placebo group (difference, 40 mL; p = 0.002). When averaged over 24 weeks, there was a clinically significant reduction in the mean total SGRQ score in subjects receiving cilomilast therapy, with a difference of 4.1 U compared with subjects who received placebo (p = 0.001). A greater percentage of subjects in the cilomilast group were exacerbation-free at 24 weeks (74%; p = 0.008) compared with placebo (62%). Adverse events were generally mild or moderate and were not unexpected for this class of medications. GI adverse events that interfered with daily activities (cilomilast, 17%; placebo, 8%) predominantly occurred within the first 3 weeks of initiating cilomilast therapy.

Conclusion: Cilomilast is an orally active, potent, and selective inhibitor of PDE-4. Cilomilast maintained pulmonary function and improved health status, and reduced the rate of COPD exacerbations during 24 weeks of treatment. This study supports the use of cilomilast, a novel, selective PDE-4 inhibitor, in subjects with COPD.

Original Research: SLEEP MEDICINE

Chest. 2006;129(1):67-75. doi:10.1378/chest.129.1.67
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Objectives: Treatment of obstructive sleep apnea syndrome (OSA) is often delayed because polysomnography, the recommended standard diagnostic test, is not readily available. We evaluated whether the diagnosis of sleep apnea could be inferred from the response to a treatment trial with nasal continuous positive airway pressure (CPAP).

Design: Study on diagnostic accuracy.

Setting: Sleep-disorders clinic of a university hospital.

Patients: Seventy-six sleepy snorers consecutively referred for sleep apnea evaluation.

Interventions: CPAP treatment trial over 2 weeks as an initial diagnostic test in comparison with polysomnography, and treatment success over ≥ 4 months.

Measurements and results: The main outcome was diagnostic accuracy of the CPAP trial. The trial result was positive if the patient had used CPAP for > 2 h per night and wished to continue therapy. This suggested sleep apnea. The trial was evaluated in terms of predicting an obstructive apnea/hypopnea index (AHI) > 10/h during polysomnography performed for validation, and in terms of identifying sleep apnea patients treated successfully over ≥ 4 months. Forty-four of 76 patients (58%) had sleep apnea as confirmed by an AHI > 10/h. The CPAP trial predicted sleep apnea with a sensitivity of 80%, a specificity of 97%, and positive and negative predictive values of 97% and 78%, respectively. In 35 of 76 sleep apnea patients (46%) with positive CPAP trial results, polysomnography could have been avoided. These patients were prescribed long-term CPAP therapy. After 4 months, 33 of 35 patients (94%) still used CPAP, and their symptoms remained improved. These patients were identified by the CPAP trial with positive and negative predictive values of 92% and 100%, respectively.

Conclusions: In a selected population, a CPAP trial may help to diagnose OSA, to identify patients who benefit from CPAP, and to reduce the need for polysomnography.

Prevalence and Correlates of Restless Legs Syndrome*: Results From the 2005 National Sleep Foundation Poll
Chest. 2006;129(1):76-80. doi:10.1378/chest.129.1.76
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Purpose: The purpose of this analysis was to investigate the prevalence and correlates of restless legs syndrome (RLS) symptoms in the 2005 National Sleep Foundation (NSF) Sleep in America 2005 Poll. The NSF poll is an annual telephone interview of a random, representative sample of US adults.

Methods: The NSF 2005 poll included 1,506 adults. Their mean age was 49 years, and 775 were women.

Results: Symptoms of RLS that included unpleasant feelings in the legs for at least a few nights a week, which were worse at night, were reported by 9.7% of individuals in this poll, including 8% of men and 11% of women. Those from the northeast United States were much less likely to be at risk than those from other regions of the country (p < 0.05). Those who were unemployed (p < 0.05) or smoked daily (p < 0.5) were more likely to be at risk for RLS, as were those with hypertension, arthritis, gastroesophageal reflux disease, depression, anxiety, and diabetes (p < 0.05 for all). Adults who were at risk for RLS appeared to also be at increased risk for sleep apnea and insomnia (p < 0.05), and were more likely to stay up longer than they planned, to take longer than 30 min to fall asleep, to drive when drowsy, and to report daytime fatigue than those who were not at risk (p < 0.05 for all). They were also more likely to report being late to work, missing work, making errors at work, and missing social events because of sleepiness than other respondents in the poll (p < 0.05 for all).

Conclusions: RLS is significantly associated with medical and psychiatric conditions, other sleep disorders, unfavorable lifestyle behaviors, and adverse effects on daytime function. Chest physicians who practice sleep medicine need to be able to identify and manage RLS, which is prevalent and is associated with considerable morbidity.

Chest. 2006;129(1):81-87. doi:10.1378/chest.129.1.81
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Objectives: In the present study, we evaluated the effect of nasal surgery on snoring time, snoring intensity, and sleep-disordered breathing. The role of abnormal cephalometry in treatment outcome was assessed.

Design: A cross-sectional prospective study.

Setting: University teaching hospital.

Patients: Forty consecutive snoring men who were referred to ENT Hospital because of a snoring problem or suspicion of sleep apnea.

Interventions: The patients underwent anterior rhinomanometry and polysomnography (PSG) with recording of snoring before and after operative treatment of nasal obstruction. Cephalometric radiographs were obtained before surgery.

Results: Nasal resistance decreased significantly in the overall patient group. Snoring time, snoring intensity, nocturnal breathing, and sleep architecture did not change after nasal surgery. Cephalometry did not predict operative outcome in these patients. Snoring intensity was found to be significantly higher during non-rapid eye movement (NREM) sleep than during rapid eye movement sleep.

Conclusions: Operative treatment of mainly structural nasal obstruction did not seem to decrease snoring intensity, snoring time, or sleep-disordered breathing in an objective assessment by PSG performed after surgery. The effect of treating inflammatory nasal changes during nocturnal breathing, as well as the role of cephalometry in the prediction of treatment outcome will need further evaluation. Higher snoring intensity related to NREM sleep may add to the sleep disturbance of a bed partner in the evening.

Topics: snoring , nose , nasal surgery
Chest. 2006;129(1):88-94. doi:10.1378/chest.129.1.88
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Study objectives: To evaluate the impact of obstructive sleep apnea syndrome (OSAS) on serum creatine phosphokinase (CK) levels.

Design: Single-center prospective cross-sectional study.

Setting: Academic sleep disorder center.

Patients: Two hundred one consecutive patients (mean [± SD] age, 54.9 ± 11.0 years; 155 men and 46 women; mean body mass index, 31.3 ± 6.9 kg/m2) with suspected sleep-disordered breathing.

Measurements and results: OSAS was confirmed in182 patients (apnea-hypopnea index [AHI], > 5 events per hour) and was ruled out in 19 patients (control subjects) by standard polysomnography. Sixty-six OSAS patients and 1 control patient showed an unexplained CK elevation. The mean baseline CK level was significantly higher in patients with severe OSAS (AHI, > 30 event per hour; n = 89) compared to those with mild-to-moderate OSAS (AHI, 5 to 30 events per hour; n = 93) and control subjects (191.4 ± 12.9 vs 134.3 ± 7.5 vs 107.1 ± 7.9 U/L, respectively; p < 0.01). Receiver operating curve analysis identified an optimal cutoff value of > 148 U/L (r = 0.660) for CK, which yielded a positive predictive value of 99%, a sensitivity of 43%, and a specificity of 95% for the diagnosis of OSAS. The mean nocturnal oxyhemoglobin saturation was the main predictor of CK level (r = 0.47; p < 0.001). Continuous positive airway pressure (CPAP) treatment resulted in a significant decline of CK levels both in patients with mild-to-moderate OSAS (n = 38; 129.7 ± 13.4 vs 96.7 ± 7.6 U/L, respectively; p < 0.001) and in patients with severe OSAS (n = 39; 187.7 ± 18.9 vs 132.2 ± 12.9 U/L, respectively; p < 0.001).

Conclusions: One third of our study population showed a mild-to-moderate elevation in CK level, which was highly predictive of OSAS. The application of CPAP therapy in OSAS patients resulted in a significant decrease in CK level. We speculate that OSAS may account for a substantial number of cases of unexplained CK elevation (ie, hyperCKemia). Further studies should address the prevalence of OSAS in patients with mild-to-moderate hyperCKemia.

Original Research: RESPIRATORY INFECTION

Chest. 2006;129(1):95-101. doi:10.1378/chest.129.1.95
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Study objectives: To report the efficacy and findings of a large-scale preventive screening program for severe acute respiratory syndrome-associated coronavirus (SARS-CoV) using amplification of the virus from a nasopharyngeal swab (NPS) obtained from the health-care workers (HCWs).

Design: A prospective observational study.

Setting: A medical center in Taiwan.

Participants: Two hundred thirty HCWs.

Intervention: NPS examination for the presence of SARS-CoV by two nested reverse transcription-polymerase chain reaction (RT-PCR) assays.

Measurements and results: During the outbreak of severe acute respiratory syndrome (SARS), NPS polymerase chain reaction screening of HCWs for SARS-CoV was performed. SARS-CoV was examined by two nested RT-PCRs and a quantitative RT-PCR. Serum-specific antibodies were assessed by enzyme immunoassay and indirect immunofluorescence. We monitored 230 HCWs, including 217 first-line HCWs and 13 non–first-line HCWs. One hundred ninety first-line HCWs and 13 non–first-line HCWs had negative results in both nested RT-PCR assays. Two first-line HCWs who were positive on both nested RT-PCR assays had SARS. They had 16,900 ± 7,920 copies (mean ± SD) of RNA per milliliter in the NPS and had detectable anti-SARS antibodies. The remaining 25 first-line HCWs were negative for the first nested RT-PCR but positive for the second nested RT-PCR. Their corresponding titers were 338 ± 227 copies of RNA per milliliter; antibodies developed in none of these 25 HCWs. The expression and function of angiotensin-converting enzyme-2 were not different among these HCWs. This study shows that colonization of SARS-CoV occurred in 25 of 217 well-protected first-line HCWs on a SARS-associated service, but they remained seronegative.

Conclusion: With the second RT-PCR assay more sensitive than the first RT-PCR assay, we are able to show that approximately 11.5% of well-protected HCWs exposed to SARS patients or specimens may have colonization without seroconversion. Only those with significant clinical symptoms or disease would have active immunity. Thus, regular NPS screening for nested RT-PCR assays in conjunction with a daily recording of body temperature in all first-line HCWs may provide an effective way of early detection.

Chest. 2006;129(1):102-109. doi:10.1378/chest.129.1.102
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Study objectives: Acinetobacter baumannii (AB) is an important cause of hospital-acquired pneumonia (HAP), and an uncommon but important cause of community-acquired pneumonia (CAP) with high mortality. To better characterize CAP-AB, we compared its clinical features and outcomes with a control group of HAP-AB patients.

Methods: This is a retrospective case-control study comparing CAP-AB and HAP-AB patients, which was performed at United Christian Hospital between July 2000 and December 2003.

Results: There were 19 cases of CAP-AB and 74 cases of HAP-AB. When compared with the HAP-AB group, the CAP-AB group had more ever-smokers (84.3% vs 55.4%, respectively; p = 0.031), more COPD patients (63.2% vs 29.7%, respectively; p = 0.014), and fewer median days of hospitalization (HAP-AB group, median, 0 days; CAP-AB group, 0 days [range, 0 to 30 days]; p = 0.049) in the previous year. The CAP-AB group had more patients with positive blood culture findings (31.6% vs 0%, respectively; p < 0.001), a higher frequency of ARDS (84.2% vs 17.6%, respectively; p < 0.001), and disseminated intravascular coagulation (DIC) (57.9% vs 8.1%, respectively; p < 0.001). The median survival time was only 8 days in the CAP-AB group, vs 103 days in the HAP-AB group (p = 0.003). Factors associated with the higher mortality in the CAP-AB group included the presence of AB bacteremia (p = 0.040), platelet count of < 120 × 109 cells/L (p = 0.026), pH < 7.35 on presentation (p = 0.047), and the presence of DIC (p = 0.004).

Conclusions: CAP-AB appears to be a unique clinical entity with a high incidence of bacteremia, ARDS, DIC, and death, when compared to HAP-AB. Further studies are needed to investigate the mechanism of the fulminant nature of CAP-AB.

Chest. 2006;129(1):110-117. doi:10.1378/chest.129.1.110
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Background: Recovery of Candida from the respiratory tract of a critically ill patient receiving mechanical ventilation (MV) usually indicates colonization rather than infection of the respiratory tract. However, interactions between Candida and bacteria, particularly Pseudomonas, have been reported. Thus, Candida colonization of the respiratory tract may predispose to bacterial ventilator-associated pneumonia (VAP).

Methods: In a multicenter study of immunocompetent critically ill patients receiving MV for > 2 days, we compared the incidence of pneumonia in patients with and without (exposed/unexposed) respiratory-tract Candida colonization, matched on study center, admission year, and MV duration.

Results: Over the 4-year study period, of the 803 patients meeting study inclusion criteria in the six study centers, 214 patients (26.6%) had respiratory tract Candida colonization. Candida albicans was the most common species (68.7%), followed by Candida glabrata (20.1%) and Candida tropicalis (13.1%). Extrapulmonary Candida colonization was more common in exposed patients (39.7% vs 8.3%, p = 0.01). Exposed patients had longer ICU and hospital stays but similar mortality to unexposed patients. The matched exposed/unexposed nested cohort study identified bronchial Candida colonization as an independent risk factor for pneumonia (24.1% vs 17.6%; adjusted odds ratio [OR], 1.58; 95% confidence interval [CI], 0.94 to 2.68; p = 0.0860); the risk increase was greatest for Pseudomonas pneumonia (9% vs 4.8%; adjusted OR, 2.22; 95% CI, 1.00 to 4.92; p = 0.049).

Conclusions: Candida colonization of the respiratory tract is common in patients receiving MV for > 2 days and is associated with prolonged ICU and hospital stays, and with an increased risk of Pseudomonas VAP.

Original Research: AIRWAY SECRETIONS

Chest. 2006;129(1):118-123. doi:10.1378/chest.129.1.118
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Objective: It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment.

Design, setting, participants: PCD patients (n = 19; mean age, 9.5 ± 3.0 years [± SD]; FEV1, 65.0 ± 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 ± 2.6 years; FEV1, 61.8 ± 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits.

Measurements: Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability.

Results: Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum.

Conclusions: It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.

Chest. 2006;129(1):124-132. doi:10.1378/chest.129.1.124
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Objective: In vitro data suggest that the S-enantiomer of albuterol can induce mucociliary dysfunction. This clinical study assesses the clinical significance of standard doses of the S-enantiomer on airway secretions in long-term intubated patients by comparing a racemic formulation of albuterol, an R-enantiomer formulation, and normal saline solution.

Design: A placebo-controlled crossover study.

Patients: Fourteen stable intubated patients with a median duration of intubation of 21 months and a median age of 72 years.

Setting: Long-term ventilator unit in skilled nursing facility.

Interventions: Following a 2-week washout period during which regularly scheduled β2-agonists were discontinued, tracheal aspirates were collected for 4 h/d for a 5-day period to establish baseline values, and the patients were then randomized in crossover manner to each of three nebulized treatments: normal saline solution, racemic albuterol, and R-albuterol. Each treatment was administered three times daily for 5 days, followed by a 2-day washout.

Measurements: Tracheal aspirates were analyzed for volume, sodium, chloride, bicarbonate, interleukin (IL)-8, IL-1β, soluble intercellular adhesion molecule, and tumor necrosis factor-α.

Results: There were no consistent significant differences among the three treatment periods either in terms of volume of secretions or in the concentrations of the electrolytes or the inflammatory indexes. However, all three treatments, including saline solution, were associated with increased secretion volume after the first dose, but this effect was not apparent on subsequent doses.

Conclusion: There were no significant differences between racemic albuterol and R-albuterol observed in this study for any of the parameters studied, suggesting that the S-enantiomer does not adversely affect airway secretions at recommended doses. In addition, the routine administration of nebulized β2-sympathomimetic agonists to stable patients undergoing prolonged intubation, for the sole purpose of changing the volume and composition of secretions of airway secretions, is not supported by the results of this study.

Original Research: ACUTE VENTILATORY FAILURE

Prolonged Invasive Ventilation Following Acute Ventilatory Failure in COPD*: Weaning Results, Survival, and the Role of Noninvasive Ventilation
Chest. 2006;129(1):133-139. doi:10.1378/chest.129.1.133
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Background: Invasive ventilation for COPD has significant mortality, and weaning can be difficult. At Papworth Hospital, we provide a specialist weaning service using noninvasive ventilation (NIV) for patients requiring prolonged invasive ventilation after recovery from acute illness. We analyzed our results for patients with COPD to identify factors associated with weaning outcome and survival.

Methods: A retrospective analysis was conducted of COPD patients admitted for weaning from invasive ventilation, from 1992 to 2003. Weaning success and survival were assessed. Associations were sought between these outcomes and age, sex, spirometry, arterial blood gas levels, APACHE (acute physiology and chronic health evaluation) II score, length of stay (LOS), and the use of NIV and long-term oxygen therapy.

Results: Sixty-seven patients were identified, all of whom were receiving tracheostomy ventilation on transfer to the Respiratory Support and Sleep Centre (RSSC). Sixty-four patients (95.5%) were weaned, and 62 patients survived to hospital discharge. NIV was used in weaning 40 patients and in the long term in 25 patients. Median survival was 2.5 years (interquartile range, 0.7 to 4.6 years). One-year, 2-year, and 5-year survival rates were 68%, 54%, and 25%, respectively. Long-term survival was inversely associated with age and LOS in the ICU and the RSSC. The provision of maintenance NIV after weaning was associated with better long-term survival, independent of age and LOS (hazard rate, 0.48; p = 0.03).

Conclusions: These results demonstrate that a specialist multidisciplinary approach, including the use of NIV, can be successful in weaning most COPD patients from prolonged invasive ventilation. The data also suggest that long-term NIV may improve survival in selected patients.

Original Research: OSTEOPOROSIS

Chest. 2006;129(1):140-146. doi:10.1378/chest.129.1.140
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Study objectives: There are no studies focused on skeletal status in patients with diffuse parenchymal lung disease (DPLD). We hypothesized that patients with DPLD referred for lung transplantation would have a high prevalence of osteoporosis related to corticosteroid use or reduced pulmonary function and exercise capacity.

Design: Retrospective cohort study.

Setting: Tertiary care center.

Patients: Eighty-six patients with DPLD referred to our center for lung transplantation evaluation between March 1999 and April 2004.

Measurements and results: Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at the lumbar spine, femoral neck, total hip, and radius at the time of referral. Criteria developed by the World Health Organization were used to define osteopenia and osteoporosis. Fifty-five patients (64%) had usual interstitial pneumonia-pattern lung disease, 14 patients (16%) had nonspecific interstitial pneumonia-pattern lung disease, and 17 patients (20%) had other forms of DPLD. Sixty-four patients (74%) were receiving corticosteroids, and 43 patients (50%) were receiving preventive therapy for osteoporosis. Eleven patients (13%; 95% confidence interval [CI], 7 to 22%) met criteria for osteoporosis at any site, and 49 patients (57%; 95% CI, 46 to 68%) had osteopenia. Lower body mass index (BMI) [adjusted odds ratio (OR), 1.3; 95% CI, 1.1 to 1.6; p = 0.007] and Hispanic ethnicity (adjusted OR, 9.7; 95% CI, 1.8 to 52; p = 0.008) were independently associated with an increased risk of osteoporosis. Linear regression analysis confirmed that BMD at the femoral neck and hip was directly associated with BMI (p < 0.002). These findings were not affected by adjustment for the use of corticosteroids or osteoporosis prophylaxis, pulmonary function, or exercise performance.

Conclusions: Reduced BMD was common in patients with DPLD who were referred for lung transplantation. Lower BMD was associated with lower BMI, whereas there was no association with other clinical factors in our cohort. Hispanic patients with DPLD had a higher risk of osteoporosis than non-Hispanic patients, independent of other variables. Given their increased risk of bone loss, patients with DPLD should undergo screening for osteoporosis and receive prophylaxis and treatment according to published guidelines.

Original Research: INTERVENTIONAL BRONCHOSCOPY

Chest. 2006;129(1):147-150. doi:10.1378/chest.129.1.147
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Study objectives: Transbronchial biopsy (TBBX) for solitary pulmonary nodules (SPNs) is usually performed under fluoroscopic guidance, but the diagnostic yield depends on lesion size and varies widely. Nodules < 3 cm frequently cannot be visualized fluoroscopically. An alternative guidance technique, endobronchial ultrasound (EBUS), also allows visualization of pulmonary nodules. This study assessed the diagnostic yield of EBUS-guided TBBX in fluoroscopically invisible SPNs.

Design: The study was a prospective trial using a crossover design.

Patients and methods: All patients with SPNs and indications for bronchoscopy were included in the study. An EBUS-guided examination was performed in patients with fluoroscopically invisible nodules. The EBUS probe was introduced through a guide catheter into the presumed segment. If a typical ultrasonic picture of solid tissue could be seen, the probe was removed and the catheter left in place. The biopsy forceps were introduced and specimens taken.

Results: One hundred thirty-eight consecutive patients with SPNs were examined. Of those, 54 patients presented with SPNs that could not be visualized with fluoroscopy. The mean diameter of the nodules was 2.2 cm. In 48 patients (89%), the lesion was localized with EBUS, and in 38 patients (70%) the biopsy established the diagnosis. The 16 patients with undiagnosed SPNs were referred for surgical biopsy; 10 of those lesions were malignant and 6 were benign. The diagnosis in nine patients (17%) saved the patients from having to undergo a surgical procedure. The only complication was a pneumothorax in one patient.

Conclusions: EBUS-guided TBBX is a safe and very effective method for SPNs that cannot be visualized by fluoroscopy. The procedure may increase the yield of endoscopic biopsy in patients with these nodules and avert the need for surgical procedures.

Translating Basic Research Into Clinical Practice

Reduced Histone Deacetylase in COPD*: Clinical Implications
Chest. 2006;129(1):151-155. doi:10.1378/chest.129.1.151
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COPD is characterized by progressive inflammation in the small airways and lung parenchyma, and this is mediated by the increased expression of multiple inflammatory genes. The increased expression of inflammatory genes is regulated by acetylation of core histones around which DNA is wound, and conversely these activated genes are switched off by deacetylation of these histones. Histone deacetylases (HDACs) suppress inflammatory gene expression, but their activity and expression (particularly of HDAC-2) is reduced in the peripheral lung and in alveolar macrophages of patients with COPD. This results in amplification of the inflammatory response as COPD progresses but also accounts for corticosteroid resistance in COPD, since HDAC-2 is required by corticosteroids to switch off activated inflammatory genes. The reduction in HDAC-2 appears to be secondary to the increased oxidative and nitrative stress in COPD lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low doses of theophylline, which is an HDAC activator. This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased.

Global Medicine

Chest. 2006;129(1):156-168. doi:10.1378/chest.129.1.156
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Seroepidemiologic and virologic studies since 1889 suggested that human influenza pandemics were caused by H1, H2, and H3 subtypes of influenza A viruses. If not for the 1997 avian A/H5N1 outbreak in Hong Kong of China, subtype H2 is the likely candidate for the next pandemic. However, unlike previous poultry outbreaks of highly pathogenic avian influenza due to H5 that were controlled by depopulation with or without vaccination, the presently circulating A/H5N1 genotype Z virus has since been spreading from Southern China to other parts of the world. Migratory birds and, less likely, bird trafficking are believed to be globalizing the avian influenza A/H5N1 epidemic in poultry. More than 200 human cases of avian influenza virus infection due to A/H5, A/H7, and A/H9 subtypes mainly as a result of poultry-to-human transmission have been reported with a > 50% case fatality rate for A/H5N1 infections. A mutant or reassortant virus capable of efficient human-to-human transmission could trigger another influenza pandemic. The recent isolation of this virus in extrapulmonary sites of human diseases suggests that the high fatality of this infection may be more than just the result of a cytokine storm triggered by the pulmonary disease. The emergence of resistance to adamantanes (amantadine and rimantadine) and recently oseltamivir while H5N1 vaccines are still at the developmental stage of phase I clinical trial are causes for grave concern. Moreover, the to-be pandemic strain may have little cross immunogenicity to the presently tested vaccine strain. The relative importance and usefulness of airborne, droplet, or contact precautions in infection control are still uncertain. Laboratory-acquired avian influenza H7N7 has been reported, and the laboratory strains of human influenza H2N2 could also be the cause of another pandemic. The control of this impending disaster requires more research in addition to national and international preparedness at various levels. The epidemiology, virology, clinical features, laboratory diagnosis, management, and hospital infection control measures are reviewed from a clinical perspective.

Topics in Practice Management

Chest. 2006;129(1):169-173. doi:10.1378/chest.129.1.169
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Pulmonary rehabilitation services benefit patients with chronic lung disease by reducing symptoms and restoring independent function. With a multidisciplinary approach to individual patient care through education, exercise, and psychosocial interventions, health-care costs and utilization may be reduced. While pulmonary rehabilitation services have typically been provided in a facility setting, many respiratory care services can be safely provided and appropriately reimbursed in the outpatient physician office setting, with appropriate physician supervision. After reviewing the utility of pulmonary rehabilitation for patients with chronic lung disease, the supervision, documentation, coding, and reimbursement requirements for providing rehabilitative respiratory care services in the outpatient office setting are detailed.

Special Features

Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines*: Report From an American College of Chest Physicians Task Force
Chest. 2006;129(1):174-181. doi:10.1378/chest.129.1.174
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While grading the strength of recommendations and the quality of underlying evidence enhances the usefulness of clinical guidelines, the profusion of guideline grading systems undermines the value of the grading exercise. An American College of Chest Physicians (ACCP) task force formulated the criteria for a grading system to be utilized in all ACCP guidelines that included simplicity and transparency, explicitness of methodology, and consistency with current methodological approaches to the grading process. The working group examined currently available systems, and ultimately modified an approach formulated by the international GRADE group. The grading scheme classifies recommendations as strong (grade 1) or weak (grade 2), according to the balance among benefits, risks, burdens, and possibly cost, and the degree of confidence in estimates of benefits, risks, and burdens. The system classifies quality of evidence as high (grade A), moderate (grade B), or low (grade C) according to factors that include the study design, the consistency of the results, and the directness of the evidence. For all future ACCP guidelines, The College has adopted a simple, transparent approach to grading recommendations that is consistent with current developments in the field. The trend toward uniformity of approaches to grading will enhance the usefulness of practice guidelines for clinicians.

Addressing Resource Allocation Issues in Recommendations From Clinical Practice Guideline Panels*: Suggestions From an American College of Chest Physicians Task Force
Chest. 2006;129(1):182-187. doi:10.1378/chest.129.1.182
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Most panels that develop clinical practice guidelines are poorly equipped to address resource allocation or cost issues associated with management options. This risks neglect, arbitrariness, lack of transparency, and methodological flaws in consideration of resource allocation. We provide recommendations for guideline panels to promote greater transparency and rigor. We suggest focusing on resource allocation issues for only a limited number of recommendations and provide criteria for selecting those in which economic considerations are likely to influence the direction or strength of the recommendation. Panels should involve a health economist to assist with the systematic review and critical interpretation of relevant economic analyses. They should carefully define the intended audience and may consider issuing alternative recommendations when available resources vary widely across target clinical settings. Targeting a limited number of recommendations for the consideration of resource allocation issues, and ensuring methodologically high-quality review, will best serve guideline panels, and the health-care providers and patients they hope to assist.

Chest. 2006;129(1):188-191. doi:10.1378/chest.129.1.188
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Performance measures and pay for performance are terms creating considerable angst among physicians today. Understanding the driving forces behind these concepts will help practitioners to strategically plan for their impact on individual physician practices and on health care in general. Medical societies can play a vital role in assisting physicians in the identification of appropriate performance measures used to gauge physician practices and by supporting efforts to develop equitable principles driving reimbursement based on adherence to those measures. Performance measures and pay for performance are terms evoking considerable angst across all sectors of the health services industry.

Chest. 2006;129(1):192-197. doi:10.1378/chest.129.1.192
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Study objectives: Much attention has been paid in recent years to optimizing the diagnosis of acute pulmonary embolism (PE). However, little is known about the changes in clot burden that occur at the level of the pulmonary arteries after documented PE. It is often problematic to distinguish between a new or residual defect on lung scintigraphy or helical CT. This may lead to falsely labeling patients with residual PE as having recurrent PE and consequent unnecessary treatment changes.

Design: We performed a systematic analysis of studies of imaging tests (radionuclide and CT) evaluating resolution rate of PE with independent assessment of predefined methodologic criteria by two investigators.

Results: We identified 29 clinical studies. Of these, 25 studies were excluded and 4 studies were included in our review. Because studies differed largely in patient selection, duration of anticoagulation, and timing of follow-up, the studies were not pooled but briefly described. The percentage of patients with residual pulmonary thrombi was 87% at 8 days after diagnosis, 68% after 6 weeks, 65% after 3 months, 57% after 6 months, and 52% after 11 months.

Discussion: This review shows that complete resolution of PE is not routinely achieved between 8 days and 11 months after diagnosis. More than 50% of patients with PE still have defects 6 months after diagnosis, after which resolution of thrombi appears to reach a plateau phase. Physicians should be aware of the high percentage of incomplete resolution of pulmonary emboli. Routine re-imaging after cessation of anticoagulant therapy in patients with PE to obtain a new baseline could be considered.

Unrecognized Sleep Apnea in the Surgical Patient*: Implications for the Perioperative Setting
Chest. 2006;129(1):198-205. doi:10.1378/chest.129.1.198
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Anesthesia and surgery both affect the architecture of sleep. Aside from the postoperative effects of anesthesia and surgery, sleep deprivation and fragmentation have been shown to produce apneas or desaturations even in patients without presumed sleep apnea. Recent epidemiologic data have placed the prevalence of obstructive sleep apnea syndrome (OSAS) at about 5% among Western countries. The problem is further hindered by the difficulty in diagnosing OSAS, as patients with OSAS may present for surgery without a prior diagnosis. Clinical suspicion for OSAS may first be recognized intraoperatively. Adverse surgical outcomes appear to be more frequent in OSAS patients. Immediate postoperative complications may intuitively be attributed to the negative effects of sedative, analgesic, and anesthetic agents, which can worsen OSAS by decreasing pharyngeal tone, and the arousal responses to hypoxia, hypercarbia, and obstruction. Later events are, however, more likely to be related to postoperative rapid eye movement (REM) sleep rebound. In the severe OSAS patient, REM sleep rebound could conceivably act in conjunction with opioid administration and supine posture to aggravate sleep-disordered breathing. REM sleep rebound has also been suggested to contribute to mental confusion and postoperative delirium, myocardial ischemia/infarction, stroke, and wound breakdown. Although the data to guide the perioperative management of patients with moderate-to-severe OSAS is scarce, heightened awareness is recommended. The selected use of therapy with nasal continuous positive airway pressure before surgery and after extubation may be beneficial.

Learning Objectives: 1. Identify common sleep architectures affected by anesthesia and surgery in the perioperative period. 2. State a perioperative complication in Obstructive Sleep Apnea Syndrome patients. 3. Identify perioperative interventions and management techniques that best facilitate improved obstructive sleep apnea syndrome patient care.

Postgraduate Education Corner: PULMONARY AND CRITICAL CARE PEARLS

Chest. 2006;129(1):206-209. doi:10.1378/chest.129.1.206
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A 47-year-old man employed as a sound technician presented to our clinic with 3-month history of chronic cough and shortness of breath. His symptoms included marked worsening dyspnea initially with activity but later with only minimal exertion. He had also noticed worsening cough, orthopnea, and ankle swelling. Based on his history of congestive heart failure, he was treated with diuretics with only mild improvements in symptoms. At presentation, dyspnea would develop with approximately 100 yards of walking.

Correspondence

Chest. 2006;129(1):210-211. doi:10.1378/chest.129.1.210
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Chest. 2006;129(1):211. doi:10.1378/chest.129.1.211
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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543