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1 Division of Pulmonary Sciences and Critical Care Medicine Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
This is the first in a series of four executive summaries of the Clinical Year in Review sessions presented at the American Thoracic Society International Conference in May, 2008. The main topics of each talk have been abstracted by the session chair based on the annotated bibliography provided by each presenter.
LUNG CANCER
Charles A. Powell
Pulmonary, Allergy, and Critical Care Medicine
Columbia University
New York, New York
Lung cancer is the leading cause of cancer-related deaths and accounts for more cancer-related deaths than the sum of the next three most common causes of cancer-related deaths (breast, prostate, and colorectal). On a promising note, the overall 5-year mortality from lung cancer has decreased slightly, from 15 to 13%. In this Clinical Year in Review, four topics related to lung cancer were discussed, including improvements in the ability to identify patients at risk for the development of lung cancer, improvements in the ability to staging the mediastinum, the role of neoadjuvant chemotherapy for patients with resectable non–small cell lung cancer, and the role of gene expression biomarkers to assist in determining prognosis and treatment response for patients with lung cancer.
The first article, by Turner and colleagues, examined whether chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer that is independent of cigarette smoking (1). This study was a secondary analysis of patients previously enrolled into the American Cancer Society Prevention Cohort II. A total of 1.2 million individuals were prospectively followed over a 20-year period. The 448,000 nonsmokers who were enrolled constituted the primary cohort for the Turner study. A questionnaire was completed by each participant asking him or her to list up to 25 medical conditions, including the diagnosis of emphysema and chronic bronchitis. The primary endpoint of this study was lung cancer death rates per 100,000 person-years. The hazard ratios (HRs) for lung cancer were increased in those individuals who had a diagnosis of emphysema alone (HR, 1.66; 95% confidence interval [CI], 1.09–2.59) or a diagnosis of both emphysema and chronic bronchitis (HR, 2.44 95% CI of 1.22–4.90), but not for those individuals with chronic bronchitis alone. Because of a known association between gender and susceptibility to both COPD and lung cancer, the authors further stratified their analysis by gender. They identified a significant interaction between chronic bronchitis and gender. There was a positive, although not statistically significant, association between chronic bronchitis and lung cancer in men with an HR of 1.59, and a protective association in women with an HR of 0.82. The strengths of this article are the large size of the cohort and its prospective nature. This study suggests a possible linkage between COPD and the pathogenesis of lung cancer that is independent of cigarette smoking, and therefore may suggest a role for chronic inflammation in the development of lung cancer.
For patients with newly diagnosed lung cancer, mediastinoscopy or thoracoscopy has been considered the standard surgical procedure to adequately stage a patient with suspicious mediastinal lymph nodes. Recently, less invasive alternatives, such as endoscopic ultrasound–guided fine needle aspiration and endobronchial ultrasound–guided fine needle aspiration, have been developed and are being more commonly used in clinical practice. The next study examined the diagnostic accuracy of three procedures to stage the mediastinum in patients with lung cancer: blinded transbronchial needle aspiration, endobronchial ultrasound–guided fine needle aspiration, and endoscopic ultrasound–guided fine needle aspiration (2). A total of 138 patients with known or suspected lung cancer were enrolled and all three diagnostic procedures were performed during a single visit. A diagnosis of cancer was considered to be positive if there was pathologic confirmation by any of the procedures, including pathologic confirmation during a subsequent mediastinoscopy or thoracotomy. Of note, any cytology that was reported as being suspicious was considered to be a positive diagnosis of lung cancer. Patients were considered to have negative staging if there was no evidence of cancer at the time of surgical staging or if there was no mediastinal enlargement during the next 6–12 months. The average time required to perform the three diagnostic procedures was 62 minutes. A positive diagnosis was obtained in 30% of the patients. The blinded transbronchial needle aspiration procedure was not very accurate diagnostically, with a sensitivity of only 36% and a negative predictive value of 78%. When examined individually, endobronchial ultrasound–guided fine needle aspiration and endoscopic ultrasound–guided fine needle aspiration were better in diagnosis of disease than the blind transbronchial needle aspiration because both tests had a sensitivity of 69% and negative predictive value of 88%. When examined in combination, endobronchial ultrasound–guided fine needle aspiration and endoscopic ultrasound–guided fine needle aspiration together yielded the best results, with a sensitivity of 93% and a negative predictive value of 97%. Endobronchial ultrasound–guided fine needle aspiration was more accurate for sampling nodes in posterior tracheal and the lower paratracheal stations, and endoscopic ultrasound–guided fine needle aspiration more accurately sampled nodes at the aortic–pulmonary artery window and paraaortic stations. The results of this study should be interpreted with caution because the sensitivity of these procedures may have been overestimated due to the inclusion of suspicious results as being positive. In addition, issues related to training for these procedures may impact the feasibility of routinely performing both procedures in a single session. However, both endobronchial ultrasound–guided fine needle aspiration and endoscopic ultrasound–guided fine needle aspiration appear to be less invasive procedures that may accurately staging the mediastinum for patients with lung cancer.
Adjuvant chemotherapy improves survival in selected patients with early resectable stage II and III and a subset of stage IB non–small cell lung cancer. Neoadjuvant chemotherapy has the potential advantage of downstaging patients and facilitating complete resection, assessing the response to chemotherapy, and reducing micrometastatic disease preoperatively. Prior studies have suggested a potential benefit to neoadjuvant chemotherapy when compared with surgery alone (3, 4). In the next article that was discussed during this session, Gilligan and colleagues assessed the effect of neoadjuvant chemotherapy with three cycles of a platinum-based therapy followed by surgery compared with surgery alone for patients with resectable non–small cell lung cancer (5). The primary outcome measure was overall 3-year survival. A total of 75% of patients were able to receive all three cycles of chemotherapy. Patients who received neoadjuvant chemotherapy were able to be downstaged with regard to their lung cancer compared with surgery alone. However, these results must be interpreted with caution because staging in the neoadjuvant group was determined preoperatively with computed tomography (CT) scanning and staging in the surgery group was determined operatively at the time of surgery. The administration of neoadjuvant chemotherapy did not result in a reduction in the health-related quality of life at 12 or 36 months. With regard to the primary outcome of overall survival, there was no evidence of benefit with neoadjuvant chemotherapy. However, the results of this study did demonstrate that neoadjuvant chemotherapy is at least feasible based on the high compliance rates and modest reports of toxicity. There are two ongoing studies in Europe and the United States that are directly comparing neoadjuvant with adjuvant chemotherapy for patients with non–small cell lung cancer. Until results of these trials are available, the present evidence indicates that the favored approach for resectable non–small cell lung cancer is surgery followed by consideration of adjuvant chemotherapy.
Tumor staging remained the strongest predictor of survival in patients with lung cancer (6). The molecular profiling of resected tumors can also provide important information about risk of recurrence and death in patients with non–small cell lung cancer (7–9). However, the prognostic gene lists reported to date overlap poorly across studies, and few of these genes have been validated independently using more quantitative assay methods. The authors of the next study examined the expression of 158 putative prognostic genes identified in previous microarray studies that was analyzed by reverse transcription quantitative polymerase chain reaction in the tumors of 147 patients with non–small cell lung cancer (10). The authors showed that the three-gene profile of syntaxin 1A (STX1A), chemokine (C-C motif) receptor 7 (CCR7), and hypoxia-inducible factor 1
(HIF1A), when combined with clinical staging, improved the ability to predict prognosis when compared with clinical staging alone. Therefore, gene expression data may add important information to the prognostic ability of clinical staging. Independent comparison of the predictive accuracy of these signatures and prospective clinical trials are appropriate and required to move this important area of research forward.
PLEURAL DISEASE
John E. Heffner
Providence Portland Medical Center
Portland, Oregon
This Clinical Year in Review session covered four important topics related to pleural disease: the role of thoracoscopy for primary spontaneous pneumothorax, the treatment of empyema, the pleural staging of lung cancer, and analysis of pleural fluid and radiologic characteristics in patients with acute pulmonary embolism.
Because patients with primary spontaneous pneumothorax have a high rate of recurrence, surgical treatment to excise blebs in the peripheral lung parenchyma is often recommended. Needle video-thoracoscopic surgery (NVTS) has been used for a decade in the management of hyperhidrosis by sympathectomy with excellent cosmetic results, but its application for pulmonary indications had not been examined. Cheng and colleagues performed a retrospective review of NVTS compared with conventional video-thoracoscopic surgery (CVTS) in the treatment of patients with primary spontaneous pneumothorax (11). The potential advantage of NVTS is the use of smaller-diameter instruments with better cosmetic results. The authors reviewed the records of 75 patients (9 female and 66 male) with primary spontaneous pneumothorax. A total of 22 patients were treated with NVTS using a needle-shaped thoracoscope with 3-mm-diameter instruments and one standard 10-mm port. The remaining 53 patients received CVTS using three conventional 10-mm ports. All patients underwent endoscopic stapling to excise the identified blebs. Neither group experienced mortality or major morbidity during the mean follow-up time of 81 months. Intraoperative blood loss, mean operative times, and the degree of postoperative wound pain were not different between the two groups. However, mean duration of pleural drainage and postoperative hospital stay were significantly less in the NTVS group (on average by 2 d for both outcomes). There was no recurrence of pneumothorax in the NVTS group and a 3.6% recurrence rate in the CVTS group. The results of this study demonstrate that NVTS can effectively manage primary spontaneous pneumothorax when compared with CVTS. However, because this study was retrospective and nonrandomized in nature, selection bias may have influenced the results. Therefore, a prospective randomized clinical trial would assist in determining the effectiveness of these two procedures in the management of primary spontaneous pneumothorax.
Talc insufflation via thoracoscopy may be used to treat patients with primary spontaneous pneumothorax if the pneumothorax fails to resolve with simple aspiration. Talc has been reported to cause pleural fibrosis (12). However, the long-term effects of talc insufflation on lung function have not been well described. The next article evaluated the long-term outcomes of patients with primary spontaneous pneumothorax who were treated with talc pleurodesis without accompanying blebectomy (13). The investigators examined 122 patients with primary spontaneous pneumothorax who had undergone thoracoscopic pleurodesis with graded talc for either prolonged air leak or a recurrence of their pneumothorax. Patients with blebs greater than 2.0 cm in size were not included in this analysis. Follow-up data were available on 63 of the patients. These patients were followed, on average, for nearly 10 years. A total of 95% of the cohort had a successful pleurodesis, and there were no episodes of acute respiratory failure associated with the pleurodesis. Long-term success was also observed in 95% of patients; recurrent pneumothoraces occurred in the remaining 5% of patients. There were no long-term abnormalities in pulmonary function in these patients, defined as median FVC and TLC at the time of follow-up. The results of this study support the evidence that talc pleurodesis does not cause pleural fibrosis with the development of restrictive pulmonary physiology.
The treatment of patients with pleural empyema remains controversial. Existing consensus-based guidelines recommend a staged-based therapeutic approach for these patients (14). Solaini and colleagues performed a 12-year retrospective analysis of 120 patients treated with video-assisted thoracic surgery (VATS) as primary therapy for empyema (15). On the basis of a predefined protocol, 82 patients were initially treated with tube thoracostomy and 38 patients underwent immediate VATS. Primary tube thoracostomy was associated with frequent treatment failures, because only 10 of the 82 patients were sufficiently treated with tube thoracostomy alone. The remaining 72 patients required a subsequent VATS procedure. Of the 110 patients who underwent a VATS procedure either initially or subsequently, only 9.2% necessitated an intraoperative conversion to a thoractomy. The mean postoperative hospital stay was 7.1 days. VATS resulted in an uncomplicated postoperative course in 89% of the patients. Of the 80 patients who completed a 6-month follow-up evaluation, 72 had a satisfactory outcome. These findings confirm previous observations that treatment with initial tube thoracostomy is unlikely to successfully drain and treat pleural infections. Therefore, subsequent surgical intervention with a VATS should not be delayed if the initial trial of tube thoracostomy is unsuccessful.
Dr. Heffner also discussed a population-based analysis of the management of pleural space infections (16). This retrospective study examined a statewide database of 4,424 patients who were hospitalized for pleural infections between 1987 and 2004. The overall incidence rate for pleural space infections increased by 2.8% per year, and the proportion of patients who underwent an operative procedure increased from 42.4% in 1987 to 58.4% in 2004. The risk of death within 30 days was less for patients undergoing operations compared with those who did not undergo surgery. The patients who required surgery were, on average, younger and had a lower comorbidity index. The positive effects of surgery on 30-day mortality remained after adjusting for age, sex, comorbidity, and insurance status, with an odds ratio of 0.42. This study demonstrates improved outcomes for patients undergoing early surgical drainage, although these positive results may be related to residual confounding and selection bias because the study design was not randomized in nature.
The presence of a malignant effusion in patients with non–small cell lung cancer results in a stage IV diagnosis with a median survival of 4 months. The next study examined the prognostic value of cytology results from an intraoperative pleural lavage for staging of lung cancer (17). Clinical records of 1,025 patients with non–small cell lung cancer who required surgery were retrospectively reviewed. Pleural fluid that was evident during the surgery was sent for cytology. If there was no fluid present, a 1-L pleural space lavage was performed with normal saline and 10 ml of the lavage fluid was sent for cytology. Patients were categorized into three groups: 21 patients with a malignant effusion or frank dissemination of tumor into the pleural space, 27 patients with a positive cytology on the pleural space lavage without frank evidence of tumor dissemination into the pleural space, and 977 patients without any evidence of tumor in the pleural space. The 5-year survival rate was 69% for those patients with a negative pleural fluid lavage, 37% for patients with a positive pleural fluid lavage, and 17% for patients with frank evidence of tumor cells in the pleural space. These results were statistically significant, especially for those patients with stage I disease. These results provide evidence that intraoperative pleural fluid lavage should be performed and could be involved in the staging and prognosis of lung cancer.
Between 23 and 48% of patients with acute pulmonary embolism will have a pleural effusion on chest radiograph. One previous study had reported that pleural effusions due to pulmonary embolism may be either transudative or exudative (18). However, pleural fluid lactate dehydrogenase was not measured in more than half the patients, and a pleural fluid protein level of 30 g/L was predominantly used to separate transudates from exudates. To further examine these findings, the next study reviewed the frequency, radiographic characteristics, and pleural fluid analysis of 230 consecutive patients with pulmonary embolism over a 9-year period (19). Spiral CT pulmonary angiography and high-probability ventilation and perfusion scans were used to diagnose pulmonary embolism for over 94% of these patients. Pleural effusions were noted in 32 and 47% of patients by chest radiograph and CT scanning, respectively. The majority of effusions were unilateral (85%), and 90% occupied less than one-third of the pleural space. A total of 21% of the effusions were loculated on CT scan, and all (100%) of the effusions were exudative in nature. The results of this study advance our understanding of the characteristics and course of pulmonary embolism–related effusions and should improve our ability to consider and diagnose pulmonary embolism in those patients that present with a pleural effusion.
EXERCISE TESTING AND PULMONARY REHABILITATION
Linda Nici
Providence VA Medical Center
Brown University Department of Medicine
Providence, Rhode Island
According to the American Thoracic Society/European Respiratory Society statement published in 2006, pulmonary rehabilitation (PR) is "an evidence-based, multidisciplinary, and comprehensive intervention for patients with chronic respiratory diseases who are symptomatic and often have decreased daily life activities. Integrated into the individualized treatment of the patient, PR is designed to reduce symptoms, optimize functional status, increase participation, and reduce health care costs through stabilizing or reversing systemic manifestations of the disease" (20). On the basis of a large body of both clinical and basic research, PR is a highly effective intervention for COPD that improves exercise capacity, symptoms, and health-related quality of life, while reducing health care–associated costs. Exercise programs remain the cornerstone of PR. In a 2003 editorial in Thorax, Morgan presented the increasing evidence that nonpharmacologic interventions including physical activity may prevent hospital admissions for patients with COPD (21).
The major topics that were discussed in this Clinical Year in Review session dedicated to exercise testing and PR were the utility of different exercise approaches, novel and adjunctive strategies to optimize exercise, functional outcomes and survival after PR, and the effect of exercise on systemic inflammation in chronic diseases. Different exercise modalities have been studied in patients with COPD. However, it is presently unclear any specific modality is superior when compared with other exercise programs. Varga and colleagues examined three types of exercise training approaches to determine their relative effectiveness in patients with moderate COPD and hyperinflation (22). A total of 71 patients were assigned to one of three treatment modalities. All three of the programs included 45-minute exercise sessions performed 3 days a week for a total of 8 weeks. The first approach was a program that consisted of exercising continuously at 80% of the pretraining work rate. The second group performed interval training starting their session with 7.5 minutes of warm-up at 50% of their pretraining work rate, followed by 30 minutes alternating between 2 minutes at 90% and 1 minute at 50%, and concluding with a 7.5-minute cool-down period at 50% of their pretraining work rate. The third group was assigned to self-paced training program that was home-based and unsupervised. Patients assigned to this third group were instructed to cycle, climb stairs, and walk in a natural environment at the same weekly periodicity and time interval. Peak work rate and minute ventilation before training were similar in all groups, suggesting a similar degree of ventilatory limitation. The study demonstrated that peak oxygen uptake, lactic acidosis threshold, and peak work rate improved in both the continuous and interval training groups compared with the self-paced training program. However, differences between the groups were only significant for peak work rate. All three of the training programs improved the patient's perception of his or her ability to exercise. The authors speculated that the home-based exercise was inferior because it lacked frequent encouragement, instruction, and interaction with other patients. Therefore, high-intensity training, whether it is a continuous or interval-based program, improves physiologic endpoints in patients with COPD.
Patients with severe COPD are often limited by dyspnea, and therefore may only be able to exercise at a relatively low intensity. As compared with exercising with both legs, one-legged exercise may allow high-intensity training and address peripheral muscle deconditioning, while partitioning exercise to a smaller muscle mass and maintaining a similar muscle-specific load. Therefore, one-legged exercise may be able to reduce the general ventilatory load and enable patients to increase their work capacity. The next study, performed by Dolmage and colleagues, examined the hypothesis that one-legged exercise training may improve aerobic capacity as compared with two-legged training (23). Nonhypoxic patients with COPD were randomized to one of two exercise programs: a two-legged bicycle program to achieve 70% intensity for 30 minutes or a one legged program exercising one leg at a time at 50% intensity for 15 minutes. Both programs involved exercise for 3 days a week for a total of 7 weeks. Patients in both groups were able to increase training intensity as well as total work over the duration of the program. The important result of this study was that patients assigned to one-legged exercise training significantly improved their peak oxygen uptake as compared with those assigned to two-legged exercise. This difference was accompanied by greater peak ventilation, lower heart rate, and a lower ventilatory response. The authors concluded that, compared with conventional two-legged cycle training, one-legged training enhances the adaptive response of peripheral muscles. This form of training modality may be effective in patients with the most severe forms of ventilatory limitation.
The next two studies examined supplemental therapies that can be used in conjunction with exercise programs to improve exercise capacity. Exercise-induced dynamic hyperinflation (DH) contributes to the decreased exercise tolerance observed in patients with COPD. Slowing the increased respiratory rate induced by exercise may decrease DH and improve overall exercise tolerance. In the next study, a total of 64 patients with moderate to severe COPD were randomized to one of thee groups: exercise alone, ventilatory feedback alone, or exercise combined with ventilatory feedback sessions (24). The exercise sessions occurred three times a week for a total of 12 weeks, with 18 cycling and 18 treadmill sessions. Using a computerized system, patients assigned to receive ventilatory feedback were trained to modify their respiratory pattern during exercise. These sessions were 30–35 minutes in duration and were accompanied by low-intensity exercise. Goals of the ventilatory feedback sessions were individualized to each patient after his or her breathing pattern was assessed in a baseline exercise stress test. The results of this study demonstrated that exercise duration was increased and less exercise-induced DH was observed in those patients assigned to receive both ventilatory feedback and exercise. On the basis of the results of this study, ventilatory feedback training could be used to modify respiratory patterns during exercise, reduce DH, and improve exercise capacity in patients with COPD.
Oxygen therapy reduces breathlessness, improves exercise capacity, and increases walking distance in both hypoxemic and nonhypoxemic patients with COPD. Breathing helium in combination with oxygen may reduce ventilatory demand, delay the development of DH, improve respiratory mechanics, and therefore increase exercise capacity as compared with breathing oxygen alone. Marciniuk and colleagues examined whether the addition of helium to oxygen will increase six-minute-walk distance in patients with COPD (25). This study was a blinded, randomized crossover trial involving 16 patients with moderate disease and significant hyperinflation. Patients underwent baseline pulmonary function testing, cardiopulmonary exercise testing, and six-minute walk. Subsequently, the six-minute walk was repeated at subsequent visits using three different combinations of gases: room air, 100% oxygen, and a mixture of 70% helium and 30% oxygen. The study demonstrated that subjects walked farther when breathing the combination of helium and oxygen compared with room air or 100% oxygen. Despite the increase walking distance, there was no improvement in symptoms of shortness of breath or leg fatigue during exercise. Clinical use of a combination of helium and oxygen is cautioned due to the need for special equipment and potential increases in cost. However, the use of helium with oxygen should be considered in selected patients during PR to allow increased exercise intensity.
The next study examined the role of peak oxygen uptake and six-minute-walk distance as predictors of survival for patients with COPD (26). The investigators studied 365 consecutive patients with COPD and performed cardiopulmonary exercise testing and six-minute walks on separate days. Patients were followed for anywhere between 3 and 121 months (mean, 67 mo) and mortality was evaluated over time using a Kaplan-Meier analysis. Using a receiver operating characteristic curve analysis, the best cutoff values were 41% of the predicted value for peak oxygen uptake and 350 m for six-minute-walk distance. Survival over a mean of 67 months in those patients who could walk farther than 350 m was 66% compared with only 39% in patients who walked less than 350 m. Similar differences were observed when patients were stratified by their peak oxygen uptake. The investigators concluded that both six-minute-walk distance and peak oxygen uptake are useful prognostic indicators of mortality, and that the much simpler to perform six-minute-walk test was as good as peak oxygen uptake as a predictor of mortality.
The final article that was discussed during this session examined the effect of exercise on systemic inflammation (27). The loss of fat-free mass is associated with worse prognosis, poorer quality of life, increased morbidity, and mortality in patients with COPD (28). The reduction of fat-free mass in these patients is likely due to an imbalance between anabolic and catabolic processes. The enhanced catabolic state in COPD may be secondary to systemic inflammation and enhanced proteolysis, leading to loss of mass and function in tissues such as skeletal muscle. PR that includes high-intensity muscle reconditioning improves skeletal muscle function and is likely an anabolic stimulus. However, PR is unlikely to reverse the increased breakdown of protein or ameliorate systemic inflammation due to its short course and the unopposed background catabolic state and reduction in physical activity. To test this hypothesis, the next study examined 40 patients before and after an 8-week exercise program. Lung function, pseudouridine urinary excretion, which is a stable urinary measure of cellular protein breakdown, and inflammatory markers (IL-6 and soluble tumor necrosis factor) were obtained at the beginning and end of the program, and 4 weeks after the conclusion of the program. Increased cellular protein breakdown was inversely related to fat-free mass, skeletal muscle function, and exercise capacity in patients with COPD regardless of severity of lung disease. Although PR improved skeletal muscle function, exercise capacity, and short-term fat-free mass, it did not reduce markers of cellular protein breakdown or systemic inflammation. These findings highlight the importance of defining body composition abnormalities in patients entering PR and of the potential role of nutritional supplementation for these patients.
SLEEP MEDICINE
H. Klar Yaggi
Yale University School of Medicine
New Haven, Connecticut
The major topics that were discussed in this Clinical Year in Review session dedicated to sleep medicine were genomics, metabolic dysfunction cardiovascular risk, and sleep deprivation.
Restless leg syndrome (RLS) is characterized by the uncomfortable urge to move one's legs in the evening. Sleep onset is delayed and when sleep occurs it is typically disturbed by highly stereotypical and regular limb or leg twitches called periodic limb movements (PLMs). A familial predisposition has been well documented in these syndromes but until recently no specific genes have been identified. Stefansson and colleagues performed a genomewide study using a case-control study design in an Icelandic discovery group (29). The study focused on patients with RLS and cases were identified based on having a positive response to a validated modified questionnaire and an objective physiologic metric of more than 5 PLMs/hour on ambulatory monitoring. A significant genomewide association was identified with a common variant in an intron of BTBD9 on chromosome 6p21.2 and was replicated in a second Icelandic sample and in a United States sample. BTBD9 is widely expressed in parts of the brain, such as the amygdala, cerebellum, hippocampus, and caudate and subthalamic nuclei, and in other organs, such as the heart, kidneys, pancreas, and liver. The BTBD9 protein is not well characterized, and its function has not been determined. An association was observed between this variant and periodic limb movements without RLS, but not for RLS without periodic limb movements. These associations suggest that this genetic variant is a gene for periodic limb movements as opposed to RLS. Of importance, none of the identified genes is known at this point to be involved in dopaminergic transmission, which has been directly implicated in the underlying pathophysiology of RLS and periodic limb movement disorder. The authors did report an association between the presence of the genetic factor and lower ferritin levels. Serum ferritin, which is an indirect measure of iron stores, was reduced by 13% for the presence of each allele carried, implicating the common variant identified in iron storage. The results of this study may explain the familiar clustering in RLS and periodic limb movement disorder and result in future therapies for these patients.
The metabolic syndrome is characterized by central obesity, insulin resistance, hypertension, and high triglycerides and low high-density lipoprotein serum concentrations. Obstructive sleep apnea (OSA) has been linked to the metabolic syndrome in adults. However, it has not been established whether sleep apnea is associated with the metabolic syndrome in children. The next study quantified the relationship between metabolic syndrome and sleep-disordered breathing in a community-based sample of adolescents who underwent overnight polysomnography and a diagnostic evaluation for the metabolic syndrome (30). The exposure variable of interest in this study was the presence of sleep-disordered breathing as determined by an apnea–hypopnea index of 5 or greater. This value has been associated with mild sleep-disordered breathing in adults. The primary outcome variable was the presence of the metabolic syndrome using an adapted diagnosis based on the criteria used in adults. Adolescents who met three of the following five criteria were considered to be positive for the metabolic syndrome: waist circumference greater than the 75th percentile for age and sex; mean systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height (or current blood pressure medication use); triglyceride levels of 97.35 mg/dl or greater; high-density lipoprotein levels less than 50.19 mg/dl; and fasting glucose of 100 mg/dl or an oral glucose tolerance test of 140 mg/dl or greater. A total of 25% of the cohort was considered to be overweight and 19% met criteria for metabolic syndrome. After adjusting for age, race, sex, and preterm status, children with sleep-disordered breathing had a significantly increased odds of having the metabolic syndrome compared with children without sleep-disordered breathing. As apnea–hypopnea index severity increased, there was a progressive increase in the proportion of children classified with metabolic syndrome. This strong association between the metabolic syndrome and sleep-disordered breathing is a novel finding among adolescents. The association between many components of the metabolic syndrome with sleep-disordered breathing observed even after adjusting for body mass index suggests that sleep-disordered breathing may contribute to the metabolic dysfunction beyond effects of overweight and obesity. These results suggest that this relationship may in part be mediated through hypoxic stress, which raises the possibility that treatment with a continuous positive airway pressure (CPAP) mask or oxygen may attenuate the risks associated with the metabolic syndrome.
There have been a number of cross-sectional and prospective studies that have independently linked OSA to a variety of cardiovascular outcomes, including stroke, myocardial infarction, and sudden death (31–33). Physiologic studies suggest that OSA provides a substrate for the development of atherosclerosis through both direct and indirect mechanisms. However, it is unclear what specific mechanism is responsible for the development of atherosclerosis and subsequent cardiovascular disease. The next study that was discussed was a randomized clinical trial of CPAP therapy for patients with severe OSA who had no evidence of cardiovascular comorbidities (34). The investigators measured carotid intima-media thickness, arterial stiffness, carotid diameter, 24-hour blood pressure, C-reactive protein, and catecholamine levels at baseline and after 4 months of CPAP therapy or no therapy. Carotid intima-media thickness can be measured noninvasively and correlates with histologic evidence of subclinical atherosclerosis. Carotid intima-media thickness is also associated with an increased risk of atherosclerotic cardiovascular and cerebrovascular accidents. After 4 months, the 12 patients randomized to the CPAP group (who had excellent compliance of approximately 6 h/night, virtually abolishing their OSA) experienced a 9% reduction in carotid intima-media thickness and a 10% reduction in carotid-to-femoral pulse-wave velocity as a measure of arterial stiffness compared with no change from baseline for the patients who did not receive CPAP therapy. These improvements in measures of early atherosclerosis were associated with reductions in markers of inflammation and sympathetic activation as evaluated by C-reactive protein and catecholamines, respectively. Importantly, there were no concurrent changes in the patients' weight, lipid levels, or blood pressure. This study provides evidence that OSA may contribute to the causation of subclinical atherosclerosis.
Orexin-A is a neurotransmitter that produces arousal, increased attention, and increased muscle tone, and is important in cognition (35). Loss of orexin cells has been shown to produce narcolepsy in animals and to be associated with this syndrome in humans (36). The final study that was discussed in this session exposed adult rhesus monkeys to normal sleep or sleep deprivation conditions in conjunction with varying doses of orexin-A delivered either intravenously or via a nasal atomizer (37). The monkeys then underwent behavioral testing consisting of match to sample testing of clip art images on a computer screen. The monkeys were rewarded for appropriate matches with fruit juice. In addition, the animals underwent positron emission tomography scanning with fluoro-2-deoxyglucose to assess local cerebral glucose metabolism. Nasal orexin had no effect under normal alert conditions. However, there was a strong influence of nasal orexin therapy on improving cognitive performance when animals were sleep deprived. Nasal orexin was significantly more effective when compared with the doses delivered intravenously. As a physiologic correlate to these changes in cognitive performance, sleep deprivation produced changes on positron emission tomography scanning in four specific brain regions. These changes were reversed by the administration of nasal orexin-A. These data provide additional evidence for the involvement of the sleep peptide orexin-A in the regulation of important cognitive processes that can be affected by physiologic perturbances such as sleep deprivation. Future clinical studies are needed to assess utility and efficacy of orexin-A.
FOOTNOTES
Conflict of Interest Statement: M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form June 18, 2008; accepted in final form July 28, 2008)
REFERENCES
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