Steven M. Scharf

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. Georges Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD

BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity

Rationale: Recent studies described association between chronic obstructive pulmonary disease (COPD) and increased risk of cardiovascular diseases (CVD). In their analysis none of these studies accounted for sociodemographic factors, health behaviors, and patient comorbidities simultaneously. Objective: To study whether COPD diagnosis is an independent risk factor for CVD. Methods: Subjects aged 40 years and older (N = 18,342) from the sample adult file of the 2002 National Health Interview Survey (NHIS) were included in the analysis. Chi-squared tests and odds ratios (OR) were utilized to compare the data. Multiple logistic regression was employed to analyze the association between COPD and CVD with simultaneous control for sociodemographic factors (age, gender, race, marital status, education, income), health behaviors (tobacco use, alcohol consumption, physical activity), and patient comorbidities (diabetes, hypertension, high cholesterol, and obesity). The analysis employed NHIS sampling weights to generate data representative of the entire US population. Results: The COPD population had increased prevalence of CVD (56.5% vs 25.6%; P < 0.0001). Adjusted logistic regression showed that COPD patients (N = 958) were at higher risk of having coronary heart disease (OR = 2.0, 95% CI: 1.5–2.5), angina (OR = 2.1, 95% CI: 1.6–2.7), myocardial infarction (OR = 2.2, 95% CI: 1.7–2.8), stroke (OR = 1.5, 95% CI: 1.1–2.1), congestive heart failure (OR = 3.9, 95% CI: 2.8–5.5), poor circulation in lower extremities (OR = 2.5, 95% CI: 2.0–3.0), and arrhythmia (OR = 2.4, 95% CI: 2.0–2.8). Overall, the presence of COPD increased the odds of having CVD by a factor of 2.7 (95% CI: 2.3–3.2). Conclusions: These findings support the conclusion that COPD is an independent risk factor for CVD.

Estimating pulmonary artery pressures by echocardiography in patients with emphysema

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organizations definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland–Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5–3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.

Sleep, Sleepiness, Fatigue, and Performance of 12-Hour-Shift Nurses

Nurses working 12-h shifts complain of fatigue and insufficient/poor-quality sleep. Objectively measured sleep times have not been often reported. This study describes sleep, sleepiness, fatigue, and neurobehavioral performance over three consecutive 12-h (day and night) shifts for hospital registered nurses. Sleep (actigraphy), sleepiness (Karolinska Sleepiness Scale [KSS]), and vigilance (Performance Vigilance Task [PVT]), were measured serially in 80 registered nurses (RNs). Occupational fatigue (Occupational Fatigue Exhaustion Recovery Scale [OFER]) was assessed at baseline. Sleep was short (mean 5.5 h) between shifts, with little difference between day shift (5.7 h) and night shift (5.4 h). Sleepiness scores were low overall (3 on a 1–9 scale, with higher score indicating greater sleepiness), with 45% of nurses having high level of sleepiness (score  > 7) on at least one shift. Nurses were progressively sleepier each shift, and night nurses were sleepier toward the end of the shift compared to the beginning. There was extensive caffeine use, presumably to preserve or improve alertness. Fatigue was high in one-third of nurses, with intershift fatigue (not feeling recovered from previous shift at the start of the next shift) being most prominent. There were no statistically significant differences in mean reaction time between day/night shift, consecutive work shift, and time into shift. Lapsing was traitlike, with rare (39% of sample), moderate (53%), and frequent (8%) lapsers. Nurses accrue a considerable sleep debt while working successive 12-h shifts with accompanying fatigue and sleepiness. Certain nurses appear more vulnerable to sleep loss than others, as measured by attention lapses. (Author correspondence: jgeiger@son.umaryland.edu)

Cardiac disease in chronic obstructive pulmonary disease.

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.

The effects of large negative intrathoracic pressure on left ventricular function in patients with coronary artery disease.

Using first-pass radionuclide ventriculography, we evaluated the effects of decreases in intrathoracic pressure (Mueller maneuver [M] to −20 to −30 cm H2O) in 14 patients with and five patients without coronary artery disease (CAD) and in 12 normal control subjects. In the patients without CAD, control ejection fraction was 0.53 ± 0.06 (SEM) and control heart rate was 83 ± 6 beats/min. These did not change during M. In the patients with CAD, control ejection fraction was 0.37 ± 0.03 and heart rate was 82 ± 7 beats/min. During M, heart rate did not change, but ejection fraction decreased to 0.33 ± 0.03 (p < 0.01). Examination of regional wall motion abnormalities showed akinesis of at least one myocardial segment in nine of 14 patients with CAD, but in none of the patients without CAD, nor in any of the 12 previously studied normal subjects (retrospectively analyzed). These data are consistent with the hypothesis that the Mueller maneuver acts to increase afterload placed on the left ventricle. Furthermore, in patients with CAD, the Mueller maneuver may have induced localized myocardial ischemia or unmasked areas of preexisting marginal function.

Chronic-intermittent hypoxia: a model of sympathetic activation in the rat

This review focuses upon the development of a small animal model that incorporates exposure to chronic-intermittent hypoxia to produce systemic hypertension similar to that experienced by humans with the obstructive sleep apnea syndrome. It has been suggested that experimentally-induced hypertension, like human hypertension, is due to activation of the sympathetic nervous system. That hypothesis is supported by physiological studies carried out in humans with obstructive sleep apnea as well as in animals exposed to chronic-intermittent hypoxia. Furthermore, recent anatomical studies of exposed animals strongly suggested that activation was widespread and included cortical and brainstem components of the sympathetic system. Such findings, while illustrating the complexity of modeling human disease in animals, also demonstrate the heuristic value of chronic-intermittent hypoxia as an experimental approach.

Burden of Concomitant Asthma and COPD in a Medicaid Population

BACKGROUND Asthma and COPD can significantly affect patients and pose a substantial economic burden for both patients and managed-care plans. This study compares utilization outcomes in patients with asthma, COPD, or co-occurring asthma and COPD in a Medicaid population, and assesses the incremental burden of COPD in patients with asthma. METHODS We queried medical claims of Medicaid patients aged 40 to 64 years with asthma and/or COPD filed between January 1, 2001, and December 31, 2003, from encounter data. COPD patients were identified based on at least one claim with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes 491, 492, 496; and asthma patients were identified on the basis of ICD-9 code 493 as diagnosis. We analyzed annual utilization and cost of hospitalizations, physician, and outpatient services attributable to asthma and/or COPD. RESULTS The analysis included a total of 3,072 asthma, 3,455 COPD, and 2,604 COPD/asthma patients. COPD/asthma co-occurring disease has higher utilization of any service type than either disease alone. Compared with asthma patients, COPD patients were 16% and 51% more likely to use physician (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.01 to 1.34) and inpatient services (OR, 1.51; 95% CI, 1.31 to 1.74), respectively; and 60% less likely to use outpatient services (OR, 0.40; 95% CI, 0.35 to 0.46). Compared with asthma patients, COPD patients and COPD/asthma co-occurring patients cost 50% (OR, 1.50; 95% CI, 1.3 to 1.74) and five times (OR, 5.25; 95% CI, 4.59 to 6.02) more for total medical services, respectively. CONCLUSION Our data suggest that patients with COPD and co-occurring COPD/asthma were sicker and used more medical services than asthma patients. The incremental burden of COPD to patients with asthma is significant.

Expression of c-fos in the rat brainstem after chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) may cause sustained systemic hypertension by increasing sympathetic neural discharge (SND). We hypothesized that CIH alters brainstem circuits modulating SND. After 30 days of CIH exposure in rats, increased c-fos labeling was seen in the nucleus of the solitary tract and ventrolateral medulla as well as other brainstem regions involved in regulation of SND. Increased expression of c-fos after CIH may indicate changes in neuronal genetic transcription which ultimately modulate SND.