Michael R. Littner

Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: A placebo-controlled trial

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. Georges Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.

The prevalence of carotid atheromas seen on panoramic radiographs of patients with obstructive sleep apnea and their relation to risk factors for atherosclerosis

PURPOSE Persons with obstructive sleep apnea syndrome (OSAS) suffer inordinately high rates of stroke, but the cause remains in doubt. Atherosclerosis (atheroma formation) of the extracranial carotid artery has been suggested as a possible cause. Because atheromas can be recognized on panoramic radiographs, this study compared their prevalence in subjects with OSAS and normal controls and analyzed their relation to atherogenic risk factors. PATIENTS AND METHODS Panoramic radiographs and medical records of 54 male subjects (mean age, 60.4 years) with OSAS (apnea/hypopnea index [AHI] of 15 or greater and a history of snoring and excessive daytime sleepiness) were assessed for atheromas and risk factors. Age-matched controls were likewise assessed. RESULTS Twelve individuals (22%) with OSAS showed atheromas on their radiographs. The radiographs of the controls showed that 3.7% had atheromas. This finding was statistically significant (P = .0079). The prevalence of type 2 diabetes mellitus among individuals with OSAS and atheroma formation (7 of 12 persons, 58%) was far greater than the prevalence of diabetes (10 of 42 persons, 24%) experienced by individuals with OSAS but free of atheroma formation. This finding was also statistically significant (P = .035). The lesions seen in both the subject and control populations were similar and were located in the neck, 1.5 to 2.5 cm inferior-posterior to the angle of the mandible. CONCLUSIONS Persons with OSAS are more likely to manifest calcified atheromas on their panoramic radiographs than age-matched controls. Type 2 diabetes is significantly more prevalent in individuals with both OSAS and calcified atheromas.

Selective subsensitization of beta-adrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol

In five subjects with mild asthma and in five normal subjects, we determined the effect of a 4 wk course of inhaled salbutamol (albuterol), 200 micrograms q.i.d., on (1) acute bronchodilator responsiveness, (2) bronchial sensitivity to inhaled histamine, (3) beta-adrenergic protection against histamine-induced bronchospasm, and (4) beta-receptor density of peripheral blood lymphocytes. We observed a diminution in central airway bronchodilator responsiveness (as measured by airway conductance responses) to acutely inhaled salbutamol and to subcutaneous terbutaline in both groups of subjects, although only the response to subcutaneous terbutaline was statistically significant (p less than 0.02). On the other hand, no impairment of small airway bronchodilator responsiveness was noted in either group of subjects when responses were measured as partial expiratory flow rates at 60% below total lung capacity. These findings suggest the development of selective subsensitization of beta-receptors in the larger central airways, where a proportionately greater amount of the inhaled beta-agonist aerosol would necessarily be deposited. A greater loss of protection against histamine-induced bronchospasm was seen in asthmatics than in normals (approximately twofold), although the difference was not significant. A modest but not significant reduction in peripheral blood lymphocyte beta-receptor density was observed by the end of the 4 wk treatment period. The possibility that the observed changes in bronchodilator responsiveness might influence the morbidity and mortality associated with bronchial asthma is discussed.

Circadian Rhythm of Plasma Renin Activity in Older Normal and Essential Hypertensive Men: Relation with Inactive Renin, Aldosterone, Cortisol and Rem Sleep

The 24-h pattern of plasma renin activity (PRA), inactive renin (IR), plasma aldosterone (PA) and cortisol was studied in 13 normal men and 12 male patients with essential hypertension, all of whom were older than 55 years. Following gradual habituation over 4 days to the sleep laboratory and intravenous lines, blood samples were obtained every 2 h between 0900-2100 h and every 30 min between 2100-0900 h, during which sleep was also monitored. Plasma renin activity showed a circadian rhythm in both groups, but mean levels were lower in the hypertensive subjects (0.92 +/- 0.03 versus 1.41 +/- 0.06 ng/ml per h). The circadian rhythm of PRA in older men appeared to follow the same pattern described in younger individuals. Rapid eye movement (REM) sleep was associated with a small decrease in PRA, but this link was only evident in the normotensive group. Mean 24-h IR levels were also lower in the hypertensive group (7.26 +/- 0.18 versus 15.10 +/- 0.47 ng/ml per h) but were not affected by clock-time and generally showed no association with the 24-h PRA cycle. Mean 24-h PA was closely related to cortisol but not to PRA in both groups. Mean PA levels of the two groups were similar. Thus, the PA:PRA ratio was higher in the hypertensive group. The higher basal PA:PRA ratio in older hypertensives that emerged over the 24-h study period may reflect increased sensitivity of the adrenal gland to angiotensin II (ANG II) in hypertension of the elderly.

The prevalence of calcified carotid artery atheromas in patients with obstructive sleep apnea syndrome

PURPOSE Persons with obstructive sleep apnea syndrome (OSAS) suffer cerebrovascular accidents at three to six times the rate of other Americans. Atherosclerosis of the cervical portion of the carotid artery has been suggested as a possible cause of these strokes. Lateral cephalometric radiographs used to determine the site of upper airway obstruction in sleep apnea patients can also image calcified cervical carotid artery atheromas. However, their prevalence in this group of patients has not been previously reported. PATIENTS AND METHODS The radiographs of 47 male subjects (mean age 59.2 years, range 45 to 77 years) diagnosed as having OSAS (apnea/hypopnea index [AHI] of > or = 15 and a history of snoring and excessive daytime sleepiness) were assessed for calcified carotid atheromas. Healthy, age-matched (+/-18 months) controls were likewise assessed. RESULTS The radiographs of the subjects with OSAS showed that 21.3% had calcified atheromas. The radiographs of the controls showed that only 2.5% had calcified atheromas. This finding was statistically significant (P = < .000001). The lesions seen in both populations were similar, and located within the soft tissues of the neck at the level of C3 and C4. The lesions were superimposed over these tissues, the prevertebral fascia, and the pharyngeal airspace. CONCLUSIONS The results of this study seem to indicate that persons with OSAS have a greater prevalence of calcified carotid artery atheromas than healthy, age-matched persons. These lesions, a possible cause of future stroke, can be detected on lateral cephalometric radiographs.

Dissociation of 24-hour catecholamine levels from blood pressure in older men.

Increased plasma norepinephrine levels have been observed in some persons with early essential hypertension. Although both plasma norepinephrine level and mean arterial blood pressure rise with age, little is known about the state of catecholamine secretion in elderly patients with essential hypertension. We studied the 24-hour cycle levels of plasma norepinephrine, epinephrine, and dopamine in 12 elderly hypertensive subjects and 13 age-matched normotensive controls (mean ages, 63.8 +/- 1.2 yr and 64.8 +/- 1.8 yr [SEM] respectively). Blood samples were obtained at bihourly intervals from 0900 to 2100 hours and every 30 minutes from 2100 to 0900 hours, during which time sleep and breathing were continuously monitored. A circadian rhythm was displayed in both groups by plasma epinephrine levels (mesor, 49 +/- 2 pg/ml and 38 +/- 1 pg/ml; amplitude, 15 +/- 2 pg/ml and 11 +/- 1 pg/ml; acrophase, 12.20 +/- 0.40 hr and 14.41 +/- 0.34 hr in the normotensive and hypertensive groups respectively) but not by plasma norepinephrine or dopamine levels. During the 24-hour cycle plasma epinephrine, but not norepinephrine or dopamine, levels were positively related to mean arterial blood pressure (r = 0.60 for the normotensive subjects, r = 0.57 for the hypertensive subjects, p less than 0.01 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphocyte beta-adrenergic refractoriness induced by theophylline or metaproterenol in healthy and asthmatic subjects.

Beta-adrenergic refractoriness was assessed in human lymphocytes following in vivo administration of the beta-adrenergic agonist, metaproterenol, the phosphodiesterase inhibitor, theophylline, or both concomitantly, to normal and asthmatic subjects. In normal subjects both beta-adrenergic receptor number and isoproterenol stimulated cAMP response decreases during therapy with metaproterenol (59 +/- 3; 51 +/- 16% of control, respectively), theophylline (76 +/- 6; 78 +/- 16), or concomitant metaproterenol and theophylline (47 +/- 4; 69 +/- 13). The asthmatic subjects were of two types; one type responding to metaproterenol or theophylline therapy by down regulation of receptor number to zero or near zero values, and a second group of asthmatics insensitive to down regulation of receptor number. The results suggest that the induction of the refractory state is different between asthmatics and non-asthmatics, and that there may be a role for cAMP in the development of beta-adrenergic refractoriness, in vivo.

Organization and Structure for Sleep Medicine Programs at Academic Institutions: Part 1—Current Challenges

EXECUTIVE SUMMARY As a field that has emerged in recent years, from multidis ciplinary roots within long-standing, traditional academic infrastructures, sleep medicine has assumed highly disparate organizational structures at each institution. Access to the creativity, talent, trainees, administration, and financial investment of one or more departments at each medical center has contributed substantially to advances in sleep and biological rhythms. At the same time, however, the variability of the support structure across institutions and the ability of specific departments to develop only the most relevant aspects of a highly multidisciplinary field has substantially limited the growth of sleep medi cine. Surveys in 2009 and 2012 by a Presidential Task Force of the Sleep Research Society suggested that strong, independent, self-sufficient, and cohesive administrative structures for sleep medicine were rare, if not absent. Little progress had been made toward organizational structures envisioned in the 2006 Institute of Medicine report, Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. This white paper, written by members of the Academic Affairs Committee and then endorsed by the Boards of Directors of both the American Academy of Sleep Medicine and the Sleep Research Society, summarizes challenges to sleep medicine that arise at academic institutions. Examples of specific challenges discussed include the absence or rarity of: sleep center responsibility for sleep faculty recruitment; recruitment packages targeted for sleep; salary equity for identical work within the same sleep center by members of different departments; better equity between academic and nonacademic salaries; reinvestment of clinical or other margins back into sleep; access by qualified individuals to academic positions regardless of original specialty training before sleep; oversight of research space and resources by sleep centers; department-blind access to trainees who stand to gain most from training in sleep

Restoration of Hypoxic Pulmonary Vasoconstriction following Normoxia in Isolated Dog Lungs Occurs in the Presence but Not in the Absence of Prostaglandin Synthesis Inhibitors

We examined the possibility that eucapnic (6% CO2) alveolar hypoxia (3% O2) in isolated dog lungs not only produces an increase in pulmonary vascular resistance but also initiates the subsequent prostaglandin (PG) dependent reduction in this hypoxic pulmonary vasoconstriction (HPV). We determined that a reduction in HPV occurred after 45 min including a 35-min period of hypoxia (prolonged hypoxia), after 45 min of intermittent hypoxia, and after 45 min of normoxia (14% O2). These reductions were PG dependent, since they were reversed or prevented by PG synthesis inhibitors in the autologous blood perfusate. In addition to the PG-dependent reduction that required 45 min to develop, a separate reduction in HPV also occurred. This reduction occurred during prolonged hypoxia, was not prevented by PG synthesis inhibitors, was reversed after 6 min of normoxia, and was reproduced in a second period of prolonged hypoxia. We conclude that alveolar hypoxia did not initiate the PG-dependent reduction in HPV, since it occurred after normoxia as well as after hypoxia. However, hypoxia appeared to contribute to a separate PG-independent reduction in HPV, since this reduction was initiated and maintained exclusively during prolonged hypoxia and was unaffected by PG synthesis inhibitors.

Home Sleep Testing for the Diagnosis of Obstructive Sleep Apnea—Indications and Limitations

The increasing prevalence and recognition of obstructive sleep apnea (OSA) coupled with an awareness of its detrimental health consequences has resulted in the need for timely and cost efficient access to diagnostic sleep testing and treatment. As a result, increased emphasis is being placed on simplified ambulatory models for the diagnosis and treatment of OSA using home sleep testing (HST). An ambulatory sleep program requires the combination of clinical assessment for identifying patients at high risk for OSA, HST for the diagnosis of OSA, and home auto-titrating positive airway pressure units for treatment. Randomized control trials evaluating the efficacy of this ambulatory approach to diagnose and treat OSA in high-risk patients without significant medical comorbidities reveal the potential for equivalent patient outcomes when compared with the use of polysomnography and in-laboratory continuous positive airway pressure titration.