Gary A. Roselle

Sleep Apnea in 81 Ambulatory Male Patients With Stable Heart Failure Types and Their Prevalences, Consequences, and Presentations

BACKGROUND Heart failure is a highly prevalent disorder that continues to be associated with repeated hospitalizations, high morbidity, and high mortality. Sleep-related breathing disorders with repetitive episodes of asphyxia may adversely affect heart function. The main aims of this study were to determine the prevalence, consequences, and differences in various sleep-related breathing disorders in ambulatory male patients with stable heart failure. METHODS AND RESULTS This article reports the results of a prospective study of 81 of 92 eligible patients with heart failure and a left ventricular ejection fraction < 45%. There were 40 patients without (hourly rate of apnea/hypopnea, 4 +/- 4; group 1) and 41 patients with (51% of all patients; hourly rate of apnea/hypopnea, 44 +/- 19; group 2) sleep apnea. Sleep disruption and arterial oxyhemoglobin desaturation were significantly more severe and the prevalence of atrial fibrillation (22% versus 5%) and ventricular arrhythmias were greater in group 2 than in group 1. Forty percent of all patients had central sleep apnea, and 11% had obstructive sleep apnea. The latter patients had significantly greater mean body weight (112 +/- 30 versus 75 +/- 16 kg) and prevalence of habitual snoring (78% versus 28%). However, the hourly rate of episodes of apnea and hypopnea (36 +/- 10 versus 47 +/- 21), episodes of arousal (20 +/- 14 versus 23 +/- 11), and desaturation (lowest saturation, 72 +/- 11% versus 78 +/- 12%) were similar in patients with these different types of apnea. CONCLUSIONS Fifty-one percent of male patients with stable heart failure suffer from sleep-related breathing disorders: 40% from central and 11% from obstructive sleep apnea. Both obstructive and central types of sleep apnea result in sleep disruption and arterial oxyhemoglobin desaturation. Patients with sleep apnea have a high prevalence of atrial fibrillation and ventricular arrhythmias.

Effect of Theophylline on Sleep-Disordered Breathing in Heart Failure

BACKGROUND Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration (periodic breathing). We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction. METHODS Fifteen men with compensated heart failure (left ventricular ejection fraction, 45 percent or less) participated in the study. Their base-line polysomnograms showed periodic breathing, with more than 10 episodes of apnea and hypopnea per hour. In a double-blind crossover study, the patients received theophylline or placebo orally twice daily for five days, with one week of washout between the two periods. RESULTS After five days of treatment, the mean (+/-SD) plasma theophylline concentration was 11 +/- 2 microgram per milliliter. Theophylline therapy resulted in significant decreases in the number of episodes of apnea and hypopnea per hour (18 +/- 17, vs. 37 +/- 23 with placebo and 47 +/- 21 at base line; P<0.001), the number of episodes of central apnea per hour (6 +/- 14, vs. 26 +/- 21 and 26 +/- 20, respectively; P<0.001), and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent (6 +/- 11 percent, vs., 23 +/- 37 and 14 +/- 14 percent, respectively; P<0.04). There were no significant differences in the characteristics of sleep, the frequency of ventricular arrhythmias, daytime arterial-blood gas values, or the left ventricular ejection fraction during the base-line, placebo, and theophylline phases of the study. CONCLUSIONS In patients with stable heart failure, oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep.

Occult Sleep-Disordered Breathing in Stable Congestive Heart Failure

Despite recent advances in its treatment, congestive heart failure associated with depressed left ventricular function is highly prevalent and continues to be associated with excess morbidity and mortality. Multiple factors may contribute to the progressively declining course of congestive heart failure. Severe nocturnal arterial oxyhemoglobin desaturation caused by sleep-disordered breathing could be a contributing factor, particularly because it has been associated with excess mortality in patients with chronic obstructive pulmonary disease [1]. Cheyne and Stokes were the first to observe periodic breathing in patients with heart failure (Cheyne-Stokes respiration). In a subsequent systematic study, Harrison and colleagues [2] reported that periodic breathing characterized by repeated episodes of apnea and hypopnea during sleep occurred in patients with congestive heart failure. Since this early observation, several investigators have used standard polysomnography to study periodic breathing during sleep in patients with congestive heart failure [3-7]. The differences in prevalence rates in these studies (36% to 100%) might have been caused by several factors, including the few patients studied (4 to 11), the varying inclusion of patients with risk factors predisposing them to sleep apnea (such as loud snoring, witnessed apnea, and obesity), the varying severity of heart failure and systolic dysfunction, the inclusion of patients with unstable (as opposed to stable, maximally treated) congestive heart failure, and the presence of other factors that may influence periodic breathing. These important factors, which were not considered in most of previous studies, could considerably affect the prevalence and the severity of sleep apnea. We determined the prevalence and effect of sleep-disordered breathing in a relatively large group of clinically well-defined patients with stable, optimally treated congestive heart failure. We also determined the predictors of sleep-disordered breathing in these patients. Methods Entry Criteria Forty-two ambulatory patients with stable congestive heart failure (no change in signs or symptoms of congestive heart failure and no change in medications for at least 4 weeks before polysomnography) and systolic dysfunction (left ventricular ejection fraction 45%) participated in the study. Patients were recruited from the cardiology and medical clinics of the Department of Veterans Affairs Medical Center, Cincinnati, Ohio. The cardiologist coinvestigator evaluated all patients to confirm that their condition was stable and that they were receiving optimal therapy, which included digoxin (26 patients), diuretics (38 patients), angiotensin-converting enzyme inhibitors (37 patients), or hydralazine (2 patients). At the time of recruitment, no information was sought about symptoms or risk factors for sleep apnea. The following were the exclusion criteria: unstable angina; unstable congestive heart failure; acute pulmonary edema; congenital heart disease; primary valvular heart disease; use of benzodiazepines or theophylline; intrinsic pulmonary diseases, including interstitial lung disease, moderate to severe chronic obstructive lung defect (percentage of the ratio of the predicted forced expiratory volume in 1 second and forced vital capacity < 68%); intrinsic renal and liver disorders; untreated hypothyroidism; and kyphoscoliosis. For uniformity, we studied only male patients (female patients are rarely referred to this center). Only 6 of the 48 patients who met the entry criteria and were asked to participate in the study refused. The main reasons for refusal were an unwillingness to stay in the hospital or an unwillingness to travel to the hospital because of distance. The study was approved by the Research and Development Committee of the Veterans Affairs Medical Center, Cincinnati, Ohio, and the Institutional Review Board at the University of Cincinnati College of Medicine. Baseline Studies After giving written informed consent, the patients were hospitalized for 2 consecutive nights. On the first day, a detailed history was obtained and physical examination and screening tests were done, including complete blood count; tests for serum electrolytes, digoxin, thyroid, and renal function; radionuclide ventriculography; determinations of arterial blood gases and pH; and pulmonary function tests. Strict criteria described elsewhere [8, 9] were used for doing pulmonary function tests and for obtaining arterial blood samples and their measurements. Because some studies [10] have suggested that a low baseline Paco 2 is a risk factor for periodic breathing, skin over the radial artery was anesthetized with 2% lidocaine to minimize pain (which could potentially induce hyperventilation during arterial blood sampling). While the patient was sitting, arterial blood was collected anaerobically in heparinized syringes during several breath cycles. Duplicate determinations of arterial blood gases and pH were immediately made with appropriate electrodes [9]. Polysomnography On the first night, patients were taken to the sleep laboratory. Surface electrodes were attached, but no recording was obtained. This adaptation night was used to minimize the first-night effect of sleeping in the laboratory. On the next night, polysomnography was done using standard techniques described previously [11-13]. For staging sleep, we recorded electroencephalograms (two channels), chin electromyograms (one channel), and electro-oculograms (two channels). Thoracoabdominal excursions were measured qualitatively by respiratory inductance plethysmography (Respitrace; Ambulatory Monitoring, Inc., Ardsley, New York) or by pneumatic respiration transducers (Grass Instrument Company, Quincy, Massachusetts) placed over the rib cage and abdomen. Airflow was qualitatively monitored using an oral-nasal thermocouple (Model TCT1R; Grass Instrument Company). Arterial oxyhemoglobin saturation was recorded using an ear oximeter (Biox IIA; BT, Inc., Boulder, Colorado). These variables were recorded on a multichannel polygraph (Model 78D; Grass Instrument Company). An apnea was defined as cessation of inspiratory airflow lasting 10 seconds or longer. An obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. A central apnea was defined as the absence of airflow and of rib cage and abdominal excursions [11-13]. However, a central apnea may not be easily distinguished from an obstructive apnea if esophageal pressure is not measured. Hypopnea was defined as a reduction of airflow lasting 10 seconds or more that was associated with at least a 4% decrease in arterial oxyhemoglobin saturation or an arousal. An arousal was defined as the appearance of waves on an electroencephalogram that were at least 3 seconds in duration [14]. The number of episodes of apnea and hypopnea per hour is referred to as the apneahypopnea index. Scoring of polysomnograms was blinded. The prevalence of sleep-disordered breathing in patients with congestive heart failure was determined using an apneahypopnea index of more than 20 episodes per hour. In a retrospective study of patients with the sleep apnea syndrome [15], an index of more than 20 apneas per hour was associated with excess mortality. Because this study was done before hypopnea was recognized, the investigators did not include it in their calculation of the index. Lower thresholds (for example, an apneahypopnea index of 10 episodes per hour) have been used in other studies; however, the clinical importance, particularly of low cutoff points, has not been adequately determined. Other Studies Holter monitoring was done during polysomnography. Three electrocardiographic channels (leads V1, V3, and V5) were recorded using a Laser SxP Holter monitor system (Marquett Electronics Inc., Milwaukee, Wisconsin). The tapes were analyzed by computer and were manually overread by the cardiologist coinvestigator. Using standard techniques [16], we calculated right and left ventricular ejection fractions from gated first-pass and multigated radionuclide ventriculograms, respectively [16]. Statistical Analysis We used the Wilcoxon rank-sum test to assess the significance of differences between the two groups because the common variance assumption required by the t-test was not appropriate for many of the measurements. A P value of less than 0.05 was considered significant. We calculated 95% CIs using the approximate degrees of freedom for the t-statistic [17]. The relations between certain pathophysiologically important variables and the apneahypopnea index were examined by regression analysis and stepwise multiple regression analysis. Calculations were done using SAS software [17]. Results The apneahypopnea index varied from 0.3 to 82.2 episodes per hour. The frequency histogram of the index is shown in Figure 1. In 23 patients (group I), the apneahypopnea indexes varied from 0.3 to 13.4 episodes per hour (mean SD, 4.4 4 episodes per hour [CI, 2.7 to 6.0 episodes per hour; median, 3.2 episodes per hour]). In the 19 patients in group II (45%), the apneahypopnea index varied from 26.5 to 82.2 episodes per hour (mean, 44 13 episodes per hour [CI, 37.6 to 50.6 episodes per hour; median, 40.4 episodes per hour]. Figure 1. Frequency distribution of the apneahypopnea index in 10-unit intervals in 42 patients with stable, optimally treated congestive heart failure. The two groups did not differ significantly in demographic and historical data (Table 1). Congestive heart failure was caused by ischemic cardiomyopathy (16 patients in group I and 13 patients in group II), idiopathic cardiomyopathy (5 patients in group I and 6 patients in group II), and alcohol-related cardiomyopathy (2 patients in group I). Table 1. Demographics, Historical Data, and Physical Examination Findings in Patients without (Group I) or with (Group II) Sleep-Disordered Breathing* The mean values for s

Sex steroid regulation of autoimmunity

The immune response of males and females is not identical but instead has been shown to be dimorphic in its nature, with females generally demonstrating a greater overall response than males. This dimorphism extends to both the humoral and cell mediated systems and appears to be mechanistically based on the differences in type and concentration of sex steroids in males vs females. Furthermore, growth hormone and prolactin secretions which are different in males and females may also be partly responsible for the observed dimorphism. Because autoimmune disease results from a pathological perturbation of normal immune function, it follows that expression of these diseases will also demonstrate a dimorphic pattern. Examples of this autoimmune dimorphism include (but are not limited to) lupus, rheumatoid arthritis and multiple sclerosis with the two former more prevalent in females than males and the latter more severe during pregnancy. To explain autoimmune dimorphism it therefore becomes necessary firstly to describe the cellular and hormonal interactions found in normal immune regulation and thereafter extrapolate these to autoimmune phenomena.

Protein energy malnutrition in severe alcoholic hepatitis : diagnosis and response to treatment

Background: Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters. Methods: Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement. Results: PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p=.0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymph...

Cell-mediated hepatic injury in alcoholic liver disease

BACKGROUND The mechanism responsible for the initiation and perpetuation of alcoholic liver disease (ALD) remains poorly understood. This investigation attempted to elucidate the role of cell-mediated immune phenomena in the pathogenesis of ethanol-induced liver injury. METHODS Frozen liver biopsy specimens from 144 patients with moderate to severe ALD were examined by the avidin-biotin immunoperoxidase technique for the expression of antigenic markers of T and B lymphocytes, natural killer cells, and class I and II MHC molecules in the tissue. RESULTS Expression of CD3 by lymphocytes correlated significantly with regenerating nodules, intralobular inflammation, central sclerosis, and abnormalities of Kupffer cells. B cells were rarely present, and natural killer cells were absent. CD3+ lymphocytes expressed either CD4 or CD8 surface molecules. Enhanced class I MHC expression correlated significantly with portal inflammation, limiting plate erosion, vascular abnormalities, and hemosiderosis. Expression of class II MHC molecules correlated significantly with necrosis, bile stasis, and Mallory bodies. CONCLUSIONS The distribution and persistence of CD4+ and CD8+ cells in actively advancing ALD, the enhanced MHC expression on hepatocytes, and their relationship to alcoholic hyalin and necrosis lend support to the hypothesis that a cytotoxic T lymphocyte-hepatocyte interaction plays a role, perhaps via lymphokine production, in the genesis or perpetuation of ALD.

Estradiol regulation of thymic lymphocyte function in the rat: Mediation by serum thymic factors

Estradiol (E2) can depress the function of the thymic lymphocytes. To determine if this response to a gonadal steroid is regulated directly or indirectly, thymic lymphocytes were incubated in vitro for 3 days in the presence of the mitogens concanavalin A (Con A) or phytohaemagglutinin (PHA) + tissue culture media + 20% specific rat serum fractions and pulse labelled with tritiated thymidine. Rat serum fractions were prepared from control, castrate, thymectomized (Tx) and castrate-Tx animals as well as from similar groups of animals treated in vivo for three days with physiological doses of E2. It was found that there was a significant enhancement of thymocyte blastogenesis in cultures incubated with castrate rat serum + Con A or PHA vs. control serum cultures (P less than 0.001). Direct replacement of E2 to castrate sera in vitro at physiological concentrations failed to depress thymocyte blastogenesis to noncastrate levels. Sera prepared from castrate animals treated with E2 at physiological concentrations was successful in depressing the blastogenic response to noncastrate levels. Sera from Tx animals did not enhance Con A induced blastogenesis, but PHA response was significantly increased (P less than 0.01) This effect was lost utilizing sera from Tx animals treated with E2. It is concluded that thymocyte function is regulated by serum factors which have their origin in the thymus, and that these factors are modulated by a gonadal steroid estradiol.

Cost-effectiveness of Interferon Gamma Release Assays vs Tuberculin Skin Tests in Health Care Workers

BACKGROUND Interferon gamma release assays (IGRAs) offer alternatives to tuberculin skin tests (TSTs) for diagnosing latent tuberculosis infection (LTBI). Unlike TSTs, IGRAs require only a single patient visit and are not affected by prior BCG vaccination, providing greater specificity. Of 2 Food and Drug Administration-approved IGRAs, the newer QuantiFERON-TB Gold in Tube test (QFT-GIT) requires less manual processing time than the QuantiFERON-TB Gold test (QFT-G). We compared the cost-effectiveness of the QFT-G, QFT-GIT, and TST for detecting LTBI in new health care workers (HCWs). METHODS A Markov state-transition decision analytic model using the societal perspective and lifetime horizon was constructed to compare costs and quality-adjusted life-years (QALYs) associated with the 3 strategies for hypothetical 35-year-old HCWs with or without prior BCG vaccination. Direct and indirect costs and probabilities were based on manufacturer data, national Veterans Health Administration records, and the published literature. Future costs and QALYs were discounted at 3% per year. RESULTS Both IGRAs were more effective and less costly than the TST, whether or not the HCW had been vaccinated with BCG previously. The incremental cost-effectiveness ratio of the QFT-G compared with the QFT-GIT was

Hepatitis B vaccination

14,092/QALY for non-BCG-vaccinated HCWs and

Prevalence of nursing home-associated infections in the Department of Veterans Affairs nursing home care units

103,047/QALY for BCG-vaccinated HCWs. There was no prevalence of LTBI at which the TST became the most effective or least costly strategy. If the sensitivity of the QFT-GIT exceeds that of the QFT-G, then the QFT-GIT is the most effective and least costly strategy. CONCLUSION Use of the QFT-G and QFT-GIT leads to superior clinical outcomes and lower costs than the TST and should be considered in screening non-BCG-vaccinated and BCG-vaccinated new HCWs for LTBI.