Konrad E. Bloch

German Version of the Epworth Sleepiness Scale

Background: The Epworth Sleepiness Scale (ESS) is a questionnaire widely used in English speaking countries for assessment of subjective daytime sleepiness. Objective: Our purpose was to translate and validate the ESS for use in German-speaking countries. Methods: A German translation of the ESS was administered to 159 healthy German-speaking Swiss and to 174 patients with various sleep disorders. Results: The mean ± SD of ESS scores in normals was 5.7 ± 3.0, in patients it was 13.0 ± 5.1 (p < 0.001). Scores were not correlated with age or gender but with the percentage of time spent at an oxygen saturation <90% (R = 0.35, p < 0.001), and the respiratory disturbance index (R = 0.26, p < 0.001) in primary snorers and sleep apnea patients. Item analysis confirmed internal consistency of the scale (Cronbach α = 0.60 in normals, and 0.83 in patients). Follow-up scores in 25 sleep apnea patients on treatment showed a reduction by 7 ± 5 points (p < 0.05). Conclusions: Our data validate the ESS for application in German-speaking populations. The simplicity, reliability and the apparent lack of relevant influences of language and cultural background on performance of the ESS makes it a valuable tool for clinical management and research.

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.

Context Very few trials have evaluated ways to prevent high-altitude pulmonary edema (HAPE). Contribution In this double-blind trial, 29 adults with a history of HAPE were randomly assigned to receive prophylactic tadalafil, dexamethasone, or placebo during a 24-hour ascent and 2-day stay at 4559 m. Compared with placebo recipients, adults taking dexamethasone less often experienced acute mountain sickness and those taking either dexamethasone or tadalafil less often had HAPE. Cautions The trial involved a small number of selected adults who rapidly ascended to a high altitude. Implications Either tadalafil or dexamethasone might help prevent HAPE in mountaineers with a history of pulmonary edema. The Editors Rapid ascent to altitudes greater than 2500 m may cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE). In nonacclimatized mountaineers, the prevalences of AMS and HAPE at 4559 m are approximately 50% and 4%, respectively (1). Individual susceptibility, rate of ascent, and preexposure to high altitude are major, independent determinants of the prevalence of AMS (2). Acute mountain sickness is not a prerequisite for HAPE. Acetazolamide (3, 4) or dexamethasone (5, 6) prophylaxis can prevent AMS, whereas nifedipine prophylaxis can prevent HAPE (7). Whether acetazolamide or dexamethasone also prevents HAPE has not been studied. Exaggerated hypoxic pulmonary vasoconstriction leading to elevated pulmonary capillary pressure (8) is the major pathophysiologic mechanism of HAPE. This elevated pulmonary capillary pressure may be caused by inhomogeneous hypoxic pulmonary vasoconstriction (9), which leads to areas that are subjected to high pressure and flow, consequent mechanical overdistention of pulmonary capillaries, and injury of the bloodgas barrier (10). This phenomenon causes extravasation of fluid, plasma proteins, and blood cells into the interstitial and alveolar spaces (11). Decreased bioavailability of nitric oxide might explain the elevated pulmonary artery pressure (12, 13). Therefore, phosphodiesterase-5 inhibitors are an attractive option to restore impaired effects of nitric oxide in persons susceptible to HAPE (1416). Constitutively impaired sodium and water transport in the lung has been thought to be an additional factor in the pathogenesis of HAPE (17, 18). Hypoxia also decreases water reabsorption from the alveolar space. Direct experimental evidence has been obtained from hypoxia-exposed rats (19), and indirect evidence derives from decreased sodium transport activity in cultured alveolar epithelial cells (20). Prophylactic inhalation of the 2-adrenergic agonist salmeterol to stimulate alveolar sodium transport (17) decreased the incidence of HAPE in susceptible persons. However, other mechanisms of action may also contribute to the preventive effects of salmeterol, because -adrenergics tighten the endothelial barrier and decrease pulmonary artery pressure (21). Dexamethasone may be an alternative therapy to prevent HAPE because it stimulates alveolar sodium and water reabsorption (22); may enhance nitric oxide availability in pulmonary vessels (23, 24); and is effective against AMS (5, 6), which may develop despite use of nifedipine as prophylaxis against HAPE (25). However, HAPE has occurred in persons who received dexamethasone for AMS (26, 27). We sought to test whether prophylaxis with dexamethasone or tadalafil reduces the risk for HAPE in adults with a history of HAPE on rapid ascent to 4559 m. Methods Sample and Setting Mountaineers with a history of HAPE were recruited through announcements in the journals of the Swiss Alpine Club and the German Alpine Club. Four women and 25 men with at least 1 documented episode of HAPE participated after providing written informed consent. Table 1 shows the age and average number of HAPE episodes for each participant. No participant spent more than 4 nights above 2500 m within 30 days before ascent to the Capanna Regina Margherita, Italy (altitude, 4559 m). Table 1. Participant Characteristics Two to 4 weeks before the study at the Capanna Regina Margherita, baseline evaluations were performed in Zrich, Switzerland (altitude, 490 m). For ascent, participants traveled to Alagna, Italy (altitude, 1100 m), ascended to 3200 m by cable car, and continued by foot to the Capanna Gnifetti (altitude, 3600 m), where they spent 1 night. The journey from the cable car arrival station (3200 m) to the Capanna Gnifetti took about 1.5 hours. The next morning, the participants continued to the Capanna Regina Margherita (about 4 hours), where they spent 2 nights. Figure 1 shows the study design. The institutional ethics boards of the University Hospital Zrich and University Hospital Heidelberg approved the study and its protocol, which was consistent with the principles of the Declaration of Helsinki. Figure 1. Flow diagram of the study. Twenty-nine participants were recruited and underwent prealtitude tests, after which they were randomly assigned to treatment groups. *Two participants in the tadalafil group were withdrawn from the study early because they required treatment for severe acute mountain sickness (AMS) with oxygen and dexamethasone before the first night at 4559 m, but high-altitude pulmonary edema (HAPE) was not diagnosed at the time of withdrawal. However, the duration of exposure to 4559 m may not have been long enough to develop HAPE. Randomization and Interventions Medication consisted of white gelatin capsules, identical in appearance, containing placebo; tadalafil, 10 mg (Cialis [Eli Lilly, Geneva, Switzerland]); or dexamethasone, 8 mg (Fortecortin [Merck, Dietikon, Switzerland]). Before the study, the pharmacist at the University Hospital Zrich packaged the medication into numbered bottles, which were assigned to individual participants according to a computer-generated list. Randomization was stratified by the number of previous episodes of HAPE (1 or 2) without blocking. Participants started taking the medication twice daily on the morning of the day before ascent to high altitude and continued intake until the end of the study. Primary End Point and Assessment of HAPE and AMS The primary end point was development of HAPE, which was assessed by clinical examination and chest radiography in each participant after the first and second nights at 4559 m or when HAPE or severe AMS occurred (Figure 1). Two physicians who were blinded to treatment assignment performed clinical examinations according to a predefined checklist in the mornings after the first and second night at 4559 m or when severe AMS or HAPE occurred. High-altitude pulmonary edema was clinically suspected at the appearance of dry cough, orthopnea, or pulmonary rales in at least 1 lung area. A posteroanterior thorax radiograph was then obtained by using a mobile unit (TRS [Siemens, Stockholm, Sweden]) at a fixed distance of 1.4 m at 95 kV and a charge of 3 to 6 mAs. Radiographs were scored retrospectively by a second radiologist who was blinded to other study results. After the lung was divided into 4 quadrants, the following scores were assigned: 1 for a questionable infiltrate, 2 for interstitial edema in less than 50% of the quadrant area, 3 for interstitial edema on 50% or more of the quadrant area, and 4 for alveolar edema. A radiograph showing interstitial or alveolar edema (score >1) in at least 1 quadrant (28) confirmed the diagnosis of HAPE. The severity of AMS was evaluated by clinical examination and was quantified by using the Lake Louise scoring protocol (29). Each participant answered the first 5 questions of the protocol that asked about the severity of headache, gastrointestinal symptoms, fatigue, lightheadedness or dizziness, and insomnia. A score of 0 to 3 points (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms) was assigned for each item. In clinical examination, a score of 0 (normal) to 4 points was given for mental status (for which 4 points indicated coma) and ataxia (for which 4 points indicated inability to stand on the heel-to-toe walking test). A score of 1 was given for peripheral edema in 1 location, and a score of 2 was given for edema in more than 1 location. The sum of all points yielded the Lake Louise score (maximum score, 25 points). A Lake Louise score greater than 4 defined AMS (30). To assess possible side effects of the study medications, we separately evaluated the Lake Louise score question that asked for information on headache severity and the degree of insomnia, and we measured blood glucose levels in addition to vital signs. To test for adherence, participants were requested to document medication intake and investigators counted the remaining capsules at each visit. Blood and urine samples were collected to measure cortisol and tadalafil, respectively. Treatment of HAPE and AMS consisted of nifedipine for HAPE, dexamethasone for AMS, and supplemental oxygen for both disorders. Participants who required treatment were withdrawn from the study. Echocardiography and Measurement of Cardiac Output Doppler echocardiography was performed by using an integrated color Doppler system with a 4.0-MHz transducer (Aplio 80 [Toshiba-Medical Systems, Oetwil am See, Switzerland]) while participants were lying in a semi-supine, left-lateral position. Systolic pulmonary artery pressure was calculated from the pressure gradient across the tricuspid valve and measured with continuous-wave Doppler echocardiography by using the modified Bernoulli equation and an estimated right atrial pressure of 7 mm Hg (8). Color flow imaging was used for alignment. The recordings were stored on magneto-optical disk for evaluation by 2 investigators who were blinded to all other data. Averages of at least 3 cardiac cycles were used. Cardiac output was measured by using beat-to-beat stroke volume measurement with impedance cardiography (Task Force Monitor [CNSystems, Graz, Austria]). Nasal Potential Measurements Diffe

Effects of Continuous Positive Airway Pressure Therapy Withdrawal in Patients with Obstructive Sleep Apnea

RATIONALE To establish a new approach to investigate the physiological effects of obstructive sleep apnea (OSA), and to evaluate novel treatments, during a period of continuous positive airway pressure (CPAP) withdrawal. OBJECTIVES To determine the effects of CPAP withdrawal. METHODS Forty-one patients with OSA and receiving CPAP were randomized to either CPAP withdrawal (subtherapeutic CPAP), or continued CPAP, for 2 weeks. Polysomnography, sleepiness, psychomotor performance, endothelial function, blood pressure (BP), heart rate (HR), urinary catecholamines, blood markers of systemic inflammation, and metabolism were assessed. MEASUREMENTS AND MAIN RESULTS CPAP withdrawal led to a recurrence of OSA within a few days and a return of subjective sleepiness, but was not associated with significant deterioration of psychomotor performance within 2 weeks. Endothelial function, assessed by flow-mediated dilatation, decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP (mean difference in change, -3.2%; 95% confidence interval [CI], -4.5, -1.9%; P < 0.001). Compared with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP (mean difference in change, +8.5 mm Hg; 95% CI, +1.7, +15.3 mm Hg; P = 0.016), morning diastolic BP (mean difference in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P = 0.008), and morning HR (mean difference in change, +6.3 bpm, 95% CI, +0.4, +12.2 bpm; P = 0.035). CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation, insulin resistance, or blood lipids. CONCLUSIONS CPAP withdrawal usually leads to a rapid recurrence of OSA, a return of subjective sleepiness, and is associated with impaired endothelial function, increased urinary catecholamines, blood pressure, and heart rate. Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA. Clinical trial registered with www.controlled-trials.com (ISRCTN93153804).

Impact of Physical Activity on Cardiovascular Risk Factors in IDDM

OBJECTIVE To study the impact of physical activity on glycemic control and plasma lipids [HDL cholesterol (HDL-C), HDL-C subfractions, triglycerides, lipoprotein(a)], blood pressure, weight, and abdominal fat and to determine the necessary short-term adaptations in diabetes management during intensive endurance training in patients with IDDM. RESEARCH DESIGN AND METHODS Well-controlled subjects with IDDM (n = 20; HbA1c = 7.6%) engaged in a regular exercise program over a period of 3 months involving endurance sports such as biking, long-distance running, or hiking. Subjects were instructed to exercise at least 135 min per week. If baseline activity exceeded this level, subjects were to increase further their physical activity as much as possible and record the type and time of such activity. RESULTS During the 3-month intervention, physical activity increased from 195 ± 176 to 356 ± 164 min (mean ± SD) per week (P < 0.001). Physical fitness as assessed by VO2max increased from 2,914 ± 924 to 3,092 ± 905 ml/min (P < 0.001), and insulin sensitivity increased significantly (steady-state plasma glucose [SSPG] decreased from 10.5 ± 4.8 to 7.0 ± 3.3 mmol/l; P < 0.01). Subsequently, LDL cholesterol decreased by 14% (P < 0.05), and HDL and HDL3-C subfraction increased by 10 (P < 0.05) and 16% (P < 0.05), respectively. Systolic and diastolic blood pressure decreased significantly from 127 ± 9 to 124 ± 8 (P < 0.05) and from 80 ± 5 to 77 ± 5 mmHg (P < 0.01), respectively. Resting heart rate decreased from 63 ± 6 to 59 ± 7 bpm (P < 0.01). Waist-to-hip circumference ratio decreased from 0.882 ± 0.055 to 0.858 ± 0.053 (P < 0.001), body weight decreased from 70.7 ± 10.4 to 68.7 ± 10.2 kg (P = 0.003), with a consequent decrease in body fat from 21.9 ± 8.2 to 18.0 ± 6.3% (P < 0.001) and an increase in lean body mass from 54.9 ± 12.2 to 56.8 ± 11.0 kg. These effects occurred independently of glycemic control. The overall frequency of severe hypoglycemic episodes was reduced from 0.14 to 0.10 per patient-year during the study period. CONCLUSIONS This study shows that increasing physical activity is safe and does not result in more hypoglycemic episodes and that there is a linear dose-response between increased physical activity and loss of abdominal fat and a decrease in blood pressure and lipid-related cardiovascular risk factors, with a preferential increase in the HDL3-C subfraction.

Radiologic emphysema morphology is associated with outcome after surgical lung volume reduction

BACKGROUND Lung volume reduction surgery is known to alleviate dyspnea and to improve pulmonary function, performance in daily activity, and quality of life in selected patients with severe pulmonary emphysema. We investigated the role of radiologically assessed emphysema morphology on functional outcome after a lung volume reduction operation. METHODS The preoperative chest computed tomograms in 50 consecutive patients who had undergone surgical lung volume reduction were retrospectively reviewed by 6 physicians blinded to the clinical outcome. Emphysema morphology was determined according to a simplified classification (ie, homogeneous, moderately heterogeneous, and markedly heterogeneous; lobe predominance). We studied the impact of these morphologic aspects on functional outcome at 3 months. RESULTS We found a fair interobserver agreement applying our classification system. Functional improvement after surgical lung volume reduction was best in markedly heterogeneous emphysema with an increase in forced expiratory volume in 1 second of 81% +/- 17% (mean +/- standard error, n = 17) compared with 44% +/- 10% (n = 16) for intermediately heterogeneous emphysema. But also in patients with homogeneous emphysema clinical relevant improvement of function could be observed (increase in forced expiratory volume in 1 second = 34% +/- 6%; n = 17). CONCLUSIONS The morphologic type of emphysema, assessed by a simplified surgically oriented classification, is an important predictor of surgical outcome. Lung volume reduction surgery may also improve dyspnea and lung function in homogeneous emphysema.

Bilateral volume reduction surgery for diffuse pulmonary emphysema by video-assisted thoracoscopy.

UNLABELLED We prospectively studied the surgical aspects, functional results, and complications of video-assisted bilateral thoracoscopic volume reduction surgery in patients with severe diffuse pulmonary emphysema. METHODS Fifteen men and five women with a mean age of 64 years (range 42 to 78 years) whose daily activity was substantially impaired by severe airflow obstruction and hyperinflation underwent thoracoscopic volume reduction surgery. The prospective preoperative assessment and postoperative assessment at 3 months included (1) pulmonary function studies, (2) grading of dyspnea, and (3) exercise performance; pulmonary function tests were also performed immediately before discharge from the hospital. RESULTS There was no perioperative mortality. All patients left the hospital after a median stay of 15 days (6 to 27 days). Only seven patients had a prolonged chest tube drainage time (>7 days). At 3 months the mean (+/- standard deviation) forced expiratory volume in 1 second had improved by 42% (+/-3.8%), from 0.80 L (+/-0.23) to 1.09 L (+/-0.28) (p < 0.001); residual volume had decreased from 5.8 L (+/-1.5) to 4.4 L (+/-1.0) (p < 0.001). Shortly before discharge the forced expiratory volume in 1 second was already 1.10 L (+/-0.26). The median 12-minute walking distance increased from 495 m (35 to 790 m) to 688 m (175 to 1035 m) (p < 0.001) and the mean maximal oxygen consumption from 10 ml/kg per minute (+/-2.5) to 13 ml/kg per minute (+/-2.3) (p < 0.0005). The patients reported a substantial relief of dyspnea with a mean decrease in the Medical Research Council score from 3.4 to 1.8.

Disability and survival in Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) leads to progressive impairment of muscle function, respiratory failure and premature death. Longitudinal data on the course of physical disability and respiratory function are sparse. Objectives: To assess prospectively physical impairment and disability, respiratory function and survival in patients with DMD over several years to describe the course of the disease with current care. Methods: In 43 patients with DMD, aged 5–35 years, yearly assessments of physical disability by the Duchenne muscular dystrophy physical Impairment and Dependence on care (DID) score, ranging from 9 (no disability) to 80 (complete dependence), and forced vital capacity (FVC), were obtained over a mean time interval of 5.4 (SD 2.1) years. Results: DID scores were correlated with age according to a hyperbolic function (f = 85.3×age/(10.05+age), R = 0.62, p<0.0001). FVC declined exponentially with age (f = 139.1×exp(−0.08×age), R = 0.52, p<0.0001). Mean age at which patients lost their ambulation was 9.4 (SD 2.4) years and they became dependent on an electric wheelchair at 14.6 (4.0) years. Age at the beginning of assisted ventilation was 19.8 (3.9) years, Three patients died during the observation period. The estimated probability of survival to age 30 years was 85% (median survival was 35 years). Conclusions: Our detailed observations of the progression of physical disability, dependence on care and respiratory impairment in patients with DMD from childhood to adult life is valuable for predicting the clinical course with current medical care. Compared with historical data, survival has improved considerably.

Nocturnal periodic breathing during acclimatization at very high altitude at Mount Muztagh Ata (7,546 m)

RATIONALE Quantitative data on ventilation during acclimatization at very high altitude are scant. Therefore, we monitored nocturnal ventilation and oxygen saturation in mountaineers ascending Mt. Muztagh Ata (7,546 m). OBJECTIVES To investigate whether periodic breathing persists during prolonged stay at very high altitude. METHODS A total of 34 mountaineers (median age, 46 yr; 7 women) climbed from 3,750 m within 19-20 days to the summit at 7,546 m. During ascent, repeated nocturnal recordings of calibrated respiratory inductive plethysmography, pulse oximetry, and scores of acute mountain sickness were obtained. MEASUREMENTS AND MAIN RESULTS Nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6,850 m), median nocturnal oxygen saturation, minute ventilation, and the number of periodic breathing cycles were 64%, 11.3 L/min, and 132.3 cycles/h. Repeated recordings within 5-8 days at 4,497 m and 5,533 m, respectively, revealed increased oxygen saturation, but no decrease in periodic breathing. The number of periodic breathing cycles was positively correlated with days of acclimatization, even when controlled for altitude, oxygen saturation, and other potential confounders, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing. CONCLUSIONS Our field study provides novel data on nocturnal oxygen saturation, breathing patterns, and ventilation at very high altitude. It demonstrates that periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3,730 m, despite improved oxygen saturation consistent with a progressive increase in loop gain of the respiratory control system. Clinical trial registered with www.clinicaltrials.gov (NCT00514826).

Effect of Short-Term Acclimatization to High Altitude on Sleep and Nocturnal Breathing

STUDY OBJECTIVE Objective physiologic data on sleep and nocturnal breathing at initial exposure and during acclimatization to high altitude are scant. We tested the hypothesis that acute exposure to high altitude induces quantitative and qualitative changes in sleep and that these changes are partially reversed with acclimatization. DESIGN Prospective observation. SETTING One night in a sleep laboratory at 490 meters, the first and the third night in a mountain hut at 4559 meters. PARTICIPANTS Sixteen healthy mountaineers. INTERVENTION Altitude exposure. MEASUREMENTS Polysomnography, questionnaire evaluation of sleep and acute mountain sickness. RESULTS Compared to 490 m, median nocturnal oxygen saturation decreased during the 1st night at 4559 m from 96% to 67%, minute ventilation increased from 4.4 to 6.3 L/min, and the apnea-hypopnea index increased from 0.1 to 60.9/h; correspondingly, sleep efficiency decreased from 93% to 69%, and slow wave sleep from 18% to 6% (P < 0.05, all instances). During the 3rd night at 4559 m, oxygen saturation was 71%, slow wave sleep 11% (P < 0.05 vs. 1st night, both instances) and the apnea/hypopnea index was 86.5/h (P = NS vs. 1st night). Symptoms of AMS and of disturbed sleep were significantly reduced in the morning after the 3rd vs. the 1st night at 4559 m. CONCLUSIONS In healthy mountaineers ascending rapidly to high altitude, sleep quality is initially impaired but improves with acclimatization in association with improved oxygen saturation, while periodic breathing persists. Therefore, high altitude sleep disturbances seem to be related predominantly to hypoxemia rather than to periodic breathing.

Sleep-related breathing disorders in patients with pulmonary hypertension.

BACKGROUND Cheyne-Stokes respiration (CSR) and central sleep apnea (CSA) are common in patients with left-heart failure. We investigated the hypothesis that sleep-disordered breathing is also prevalent in patients with right ventricular dysfunction due to pulmonary hypertension (PH). METHODS We studied 38 outpatients (median age, 61 years; quartiles, 51 to 72) with pulmonary arterial hypertension (n = 23) or chronic thromboembolic PH (n = 15). New York Heart Association (NYHA) class was II to IV, and median 6-min walk distance was 481 m (quartiles, 429 to 550). In-laboratory polysomnography (n = 22) and ambulatory cardiorespiratory sleep studies (n = 38) including pulse oximetry were performed. Quality of life and sleepiness by the Epworth sleepiness score were assessed. RESULTS The median apnea/hypopnea index was 8 events/h (quartiles, 4 to 19), with 8 central events (quartiles, 4 to 17), and 0 obstructive events (quartiles, 0 to 0.3) per hour. Seventeen patients (45%) had > or = 10 apnea/hypopnea events/h. Comparison of 13 patients with > or = 10 CSR/CSA events/h with 21 patients with < 10 CSR/CSA events/h (excluding 4 patients with > or = 10 obstructive events/h from this analysis) revealed no difference in regard to hemodynamics, NYHA class, and Epworth sleepiness scores. However, patients with > or = 10 CSR/CSA events/h had a reduced quality of life in the physical domains. Ambulatory cardiorespiratory sleep studies accurately predicted > or = 10 apnea/hypopnea events/h during polysomnography in patients who underwent both studies (area under the receiver operating characteristic curve, 0.93; SE +/- 0.06; p = 0.002). The corresponding value for pulse oximetry was 0.63 +/- 0.14 (p = not significant). CONCLUSIONS In patients with PH, CSR/CSA is common, but obstructive sleep apnea also occurs. Sleep-related breathing disorders are not associated with excessive sleepiness but affect quality of life. They should be evaluated by polysomnography or cardiorespiratory sleep studies because pulse oximetry may fail to detect significant sleep apnea.