Repeated lumbar punctures within 3 days may affect CSF biomarker levels

Lumbar puncture (LP) is a common way of collecting cerebrospinal fluid (CSF) both in the clinic and in research. In this extension of a study on the relationship between sleep deprivation and CSF biomarkers for Alzheimer’s disease, we investigated CSF biomarker dynamics in relation to rebound sleep after sleep deprivation. Two LPs were performed within 3 days in 13 healthy volunteers. We noticed an unexpected sharp rise in biomarker concentrations in the second sample and therefore repeated the experiment, but without sleep intervention, in four additional individuals. The findings were similar in these subjects, suggesting an inherent methodological problem with repeated LPs. The result corroborates findings in studies with repeated CSF collection via indwelling lumbar catheters, and needs to be addressed in, for instance, pharmacodynamic studies employing these techniques

Ion concentrations in cerebrospinal fluid in wakefulness, sleep and sleep deprivation in healthy humans

Sleep is controlled by a circadian rhythmicity, via a reduction of arousal-promoting neuromodulatory activity, and by accumulation of somnogenic factors in the interstitial fluid of the brain. Recent experiments in mice suggest that a reduced neuronal excitability caused by a reduced concentration of potassium in the brain, concomitant with an increased concentration of calcium and magnesium, constitutes an important mediator of sleep. In the present study, we examined whether such changes in ion concentrations could be detected in the cerebrospinal fluid of healthy humans. Each subject underwent cerebrospinal fluid collection at three occasions in a randomized order: at 15:00 hours–17:00 hours during waking, at 06:00 hours–07:00 hours immediately following 1 night of sleep, and at 06:00 hours–07:00 hours following 1 night of sleep deprivation. When compared with wakefulness, both sleep and sleep deprivation produced the same effect of a small (0.1 mm, about 3%), but robust and highly significant, reduction in potassium concentration. Calcium and magnesium concentrations were unchanged. Our results support a circadian modulation of neuronal excitability in the brain mediated via changes of the interstitial potassium concentration

Failure of recombinant factor VIIa in a patient with severe polymicrobial sepsis and postoperative uncontrolled intraabdominal bleeding

<p>Abstract</p> <p>Background</p> <p>This report discusses a case of unsuccessful treatment with recombinant factor VIIa (rFVIIa) in off-label use. The need for international guidelines concerning the off-label use of rFVIIa is outlined as well as the need for methods to control the efficacy of rFVIIa objectively.</p> <p>Case presentation</p> <p>54 year old male with severe polymicrobial sepsis due to a perforated diverticulitis of the sigmoid colon and consecutive overt disseminated intravascular coagulation. He suffered severe intraabdominal bleeding after abdominal surgery despite conventional haemostatic support. Repeated applications of factor VIIa temporarily improved coagulation essays but did not stop clinical bleeding. The patient died in multiorgan failure due to septic and haemorrhagic shock.</p> <p>Conclusion</p> <p>Off-label use of rFVIIa could result in more side effects than could be expected from literature because of a publication bias. However for most off-label applications large prospective, randomised and controlled trials to confirm the positive findings are missing. For the future, not only guidelines concerning the off-label use of rFVIIa are urgently needed but also guidelines for monitoring the efficacy of rFVIIa.</p

A new instrument for measuring anticoagulation-related quality of life: development and preliminary validation

BACKGROUND: Anticoagulation can reduce quality of life, and different models of anticoagulation management might have different impacts on satisfaction with this component of medical care. Yet, to our knowledge, there are no scales measuring quality of life and satisfaction with anticoagulation that can be generalized across different models of anticoagulation management. We describe the development and preliminary validation of such an instrument – the Duke Anticoagulation Satisfaction Scale (DASS). METHODS: The DASS is a 25-item scale addressing the (a) negative impacts of anticoagulation (limitations, hassles and burdens); and (b) positive impacts of anticoagulation (confidence, reassurance, satisfaction). Each item has 7 possible responses. The DASS was administered to 262 patients currently receiving oral anticoagulation. Scales measuring generic quality of life, satisfaction with medical care, and tendency to provide socially desirable responses were also administered. Statistical analysis included assessment of item variability, internal consistency (Cronbach's alpha), scale structure (factor analysis), and correlations between the DASS and demographic variables, clinical characteristics, and scores on the above scales. A follow-up study of 105 additional patients assessed test-retest reliability. RESULTS: 220 subjects answered all items. Ceiling and floor effects were modest, and 25 of the 27 proposed items grouped into 2 factors (positive impacts, negative impacts, this latter factor being potentially subdivided into limitations versus hassles and burdens). Each factor had a high degree of internal consistency (Cronbach's alpha 0.78–0.91). The limitations and hassles factors consistently correlated with the SF-36 scales measuring generic quality of life, while the positive psychological impact scale correlated with age and time on anticoagulation. The intra-class correlation coefficient for test-retest reliability was 0.80. CONCLUSIONS: The DASS has demonstrated reasonable psychometric properties to date. Further validation is ongoing. To the degree that dissatisfaction with anticoagulation leads to decreased adherence, poorer INR control, and poor clinical outcomes, the DASS has the potential to help identify reasons for dissatisfaction (and positive satisfaction), and thus help to develop interventions to break this cycle. As an instrument designed to be applicable across multiple models of anticoagulation management, the DASS could be crucial in the scientific comparison between those models of care

Sleep and cardiometabolic comorbidities in the obstructive sleep apnoea-COPD overlap syndrome: data from the European Sleep Apnoea Database

Aim The impact of obstructive sleep apnoea (OSA)-COPD overlap syndrome (OVS) on sleep quality and cardiovascular outcomes has not been fully explored. We aimed to compare clinical and polysomnographic characteristics of patients with OVS versus patients with OSA, and to explore pathophysiological links between OVS and comorbidities. Study design and methods This cross-sectional analysis initially included data from 5600 patients with OSA and lung function in the European Sleep Apnoea Database. Two subgroups of patients with OSA (n=1018) or OVS (n=509) were matched (2:1) based on sex, age, body mass index and apnoea-hypopnea index at baseline. Results After matching, patients with OVS had more severe hypoxia, lower sleep efficiency and presented with higher prevalences of arterial hypertension, ischaemic heart disease and heart failure compared with patients with OSA. OVS was associated with a significant decrease in sleep efficiency (mean difference (beta) -3.0%, 95% CI -4.7 to -1.3) and in nocturnal mean peripheral oxyhaemoglobin saturation (S-pO2) (beta -1.1%, 95% CI -1.5 to -0.7). Further analysis revealed that a decrease in forced expiratory volume in 1 s and arterial oxygen tension was related to a decrease in sleep efficiency and in mean nocturnal S-pO2. A COPD diagnosis increased the odds of having heart failure by 1.75 (95% CI 1.15-2.67) and systemic hypertension by 1.36 (95% CI 1.07-1.73). Nocturnal hypoxia was strongly associated with comorbidities; the mean nocturnal S-pO2 and T90 (increase in time below S-pO2 of 90%) were associated with increased odds of systemic hypertension, diabetes and heart failure but the oxygen desaturation index was only related to hypertension and diabetes. Conclusion Patients with OVS presented with more sleep-related hypoxia, a reduced sleep quality and a higher risk for heart failure and hypertension.The ESADA study group received unrestricted funding grants from the Respironics and Resmed Foundations, and an unrestricted collaboration grant from Bayer AG

Insomnia symptoms combined with nocturnal hypoxia associate with cardiovascular comorbidity in the European sleep apnea cohort (ESADA)

Purpose: The aim of the current study was to further investigate the concept of previously reported high occurrence of comorbidities in obstructive sleep patients (OSA) with insomnia-like symptoms. We hypothesized that this finding at least partly is mediated by nocturnal hypoxia. Moreover, we speculated that the spectrum of the clinical OSA phenotypes differs between European geographical regions.Methods: Cohort of the European Sleep Apnea Database (n = 17,325; 29.9% females) was divided into five subcohorts according to geographical region (North, East, South, West, Central) and further into four clinical presentation phenotypes based on daytime symptoms (EDS) and characteristics suggestive of insomnia.Results: The insomnia phenotype (alone or together with EDS) dominated in all European regions. Isolated insomnia, however, was less common in the West. Insomnia phenotype was associated with the highest proportion of cardiovascular comorbidity (51.7% in the insomnia vs. 43.9% in the EDS type). Measures of nocturnal hypoxemia were independently associated with cardiovascular comorbidity in phenotypes with insomnia-like symptoms. The burden of comorbidities was high across all geographical regions and clinical phenotypes. Regional differences were clinically relevant for age (48 vs. 54 years), BMI (29 vs. 34 kg/m2), and ODI (15 vs. 32/h).Conclusion: High prevalence of particularly cardiovascular comorbidity among patients with insomnia-like symptoms was linked to nocturnal hypoxemia. Considerable differences in clinical presentation were found among OSA patients across Europe. Our data underline that physicians should ask their patients with suspected OSA also for insomnia symptoms. It remains to be explored if a reduction of nocturnal hypoxemia predicts the improvement of insomnia symptoms.</p

Arterial bicarbonate is associated with hypoxic burden and uncontrolled hypertension in obstructive sleep apnea - The ESADA cohort

Objective: Blood bicarbonate concentration plays an important role for obstructive sleep apnea (OSA) patients to maintain acid-base balance. We investigated the association between arterial standard bicarbonate ([HCO3-]) and nocturnal hypoxia as well as comorbid hypertension in OSA. Methods: A cross-sectional analysis of 3329 patients in the European Sleep Apnea Database (ESADA) was performed. Arterial blood gas analysis and lung function test were performed in conjunction with polysomnographic sleep studies. The 4% oxygen desaturation index (ODI), mean and minimum oxygen saturation (SpO2), and percentage of time with SpO2 below 90% (T90%) were used to reflect nocturnal hypoxic burden. Arterial hypertension was defined as a physician diagnosis of hypertension with ongoing antihypertensive medication. Hypertensive patients with SBP/DBP below or above 140/90 mmHg were classified as controlled-, uncontrolled hypertension, respectively. Results: The [HCO3-] level was normal in most patients (average 24.0 ± 2.5 mmol/L). ODI, T90% increased whereas mean and minimum SpO2 decreased across [HCO3-] tertiles (ANOVA, p = 0.030, &lt;0.001, &lt;0.001, and &lt;0.001, respectively). [HCO3-] was independently associated with ODI, mean SpO2, minimum SpO2, and T90% after adjusting for confounders (β value [95%CI]: 1.21 [0.88–1.54], −0.16 [-0.20 to −0.11], −0.51 [-0.64 to −0.37], 1.76 [1.48–2.04], respectively, all p &lt; 0.001). 1 mmol/L elevation of [HCO3-] was associated with a 4% increased odds of uncontrolled hypertension (OR: 1.04 [1.01–1.08], p = 0.013). Conclusion: We first demonstrated an independent association between [HCO3-] and nocturnal hypoxic burden as well as uncontrolled hypertension in OSA patients. Bicarbonate levels as an adjunctive measure provide insight into the pathophysiology of hypertension in OSA

Clinical Phenotypes and Comorbidity in European Sleep Apnoea Patients

BackgroundClinical presentation phenotypes of obstructive sleep apnoea (OSA) and their association with comorbidity as well as impact on adherence to continuous positive airway pressure (CPAP) treatment have not been established.MethodsA prospective follow-up cohort of adult patients with OSA (apnoea-hypopnoea index (AHI) of >= 5/h) from 17 European countries and Israel (n = 6,555) was divided into four clinical presentation phenotypes based on daytime symptoms labelled as excessive daytime sleepiness ("EDS") and nocturnal sleep problems other than OSA (labelled as "insomnia"): 1) EDS (daytime+/nighttime-), 2) EDS/insomnia (daytime+/nighttime+), 3) non-EDS/noninsomnia (daytime-/nighttime-), 4) and insomnia (daytime-/nighttime+) phenotype.ResultsThe EDS phenotype comprised 20.7%, the non-EDS/non-insomnia type 25.8%, the EDS/insomnia type 23.7%, and the insomnia phenotype 29.8% of the entire cohort. Thus, clinical presentation phenotypes with insomnia symptoms were dominant with 53.5%, but only 5.6% had physician diagnosed insomnia. Cardiovascular comorbidity was less prevalent in the EDS and most common in the insomnia phenotype (48.9% vs. 56.8%, p<0.001) despite more severe OSA in the EDS group (AHI 35.0 +/- 25.5/h vs. 27.9 +/- 22.5/h, p<0.001, respectively). Psychiatric comorbidity was associated with insomnia like OSA phenotypes independent of age, gender and body mass index (HR 1.5 (1.188-1.905), p<0.001). The EDS phenotype tended to associate with higher CPAP usage (22.7 min/d, p = 0.069) when controlled for age, gender, BMI and sleep apnoea severity.ConclusionsPhenotypes with insomnia symptoms comprised more than half of OSA patients and were more frequently linked with comorbidity than those with EDS, despite less severe OSA. CPAP usage was slightly higher in phenotypes with EDS

Clinical Phenotypes and Comorbidity in European Sleep Apnoea Patients

Background Clinical presentation phenotypes of obstructive sleep apnoea (OSA) and their association with comorbidity as well as impact on adherence to continuous positive airway pressure (CPAP) treatment have not been established. Methods A prospective follow-up cohort of adult patients with OSA (apnoea-hypopnoea index (AHI) of 655/h) from 17 European countries and Israel (n = 6,555) was divided into four clinical presentation phenotypes based on daytime symptoms labelled as excessive daytime sleepiness ("EDS") and nocturnal sleep problems other than OSA (labelled as "insomnia"): 1) EDS (daytime+/nighttime-), 2) EDS/insomnia (daytime+/nighttime+), 3) non-EDS/noninsomnia (daytime-/nighttime-), 4) and insomnia (daytime-/nighttime+) phenotype. Results The EDS phenotype comprised 20.7%, the non-EDS/non-insomnia type 25.8%, the EDS/ insomnia type 23.7%, and the insomnia phenotype 29.8% of the entire cohort. Thus, clinical presentation phenotypes with insomnia symptoms were dominant with 53.5%, but only 5.6% had physician diagnosed insomnia. Cardiovascular comorbidity was less prevalent in the EDS and most common in the insomnia phenotype (48.9% vs. 56.8%, p<0.001) despite more severe OSA in the EDS group (AHI 35.0\ub125.5/h vs. 27.9\ub122.5/h, p<0.001, respectively). Psychiatric comorbidity was associated with insomnia like OSA phenotypes independent of age, gender and body mass index (HR 1.5 (1.188-1.905), p<0.001). The EDS phenotype tended to associate with higher CPAP usage (22.7 min/d, p = 0.069) when controlled for age, gender, BMI and sleep apnoea severity. Conclusions Phenotypes with insomnia symptoms comprised more than half of OSA patients and were more frequently linked with comorbidity than those with EDS, despite less severe OSA. CPAP usage was slightly higher in phenotypes with EDS