Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a decline in renal function at late disease stage when the majority of functional renal parenchyma is replaced by cystic tissue. Thus, kidney function, assessed by estimated glomerular filtration rate (eGFR) does not well represent disease burden in early disease. Here, we investigated various urinary markers for tubular injury and their association with disease burden in ADPKD patients at early disease course.2 were eligible for this cross-sectional study. Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1), and Uromodulin (UMOD) were investigated by Enzyme-Linked Immunosorbent Assay. Clara Cell Protein 16 (CC16) was investigated by Latex Immuno Assay. Cryoscopy was performed to assess urine osmolality and Urinary Albumin-to-Creatinine Ratio (UACR) was calculated. The association and the predictive properties of the markers on eGFR and height adjusted total kidney volume (htTKV) was evaluated using multiple regression analysis, incorporating different control variables for adjustment. Internal bootstrapping validated the obtained results.ADPKD patients between 18 and 40 years with an eGFR greater or equal to 70 ml per min per 1.73m2) the total kidney volume was negatively correlated with eGFR and UMOD and positive associated with age, UACR, KIM-1 and urine osmolality after adjustment for possible confounders. Urine osmolality and htTKV were also associated with eGFR, whereas no association of CC16, NGAL and UMOD with eGFR or htTKV was found.In 139 ADPKD patients (age 31 ±7 years, mean eGFR of 93 ± 19 ml per min per 1.73 mUACR and urinary KIM-1 are independently associated with kidney size but not with renal function in our study population. Urine osmolality was associated with eGFR and kidney volume following adjustment for multiple confounders. Despite statistical significance, the clinical value of our results is not yet conceivable. Further studies are needed to evaluate the property of the aforementioned biomarkers to assess disease state at early ADPKD stage. Due to glomerular hyperfiltration of the remaining nephrons kidney function stays stable over decades. Thus, traditional markers for kidney function like serum creatinine and estimated glomerular filtration rate (eGFR) have limited ability to accurately assess disease state and to predict progression in the early course of ADPKD. Increasing evidence suggests that total kidney volume qualifies as a marker for disease progression in ADPKD [Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney diseases. It is characterized by a decline of glomerular filtration rate at advanced disease stage and a high inter- and intrafamilial variability in age of end stage renal disease (ESRD) onset, implying a challenge to predict individuals’ disease progression. The development and continued accretion of cysts, as the most prominent feature in ADPKD, leads to a massive enlargement of the kidney and, subsequently, to a loss of its function. So far, no disease modifying treatment is available, except the recent approval of the vasopressin Vin ADPKD . In factRenal cystogenesis in ADPKD is a complex process, characterized by abnormalities in tubular cell proliferation, fluid secretion, extracellular matrix formation, and cell polarity . The pro2 as shown in PKD1 or PKD2 genes was required for enrolment of patients without family history . The study was conducted according to the Declaration of Helsinki and Good Clinical Practice Guidelines and was approved by the local ethical board. All patients provided written informed consent.Subjects of the well-described SUISSE ADPKD cohort were eligible for enrolment ,19. MaleSubjects were invited to the outpatient clinic at the Division of Nephrology . At study visit the medical history was obtained, including medication and ADPKD related complications. Blood pressure measurement was done in duplicate at each arm after 5 minutes of rest in sitting position using an oscillometric blood pressure device . Hypertension was defined as systolic blood pressure above 140 mmHg and/or diastolic blood pressure above 90 mmHg or antihypertensive treatment. Fasting spot urine samples were collected after voiding the first urine of the day to measure creatinine beside the potential biomarkers. Blood samples were centrifuged and aliquoted, according to a standardized process, to obtain serum. Serum and spot urine aliquots were stored at—80°C before analysis.μg/ml; EMD Millipore, Temecula, CA) was used to establish the standard curve [At study visit, serum creatinine was measured according to modified Jaffé method traceable to an isotope-dilution mass spectroscopy reference. Estimated GFR was calculated by applying the CKD-EPI equation . NGAL  and signal perception was obtained with an eight-channel antero-posterior-phased array surface coil. Trans-axial sequences consisted of two breathhold T1-weighted fast-spoiled gradient echo sequences with 3 and 4 mm slice thicknesses. Additionally, a trans-axial T2-weighted fast spin echo sequence with respiratory triggering was performed with 3 mm slice thickness. Right and left kidney volumes were measured and calculated using the Advantage Windows workstation . Total kidney volume (TKV) was calculated by adding the volume of the left and right kidney. Measurements of renal volume were done in a blinded way by two trained and independent observers. The renal hilum and the vessels were excluded from renal volume calculation. Variability was calculated as concordance correlation coefficients (95% CI) and were 1.000 (0.999–1.000) for intraobserver and 0.996 (0.995–0.999) for interobserver correlations .SAS 9.4 was used for data analysis. A plausibility check of the data preceded the statistical analysis. Univariate methods were used to characterize study population. Values are given in means with standard deviation. TKV and height adjusted kidney volume (htTKV) are reported as median because of a skewed distribution of these parameters. Median is reported with interquartile range.Spearman’s correlation coefficient (r) was calculated to describe the correlation between biomarkers and eGFR and htTKV. To calculate r, reflecting the relative variance part, all values of the parameters are sorted and given a rank . A posit2 and p-value were calculated as statistic measures. R2, the coefficient of determination, reflects the proportion response variation that is explained by the predictors [th and 97.5th percentile confidence intervals for each model. Our dataset was used as a pool from which 500 new datasets of the same size were randomly drawn with replacement to internally validate our model results.The association of biomarkers with eGFR and htTKV was evaluated by incorporating different control variables for adjustment and following a multiple linear regression approach. A stratum specific correlation analysis was performed for binary and ordinal variables. Multiple regression analysis gives information about importance and size effect of the predictors on the response variable, and about the interaction between predictors. Prerequisites, like the independence of predictors to each other, were evaluated and fulfilled. The models were determined with scatterplots and correlation analysis to verify linearity between outcome variable and predictors. Subsequently the regression equation was formed. Adjusted Redictors . Predictedictors . The smaedictors . Bootstr2 and 74 (53%) of the patients had an eGFR greater than 90 ml per min per 1.73 m2. The median TKV was 860 cm3  and 52 (37%) patients had a TKV greater than 1000 cm3. The median htTKV was 455 cm3 . The mean body mass index (BMI) was 24±4 kg per m2, 5 (4%) patients had a BMI lower than 18.5 kg per m2 and 53 (38%) patients a BMI above 25 kg per m2 (Between April 2006 and April 2011 139 ADPKD patients were consecutively enrolled in the study. The mean age was 31±7 years and 85 (61%) patients were male. Hypertension was present in 82 (78%) patients, and 80 (58%) patients received antihypertensive medication. Among those, 50 patients received angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), 16 received diuretics and 14 were treated with calcium antagonists. The mean eGFR was 93±19 ml per min per 1.73 mg per m2 .2O . The median values were 9.8 μg per g creatinine  for NGAL, 274.6 ng per g creatinine  for KIM-1, and 16.3 mg per g creatinine  for UMOD. In the whole cohort, UACR was 14.0 mg per g creatinine  and the median for CC16 was 2.8 μg per l per g creatinine . The median of KIM-1 was significantly higher among patients with TKV above 1000 cm3 than among patients with TKV lower or equal 1000 cm3. Osmolality, NGAL, UMOD, UACR and CC16 were similar among patients with an eGFR above 90 ml per min per 1.73m2 and less or equal 90 ml per min per 1.73m2.The results of the urinary parameters osmolality, NGAL, KIM-1, UMOD, UACR and CC16 were tabulated for the complete cohort and stratified for eGFR and TKV . Osmolala priori known biological factors, e.g. age, gender, and glomerular filtration rate. Predictive variables were chosen in a predefined step-wise approach: In model 1 (2 = 0.2055) with an AIC of -199.6. Bootstrapping revealed a percentile confidence interval of 0.0987 and 0.3374.Simple and multiple linear regression analysis were applied to delineate the independent associations of urinary biomarkers with eGFR and htTKV. Kidney volume is affected by a number of  model 1  eGFR , and the AIC to -210.7  had a larger association with eGFR compared with osmolality (β = 0.22936). The adjusted R2 for this model is 0.2515  and thus approximately 25% of eGFR variation is explained by htTKV and osmolality.Subsequently different models were established to predict eGFR. In model 1  htTKV an2 of 0.2209. A percentile confidence interval of 0.1319 to 0.3738 was obtained in bootstrap validation. The predictor htTKV has the largest impact on the outcome in this model (β = -0.48736) and osmolality showed the second largest value for standardized estimate (β = 0.21857). UACR has a comparably low β.In model 2  the pred2 and AIC. Bootstrapping revealed a percentile confidence interval of 0.1674 to 0.4153.In model 3  the paraThe cystogenesis in ADPKD replaces functional renal parenchyma and leads to a loss of kidney function during patients’ lifespan. Since GFR, a traditional parameter of renal function, is not able to accurately assess disease state in the early disease course, the interest in establishing urinary biomarkers for ADPKD has increased. In this cross-sectional study, we investigated the potential biomarkers osmolality, UACR, NGAL, UMOD, CC16, KIM-1 at a single time point in spot urine samples of 139 ADPKD patients with preserved renal function. Robust statistical approach demonstrated that urinary KIM-1, urinary osmolality and UACR are independently associated with kidney volume in our cohort of ADPKD patients.An increase in urinary KIM-1, that is only fractionally expressed under physiological conditions, reflects tubular damage in the proximal S3 tubule segment as shown in acute and chronic kidney injury . In our A defect in osmoregulation has been shown in animal models of ADPKD as well as in patients –33. The Albuminuria is known as marker for kidney damage for years. Urinary albumin excretion is routinely assessed in the diagnosis of renal injury, due its urinary appearance prior to GFR decline in different renal diseases. Albuminuria is associated with CKD progression, decreasing eGFR, increasing TKV, myocardial infarction and mortality ,35–39. Ind and third year follow up, no association of NGAL quartiles with kidney volume and function were seen. Furthermore they showed highly elevated NGAL levels in cystic fluid in ADPKD patients compared to urine and serum values of healthy and of patients with AKI. The discrepancy of NGAL levels in urine and in cyst fluid may be attributable to a missing communication between tubules and detaching cysts in ADPKD [KIM-1, urine osmolality and UACR are independently associated with disease state in our study, but no association of NGAL, UMOD and CC16 with kidney volume and function at early ADPKD state was found. NGAL has been extensively studied as biomarker in acute kidney injury, but only limited data is available reporting NGAL levels in ADPKD –11,40. BTo our knowledge, UMOD and CC16 levels have not been reported in ADPKD so far. In our study, no association of UMOD and CC16 with renal function and kidney volume was observed. Decreasing levels of urinary UMOD, which is the most abundant protein in human urine, have been reported in various settings of CKD –15. SincOur cross-sectional study has to be interpreted in the context of the study setting. We report independent association between biomarkers and outcome of a relatively high number of young ADPKD patients. We are not able to conclude about causal relationships between urinary biomarkers and outcome parameter. The parameters were only investigated at a single time point and we are not able to infer whether or not biomarker excretion precedes decrease in renal function and increase in kidney volume. Furthermore, our results are based on a single centre in the absence of comparative groups of healthy volunteers or other CKD patients, making it impossible to assess the specificity of our findings for ADPKD. To partially account for the study limitations, we performed internal validation of our data set by bootstrapping. Despite adjustment for multiple confounders of our predictive models, we are not able to fully eliminate the potential for bias and confounding. We followed a robust and reliable statistical approach to investigate the diagnostic properties of different urinary biomarkers in a large cohort of ADPKD patients in early disease stage. Based on our results we hypothesize that osmolality, UACR and KIM-1 may have the property to assess disease state at early ADPKD disease course, whereas NGAL, UMOD and CC16 seem not to qualify as biomarkers. Further studies are necessary to define the biomarker properties of the investigated parameter to predict disease burden in ADPKD.


The key aim of triage in chest pain patients is to identify those with high risk of adverse cardiac events as they require intensive monitoring and early intervention. In this study, we aim to discover the most relevant variables for risk prediction of major adverse cardiac events (MACE) using clinical signs and heart rate variability.A total of 702 chest pain patients at the Emergency Department (ED) of a tertiary hospital in Singapore were included in this study. The recruited patients were at least 30 years of age and who presented to the ED with a primary complaint of non-traumatic chest pain. The primary outcome was a composite of MACE such as death and cardiac arrest within 72 h of arrival at the ED. For each patient, eight clinical signs such as blood pressure and temperature were measured, and a 5-min ECG was recorded to derive heart rate variability parameters. A random forest-based novel method was developed to select the most relevant variables. A geometric distance-based machine learning scoring system was then implemented to derive a risk score from 0 to 100.Out of 702 patients, 29 (4.1%) met the primary outcome. We selected the 3 most relevant variables for predicting MACE, which were systolic blood pressure, the mean RR interval and the mean instantaneous heart rate. The scoring system with these 3 variables produced an area under the curve (AUC) of 0.812, and a cutoff score of 43 gave a sensitivity of 82.8% and specificity of 63.4%, while the scoring system with all the 23 variables had an AUC of 0.736, and a cutoff score of 49 gave a sensitivity of 72.4% and specificity of 63.0%. Conventional thrombolysis in myocardial infarction score and the modified early warning score achieved AUC values of 0.637 and 0.622, respectively.It is observed that a few predictors outperformed the whole set of variables in predicting MACE within 72 h. We conclude that more predictors do not necessarily guarantee better prediction results. Furthermore, machine learning-based variable selection seems promising in discovering a few relevant and significant measures as predictors. Chest pain is one of the leading causes of visits to the emergency department (ED). PatientVarious systems exist for stratifying the risk of acute coronary syndromes (ACS)-6. The tMost scoring systems use clinical vital signs such as heart rate, respiratory rate, blood pressure, temperature and pulse oximetry for risk stratification model derivation, but the2). Demographic data such as age, race, gender, and medical history were also retrieved from the ED charts.This was a prospective observational study on a convenience sample of 702 patients presenting to the ED of SGH, a tertiary hospital in Singapore, serving more than 135,000 patients in the emergency care setting annually. Patients who were at least 30 years of age and with undifferentiated non-traumatic chest pain were included in the study. Monitoring was done with an ECG sensor  and a data acquisition device  over an uninterrupted recording period of 5 minutes. Patients were excluded if their ECG recordings contained sustained arrhythmias or large segments of noise or artifact. Patients who were transferred to another hospital or discharged against medical advice within 72 h of arrival at the ED were also excluded. Following the guidelines by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, a totalPatients were followed up to discharge from hospital or in-hospital death. The primary outcome was defined as a composite of four major adverse cardiac events (MACE) within 72 h of patient’s arrival at the ED. MACE in this study included death, cardiac arrest, sustained ventricular tachycardia (VT), and hypotension requiring inotropes or intra-aortic balloon pump (IABP) insertion. The outcomes were retrieved from the ED charts and outcome decisions were made by physicians.Ethics approval was obtained from the Singapore Health Services  Centralized Institutional Review Board (CIRB Ref: 2009/871/C) with a waiver of patient consent. This study was conducted from March 2010 to April 2012 at the Emergency Department (ED) of Singapore General Hospital (SGH).Variable selection in statistics and machine learning is a process of determining a subset of relevant variables for model construction. Irrelevant variables usually do not contribute to model building and may even degrade the prediction performance. Automatic variable selection methods have been widely adopted in clinical studies such as for predicting acute myocardial infarction mortality.We have previously studied the use of combined HRV parameters and clinical signs for patient outcome prediction,24 whereIn this study, we proposed a novel variable selection framework based on ensemble learning, in which random forests (RF) was chosp-value, it was excluded. Figure Our proposed variable selection framework is elaborated as follows. Firstly, 29 out of 673 patients (without MACE) were randomly selected and combined with all 29 patients (with MACE) to construct a new subset, on which RF was used to pick eight top-ranked variables. Secondly, the above random sampling process was repeated 500 times to create an ensemble of top-ranked variables. Thirdly, variables in the ensemble were accumulated and sorted according to their corresponding occurrences. As a result, a total of 500 individual models were created by RF, with each picking eight variables to form an ensemble of predictors. In this particular study, eight top-ranked variables were determined as potential predictors of the primary outcome. To optimize the selected variables for future validation, 10-fold cross-validation was implemented to avoid over-training during model construction. Lastly, the statistical significance of each variable was measured. If any one of the eight selected variables was not significant in terms of The classification and regression training package in R proVariable selection was the process of choosing a set of variables for the subsequent risk prediction. In this study, a machine learning (ML) based intelligent scoring system  or medians (interquartile range) and were analyzed using the Mann–Whitney test. SPSS version 17.0 , MATLAB R2009a , and R version 2.15.1  were employed for data analysis.Performance evaluation was carried out with the leave-one-out cross-validation (LOOCV) strategy to get unbiased estimation of the model performance. In this study with 702 samples, 702 iterations were required for performance evaluation. In iteration, one sample was used as the testing sample while the remaining 701 samples were used for training. The risk score prediction process was repeated 702 times so that each sample was tested individually. Risk scores were then obtained for the entire dataset and a threshold was derived to report sensitivity and specificity.p-value <0.05.A package developed in MATLAB was used to analyze ECG for HRV, calculate risk scores, and report prediction performance measures. To further evaluate differences in discrimination between models, pair-wise AUC comparisons using bootstrap method were performed with a ROC comparison package. StatistA total of 702 patients were recruited for the study; 29 of them met the primary outcome (MACE within 72 h). Characteristics of recruited patients are presented in Table p-value of <0.05. Temperature, oxygen saturation and pain score , and STD, sdHR, RMSSD, pNN50, NN50, TINN, HF power and Total power of HRV parameters were not considered statistically significant. As observed in Figure p-value. Ultimately, these eight variables were chosen for model building and analysis.Figure The performance of the intelligent scoring system with different numbers of selected variables is summarized in Table Furthermore, a linear logistic regression model with forward selection was created where the predicted score ranges from 0 to 1. Six variables including Glasgow Coma Scale, respiratory rate, DBP, pain score, STD, and avHR were chosen for model building. The regression score yielded an AUC of 0.632 (95% CI: 0.564 - 0.7). A cutoff score of 0.11 gave a sensitivity of 58.0% (95% CI: 47.3% - 68.8%) and specificity of 55.7% (95% CI: 51.8% - 59.6%), respectively.p-value 0.28), and performed better compared to TIMI score  and MEWS score .A pair-wise discrimination comparison of models is presented in Table This study is a continuation of our previous work on applying both HRV and clinical signs for outcome prediction. In thisMany scoring systems have been proposed to measure the risk of adverse events in acute patients. However, no study has yet been done on performance-driven model building with random forest (RF)-based variable selection. With the RF technique, we derived a novel variable selection process integrating the strengths of both machine learning and statistics. Artificial intelligence has been used in the medical field for many years,33. Due p-value) variable selection methods were able to pick up significant variables such as SBP, avHR and aRR. It is worth noting that avHR (average of the instantaneous heart rate) and aRR  were correlated and both were selected for building the scoring model. In a conventional statistics approach, these two variables will not appear in the same prediction model. However, in a machine learning method, variable selection is performance-driven where both prediction performance and statistical significance play important roles in the selection process.A total of 23 variables consisting of 15 HRV and eight clinical signs were investigated for their associations with the primary outcome. The results showed that several HRV parameters and clinical signs were significant in predicting MACE within 72 h. It has also been reported that patients with “normal” vital signs may be more ill than they appeared, and theWith these selected variables, triage (in terms of risk prediction) can be done within a shorter time to determine priority of patients’ treatments. Fast response is of great value in triage because resources are usually limited for all patients to receive immediate attention. In this scenario, a few yet significant variables will benefit the triage from two aspects. From software modeling perspective, they will maintain a balance between model complexity and prediction performance because including too many predictors may lead to a loss in precision, whereas omitting important variables may result in biased prediction. From haOur study has several limitations. Since this is a single-center pilot study at an acute tertiary hospital in Singapore, the number of recruited patients is small and our findings may not be generalizable to other populations. The endpoints in this study are heterogeneous while the event rate is still low. This creates difficulty in associating predictive variables with specific outcomes. The TIMI outcomes  might be adopted to standardize model derivation and for comparison across several risk scoring methods in chest pain patients presented to the ED.While we adopt random forest for variable selection, there are several other techniques available for selecting significant variables. Small sIn future work, exploration of other potential predictive variables will be considered. Gender has been reported to be useful for patient outcome prediction; 12-leadThis study expands our understanding that only a few predictors are needed in risk stratification of MACE within 72 h. With the proposed variable selection method, a machine learning scoring system outperforms traditional risk stratification systems such as TIMI and MEWS. We have seen that blood pressure and some HRV parameters achieved better prediction performance than a larger set of clinical signs and HRV parameters. It shows that more predictors do not necessarily guarantee better prediction results. Furthermore, variable selection presents potential to simplify scoring systems with just a few relevant measures as predictors, and the machine learning based scoring system demonstrates its adaptability to changes of variables.2: Oxygen saturation; SVM: Support vector machine; TI: Triangular index; TIMI: Thrombolysis in myocardial infarction; VLF: Very low frequency; VT: Ventricular tachycardia.ACS: Acute coronary syndrome; AMI: Acute myocardial infarction; AUC: Area under ROC curve; BP: Blood pressure; CABG: Coronary artery bypass graft; CIRB: Centralized Institutional Review Board; DBP: Diastolic BP; ECG: Electrocardiogram; ED: Emergency department; GCS: Glasgow coma scale; GRACE: Global registry of acute coronary events; HF: High frequency; HR: Heart rate; HRV: Heart rate variability; IABP: Intra-aortic balloon pump; LF: Low frequency; LOOCV: Leave-one-out cross-validation; MACE: Major adverse cardiac events; MEWS: Modified early warning score; ML: Machine learning; PCI: Percutaneous coronary intervention; RF: Random forests; ROC: Receiver operating characteristic; SBP: Systolic BP; SGH: Singapore general hospital; SingHealth: Singapore health services; SpOMarcus Eng Hock Ong and Nan Liu have a patent filing related to this study . Marcus Eng Hock Ong and Zhiping Lin have a patent filing related to this study . Marcus Eng Hock Ong and Zhiping Lin also have a licensing agreement with ZOLL Medical Corporation for the patented technology. There are no further patents, products in development or marketed products to declare. All the other authors do not have either commercial or personal associations or any sources of support that might pose a conflict of interest in the subject matter or materials discussed in this manuscript.NL and MEHO planned and established the project, performed data analysis, and drafted the manuscript. ZXK, JG, and BPT performed data collection and data analysis. BH performed detailed statistical analysis. ZL drafted the manuscript and reviewed critical revisions. All authors took part in manuscript writing and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6947/14/75/prepub


A diagnosis of hypertension based on an oscillometric measurement should be confirmed by an auscultatory method. Currently other two methods are used in children to measure BP values: ambulatory blood pressure monitoring (ABPM) and home blood pressure measurement. In children the use of ABPM has significant limitations due to the lack of reference values. It allows to identify “white coat hypertension” , “masked hypertension”  and subjects with or without reduced physiological day-night blood pressure variations (dipping) [In pediatric age diagnosis of hypertension is defined using a statistical criterion, the limit being the 95th percentile of the distribution of the blood pressure values, according to gender, age and height . Pre-hypdipping) . A new mdipping) . Even in


Elevated blood pressure is frequently seen in acute stroke, and patients with lacunar and nonlacunar infarcts may have different underlying mechanisms for increase in blood pressure. The impact of hypertension as a risk factor may also vary. The aims of the present study were to investigate blood pressure in patients presenting with lacunar syndromes but with different anatomical subtypes of stroke, to explore the impact of subtype on blood pressure, and to identify stroke-related factors associated with hypertension.χ2-test, t-test, and Mann–Whitney U test, as appropriate. We performed linear regression to analyze the association between blood pressure and lacunar infarct, and multiple linear regression to adjust for other covariates.Consecutive patients presenting with an acute lacunar syndrome were enrolled. Patients were classified into a lacunar or nonlacunar group based on radiological verified infarcts. Blood pressure was measured. Between-group differences were analyzed by One hundred thirteen patients were included. Seventy five percent had lacunar and 25% nonlacunar infarcts. There was no significant difference in clinical severity between the two groups. In the linear regression model, we found a significant association between blood pressure and lacunar infarct. No other factor was significantly associated with blood pressure in the two groups.Lacunar infarcts may be independently associated with higher blood pressure compared to nonlacunar infarcts with the same clinical severity. Blood pressure differences between different subtypes of stroke may not be related to clinical severity but to the underlying cause of stroke. Ischemic stroke is anatomically differentiated in lacunar, cortical, and large subcortical infarcts. Lacunar infarcts are located deep in the brain, and are caused by occlusion of a single perforating end artery. Hypertension is the single most important risk factor in all strokes. Traditionally, it was thought that high blood pressure (BP) was strongly associated with lacunar infarct in particular Fisher , but newHypertension in acute stroke may be a marker of stroke severity but also a physiological response to maintain perfusion in the ischemic penumbra. In 75–80% of patients with acute stroke, blood pressure is transiently elevated with a spontaneous decrease within the following days . Patients who were treated with intravenous thrombolysis were included, even when their symptoms lasted less than 24 h. Exclusion criteria were intracerebral hemorrhage and transient ischemic attack . Patients who had no visible acute infarct on radiological examination were excluded.The patients underwent standard examination at our stroke unit, including blood samples, electrocardiogram records (ECG), cerebral computed tomography (CT) at admittance and color duplex of precerebral and intracranial arteries. We registered stroke risk factors , and defined prestroke hypertension as on-treatment with antihypertensive drugs. Elevated blood pressure was defined as systolic BP > 140. Hypercholesterolemia was defined as on-treatment with lipid-lowering drugs or total cholesterol >5 mmol/L, or low-density lipoprotein cholesterol >3 mmol/L. Findings of symptomatic carotid or middle cerebral artery stenosis ≥50% were registered. Patients underwent magnetic resonance imaging (MRI) with diffusion-weighted images (DWI) within a week after admittance to hospital . Due to capacity problems in the MRI scanning, 33 patients underwent only CT scanning. Isolated acute ischemic lesions on DWI or CT were defined as lacunar infarcts if <15 mm and located subcortically or in the brainstem  registrations included in this study were performed immediately after admission and bedside 6 o’clock in the morning on day 3, and were registered prospectively. BP measurements were performed after standardized protocol, with fully automatic arm blood pressure monitors with the patient in a supine position.Patients were categorized into two groups based on the size and localization of the infarct, that is, the lacunar infarct group (LI) and the nonlacunar infarct group (NLI).-t-test. Normality of continuous variables was assessed by inspecting the histograms. The Mann–Whitney test was used to compare continuous variables showing a non-normal distribution. Categorical variables were compared using the χ2 test. Linear regression analysis was performed to identify association between blood pressure (at admission and day 3) and lacunar infarct. The regression coefficients are presented as the average difference with 95% confidence intervals (CI) between those with and without lacunar infarct. Covariates in the multiple regression models were: age, gender, hypercholesterolemia, diabetes, large vessel disease, prestroke hypertension, smoking, and NIHSS. We performed backward elimination, removing variables with significance level P > 0.05 one by one, to see if any of the other factors were associated with systolic blood pressure day 3, see Table Data were analyzed using SPSS version 19 . All significance tests were two-tailed and performed at the 5% level. Continuous variables were expressed as means (±SD) or medians (IQR), and were compared using StudentOral and written informed consent was obtained from all included patients. The study was approved by The Regional Committee for Ethics in Medical Research.One hundred forty seven patients presenting with symptoms compatible with a lacunar syndrome were recruited. Thirty three patients underwent only CT scanning, 114 patients both CT and DWI. Thirty four patients had no sign of acute ischemic lesion on CT or DWI and were excluded from the analyses due to uncertainty about stroke subtype, see Fig.P = 0.002). Characteristics and vascular risk factors regarding patients with LI and NLI are presented in Table The mean age was 70.1 years (SD = 11.5), and 69% were men. The median NIHSS score was 3 (IQR 2–4) at admission and 1 (IQR 0–3) at discharge, whereas the median mRS score was 2 (IQR 1–3) at discharge and median Barthel ADL index (day 2–4) was 20 (IQR 16–20). Of 75.2% of the patients had systolic BP > 140 mm Hg at admission and 54.9% had used antihypertensive medication before admission (prestroke hypertension). There were significantly more patients with systolic BP > 140 among patients with lacunar infarct (LI) than non-lacunar infarct (NLI) on day 3. The systolic blood pressure at day 3 was significantly higher in the LI group than the NLI group . None of the other covariates was significantly related to the blood pressure, see Table P = 0.777 and P = 0.887, respectively).In the linear regression model, there was a significant association between systolic BP (both at admission and at day 3) and lacunar infarct, see Tables To our knowledge, this is the first study to compare blood pressure in patients with lacunar and nonlacunar infarcts with the same severity of neurological impairments. In this study, patients with acute lacunar infarcts had significantly higher blood pressure on day 3 compared to patients with acute non-lacunar infarcts, regardless of prestroke hypertension. This applies to both diastolic and systolic blood pressure. There was a significant association between blood pressure and lacunar infarct, both at admission and day 3. In contrast to other studies comparing subtypes of stroke, our patient groups had the same severity regardless of subtype. All patients included in this study presented with a clinical lacunar syndrome due to lacunar or nonlacunar infarcts. None of the nonlacunar infarcts were due to occlusion of a major vessel. Accordingly, there was probably a diminutive edema around the infarcts, and therefore a negligible edema effect on the blood pressure. In patients with a major stroke, the blood pressure may rise because of the large volume effect and high intracranial pressure, as a compensatory mechanism, but this was most likely not the case in our study. Smoking was significantly more frequent among patients with lacunar infarct. Earlier studies have documented that smoking is associated with an increased risk of hypertension  in patients with lacunar infarct, suggesting chronic pathology of the small vessels (Immink et al. Jackson and Sudlow discussed the importance of risk factor-free classifications of stroke subtypes when comparing risk factor profiles between lacunar and nonlacunar subtypes (Jackson and Sudlow The present study indicates that lacunar infarcts may be independently associated with higher blood pressure compared to nonlacunar infarcts with the same severity of neurological impairments. Blood pressure differences between different subtypes of stroke may not be related to clinical severity but to the underlying cause of stroke. Hypertension in the acute phase of lacunar infarct is not proven to be harmful but is strongly linked to lacunar infarcts as a risk factor. Further studies of blood pressure in the different etiological subgroups of stroke are needed in order to differentiate treatment. We recommend using risk factor-free definitions and ensuring that infarcts are radiologically verified.


Narcolepsy with cataplexy (NC) is a neurological sleep disorder characterized by very low or undetectable concentration of hypocretin-1 in the cerebrospinal fluid. It has been recently found that patients with NC have disturbed circadian pattern of blood pressure, with more frequent non-dipping, compared to healthy controls. It has been hypothesized that lack of hypocretin may lead to increase in nocturnal blood pressure. This increase may result also from disturbed sleep architecture regardless of the deficiency of hypocretin. The aim of this study was to compare changes in values of daytime and nighttime blood pressure in NC patients and in patients with disturbed nocturnal sleep due to other sleep disorders. We have retrospectively compared polysomnographic and clinical data of 8 NC patients and 7 age- and sex controls suffering from insomnia. We have compared sleep architecture, mean blood pressure values and dipping pattern in both groups. The groups did not differ in terms of disturbances of sleep architecture. We have not found any statistical differences in values of daytime and nocturnal blood pressure. Non-dipping was equally frequent in both groups (87.5 and 85.7 %). Our results suggest that observed abnormalities in circadian changes of blood pressure values result from disturbed sleep architecture than from deficiency of hypocretin. Patients with sleep disorders should be carefully observed for the presence of increased blood pressure and other vascular risk factors. Narcolepsy with cataplexy (NC) is a neurological sleep disorder characterized by the presence of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Nocturnal sleep disturbances and automatic behaviors during the day are also present in the disease . It was One of the most prominent traits of the circadian rhythm of the cardiovascular system is the nocturnal decrease of the blood pressure (BP)—so-called dipping. This phenomenon has a crucial clinical significance—decrease in nocturnal values of blood pressure that below 10 % of the daytime values  or increase of the BP during the night (“inverse dipping”) are major cardiovascular risk factors .Non-dipping pattern of nocturnal blood pressure was recently found in NC patients in two studies , 7. The Increased cardiovascular risk or non-dipping has been found also in other sleep disorders, like insomnia . It mighThe aim of this study was to compare changes in values of daytime and nighttime blood pressure in NC patients and in patients with disturbed nocturnal sleep due to insomnia.We have performed a retrospective analysis of polysomnographic, laboratory and clinical data of 8 patients diagnosed in VitalMed Helsinki Sleep Clinic with NC. All the patients were diagnosed according to the International Classification of Sleep Disorders (ICSD-2) . We haveWe have randomly selected 7 sex- and age-matched controls from the patients that underwent a diagnostic polysomnography (PSG) in VitalMed Helsinki Sleep Clinic and were diagnosed with insomnia. We have excluded patients diagnosed with sleep-related breathing disorders (SRBD) as the influence of SRBD on the function of cardiovascular system is very significant and well described. As the NC patients, controls were free of taking any drugs that might have altered their sleep architecture during the PSG. Their clinical and laboratory data  were taken from their medical files.Data of all the patients were anonymized prior to selection of the patients. Only archival data of the patients were analyzed. The protocol of the study was approved by the Independent Bioethical Committee for Scientific Research at the Medical University of Gdansk.Patients underwent a single polysomnographic study. All the recordings were performed with SOMNOscreen plus PSG system . Sleep recording included four EEG leads, two bilateral electro-oculogram leads (EOG), bilateral chin electromyographic leads (EMG), two surface EMG leads placed on the left and right anterior tibialis muscles (recording periodic limb movements (PLMs) in sleep and wake). Respiration was recorded with nasal cannula, thoracic and abdominal strains and finger oxymetry. ECG was recorded with single precardial lead. The PSG included beat-to-beat blood pressure measurement that was performed with measurement of pulse transit time (PTT) . The meaRecordings were scheduled to start at 09.00 PM and to end at 06.30 AM, with 9 h and 30 min of recording. The patients were allowed to sustain their normal activity and were not forced to stay in bed for at least 1 h after beginning of the recording.The PSG recordings were scored according to American Academy of Sleep Medicine guidelines . The folFor the assessment of the cardiovascular system the following values were calculated: mean systolic and diastolic blood pressure  during the “day”  and during the night (defined as the time between “lights-off” and “lights-on” moments), the difference between “day” and night mean values of the SBP and DBP (delta_SBP and delta_DBP) and the percentage of the BP values reduction during the night . Patients with decrease of mean blood pressure (systolic or diastolic) during the night smaller than 10 % of mean blood pressure during the “day” were considered as “non-dippers”. Mean heart rate (HR) during the “day” and the night and the “day”-night HR difference (delta_HR) were also calculated. Sympatho-vagal balance (SVB) was assessed by calculating an average ratio between low (LF) and high frequency (HF) compononents of heart rate variability (HRV) spectra.Recordings of 8 NC patients and 7 insomnia patients were analyzed. The demographic and clinical data of the patients are presented in Table Data on hypocretin-1 level in cerebrospinal fluid were available for all NC patients. Hcrt-1 was undetectable in 5 cases, and its concentration ranged from 27.00 to 69.00 in 3 cases. Data on haplotype HLA DQB1*0602 were collected in 8 patients—all of them were positive. Data on haplotype HLA DQB1*0602 and Hcrt-1 level in cerebrospinal fluid were available for 4 control patients—all of them were negative for HLA DQB1*0602 and had Hcrt-1 level above 110 pg/ml.There were no statistically significant differences in the sleep parameters between the groups with an exception for longer REM latency in the NC group. The sleep parameters of the NC patients and the control patients are presented in Table There were no statistically significant differences between the groups regarding mean values of blood pressure and heart rate during “day” and night. The average sympatho-vagal balance did not differ significantly between the groups Table .Table 3MThere was a trend for less-pronounced nocturnal dipping in the narcoleptic group although the difference did not reach the statistical significance. The numbers of dippers were equal in both groups Table .Table 4MNocturnal dipping of blood pressure is an important physiologic phenomenon and non-dipping is a relevant risk factor for cardiovascular diseases. That is why clarifying the mechanisms of dipping has a crucial meaning. We have found that narcoleptic patients do not differ statistically from patients with insomnia in terms of values of blood pressure and presence of non-dipping. The prevalence of non-dipping was very high in both groups but did not differ between them. The control group (patients with insomnia) did not differ from the narcoleptic group in terms of demographic traits. Both groups had similarly disturbed nocturnal sleep. The only difference between the groups was the etiology of sleep disorders: presence or absence of hypocretin deficiency. The fact that we did not find any differences in values of blood pressure and in the values of nocturnal dipping of blood pressure between the groups suggests that the hypocretin status does not influence the cardiovascular parameters. High prevalence of “non-dippers” in both groups suggest that the disorders of sleep architecture, regardless of their etiology, may play a significant role in increasing the cardiovascular risk.The relation between narcolepsy and blood pressure has been studied in animal models and the results are ambiguous. Schwimmer et al. found that blood pressure in narcoleptic rats is lower than in wild-type animals, which present decrease of the values of blood pressure during transition from wake to NREM sleep . ShirasaData on circadian shifts of blood pressure in patients with narcolepsy-cataplexy are scarce and unambiguous. Guilleimnault et al. compared nocturnal blood pressure in narcoleptic patients and healthy controls . No signNarcoleptic patients in our study had higher values in Epworth Sleepiness Scale implicating higher level of daytime sleepiness. That could result in lower intensity of physical activity, which in turn could lead to lower values of blood pressure. That may partly explain the lack of significant difference between the daytime and nighttime values of blood pressure in the narcoleptic patients.Recently two studies on blood pressure and nocturnal dipping in narcolepsy were published. Grimaldi et al. in a study comparing 10 narcoleptic patients and 12 healthy controls found significantly blunted decrease in blood pressure in NC patients compared with the controls. Narcoleptic patients in our study had lower values of decrease in blood pressure (Delta_SBP and Delta_DBP) but this difference did not reach statistical significance. Grimaldi et al. were comparing narcoleptics and healthy subjects . There wOur study has some limitations. It was a study with a small number of patients and the control group was not homogenous, which may weaken the conclusions. We were focused on the phenotype of the disordered sleep and not on the aetiology of the sleep disorder. That enabled us to notice that non-dipping may be present in sleep-disordered subjects, regardless of the pathomechanism of the sleep disorder. The retrospective character of the study allowed for precise inclusion of the patients and controls that makes conclusions more reliable. Data on daytime blood pressure do not come from 24-h monitoring of blood pressure. Values of daytime blood pressure were acquired from early evening and early morning hours—period of less intense activity. Due to that BP values could have been reduced and thus influencing the values of dipping. Nevertheless, the patients were sustaining their normal activity after beginning of the recording. It must be also remembered that stay at the sleep laboratory and a PSG study was a completely new experience for the patients leading to some form of arousal. Thus the recorded BP values contain information about daytime BP values of the patients. As this limitation applies for both compared groups, the conclusions still may be drawn. Another limitation is lack of healthy control group—absence of non-dipping in patients with normal sleep would be another evidence for hypothesis that non-dipping may result from sleep disturbances.The strength of our study is the selection of patients. We were analyzing PSG recordings of drug-naïve and drug-free NC patients that allows to exclude any influence of stimulating drugs on the blood pressure values. Both groups did not differ in terms of sleep parameters. The clinical phenotype of disturbances in sleep architecture was similar in both groups but the etiology of those disturbances was different. This allows us to conclude that lack of nocturnal dipping of blood pressure is frequent in narcoleptic patients but is not more frequent than in patients with other sleep disorder (insomnia). That suggests that it is not the deficiency of hypocretin that leads to abnormalities in nocturnal blood pressure but the disruption of sleep architecture, regardless of its etiology although due to small number of study participants it is a very preliminary conclusion. An interesting way of verifying this hypothesis in the future would be comparing values of nocturnal dipping of BP in narcoleptic patients with and without hypocretin deficiency. That requires a more strict assessment of cardiovascular risk in the whole clinical population of sleep-disordered patients.


Benefis Medical Group, in Great Falls, Montana, improved identification and treatment of hypertension through multifaceted interventions. The interventions included adopting policies for collection of vital signs, enhancing system-level reporting capability, tracking patients for the registry, and conducting patient outreach activities. From baseline to follow-up (December 2012 through September 2013), the percentage of patients with a documented blood pressure increased from 67% to 80%, the percentage diagnosed with hypertension increased from 16% to 36%, and the percentage with blood pressure control increased from 41% to 64%. Benefis Medical Group plans to sustain the successful evidence-based strategies that were adopted.  High blood pressure is a major modifiable risk factor for heart disease, stroke, and kidney disease . One in Benefis Health System is a nonprofit independent health care system based in Great Falls, Montana. The system, which uses NextGen  electronic health record (EHR), includes a 516-bed hospital, an extended care and rehabilitation facility, and BMG, which consists of 130 employed physicians and advanced practice professionals and 3 primary care practices. BMG’s providers had an adult patient population of more than 13,000 during the study period (December 2012–September 2013). A multidisciplinary team worked on the project and included 15 health care providers from internal medicine, family practice and obstetrics and gynecology practices, along with personnel from administrative staff, information technology, and their quality improvement team. The team joined the American Medical Group Foundation’s Measure Up/Pressure Down blood pressure campaign and during 7 months participated in 10 online conferences (BMG implemented selected evidence-based strategies to improve blood pressure identification and control . All vitDuring the 10-month period, the percentage of patients with a documented blood pressure increased from 67% at baseline to 80% after the project, and the percentage of adult patients diagnosed with hypertension increased from 16% to 36%, resulting in more than 4,000 adult patients with a hypertension diagnosis. In addition, blood pressure control improved by 23 percentage points, from 41% at baseline to 64% after the project.BMG adopted evidence-based strategies for identifying and controlling hypertension for their population using best practices supported by its EHR. The providers became aware of blood pressure control as an issue to be addressed at each visit. Patients with elevated blood pressures were formally diagnosed and tracked. The efforts proved to be not only sustainable but were subsequently expanded to the larger patient population that included 2 specialties. The Community Transformation Grant enabled BMG to develop the IT infrastructure and the clinical hypertension control strategies that were used to report PQRS Measure 317, Screening for High Blood Pressure, as part of attesting to the Meaningful Use incentives program. BMG was able to expand the strategies to additional practices within BMG in subsequent years so they could begin reporting PQRS 236, Controlling High Blood Pressure, for the whole group.There are important limitations to the findings. Patients lacking blood pressure readings during the measurement period could have been classified as having uncontrolled hypertension, thus affecting the overall improvement.In summary, the seed grant provided the impetus for a small group practice to review, adapt, and successfully adopt the necessary activities in a stepwise fashion to improve the recognition and control of hypertension in their patient population, an important public health goal. BMG plans to sustain the successful evidence-based strategies that were adopted.


Patients with asthma may accelerate the average decline in lung function that is related to ageing (±30ml/year) . The aimProspective cohort with 9 years of follow up. Inclusion criteria: diagnosis of asthma and at least one year of use of inhaled corticosteroids before enrollment. Every three months patients had a multidisciplinary evaluation and they received free medication  monthly. Spirometry was performed anually in a Koko® spirometer according to the ATS protocol. Brazilian standards reported by Pereira  were use1. Median (interquartile range)values of lung function at baseline were: FEV1pre-BD1.76L(1.38-2.2) - 67%(55.25-81.5) of predicted, FEV1post-BD1,86L(1.55-2.41)- 75%(63-88). After 9 years of follow up, lung function values were: FEV1pre-BD1.54L(1.21-1.97)-64.3%(50.6-76.3), FEV1post-BD1.77L(1.38-2.23)-71.04%(57.64-83.43).Reversibility to bronchodilator was stable throughout the study. During the follow up,there was a decline of 10mL/year in FEV1(post-BD). Thirty patients had uncontrolled asthma by ACQ score in their last evaluation. Among these patients, we found lower lung function and more reversibility to bronchodilator in the end of the study with FEV1pre-BD1,35L, indicating a reduction of 45mL/year in basal function, but they have better reversibility with median(IR) 275mL(153-388) and 17.3%(11.16-29.6). 56.4% patients had positive skin prick test to aeroallergens. Lung function in patients with a negative test, was lower [median (IR) FEV1pre-BD1.42L(1.14-1.81)] in comparison to FEV1pre-BD1.67L(1.26-2.23)among atopics, the non atopics presenting a decline of 38mL/year in their lung function, not significantly different from the atopics. Only 9 patients did not have rhinitis. They had the lowest lung function with a FEV1pre-BD1.22(1.10-1.38), with a loss of 60mL/year in FEV1pre-BD.After 9 years of regular treatment ACQ score improved significantly [median points (IR) 0.83(0.33-1.83)].Interim analysis of 94 patients is present herein. Eighty(85.1%) patients were female. Their mean age(+SD) was 53.37(+14.19)years. 49(52.1%) of them were overweighted or obese according to bioimpedance measurements. Eigth patients(8.51%) had no immediate reversibility after bronchodilator use, measured by FEVLong term treatment controls symptoms of asthma and protects against decline in lung function. Uncontrolled asthma, nonatopic asthma and the absence of rhinitis appear to be related to a trend to a increased decline, though not statistically significant.


Peritoneal insufflation results in hemodynamic changes during laparoscopic cholecystectomy. The aim of the present work is to test whether non-invasive applanation tonometry is suitable for reflecting these hemodynamic alterations.41 patients undergoing laparoscopic cholecystectomies were monitored using the SphygmoCor pulse wave analysing system. Peripheral blood pressures (PBP), central aortic blood pressures (CBP), augmentation index (ALX@HR75) and subendocardial viability ratio (SVR) were measured at rest (Phase 1), after anesthetic induction (Phase 2), after peritoneal inflation (Phase 3) and after peritoneal deflation (Phase 4).Induction of anesthesia resulted in a statistically significant reduction in both the peripheral blood pressure and central aortic pressures, accompanied by a decrease in augmentation pressure and augmentation index. Peripheral blood pressures did not change along with the peritoneal cavity insufflation, except for a moderate increase in systolic blood pressure. In contrast to this, an increase could be observed in central aortic pressure  which was accompanied by increased augementation pressure  and augmentation index , indicating a rise in peripheral arterial stiffness.The Sphigmocor pulse wave analysis system can be reliably used for detecting and monitoring cardiovascular changes occurring during laparoscopic cholecystectomy. It has been proven by previous studies that inducing a positive pressure within the intraperitoneal cavity during laparoscopic surgical interventions results in numerous cardiovascular, neuroendocrine and renal changes . These cDuring preoperative anesthesiological consultation it is a frequent question whether laparoscopic cholecystectomy can be performed safely in patients with known cardiovascular risk factors. It is worth mentioning that in a study of low risk patients undergoing laparoscopic cholecystectomy, 2 out of 16 patients had acute ST changes on their ECG . In viewSo far, cardiovascular consequences occurring during laparoscopic procedures have been assessed either during animal experiments  or by us2-pneumoperitoneum may be accurately assessed intraoperatively by non-invasive applanation tonometry. Our results were compared with data obtained from the literature.Along these lines, we tested the hypothesis that cardiovascular changes caused by COA total of 41 consecutive patients undergoing elective laparoscopic cholecystectomy for symptomatic cholelithiasis without cholangiography or choledochotomy were enrolled in this prospective case-series. The patients were all in good health, classified as ASA I and II. This study was conducted with approval from the University of Debrecen Medical Ethics Committee . A written informed consent to participate was obtained from all patients included in the study. Patients with diabetes mellitus, untreated hypertension, atrial fibrillation, morbid obesity (body mass index [BMI] > 35), infection, psychiatric or neurologic conditions impairing patients’ ability to cooperate were excluded from the study.2 was used to ensure normoventilation . Intraoperative crystalloid infusion was administered at 7 mL/kg per hour. During anesthesia body temperature was maintained between 36,0 and 36,5°C by heating blankets.General anesthesia was administered to all patients according to the same protocol. During the patient’s stay in the preparation area, 15 ml/kg/BW of Ringer’s acetate solution was infused for a period of 2 hours. As premedication, oral midazolam (0.15 mg/kgBW) was administered 30 minutes before the induction of anaesthesia. Following preoxygenation (2 minutes) by face mask, anesthesia was induced with intravenous propofol (2 mg/kg BW) and fentanyl (3-5 μg/kgBW). Rocuronium 0.6 mg/kgBW was used to facilitate tracheal intubation and maintain muscle relaxation. After intubation, the lungs were ventilated with a mixture of air/oxygen (50/50%). For maintenance of anesthesia sevoflurane (2 vol%) and intermittent doses of fentanyl were applied. Sevoflurane was titrated in order to keep the bispectral index (BIS) values between 40 and 50. Ventilation was mechanically controlled at a frequency and tidal volume sufficient for maintaining normocapnia. PEEP was not administered (ZEEP). End expiratory CO2 intraperitoneal pressure was maintained automatically at a recommended 12-14 mmHg by a CO2 insufflator at an insufflation rate of 1 to 1,5 L/min with the patients placed in the 20° reverse Trendelenburg position (rT). On confirming the appropriate placement of the video laparoscope, each patient’s position was changed to a left lateral tilt (10°-15°). Once the surgery was completed, the abdomen was deflated and each patient was returned to the horizontal position.The surgical technique was similar for all patients. CORoutine intraoperative patient monitoring included continuous five-lead electrocardiography, pulse oximetry, non-invasive blood pressure measurements, peak airway pressures, capnography, as well as BIS monitoring for assessment of depth of anesthesia. Neuromuscular monitoring was performed to control the neuromuscular block throughout the course of anesthesia using TOF Watch SX acceleromyograph.The SphygmoCor pulse wave analysing system was used for monitoring cardiovascular function, which is a non-invasive method based on applanation tonometry . During Measurement of central aortic pressure and aortic pressure waveform: A conventional cuff pressure measurement was used for calibration. After applanation tonometry SphygmoCor derived a complete waveform for the whole cardiac cycle for the aortic pulse. A combination of the two methods makes it possible to analyse the coupling between the ejecting heart and the pressure load.Measurement of augmentation pressure and augmentation index: Augmentation pressure is based on the principle that there is a reflected pressure from the periphery that appears in the aortic pressure waveform. The amount of augmentation reflects the stiffness of the peripheral arterial tree: it increases along with higher stiffness. In order to make the value of augmentation index independent from the individual changes of pulse rate, the device calculates a corrected augmentation index (ALX@HR75).Subendocardial viability ratio: This parameter is calculated by the device by dividing the area under the systolic and diastolic part of the curve. A ratio under 100% reflects underperfusion of the subendocardium.Hemodynamic measurements were repeated in different phases of the procedure: Before induction of anesthesia ; 5 minutes after induction of anesthesia (Time 2.); 5 minutes after inflation of the peritoneal space (Time 3.) followed by repeated measurements every 10 minutes and 5 minutes after deflation of the peritoneal cavity (Time 4).Means and standard deviation were calculated for all values. Repeated measure analysis of variance was used for all values to check the time main effect of the laparoscopic procedure, i.e. whether laparoscopic cholecystectomy overall had any significant hemodynamic effect. Pairwise comparisons of all parameters were performed in order to check the effect of inflation and deflation of the peritoneal space by taking the values obtained after induction of anesthesia as reference value. A p < 0.05 was considered as a statistically significant difference.A total of 41 patients entered the study. There were 33 females and 8 males with an average age of 52.3 ± 15.4 years.As shown in Table Table Peripheral and central blood pressures returned to the preinduction values after peritoneal insufflation (comparison of Phase 1 and 3). The only parameter that showed a gradual increase was augmentation index  also returned to the pre-insufflation value. Figure In this cohort study we used a new non-invasive technique for assessing the cardiovascular changes that occur during laparoscopic cholecystectomy, the Sphigmocor pulse wave analysis. The method has already been tested in different clinical conditions such as arterial hypertension, diabetes mellitus, systolic heart failure and preeclampsia –13. In a2O) is applied [Similar to previous reports we were able to detect a significant decline of the systemic blood pressure after anesthetic induction which was accompanied by a decrease in augmentation index, reflecting the stiffness of the peripheral vessels , 14, 15. applied .2 during pneumoperitoneum. Mechanical effects of pneumoperitoneum may decrease renal flow, activating the renin-angiotensine-aldosteron system, may result in the compression of the abdominal veins and the aorta. It has also been proven that inducing pneumoperitoneum leads to an increased production of vasopressin, adrenalin, noradrenalin, renin and cortisol, which is in correlation with the changes of mean arterial pressure and systremic resistance [In a previous review Wahba an co-workers  summarizsistance . Accordisistance . Consequsistance . In our The principal basis of the pulse wave analysis system is that the peripheral arterial pressure waveform may be used for the reconstruction of central (aortic) pressure. The method behind this is applanation tonometry, which ensures the sensitive detection of the radial artery pulse waveform. It is generally accepted that the characteristics of the peripheral pulse reflect the changes in arterial diameters, wall elasticity, wall thickness and the condition of the peripheral vascular beds. The main attribute of SphygmoCor is its ability to derive the central aortic pressure waveform non-invasively from the pressure pulse recorded at a peripheral site, usually at the upper arm  .The intraoperative use of the device is limited by the position of the radial artery, i.e. in some surgical scenarios it may disturb the surgical team, making monitoring impossible. Another limitation to be mentioned is operator-dependency: for reliable monitoring it is necessary to have previous experience with the technique. Finally, the main limitation of this study is the lack of a control group, i.e. other hemodynamic measurements were not used. However, this trial is a pilot application of applanation tonometry in this field. As this is a non-invasive method, in this first, pilot step of our investigations we intended to compare hemodynamic changes with those that used invasive monitoring techniques reported in the literature.In conclusion: in this study we have shown that the Sphigmocor pulse wave analysis system can be reliably used for detecting and monitoring cardiovascular changes occurring during laparoscopic cholecystectomy. Further studies are needed to prove whether the method may be helpful in delineating critical situations in patients with limited cardiovascular reserve (ASA III-IV patients) by defining cut-off values of safety and to help in guiding abdominal insufflation and tilting during the procedure as suggested in previous reports .


The two most commonly used uterotonic drugs in caesarean section are oxytocin and carbetocin, a synthetic oxytocin analogue. Carbetocin has a longer half-life when compared to oxytocin, resulting in a reduced use of additional uterotonics. Oxytocin is known to cause fewer cardiovascular side effects when administered as a short-infusion compared to as an intravenous bolus. Based on these findings, we aim at comparing carbetocin 100 mcg given as a slow intravenous bolus with carbetocin 100 mcg applied as a short-infusion in 100 ml 0.9 % sodium chloride in women undergoing a planned or unplanned caesarean delivery. We hypothesise uterine contraction not to be inferior to a bolus application (primary efficacy endpoint) and greater haemodynamic stability to be achieved after a short-infusion than after a bolus administration, as measured by heart rate and mean arterial blood pressure (primary safety endpoint).This is a prospective, double-blind, randomised controlled, investigator-initiated, non-inferiority trial taking place at the University Hospital Basel, Switzerland.Uterine tone is quantified by manual palpation by the obstetrician using a linear analogue scale from 0 to 100 at 2, 3, 5 and 10 minutes after cord clamping. We will evaluate whether the lower limit of the confidence interval for the difference of the maximal uterine tone within the first 5 minutes after cord clamping between both groups does not include the pre-specified non-inferiority limit of −10. Both haemodynamic secondary endpoints will be analysed using a linear regression model, adjusting for the baseline value and the dosage of vasoactive drug given between cord clamping and 1 minute thereafter, in order to investigate superiority of a short-infusion as compared to a bolus application.We will follow the extension of CONSORT guidelines for reporting the results of non-inferiority trials.Haemodynamic stability and adequate uterine tone are important outcomes in caesarean sections. The results of this trial may be used to optimise these factors and thereby increase patient safety due to a reduction in cardiovascular side effects.NCT02221531 on 19 August 2014 and www.kofam.ch SNCTP000001197 on 15 November 2014.Clinicaltrials.gov  Uterotonic drugs are routinely used after caesarean section (CS) to reduce blood loss and the risk of postpartum haemorrhage (PPH) . PPH is The two most commonly used uterotonic drugs after operative delivery are oxytocin and carbetocin, a synthetic oxytocin analogue. Carbetocin has some advantages over oxytocin due its four- to ten-times longer half-life , allowinCarbetocin is associated with cardiovascular side effects including hypotension and a compensatory increase in heart rate similar to those of oxytocin , 9. AccoIn this randomised controlled trial, we aim to investigate whether carbetocin 100 mcg applied as a short-infusion in 100 ml 0.9 % sodium chloride as compared to a bolus injection minimises the cardiovascular side effects (first secondary safety endpoint) without compromising uterine tone (primary efficacy endpoint) in women undergoing a planned or unplanned caesarean delivery.www.kofam.ch SNCTP000001197 and clinicaltrials.gov NCT02221531).This is a prospective, single-centre, randomised, double-dummy, investigator-initiated, non-inferiority trial conducted at the University Hospital Basel, Switzerland. Study recruitment commenced in December 2014 and is expected to last for 16 months. The study was approved by the regional Ethics Committee (Ethikkommission Nordwestschweiz (EKNZ), EKNZ 2014–088, 13 March 2014). The study was registered in a national and an international trial registry  using variable block sizes between 2 and 8. The list is safely stored in a separate and sealed file, which will only be opened if unblinding becomes necessary. This is considered to be unlikely since the concomitant treatment in case of insufficient uterine tone is independent of the mode of administration of carbetocin.Subjects are randomised on arrival in the operating theatre to minimise the risk of dropouts after randomisation. To achieve similar numbers, randomisation is stratified for planned or unplanned CS Fig. .Fig. 1TrTwo members of the study team (ES and SDK) ensure correct administration of the study drug, transfer of the haemodynamic parameters, and collect intraoperative data, neither of whom is involved in the patients’ care. The study nurse (ES) always prepares the study drug. Correspondingly, patients, all care providers (obstetric and anaesthesia team) as well as the statistician (SDK) will remain blinded to group allocation until the data are analysed.Participants are identified at their pre-anaesthesia visit and by screening the daily list of patients scheduled for a CS Fig. . The stuEligibility is routinely assessed by the anaesthesia or obstetric team in order to decide whether the patient is competent to provide consent to participate in the study. Written informed consent will be obtained from all participants. Participants are clearly informed that trial participation is voluntary and that they are free to withdraw at any time without effect on subsequent care. Recruitment of study participants by all members of the research team is in line with the guidance for Good Clinical Practice for obtaining consent .Healthy women with a singleton pregnancy undergoing a planned or unplanned CS after at least 37 completed weeks of gestation under regional anaesthesia  aged older than 18 years and with signed informed consent are eligible.The following exclusion criteria are being applied: (1) emergency CS, (2) unplanned CS due to fetal distress, (3) maternal comorbidities such as severe cardiovascular disorders including (pre-)eclampsia, kidney or liver disorders, coagulopathies, as well as epilepsy, (4) uterine malformation, (5) fetal malformation, (6) known hypersensitivity to carbetocin or oxytocin, and (7) the inability to read and understand the participant’s information.After arrival of the patient in the operating theatre, the patient is positioned with a left uterine tilt to avoid aorto-caval compression. A fluid co-load of 500 ml hydroxyethyl starch HES 6 % is infused while the patient is monitored with pulse oximeter, electrocardiogram and non-invasive blood pressure cuff around the upper arm. Spinal anaesthesia by single-shot technique using hyperbaric bupivacaine 0.5 % 10 mg, fentanyl 10 mcg and morphine 100 mcg is applied in right lateral position. If an epidural catheter is already in place, 15–20 ml lidocaine 2 % with carbon dioxide and adrenaline 1:200,000 are administered through the catheter after an intrathecal or intravasal displacement has been excluded. After the application of the spinal anaesthesia, the patient is positioned in a left-tilted recumbent position. The CS is performed according to the in-house standard procedure applying the Misgav Ladach method for the laparotomy . FollowiAfter cord clamping, each patient will receive a 1-ml bolus and a short-infusion of 100 ml 0.9 % sodium chloride, one of which contains of carbetocin 100 mcg and the other of placebo (double-dummy technique). The study intervention only contains the mode of administration of carbetocin. An independent study nurse prepares the study medication (1-ml bolus and 100-ml short-infusion with or without carbetocin 100 mcg). The nurse is the only involved person with access to the randomisation results. All syringes and short-infusions will be labelled according to the Good Manufacturing Practice Guidelines with the study number (1–140) being the only differentiating feature between the study drugs.In case of insufficient uterine tone, the patient will be treated according to the current standard of care. There are six options: (1) uterine massage, (2) sulprostone 4–8 mcg/min, (3) 600 mcg misoprostol rectal, (4) oxytocin infusion 20–40 U/2 h, (5) Bakri™ balloon, and (6) surgical (including Tachosil®) or radiological (embolisation) intervention. The choice of one or several of these interventions is according to the severity of uterine atony and at the discretion of the treating obstetrician.Haemoglobin and haematocrit levels are measured preoperatively and 2 days postoperatively in order to estimate the perioperative blood loss taking into account the calculated pregnancy blood volume and the percent blood volume lost , 16.All participants have a follow-up visit 2 days postoperatively to rule out side effects of carbetocin and to ensure that no further problems have arisen.The Ethics Committee agreed that monitoring would be performed by the interdisciplinary study team. This team will evaluate the progress of the trial, verify the accuracy and completeness of the case report forms (CRFs), and ensure that all protocol requirements and investigator’s obligations are being fulfilled. The progress of the trial is evaluated every second month. The overall distribution of uterine tone will be assessed after 2 and 8 months in a blinded way, i.e. without considering group allocation. Extreme values are investigated further by reviewing the intraoperative course and by determining reasons for low uterine tone.The primary efficacy endpoint of this trial is the maximum uterine tone within the first 5 minutes after cord clamping assessed by manual palpation, and rated on a linear analogue scale (LAS) from 0 (completely atonic) to 100 (fully contracted), by the obstetrician.The haemodynamic parameters  are considered as primary safety endpoints.Mean change over time of uterine tone measured 2, 3, 5 and 10 minutes after cord clampingMedian dose of as well as number of patients requiring vasoactive drugs during CS: phenylephrine, ephedrine, atropine, nitroglycerine during the time period before cord clamping, between cord clamping until 1 minute after the end of the short-infusion, and between the second measurement and the end of surgeryMean estimated blood loss within the first 48 hours calculated by multiplying the calculated maternal blood volume by the percent of blood volume lost Need for additional uterotonics (type and amount) during or immediately after surgeryTolerability assessment intraoperatively and 2 days postoperatively by monitoring the following side effects of the study drug: ST segment analysis to detect signs of myocardial ischaemia, angina pectoris, facial flushing, headache, nausea and vomitingAdministration of any blood product  or coagulation factors such as tranexamic acid or fibrinogen during or immediately after surgeryMedian time and type of placenta removal, i.e. by cord traction or manuallyThe obstetrician provides an assessment of the uterine tone by manual palpation using a LAS ranging from 0 to 100. Manual palpation of the uterus is the standard used to assess uterine tone in daily clinical practice.Blood pressure is measured non-invasively using a cuff on the upper arm. All haemodynamic data  are recorded and stored in the anaesthesia monitor . The programme ixTrend from ixellence  is used to ensure direct transfer from the monitor to the study computer.To be 80 % sure that the lower limit of a one-sided 97.5 % confidence interval (CI) will be above the non-inferiority limit of −10 points on the LAS, 63 patients per group are required assuming a standard deviation (SD) of 20. Offsetting a maximal dropout of 10 %, this leads to a total sample size of 140 patients. The non-inferiority margin has been defined to be −10 on the LAS by the four most senior obstetricians at our institution. The SD had been derived from the results of a trial by Butwick et al., who used the same scale to assess the uterine tone .All data from patients will be stored anonymously. Each patient will be assigned a unique patient-identity (ID) consisting of a three-digit number. The patient’s ID, name and date of birth will be stored separately in a different file in order to be able to examine queries in case of implausible values (reversible anonymisation). Only members of the study team have access to the data.An electronic database featuring web-based access and using a secure (Secure Sockets Layer: SSL) connection is used for data entry. The database is password-protected and all data are encrypted. A consistency check is performed by logical data testing on the browser and on a random sample of 5 % by an independent study member.The following baseline characteristics will be used to investigate comparability of both trial arms: age, body mass index, parity, gravidity, gestational week, risk factors for PPH, number of previous CS, planned or unplanned CS, reason for CS, experience level of the obstetrician, batch number. Continuous variables will be described by using the mean (SD) or median (interquartile range) as appropriate, categorical variables by using count (percentage).In order to answer the primary research question, a CI of the mean difference in LAS score of the maximal uterine tone within the first 5 minutes after cord clamping will be calculated. If the lower limit of this CI does not include the pre-specified non-inferiority limit of −10, an inferiority of a short-infusion of more than 10 points on the LAS as compared to a bolus application is unlikely. In order to improve efficiency, an additional model will be built adjusting for the most relevant confounders, such as experience of the obstetrician, parity or number of previous CS, number of risk factors for PPH , duration of surgery, and duration of antenatal oxytocin infusion. In order to compare the change of the uterine tone over time between both study groups, a generalised estimation equation (GEE)  will be The haemodynamic secondary outcomes  will be analysed using a linear regression model adjusting for the corresponding baseline value and the amount of vasoactive drug administered during this period. In a further analysis, the course over time of mean arterial pressure and heart rate will be modelled using a GEE model with an exchangeable correlation matrix, using a knot at the average time of the lowest mean arterial pressure adjusted for the dosage of vasopressors administered, in order to compare the trend over time in both groups. Moreover, the change over time in blood pressure and heart rate will be displayed graphically. The incidence of any clinically relevant ST segment changes in both groups will be compared using a chi-squared or a Fisher’s exact test as appropriate. Further secondary endpoints will only be analysed descriptively. The comparison of the calculated blood loss will be adjusted in a linear regression model for whether or not the mother is breastfeeding.All analyses and graphs will be performed using Intercooled Stata Version 13.1 for Mac . We will follow the Consolidated Standards of Reporting Trials (CONSORT) statement and its extension for non-inferiority trials for the future report , 19.A per-protocol and an intention-to-treat analysis will be performed, and only if both approaches support non-inferiority will the trial be considered as supporting our non-inferiority hypothesis.Participants are asked about any side effect including (serious) adverse events immediately and 2 days postoperatively. All these events are recorded and monitored until the patient has completely recovered or until no causal relationship to the study drug administration has been established. All serious adverse events will be reported to the Ethics Committee and the sponsor within the appropriate time frame.The trial will be terminated early in the event of relevant safety concerns that threaten the study participants in any way. Therefore, we will monitor the incidence of PPH in a blinded manner and stop the study early for safety concerns if the incidence rate should rise above the average value of about 5 % PPH in CS .This randomised controlled investigator-initiated trial prospectively evaluates how the uterine contractility and haemodynamic parameters are affected by the mode of administration of carbetocin in patients undergoing a CS. Based on the findings of reduction in cardiovascular side-effects with a short-infusion as compared to a bolus injection found for oxytocin , our stuThe aim of this trial is to reach greater haemodynamic stability using the slower administration method (primary safety endpoint) while ensuring non-inferiority with regard to the uterine tone (primary efficacy endpoint) and ultimately the risk of elevated blood loss. Since superiority in haemodynamic endpoints can be achieved with fewer patients, we decided to choose as our primary endpoint non-inferiority in uterine tone.We consider the choice of the appropriate measurement of our primary endpoint as a main challenge in this trial. The choice of our primary outcome is based on a randomised controlled trial performed by Butwick et al.  who alsoWe chose haemodynamic stability, defined as lowest mean arterial pressure and highest heart rate within the first 5 minutes after the administration of the carbetocin. After evaluating the options for continuous invasive and non-invasive blood pressure measurements, we have decided to measure blood pressure non-invasively using a cuff on the upper arm. We have considered the accuracy and the precision of the continuous non-invasive methods insufficient to justify their use in the context of this trial. Although the risk for complications of an intra-arterial catheter is low , the potThis sample size allows showing a superiority of the short-infusion over the bolus administration in mean arterial blood pressure by at least 5 mmHg with 80 % power and a type-1 error of 5 % assuming a SD of 10. Thus, even a clinically irrelevant difference in efficacy could be found with our data. However, we need to acknowledge that we are not able to show a minor difference in the incidence of serious drops in blood pressure with our sample size.This trial will include patients undergoing a planned and an unplanned CS. Patients undergoing a unplanned CS often have already received oxytocin to induce or enhance labour, thus, showing a different response to the intraoperative dosage of carbetocin. Therefore, we are using a stratified randomisation for planned and unplanned CS. Excluding these patients would limit the generalisability of our study results.Poor recruitment is the most frequently reported cause for discontinuation of a clinical trial . HoweverHaemodynamic stability and adequate uterine contractility are important outcomes in CS. The results of this trial may be used to optimise these factors and thereby increase safety in parturients due to reduced cardiovascular side effects.The trial is currently enrolling patients. Upon submission of this manuscript, 60 % of the patients have been enrolled. The average enrolment rate is three (range one to seven) patients every week.


There is limited information on the causes of death in asthma patients.To determine the causes of death in hospitalized asthmatic patients and to compare with those observed in COPD patients and non-respiratory individuals, with a particular interest in associations with previous cardiovascular disease.Retrospective case–control study which analyzed the deaths of all hospitalized patients admitted for any reason during January, April, July and October of 2008 in 13 Spanish centers. Medical records of deceased patients were reviewed, and demographic and clinical data were collected.A total of 2,826 deaths  were included in the analysis, of which 82 (2.9%) were of patients with asthma and 283 (10%) with COPD.The most common causes of death in asthma patients were cardiovascular diseases (29.3%), malignancies (20.7%) and infections (14.6%); in COPD patients they were malignancies (26.5%), acute respiratory failure (25.8%) and cardiovascular diseases (21.6%). Asthma, compared to COPD patients, died significantly less frequently from acute respiratory failure and lung cancer. A multivariate logistic regression analysis failed to associate asthma with cardiovascular deaths.Cardiovascular disease is the most frequent cause of death among hospitalized asthma patients. The specific causes of death differ between asthma and COPD patients. After the epidemics of asthma deaths during the 1990s, numerous International  and natiUnlike COPD, for which mortality has risen during the same period , the redIn asthma, the possible causes of death are still not well understood, except for the recognized reduced contribution of severe asthma exacerbations. The few studies available are limited to those designed with other epidemiological objectives ; others Furthermore, the bronchial and systemic inflammation and the clinical impact of the associated comorbidities in asthma -23 have Our study was designed with two objectives: to determine the causes of death of patients with asthma compared with those of patients with COPD; and to establish a possible relationship between deaths from asthma and cardiovascular diseases. In Spain about 68% of deaths occur in hospitals with certain regional geographic variation . We beliObservational, retrospective, cross-sectional, multi-centre study conducted in a large group of patients who died while admitted in hospital.Fieldwork included all deaths in admitted patients during the months of January, April, July and October (months taken as representative of each of the four seasons) of 2008 in thirteen Spanish secondary and tertiary hospitals. The clinical records of all deceased patients were reviewed, and the following data were collected: demographic data; existence of risk factors for cardiovascular diseases ; and specific causes of death, distinguishing specifically lung cancer within neoplastic disorders, the pneumonia within infections; and within cardiovascular disease, peripheral arteriopathy, ischemic cardiopathy, cerebrovascular disease or heart failure. In addition, in patients with asthma, severity and control  with objective tests like either significant variability of the spirometric flows performed by applying a bronchodilatator or bronchoconstriction challenge test; alternatively, a label of moderate degree of certainty was given in absence of the above mentioned criteria and any of the following: the patient clinical record reported symptoms compatible with asthma, prescription of asthma drugs or an indication that the attending physician during the hospital admission presumed the asthma diagnosis. Indistinguishable cases from COPD, bronchiectasis or residual pulmonary lesions after tuberculosis co-existed, were excluded from the analysis. A diagnosis of COPD was considered when there was a diagnostic medical report (signed by a pulmonologist) supported by poorly reversible airflow limitation with a post-bronchodilator FEV1/FVC ratio < 0.70 ( GOLD criteria) .A descriptive analysis was carried out for all variables collected. Summary results were expressed as percentages, frequencies and number of observations for qualitative variables, and as means with standard deviation for quantitative variables.We check the normality or otherwise of the sample using the Kolmogorov Smirnov. Comparisons between groups were performed using the χ 2 test for categorical variables; and for quantitative variables, the ANOVA test, or the Kruskall-Wallis test if values did not have a normal assumption. For control of type I error rate, we penalized or adjusted p values for multiple comparisons. A multivariate logistic regression analysis was performed to determine the possible independent association of a previous diagnosis of asthma with death due to cardiovascular disease; this latter was considered both globally and stratified by four predetermined categories . The dependent variable was death by cardiovascular diseases and the independent variables, a previous diagnosis of asthma or COPD, age, sex, smoking, previous history of diabetes mellitus, obesity, hyperlipidaemia, and arterial hypertension. Comparisons with a p value <0.05 were considered statistically significant.The cause of death was determined according to certification that existed in medical history signed by the doctor who treated the patient, no death was excluded. A total of 2,826 deaths were included in the analysis. Of these, 1,583 (56%) were men. The mean ± SD age was 75 ± 14 years . The most frequent causes of death observed in the total sample were: 746 (27%) malignancies, of which 173 (23%) were lung cancer; 710 (25.7%) cardiovascular diseases ; and 597 infections (21%), of which 332 (54.6%) pneumonia. Farther 251 deaths were observed gastrointestinal origin (9%) and 206 from respiratory failure .Table The most frequent causes of death in asthmatics Table  were carThe clinical and functional respiratory characteristics of cases with asthma are shown in Table The results of the multivariate analysis to determine the risk factors associated with death by cardiovascular diseases, are shown in Table The main results were not substantially modified when asthmatics were divided according to the degree of certainty of the asthma diagnosis.The main finding of the present study was that cardiovascular diseases are the most frequent cause of death in patients with asthma. And compared with COPD patients, deaths due to exacerbations and malignancies were less frequent. These findings are particularly relevant given the limited information on this topic.Our study was designed to include deaths of patients with asthma of any age and both sexes; consequently it probably is more representative to the total population of asthmatics than previous studies carried out in specific sub-groups. For instance, de Marco et al19 evaluated the causes of death of 47 asthmatics aged 20 to 44 years, and found that 34% died due to malignancies and 17% of accidents. Similarly, Camargo et al [Another key results from our study comes from the inclusion of deaths of COPD patients. Whereas in asthma cardiovascular diseases constitute the most frequent cause (29.3%), malignancies were the most frequent cause (26.5%) in COPD, likely associated with a higher cumulative tobacco exposure. Similarly, patients with asthma died less frequently than patients with COPD of respiratory failure or during exacerbation of their disease (6.0% vs. 25.5%), due to lung cancer (1.2% against 14.5%) and due to pneumonia (6% against 10.3%). The finding that patients with asthma, in contrast to COPD patients, die relatively infrequently from an exacerbation of their disease, was well-documented in several earlier series. Silverstein et al  found in2), in comparison with the two reference groups as suggested elsewhere [Paradoxically, since patients with asthma are nowadays more likely to survive with close to normal longevity, it resulted in an increase in prevalence of certain comorbidities associated with the disease having a significant impact on their quality of life and probably also on their specific causes of death . Among olsewhere , it coullsewhere , reportiAlthough the study is subject to the customary methodological limitations due to the retrospective collection of information from patients clinical records, we consider that, with our choice of study design with two reference populations this potential limitation was lessened. Data quality on causes of death is greater when obtained from hospital charts in comparison when obtained via death certificates of deaths occurring outside the hospital context, in which the nature of the cause of death can often be questionable. Perhaps one strength here is the rigor employed in the assumption of the diagnosis of asthma in all deaths analyzed. Anyway, our conclusions must be tempered by the large number of statistical tests carried out.To conclude, the most common causes of death of asthmatics in our study were those related to cardiovascular diseases and, unlike COPD patients, there were significantly fewer deaths due to exacerbation and lung cancer. These findings are relevant, as mortality in asthma has been analyzed only partially and mostly within subgroups. We did not observed an association between suffering asthma and death from a cardiovascular disease, but similar studies need to be conducted with larger samples of asthmatics, in which causes of death should be analyzed rigorously. Until such information be available, the present study could provide arguments for adopting a more proactive attitude in routine clinical practice, towards the prevention and treatment of cardiovascular diseases in patients with asthma, particularly in those of advanced age.The authors declare that they have no competing interest.The work presented here was carried out in collaboration between all authors. GS, VP, JBS defined the research theme and wrote the paper. GS, VS, designed methods, analyzed the data, interpreted the results. CC-L, CA, RV-O, JS, AB-Q and AP co-designed the dispersal and co-worked on associated data collection and interpretation. All authors have contributed to, seen and approved the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/13/73/prepub