Asthma is a chronic inflammatory airway disease characterized by reversible obstruction, inflammation and hyperresponsiveness to different stimulus. Aerobic and breathing exercises have been demonstrated to benefit asthmatic patients; however, there is no evidence comparing the effectiveness of these treatments.NO) and systemic inflammatory cytokines will also be evaluated as possible mechanisms to explain the benefits of both interventions.This is a prospective, comparative, blinded, and randomized clinical trial with 2 groups that will receive distinct interventions. Forty-eight asthmatic adults with optimized medical treatment will be randomly divided into either aerobic (AG) or breathing exercises (BG). Patients will perform breathing or aerobic exercise twice a week for 3 months, totalizing 24 sessions of 40 minutes each. Before intervention, both groups will complete an educational program consisting of 2 educational classes. Before and after interventions, the following parameters will be quantified: clinical control (main outcome), health related quality of life, levels of anxiety and depression, daily living physical activity and maximal exercise capacity (secondary outcome). Hyperventilation syndrome symptoms, autonomic nervous imbalance, thoracoabdominal kinematics, inflammatory cells in the sputum, fraction of exhaled nitric oxide (FEAlthough the benefits of breathing and aerobic exercises have been extensively studied, the comparison between both has never been investigated. Furthermore, the findings of our results will allow us to understand its application and suitability to patients that will have more benefits for every intervention optimizing its effect.NCT02065258.Clinicaltrials.gov; Identifier:  Asthma is a chronic inflammatory disorder of the airways that involves many cells and cellular elements. The disease severity can be classified as intermittent or persistent , and this classification considers the presence of diurnal and nocturnal symptoms, necessity of medication, frequency of exacerbation, physical activity limitations and pulmonary function. The chrThe asthma symptoms experienced during DLPA or the fear of triggering symptoms may keep asthmatic subjects from engaging in physical exercise, and the patients tend to be less physically active and less conditioned than healthy individuals. In addiAsthma does not have a cure but its clinical manifestations can be controlled with the appropriate treatment. The goal for asthma treatment is to achieve and maintain asthma control, and the treatment is based on medication (controllers and relievers). Clinical control is defined as an effective management of the characteristics of the disease, which include control of the following symptoms: nocturnal awakening, reliever use and activity limitation. HoweverThere is evidence suggesting that aerobic training improves fitness and health related quality of life (HRQoL). AdditioWhich exercise intervention is more effective to improve clinical control in patients with moderate and severe asthma?Which are the mechanisms involved to improve clinical control in both interventions?The research questions were:This trial was designed as a prospective, comparative, blinded, and randomized clinical trial with 2 groups that will receive distinct interventions. See the study design in Figure Patients will be recruited from an outpatient clinic that assists moderate and severe asthmatic patients in an University Hospital. The Clinics Hospital Ethics Committee approved the study (0097/10). All participants gave written informed consent before data collection began.Eligible patients will be randomized to either breathing or aerobic exercise interventions. The randomization schedule was computer-generated by the chief investigator who will not be involved in the recruitment or treatment of the patients.The Hospital Ethics Committee approved the study and patients must provide written informed consent before any study procedures be performed. Asthma diagnosis and treatment will be based on the guidelines of the Global Initiative for Asthma.2; sedentary ; medical treatment for at least 6 months; and clinically stable .Age between 25 and 65 years-old; both genders; body mass index (BMI) <35 Kg/mSmokers; participants in another research protocol; patients that are incapable of exercising; unable to understand any questionnaire; any other medical condition that confers greater morbidity than asthma  which will be confirmed by physician review; currently pregnant.Before the interventions, both groups will complete an educational program that consists of 2 classes performed once a week and lasting 2 hours each. Presentations and group discussions will include information about asthma pathophysiology, medication skills, self-monitoring techniques, and environmental control and avoidance strategies according to previous studies.It will be performed on a treadmill with an initial intensity of 60% and reaching a maximum intensity of 80% of the predicted heart rate during training. The intensity values will be calculated using Karvonen’s formula (1957). Breathing exercise will be based on Yoga’s breathing techniques and willAll participants will be required to maintain their normal medical regimens during the interventions.2-agonist). Patient’s will be scored on a scale ranging from 0 to 6 (0 = without limitation and 6 = maximum limitation). The clinical score of forced expiratory volume  will be scored on similar scale. The items will be calculated, and the scores of the ACQ will be the average from 7 items between 0 (fully controlled) and 6 (severely uncontrolled). The cutoff will be adopted from previously developed studies, considering controlled (ACQ <0.75 points), not well controlled or poorly controlled asthma (ACQ > 1.5 points). A clinically effective treatment results in a 0.5 point decrease in the score after the intervention[The asthma control questionnaire (ACQ) will be rvention.The asthma quality of life questionnaire (AQLQ) and the An accelerometer  will quantify the absolute change in DLPA. The accelerometer records the total daily number of steps, the number of steps performed at moderate intensity (≥110 steps per minute) and the time spent during DLPA. The assessment will be performed over a period of 7 days, and the DLPA will be quantified before and after the interventions. The accelerometer automatically records the total number of steps during the 7 days, and each patient will record their amount of moderate intensity DLPA in a dairy. The accelerometer will be used to average the number of steps performed during the 5 day period (disregarding the first and last days).Shuttle walking test will ass1 (from baseline) will be characterized as a positive response to the bronchodilator.It will be evaluated using spirometry  before and after the inhalation of 200 mg of salbutamol. Technical procedures of spirometry will be performed as recommended by the American Thoracic Society and European Respiratory Society. PredictNijmegen questionnaire will be used to assess hyperventilation symptoms. We will compare the differences between the 2 treatments in the absolute change in hyperventilation symptoms post-intervention. The Nijmegen questionnaire is composed of 16 questions that quantify abnormal breathing;  to 4 (very often)). A total score of ≥23 establishes hyperventilation syndrome with a sensitivity of 91% and a specificity of 95%.Patient’s heart rate variability (HRV) will be assessed at rest pre and post-intervention by a heart rate monitor  as previously described and dataIt will be evaluated using optoelectronic plethysmography , as previously described. Video iNO). Before the sputum collection, subjects will be advised to blow their nose and rinse their mouth with water and swallow it to reduce contamination of the sputum specimen with postnasal drip and saliva. Then, patients will inhale 400 μg of salbutamol followed by a 3% hypertonic saline solution inhaled over 15 min using an ultrasonic nebulizer with an output of 2.4 mL.min-1 and a mass median aerodynamic diameter of 4.5 μm as previously described[6.mL-1. Differential cells counts will be classified as eosinophils, lymphocytes, neutrophils, macrophages, squamous cells, goblet cells, and ciliated cells on the basis of their morphology by a single-blinded investigator.It will be quantified in collected sputum samples and exhaled fraction of nitric oxide (FEescribed. Sputum FENO will be measured according to the ATS/ERS guidelines (2011)[2O to avoid air contamination from the nasal cavity). Exhaled air will be filtrated before being collected into the bag, and the expiratory pressure achieved by the individual will monitored by a manometer. All collected samples will be mixed 10 s before the determination of NO concentration by chemiluminescence  and analyzed up to 24 h after sample collection. The equipment will be calibrated before each analysis.s (2011). BrieflyIt will be quantified in 15 mL of blood sample obtained at rest. Patients will be advised to fast for at least 8 hours not carry out physical activity and not ingest alcoholic and/or caffeinated beverages for 24 hours before the blood collection. Blood samples will be centrifuged at 1800 rpm for 10 minutes at 0°C and will be stored at -70°C. Th1 , Th2 , and anti-inflammatory (IL-10 e IL-1ra) cytokines as well as osteopontin will be quantified in duplicate by using commercial cytometric bead array kits . Serum levels of cortisol will be analyzed by fluoroimmunoassay using the AutoDelfia system .To appropriately describe our patients, we will collect basic demographic and medical information including age, smoking status, ethnicity, gender role and anthropometrics (height and weight). It will also be collected self-reported details of current and lifetime history of diagnosis of asthma, other respiratory diseases, cardiovascular disease risk factors, cancers, auto-immune diseases, and all current medications. All reported clinical data will be verified by a hospital medical record review.t test. An estimated drop-out rate of 20% was used to determine the final target sample size of 48 patients.It was estimated based on a minimal important difference of 0.5 points on the ACQ questionnaire with a standard deviation of 0.72. A samplData normality will be evaluated with the Kolmogorov-Smirnov test. The comparison of the clinical control and other variables will be made by a two-way analysis of variance (ANOVA) with repeated measures followed by the Student-Newman Keuls post-hoc test to identify significant differences. The level of statistical significance will be set at 5% (p < 0.05).All main analyses will use intention-to-treat, considering all patients as randomized regardless of their adherence to the treatment protocol or completion of post-intervention assessments. These analyses will be used to define the efficacy of aerobic and breathing exercises to influence asthma control.Asthma symptoms have a significant impact on patient’s life and the proper clinical treatment is very important to reduce those symptoms; however, sometimes clinical control is difficult, despite the appropriate amount of prescribed medication. Aerobic and breathing exercises have been considered important as complementary therapies in addition to the pharmacological treatment mainly for patients with controlled or partially controlled asthma, because they improve disease control. In addiThe proposal of our study, comparing the benefits of aerobic and breathing exercises training on clinical control, seems quite relevant because even if both techniques have similar effects in reducing asthma symptoms, we will further investigate some mechanisms in order to understand how patients develop their benefits at each and every intervention. There is evidence that aerobic exercises improve cardiovascular fitness, resistance to stress and health related quality of life (HRQoL) as well as decrease dyspnea, incidence of exercise-induced bronchospasm, use of corticosteroids, inflammatory parameters, anxiety and depression related to asthma. A recenIn addition, the practice of breathing exercises have been shown to improve HRQoL, peak expiratory flow, asthma symptoms as well as to reduce the levels of hyperventilation symptoms, anxiety and depression and medication consumption. A recenAlthough the benefits of breathing and aerobic exercises have been extensively investigated, the comparison between both interventions has never been performed. Then, this study will be the first to make this comparison and to investigate several physiological mechanisms which may be triggered either by aerobic training or by breathing exercises. Furthermore, the findings of our results will allow us to understand its application and suitability to patients that will have more benefits for every intervention optimizing its effect.We declare that the study in is ongoing and we are still analyzing data.


Adenosine stress testing in conjunction with radionuclide myocardial perfusion imaging has become a common approach for the detection of coronary artery diseases in patients who are unable to perform adequate levels of exercise. However, specific electrocardiographic alterations during the test have been rarely described. Using a Chinese population, the aim of the present study was to provide a detailed electrocardiographic profile of adenosine stress testing. The study population included 1,168 consecutive outpatients who had undergone adenosine-induced stress myocardial perfusion imaging. Electrocardiographic data during and immediately following the adenosine infusion were collected, and the corresponding myocardial perfusion images were assessed. During adenosine infusion, 174 transient and 47 persistent arrhythmic events occurred in 110 patients (9.42%). Furthermore, frequent premature atrial contractions occurred in 65 individuals and frequent premature ventricular contractions were observed in 73 individuals. Atrioventricular block (AVB) occurred in 75 patients [first degree (I°) AVB, 16; second degree (II°) AVB, 58; third degree AVB, 1), while sinoatrial block occurred in eight patients. ST depression emerged in 69 patients. Patients with a baseline I° AVB had an increased risk of a II° AVB, and patients exhibiting baseline ST depression were more likely to have a further depressed ST segment during the stress test . Following adenosine infusion, 10 patients (0.86%) exhibited newly occurred arrhythmic events. However, no patient presented with acute myocardial infarction or sudden mortality. In conclusion, the results demonstrated that adenosine infusion was a safe method, despite the relatively high incidence of arrhythmic events. The majority of arrhythmias that occurred during infusion were transient, were reversible with the termination of infusion and did not indicate abnormal perfusion results. Pharmacological stress testing in conjunction with radionuclide myocardial perfusion imaging has been used as an alternative to dynamic exercise testing for the detection of coronary artery disease and risk stratification in patients who are unable to perform adequate levels of exercise –3. AdenoBetween May 2010 and January 2012, outpatients with potential diagnoses of coronary artery disease, who had undergone adenosine-induced stress using Technetium-99m sestamibi (99mTc-MIBI) single photon emission computed tomography (SPECT) myocardial perfusion imaging at Fuwai Hospital , were prospectively enrolled in the study. The contraindications for adenosine stress testing included the occurrence of myocardial infarction within two months, unstable angina, hypotension (systolic blood pressure of <90 mmHg), hypertension , New York Heart Association  was infused at a constant rate of 140 μg/kg/min through a peripheral venous catheter, using an accurate computerized infusion pump  over 6 min . At the third minute of adenosine infusion, 925 MBq 99mTc-MIBI  was injected as a bolus through the contralateral cubical vein and the adenosine infusion was continued for an additional 3 min. The heart rate and a 12-lead electrocardiogram (ECG) were recorded continuously at the baseline (at least 2 min prior to the infusion), during infusion and for at least 3 min after the termination of infusion. ECG data were analyzed by an experienced electrophysiologist, according to the 2008 AHA/ACCF/HRS recommendations for the standardization and interpretation of the ECG . Projection data were acquired from 16 views over 180° from 45° right anterior oblique to 45° left anterior oblique, with 25 sec per view, on a 64×64 matrix. The image slices were analyzed visually by two experienced nuclear cardiologists in consensus based on 17 segments. Rest images were obtained the following day if the stress images were abnormal. The final perfusion results were determined by comparing the stressed images with the rest images. Reversible and irreversible defects were defined as ischemia and infarction, respectively, and if both patterns existed, the condition was defined as ischemia combined with infarction.2 test was used to analyze the categorical variables. Logistic regression analysis was used to determine the risk factors. P<0.05 was considered to indicate a statistically significant difference.Statistical analysis was performed using SPSS 19.0 software . Continuous variables are expressed as the mean ± standard deviation, while categorical variables are presented as frequencies. The Student’s t-test was used to compare the differences in continuous variables, while the χA total of 1,168 patients  were enrolled in the study. Of these individuals, 330 patients had type 2 diabetes mellitus, 230 patients had hypertension and seven patients had undergone a previous percutaneous coronary intervention .Blood pressure, heart rate and electrocardiographic intervals at the baseline, at the maximal response during adenosine infusion and at 2 min after the completion of adenosine administration are summarized in Baseline ECG characteristics are summarized in Newly occurred arrhythmias during adenosine infusion are summarized in Of the 1,168 patients, newly occurred ST depression (>0.1 mV) was observed in 69 patients (5.91%). During the adenosine stress test, no patient presented with acute myocardial infarction or sudden mortality, and no patient required specific treatment.With regard to the correlations between the gender, age and baseline ECG characteristics of the patients and the development of II° AVB during adenosine infusion, only the baseline I° AVB was determined to be a predictor [P<0.001; odds ratio (OR), 28.68; 95% confidence interval (CI), 8.81–93.31; Following the completion of adenosine infusion, 10 patients (0.86%) presented with newly occurred arrhythmias, including II° AVB in four patients, II° and III° AVB in one patient and SAB in five individuals . The epiPerfusion imaging revealed ischemia in 79 patients (6.76%), infarction in 10 patients (0.86%) and ischemia combined with infarction in seven patients (0.60%). Logistic regression analysis demonstrated that male patients and those who had newly occurred ST depression during adenosine infusion had an increased risk of abnormal perfusion results   and JapaFinally, although the incidence is low –21, a coThe current preliminary study has a number of inherent limitations due to its single-centered research nature. In addition, the sample size was relatively small, which may lead to selection bias. Therefore, a randomized multicentered trial that includes a greater number of patients is required to confirm the ECG profiles of adenosine stress testing in a Chinese population.In conclusion, based on a Chinese population, the findings of the present prospective study indicate the safety of adenosine pharmacological hyperemia in conjunction with radionuclide perfusion imaging. Despite the relative high incidence of arrhythmic events, the majority of arrhythmias that occurred during adenosine infusion were transient and did not indicate abnormal perfusion results.


Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing.332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected.Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change , heart rate change  and maximal predicted heart rate  were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12–24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change , and heart rate change  as compared to those who drank coffee 12–24 hours prior to testing (group 2).Caffeine exposure 12–24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing. Myocardial perfusion imaging (MPI) has been extensively used for detecting coronary artery disease, assessing viable myocardium, and evaluating the effect of different therapeutic interventions . VasodilThe American Society of Nuclear cardiology recommends against the consumption of caffeinated food andbeverages or foods containing other methylxanthines (chocolate) for at least 12 hours prior to regadenoson administration (ASNC 2009). Caffeine, a , is a non-selective competitive inhibitor of all adenosine receptors particularly A2A receptors .Few studies assessed the interaction of regadenoson and caffeine. In conscious dogs, intravenous administration of caffeine at 1–10 mg/kg, followed by regadenoson injection 45 minutes later, did not significantly affect regadenoson induced coronary blood flow (CBF), but reduced the duration of the 2-fold increase in CBF. It also blunted heart rate and blood pressure change . In a raThe effect and duration of caffeine exposure on blood pressure, heart rate, and percent of maximal predicted heart rate among subjects undergoing pharmacological stress testing with regadenoson is not clear. We hypothesized that chronic caffeine intake with only 12–24 hours cessation prior to regadenoson stress testing according to drug labeling recommendation, affects maximal heart rate and blood pressure response as compared to non-caffeine consumption or more prolonged interruption. The aim of the current study is to assess the effect of habitual caffeine consumption on blood pressure, heart rate, percentage of predicted heart rate and percentage change in heart rate among subjects undergoing vasodilator stress testing with regadenoson.The study protocol was approved by the Indiana University institutional review board for research. Written informed consent was obtained from all subjects. Subjects referred for regadenoson stress testing were enrolled. Patients with combined exercise and regadenoson stress testing were excluded from analysis. As per the protocol of our institution, all patients were asked to not consume caffeinated beverages or xanthine containing foods for at least 12 hours prior to study. Moreover, all patients were asked to take their routine daily medications. Baseline demographic data and medical comorbidities were collected on all subjects. Information on amount, frequency, and last exposure to caffeine, chocolate, and caffeinated soft drinks were collected prospectively prior to performance of cardiac stress test. Caffeine exposure was classified according to none recently, last exposure of at least one cup of coffee 12–24 hours prior to regadenoson stress test, and >24 hours prior to stress test. Consumption of one cup of black or green tea was considered equal to one cup of coffee, and subjects who consumed tea were included in the coffee consumption group for analysis. Subjects’ heart rate (HR), and blood pressure were recorded at baseline instantaneously before administration of regadenoson. Subjects remained in a supine position throughout the test. Change in heart rate (changeHR) during the stress test was calculated by subtracting resting (restingHR) from peak heart rate (peakHR) recorded within 5 minutes after administration of regadenoson. Change in systolic blood pressure (changeSBP) was calculated by subtracting resting (restingSBP) from peak systolic blood pressure (peakSBP) recorded within 5 minutes after administration of regadenoson. Maximal predicted heart (MHR) rate was calculated using 220-age (years) and percent maximal predicted heart rate (%MPHR) was calculated by peakHR over MHR and multiplying by 100 (%MPHR = (peakHR/MHR)*100). Percent change in heart rate (%ChangeHR) was calculated by changeHR over restingHR and multiplying by 100. Incidence of patient reported side effects were prospectively recorded .Non-coffee drinkers (group 1) were compared to subjects who had consumed coffee within 12 to 24 hours (group 2) or more than 24 hours (group 3) prior to regadenoson administration.2 test and continuous variables were computed using student t test. Statistical significance was defined as p-value < 0.05.Baseline demographic and clinical variables are descriptively summarized. Continuous variables are expressed as mean ± SD. Categorical data are presented as percent frequency. Unpaired two-sided Student’s t-test was used to compare normally distributed continuous data between two groups. One-way analysis of variance test (ANOVA) and post hoc Tukey comparisons were used to determine difference between different groups based on coffee consumption. Categorical variables were compared using the χp<0.1 in univariable analysis and if adjustment for the variables resulted in at least a 10% change in the estimate of the overall association.Multivariable linear regression with change in systolic blood pressure (SBP), HR, and percent maximal predicted heart rate achieved at peak exercise as outcome variables was performed for non-coffee drinkers, subjects exposed to coffee 12 to 24 hours and more than 24 hours before regadenoson administration. Exposure to coffee 12 to 24 hours prior was used as the reference category. Adjustment for known confounders was based on clinical variables known to affect caffeine metabolism, as well as clinical variables with Baseline characteristics of the study subjects are described in . SubjectSBP change , HR change  and %MPHR  were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12–24 hours prior (group 2). %Change HR  was not significantly different between group 1 and 2.There was no significant difference in SBP change , HR change , %MPHR , and %Change HR  between non-coffee drinkers (group 1) and those who drank coffee >24 hours prior (group 3). Moreover, subjects who drank coffee >24 hours prior (group 3) exhibited higher SBP change  and HR change  as compared to those who drank coffee 12–24 hours prior to testing (group 2). MPHR  and %Change HR  were higher among group 3 compared to group 2 but failed to achieve statistical significance  Fig 1)..Fig 1).After adjusting for age, race, weight, chocolate consumption, diuretics use, history of coronary artery disease, past myocardial infarction, asthma, calcium channel blocker and beta blocker use, Change SBP (p = 0.003), Change in HR (p = 0.046) and %MPHR (p = 0.015) remained significantly different between non-coffee drinkers (group 1) and subjects who consumed coffee 12–24 hours prior (group 2) in multivariable regression analysis. Moreover, on multivariable regression analysis, Change SBP (p = 0.031), Change HR (p = 0.019), and %Change HR (p = 0.041) remained significantly different between subjects who drank coffee 12–24 hours (group 2) and subjects who drank coffee more than 24 hours prior.Among subjects who drank coffee 12–24 hours (group 2) prior to regadenoson administration, the number of coffee drinks did not have any effect on Change HR, Change SBP, MPHR and %Change HR .The number of self-reported adverse effects was lower in subjects exposed to caffeine 12–24 hours prior to regadenoson (group 2), as compared to >24 hours prior . Group 2 developed less abdominal pain , nausea  and dizziness  when compared to groups 1 and 3.In our study, subjects who were coffee naive (group 1) or those who consumed coffee more than 24 hours prior (group 3) demonstrated significantly larger change in heart rate and systolic blood pressure when compared to subjects exposed to coffee within 12–24 hours (group 2) prior to regadenoson exposure.The blunted rise in heart rate and systolic blood pressure observed in subjects with recent exposure to caffeine may be attributed to the long caffeine half-life in some patients. Caffeine  bioavailability is 100%, with peak level achieved within 15 to 45 minutes . It is mCaffeine is a competitive inhibitor of adenosine A1, A2A and A2B receptors . ChronicIn addition, A2A receptors are present in the atrium and are able to activate ryanodine receptors . RyanodiOur study had many limitations. First, we did not measure blood caffeine level and thus we did not assess the association between serum caffeine level and effect on HR, BP and %MPHR response. Second, patient recall bias of caffeine consumption might have contributed to our results. We could not control for the potential possibility of patients underreporting their caffeine consumption in order to avoid stress test delay or cancelation. Altered sympathetic tone, variable chemoreceptor response, as well as vasodilatory effects by caffeine and regadenoson could have contributed to changes in heart rate and blood pressure response. Moreover, it is difficult to assess variations in caffeine dosing based on beverage types.Caffeine exposure within 12–24 hours prior to regadenoson MPI seems to attenuate the hemodynamic effect of regadenoson as indicated by blunting of heart rate and systolic blood pressure rise. Further studies are needed to examine the possible impact of caffeine exposure within 12–24 hours as currently endorsed in the FDA label on diagnostic sensitivity and specificity of regadenoson stress imaging.


Of these, 107 patients underwent CRP (mg/l) and LVMI , inflammation score based on CRP, IL-6 and TNF-α  and VCAM-1  were associated with higher LVMI. These models were adjusted for age, gender and primary renal disease, and for confounders that on top changed the beta with ≥10%, i.e. diuretic use (for IL-6 and inflammation score).The results suggest that in predialysis CKD patients, inflammation as well as endothelial dysfunction may play an important role towards the increase in LVMI. Left ventricular hypertrophy (LVH) is perhaps the strongest integrator of cardiovascular risk in hypertensive patients . MoreoveBoth inflammation and endothelial dysfunction markers are potential risk factors for LVH in CKD patients. Experimental models and a variety of clinical studies in systemic hypertension and in heart failure document that inflammation is fundamental for the development and progression of myocardial hypertrophy and for the evolution of this alteration towards overt heart failure . Moreove2·71 (LVMI) in predialysis CKD patients with hypertension or using antihypertensive medication.With this background in mind we designed a longitudinal study aimed to investigate the association of inflammation markers C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and endothelial dysfunction markers intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) with LVM indexed for heightThis study includes consecutive incident adult CKD patients who visited the outpatient CKD clinics of two hospitals in Greece in 2004 or 2005. Prior to the study, patients had been followed up for three months to confirm the presence of CKD. The definition of CKD was based on the guidelines of the Kidney Disease Outcomes Quality Initiative , while tIn total, 206 CKD patients fulfilled the criteria as described above. Of these, we excluded 24 CKD patients with (1) no hypertension (getting a more homogeneous patient population as hypertension is an important risk factor for increased LVM); (2) no baseline data on the independent variables ; or (3) no baseline data on the outcome variable (LVM). As such, this study included 182 CKD patients . Data is provided in Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or the use of antihypertensive medication. The study was approved by the Ethical Committee of the General Hospital of Veria and the Ethical Committee of the University Hospital of Ioannina, and patients participated after providing written informed consent.At study entry the patients underwent a detailed review of their medical history and careful clinical examination. Additionally, baseline characteristics, including demographics, primary renal disease, diabetic status, smoking habits, medication, and blood pressure were assessed. A full haematology and biochemical screen was performed, whereas estimated glomerular filtration rate (eGFR) (ml/min/1.73m²) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation . AdditioBlood samples were taken from a peripheral vein under fasting conditions. Serum samples were separated from clotted blood (after 30 min) by centrifugation (10 to 15 min at approximately 1000 x g), aliquoted and stored at -80°C until assay. Samples were measured between 2006 and 2007, at the Laboratory for Study of Kidney Diseases of the Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital of Thessaloniki. For this storage period, samples are considered quite stable and the degradation rate low (variation < 15%). Samples aliquots were thawed just once for the measurement. Serum levels of ICAM-1 and VCAM-1 were measured by a sandwich enzyme immunoassay technique (ELISA) using commercially available standard kits . ELISA system sensitivity was <2 ng/ml for both ICAM-1 and VCAM-1. Serum IL-6 and TNF- α were measured by a high sensitivity ELISA . Sensitivity of the ELISA system was <0.5 pg/ml for both IL-6 and TNF-α. The intra-assay coefficient of variation (CV%) was 3.5 to 6.8% for ICAM-1 and VCAM-1 and 7.1 to 10.3% for IL-6 and TNF-α. The inter-assay CV% was 6.2 to 9.4% for ICAM-1 and VCAM-1 and 7.3 to 10.8% for IL-6 and TNF-α. The concentrations of all molecules were calculated by reference to standard curves performed with the corresponding recombinant molecule. All serum samples were tested in duplicate. In 30 healthy blood donor volunteers ICAM-1 values ranged from 157–480 ng/ml, VCAM-1 327–750 ng/ml, IL-6 0.552–7.18 pg/ml and TNF-α <1.0 pg/ml (data not shown).Serum CRP levels were measured by high sensitivity immunoturbidimetry, enhanced latex technology . The lower detection level was 0.1mg/L and measuring range was 0.1–306 mg/L. Intermediate precision was for a mean CRP level 13.3 mg/L (CV: 2.1%) and for mean CRP level 0.53 mg/L (CV: 8.4%). Expected range for adults is <5.0 mg/L. Cut-off points for CVD risk assessment: <1.0 mg/L low, 1.0–3.0 mg/L average, >3.0 mg/L high .LVM was assessed by 2D-mode echocardiogram, by a single cardiologist from each hospital who followed a predefined protocol as is described more extensively elsewhere .2·71) (LVMI). The height-based indexing of LVM was specifically chosen to minimize any potential distortion attributable to extracellular volume expansion (surface area indexing being weight-sensitive), as recommended in previous studies in CKD [The primary outcome was LVM indexed for height g/m·71 (LVMIs in CKD .not in the highest tertile), 1 point , 2 points  or three points .In accordance to a previous study , we calcTo compare the patient characteristics across LVMI categories (in tertiles) we used tests for trend of means , and medians , and a chi-square test for trend provided . A two-tailed p-value lower than 0.05 was considered as statistically significant.For the cross sectional analysis, we used linear regression analysis to test the association between both inflammation markers and endothelial dysfunction markers with LVM. Model 1 was an unadjusted model. Model 2 was adjusted for three main variables fulfilling the criteria for confounding  i.e. ageFor the longitudinal analyses, linear mixed models were used to analyze the association between the inflammation markers and endothelial dysfunction markers with LVM. Linear mixed models appeared to be most suitable for the analysis of longitudinal data, and provide effect estimates unaffected by drop out of follow-up measurements . Moreoveth-75th percentile) age was 68.1 (60.5–73.4) years, median CRP was 2.0 (0.73–4.5) mg/l, median IL-6 was 3.1 (2.1–4.5) pg/ml, median TNF-α was 1.9 (1.4–2.9) pg/ml, median ICAM-1 was 254.5 (205.5–328.4) ng/ml, and median VCAM-1 was 842.3 (623.0–1148.3) ng/ml. Furthermore, the median baseline LVM indexed for height was 69.4 g/m2·71 .At baseline, age, body mass index, waist circumference, tryglycerides, and pulse pressure increased with increasing LVMI , we used the definition of CKD based on the guidelines of the Kidney Disease Outcomes Quality Initiative as published in 2002. Second, our study design is purely observational. Although we were able to adjust for many potential confounders, residual confounding remains possible because we could not adjust for confounders that were not measured or were unknown. Third, again due to observational nature of our findings, causality cannot be inferred from our data. However, in the quest for causality longitudinal studies rank higher than cross-sectional studies in the ladder of evidence  and as sThis is the first longitudinal study in predialysis CKD patients on mechanisms of increased LVMI involving inflammation markers and endothelial dysfunction markers. In these patients, both IL-6 and an inflammation score based on CRP, IL-6 and TNF-α, as well as VCAM-1 were coherently associated with LVMI.S1 File(SAV)Click here for additional data file.


We do not know the physiological benefits of this approach to improve respiratory system mechanics in acute respiratory distress syndrome (ARDS) patients when mild hypercapnia is of no concern.End-inspiratory pause (EIP) prolongation decreases dead space-to-tidal volume ratio (Vd/Vt) and PaCO2O; or (3) inspiratory–expiratory ratio 1:1. Third phase, the Vt was decreased (30 mL every 30 min) until PaCO2 equal to baseline was reached. FiO2, PEEP, airflow and respiratory rate were kept constant.The investigation was conducted in an intensive care unit of a university hospital, and 13 ARDS patients were included. The study was designed in three phases. First phase, baseline measurements were taken. Second phase, the EIP was prolonged until one of the following was achieved: (1) EIP of 0.7 s; (2) intrinsic positive end-expiratory pressure ≥1 cmH2 . In the third phase, the decrease in Vt  allowed to decrease plateau pressure and driving pressure  and increased respiratory system compliance from 29 ± 9 to 32 ± 11 mL/cmH2O (p = 0.001). PaO2 did not significantly change.EIP was prolonged from 0.12 ± 0.04 to 0.7 s in all patients. This decreased the Vd/Vt and PaCO2 in passively ventilated ARDS patients. This produced a significant decrease in plateau pressure and driving pressure and significantly increased respiratory system compliance, which suggests less overdistension and less dynamic strain.Prolonging EIP allowed a significant decrease in Vt without changes in PaCO Pplat) may limit management of ventilatory adjustments. In particular, the functional consequences of hypercapnia and respiratory acidosis may differ considerably depending on a patient’s condition, and they may involve almost any physiological function , and airway resistance (cmH2O/L/s) was calculated as (peak airway pressure − plateau pressure)/Flow. Predicted body weight (PBW) was calculated as follows: 50 + 0.91(height in cm-152.4) for men and 45.5 + 0.91(height in cm-152.4) for women [2 gradient (P(a-et)CO2) was calculated in each study phase. We used Puritan Bennett™ 840  and Dräger Evita XL  ventilators. All the ventilators used have a compressible volume compensation system.Ventilatory settings and airway pressures were recorded directly from the ventilator monitoring system. Plateau pressure was measured during an end-inspiratory pause. Dead space was calculated using the Enghoff modification of the Bohr equation : Vd/Vt =ad space . Drivingor women . Arteriat test and the Pearson linear correlation to compare data and correlations between phases and variables, respectively. A two-tailed p value less than 0.05 was considered statistically significant. The SPSS® Statistics  statistical software was used for statistical analysis.Data are expressed as mean ± standard deviation. The results were analyzed using one-way analysis of variance for repeated measures (ANOVA) with the Greenhouse–Geisser correction. We performed the Kolmogorov–Smirnov test to confirm normal data distribution. Since the distribution of the data was normal, we used the Student’s 2 during the second phase of the study. The study was performed 5 ± 4 days after starting mechanical ventilation. Table One of the 14 patients enrolled in the study was excluded from the analysis due to fever, tachypnea and unstable EtCOp < 0.001). This EIP change was performed maintaining PEEPi <1 cmH2O  and without the I/E inverse ratio ventilation . EIP prolongation decreased Vdphys and PaCO2 significantly with respect to basal conditions . The decrease in PaCO2 levels due to EIP prolongation was correlated with the drop in Vdphys . Individual changes in PaCO2 and in Vdphys are shown in Figs. Baseline EIP was 0.12 ± 0.04 s, and it was increased to 0.7 ± 0 s in all patients (p < 0.001) and EtCO2 . Basal Vdphys and P(a-et)CO2 had a close correlation . The change in Vdphys and the change in P(a-et)CO2 between the first and second phase also showed a close correlation .Between the first and second phase, significant decreases were observed in both the Vd/Vt ratio . In the third phase, as per protocol design, the PaCO2 and pH values were statistically identical to those at baseline .In the third phase (EIP prolongation and Vt reduction), the Vt was significantly reduced as compared to previous phases . The Vdphys and Vt at baseline were strongly correlated . Additionally, the Vt reduction was tightly correlated with the decrease in Vdphys . Respiratory system mechanics, gas exchange, hemodynamics, and temperature data throughout the study are also given in Table The Vd2 levels. Indeed, the decrease in tidal volume led to a significant decrease in Pplat and ∆Paw, and it also improved the respiratory system compliance.The main finding of our study was that the end-inspiratory pause prolongation allowed to decrease tidal volume while maintaining similar PaCO2 elimination and decreases dead space and PaCO2 levels [2 is time dependent, and EIP prolongation increases the time available for alveolar gas exchange [2 (around 11 %). Despite these beneficial effects of prolonged EIP and the direct relationship between inspiratory time and enhanced CO2 elimination [Several studies have shown that prolongation of EIP enhances CO2 levels –18. Diffexchange , 23, 24.mination , 18, EIPmination , 26. Nev2 levels that was similar to previously reported [2 . These changes observed in our patients may be explained by the increase on the time available for distribution and diffusion of inspired tidal gas within resident alveolar gas during EIP prolongation [Prolongation of EIP in our patients caused a significant decrease in dead space and PaCOreported –18. Whenongation . Indeed,ongation , 27, 28.phys, expressed in mL, decreased significantly between phases 2 and 3. This is explained by the significant reduction in Vt  during the third phase as compared to the previous phases, and thus Vd/Vt ratio did not change. The fact that the reduction in Vt in the third phase was accompanied by a significant decrease in Vdphys and ΔPaw (with a significant increase in compliance) suggests that some degree of overdistension might be present at baseline.Comparing the second (isolated EIP prolongation) and third (EIP prolongation and Vt reduction) phases, our data showed that the Vd/Vt ratio remained unchanged. However, the Vd2 and ventilator mechanical load [2 in all these studies [2.As previously described, low tidal volume ventilation in ARDS may induce hypercapnia and, secondarily, induce pulmonary artery hypertension that may impair right ventricular function  and evencal load  without cal load . Althougcal load , two stucal load , 17 did cal load . However studies –18 were 2 levels but produced dynamic hyperinflation and reduced the cardiac index. In our patients, EIP prolongation was achieved with a relatively high inspiratory flow rate (1 L/s), thus avoiding inverse I/E ratio. This was a safe strategy to decrease PaCO2 levels, while keeping respiratory rate constant (22 breaths/min) and not generating PEEPi.Another technique used to decrease hypercapnia is to increase the respiratory rate. However, in ARDS patients, several studies have shown that a high respiratory rate led to gas trapping and induced PEEPi , 34. In In our study, the reduction in Vt to maintain isocapnia was modest. Should major reductions in Vt were required, then the use of invasive extracorporeal carbon dioxide removal devices had to be considered in order to avoid acute hypercapnia .2 [2 levels during EIP prolongation. This finding was not confirmed in our study. We speculate that the length of time that patients are maintained with EIP prolongation and the mean airway pressure achieved during extended EIP may have contributed to this finding. Indeed, in Mercat’s study [2O and an I/E ratio 1.1. In contrast, in Devaquet’s study [2O, respectively), and the I/E ratios achieved were 1:1.5 in Devaquet’s study and 1:1.7 in ours.Studies analyzing the EIP prolongation did not describe changes in PaO2 , 18, exc2 . This la’s study , EIP prop < 0.001), maintaining PaCO2 levels equal to baseline. These sequential ventilatory changes were accompanied by a reduction in Vdphys. Also, when PaCO2 returned to baseline due to a reduction in Vt, we found a significant decrease in Pplat and an increase in Crs. In addition, these changes in ventilatory mechanics were accompanied by a significant decrease in ∆Paw. All those findings could be explained by a degree of baseline overinflation even though our initial Vt was low [phys at the onset of the study and the tight correlation between the decrease in Vt and Vdphys at the end of the study. Our patients were basally ventilated with parameters similar to those used in previous studies [2O) than in Mercat and Devaquet studies . Our findings thus suggest that if PaCO2 is clinically tolerable, EIP prolongation in ARDS provides physiological benefits including a small and consistent decrease in Vt which may help decrease dynamic strain [The main novelty of our study is that prolonging EIP allowed to reduce Vt by 11 %  could underestimate dead space fraction . In our 2 levels. In addition, when PaCO2 levels are of no clinical concern, EIP prolongation allows us to further decrease tidal volume. This, in turn, decreases plateau airway pressure, driving airway pressure and improves respiratory system compliance, suggesting less overdistension and less risk of dynamic strain and lung injury. Therefore, the use of this simple ventilator maneuver during mechanical ventilation in sedated and paralyzed ARDS patients merits consideration.In conclusion, our data indicate that EIP prolongation is a simple and feasible strategy to decrease dead space and PaCO


Resistant hypertension (RH) may be one of the cause of the plateau in improving the control rate in hypertension (HT) management. The misdiagnosis of RH by clinic blood pressure (BP) is important clinical problem. Aim of the study were to investigate the prevalence of RH by ambulatory blood pressure monitoring (ABPM) and the factor associated with control status of ambulatory BPs.For 1230 subjects taking one or more antihypertensive medication (AHM) enrolled in the Korean Ambulatory Blood Pressure Monitoring (Kor-ABP) registry, the prevalence of RH was calculated which was defined as uncontrolled BP by three AHM classes including diuretic or BP in need of four or more AHM classes. The prevalence determined by clinic versus ambulatory BP was compared.n = 1230). Among them 72 subjects were taking three AHM drugs including diuretics and 105 subjects were taking four or more AHM classes. With uncontrolled daytime ambulatory BP in 41 among 72 subjects, prevalence of RH was 11.9 % (146/1230). By using nighttime BP criteria, there was significant difference in the prevalence of RH for clinic versus nighttime BP . For control status of daytime BP, masked uncontrolled BP was 16.9 % and controlled BP with white-coat effect was 14.1 %. For nighttime BP control status, odd ratios for smoking (0.624), drinking (1.512), coronary artery disease (0.604), calcium antagonist (1.705), and loop diuretics (0.454) were all significant.The age was 59.3 ± 12.5 years, and 44.3 % were female (The prevalence itself was 11.9 % by daytime BP and it was significantly higher when using nighttime BP criteria. Control status of daytime BP was misclassified in 31.0 %. Smoking, drinking, coronary artery disease, calcium antagonist, and loop diuretics were associated with nighttime BP control status. Resistant hypertension (RH) is defined as the hypertension (HT) which cannot be controlled below the target blood pressure even if treated with three or more antihypertensive medications (AHM) classes one of which was diuretics or HT which requires four or more AHM classes regardless whether the blood pressure was controlled or not . In receAs shown in the recent clinical trial, the learning from the misdiagnosis of RH using only clinic BP made out-of-office BP measurement, preferably ABPM, as the essential component of the evaluation before adopting the new therapeutic modality . So far,So the aim of the present study is, firstly, to identify the true prevalence of RH by analyzing the multicenter ABPM registry data in Korea (Kor-ABP registry) and to identify the diagnostic errors of clinic BP in the diagnosis of RH. Secondly, it is to identify the demographic and clinical factor related to the treatment resistant condition in the subject treated three or more AHM classes.Among 3766 subjects who were enrolled for Kor-ABP registry during the period from 1st August, 2009 to the end of 2012, 1242 subjects with relevant clinical information and who were treated with at least one AHM were selected for the study. The subject was registered by 27 referral hospitals as described in the previous study  less thaInformation included from the medical records covered: age, gender, height, weight, abdominal circumference, presence of diabetes mellitus (DM), hyperlipidemia, presence of clinical cardiovascular disease, time of diagnosis, mode of treatment, and prescribed medications.And the questionnaire for each subjects included: smoking status, alcohol intake, extent of physical exercise, family history of HT and premature cardiovascular death, past medical history; HT, DM, hyperlipidemia, stroke, coronary artery disease (CAD), and heart failure.The collected information for the AHM was the commercial names of the drugs and dosing at the time of enrollment.Clinic BP was measured using an A&D UA-767, which passed European Society of Hypertension protocol and International Protocol [http://www.dableducational.org or passed the recommended validation protocols [pulse rate above 120 beats per minutesystolic or diastolic blood pressure more than 25 mmHg above or below the previous and subsequent readingspulse pressure below 15 mmHg .ABPM data were gathered as the form of raw data files uploaded to the study website. The device used in the study institute was all recommended as summarized in the website rotocols . The rawrotocols :pulse raThe definition of the resistant hypertension was uncontrolled BP even if using three drug classes one of which included diuretics or the BP status requiring treatment using four or more drugs regardless of the control status . The numBP was categorized as controlled and uncontrolled status according to the various criteria. By clinic BP criterion, the BP lowered below 140/90 mmHg was regarded as controlled status. As for daytime, nighttime, and 24 h BPs, the BPs lowered below 135/85 mmHg, 120/70 mmHg, and 130/80 mmHg were regarded as controlled status, respectively .For the subjects taking three or more AHM including diuretics, according to the control status defined by various criteria, the subject with controlled BP status was grouped as responsive group, whereas the subject with uncontrolled BP status was grouped as the resistant group.Dyslipidemia was defined as the total cholesterol ≥ 240 mg/dL, triglyceride ≥ 150 mg/dL, HDL < 45/50 mg/dL in male and female, respectively, or the use of statin. The diabetes was defined as fasting blood glucose ≥ 126 mg/dL, hemoglobin A1C > 6.5 %, or the use of antidiabetic medication. The chronic kidney disease (CKD) was defined as eGFR calculated by CKD-EPI equation between 30 and 60 ml/min/1,73m2 [The study protocol was approved by the clinical research ethics committees in all hospitals involved in the study.All data were expressed as mean ± standard deviation. The statistical significance of the differences in mean values was evaluated using student t-test or analysis of variance (ANOVA). The chi square test and Fisher’s exact test were used to ascertain the statistical significance of the categorical difference between groups. The differences in diagnostic category between clinic versus ambulatory BPs were evaluated using McNemar’s test. Test for inter-rater reliability using the kappa test statistics with 95 % confidence interval were performed to determine the consistency of the two methods of measuring blood pressure.p < 0.05. All data processing and analysis were performed using SAS 9.4 .Multiple logistic regression analysis was performed to examine the association between resistant group defined by various BP criteria and the clinical factors. The independent variable included age, sex, Mets, family history of HTN, physical activity, drinking and smoking status, DM, CKD, history of stroke, CAD, heart failure, the use of ACEI or angiotensin receptor blocker (ARB) as renin angiotensin system (RAS) blockade, beta blocker (BB), calcium channel blocker (CCB), and loop diuretics, and the use of optimal dosage. Optimal dosage was defined as the case all of the drug dosage should be ≥ 50 % of the maximum recommended dosage. Statistical significance was defined by a confidence interval of 95% and n = 1230). Body mass index was 25.2 ± 3.7 in male and 24.9 ± 3.6 in female (p = 0.0984). Smoking and drinking were more frequent in male than female . Family history of HT was present in 46.0 %. High GCR was 83.3 % and coronary artery disease, stroke and heart failure were 25.7 %, 12.6 %, and 4.8 %, respectively. CKD was observed in 10.6 %.The age was 59.3 ± 12.5 years, and 44.3 % were female (ARBs prescribed were irbesartan (23.1 %), olmesartan (19.0% ), telmisartan (15.7 %), valsartan (15.7 %), losartan (12.4 %), candesartan (8.3 %), fimasartan (1.7 %), and eprosartan (4.1 %). Fixed drug combination was prescribed in 48.7 % for ARB and diuretics. The majority of ACEI was perindopril (70.5 %). BBs prescribed were bisoprolol (39.3 %), carvediolol(29.9 %), nebivolol(12.0 %), atenolol(12.0 %), and etc(2.5 %). CCBs prescribed were amlodipine (49.1 %), slow release form of nifedipine (15.7 %), diltiazem (8.3%), and etc (26.8 %). Diuretics prescribed were dihydrochlorthiazide (65.9 %), loop diuretics (17.4 %), indapamide (7.5 %), and spironolactone (6.6 %).As shown in Table p < 0.0001). As for clinic BP, BP of 42 among 83 subjects taking three drugs including diuretics were uncontrolled.When the dosage of each drug ≥ 50 % of the maximum recommended or approved dose for hypertension was considered effective treatment, 83 subjects took three drugs including diuretics and 83 subjects took four or more drug classes and the categorization was differed (McNemar BP in 41 (56.9 %), 41 (56.9 %), 54(75.0 %), and 4765.2 %) subjects of the 72 subject taking three AHMs including diuretics were not controlled by clinic, daytime, nighttime, and 24 h BP criteria , 10.4 % (129/1230), 11.2 % (139/1230), 10.8 % (134/1230) according to the criteria by clinic, daytime, nighttime, and 24 h BPs, respectively.n = 105) were classified as RH. As shown in Table According to the definition of RH, the subject with uncontrolled BP among 72 subjects taking three AHMs including diuretics and all of the subjects taking four or more AHMs (n = 55), 33.4 % (n = 59), and 28.8 % (n = 51) were misclassified as uncontrolled BP due to white-coat effect or misclassified as controlled BP due to masking by the clinic BP. For control status of daytime BP, masked uncontrolled BP was 16.9 % and controlled BP with white-coat effect was 14.1 %. Masked uncontrolled HT was more frequently observed when using nighttime BP criterion than daytime BP criterion . Because daytime BPs in 31 subjects were controlled as shown in Table As shown in Table As shown in Table As shown in Table The most important finding of the present study is that the prevalence of RH is 11.9 %, which was within the 95 % confidence interval of the prevalence of the previous reports . As noteAnd without considering the optimal dosage criteria, the prevalence was overestimated by 1 ~ 2 % in our study which was partially consistent but the difference was not as striking as reported in the previous study .In addition, our study identified the related clinical factor for the uncontrolled BP group in spite of optimal medical therapy. There was no relation suggested by Mets to uncontrolled BP group. It can be explained by the risk profile of subjects requiring three or more drugs and coronary artery disease patients too different to be compared with the most populations where Mets implied cardiovascular risk . SmokingOur study showed that CAD is consistently associated with controlled group. This finding can be potentially explained by routine use of beta blockade or RAS blockade when BP level is tolerable. Another interesting finding of our study is that heart failure is associated with daytime controlled BP group. This finding also can be explained by the standard regimen of heart failure which includes RAS blockade, beta blocker, and diuretics and mimics RH situation. Specifically, systolic heart failure patients are so sensitive to the dosage of AHM that they usually have relatively low or well controlled BP. This postulation is partly consistent with the finding that loop diuretics were more frequently prescribed in the controlled BP group. But in RH situation, heart failure itself can be aggravated by high or uncontrolled BP so that multiple drug treatment might not be the result of the standard therapy of heart failure but more likely be the attempt of controlling BP as the primary reason for heart failure.In our study, as an independent variables in the multiple logistic regression analysis, “optimal dosage” was included so that the effect the suboptimal dosage possibly more frequently used in heart failure such as beta blocker could be adjusted. Because the proportion of the heart failure was 4.8% in our study, further study is needed for the relationship between heart failure and the RH.The relation of AHM class to the uncontrolled BP group is very difficult to explain because our study is a cross-sectional study. The association of ARB is different from the CCB in regard to the nighttime BP. Because CCB is very potent drug to reduce BP the association can be demonstrated the perceived role of CCB in RH. But it could be a result of a secondary failure of BP control by CCB resulting in reflex sympathetic activation. Further prospective study is needed to answer if this finding is due to the pharmacological property of those drugs such as the half-life or specific effect on the nighttime BP. For the loop diuretics, it is very well known that enough diuretic therapy is very important to deal with RH. Out finding is consistent with the role of diuretics in RH. But because the use in heart failure may be a confounding factor, further study is needed.In terms of ABPM versus home BP monitoring issues, our study showed that the nighttime BP criteria can be characterized by increased prevalence of RH and more clinical factors were related. Even though the diagnostic thresholds by ABPM based on the cardiovascular outcomes have been reported in many studies –25, it iThe prevalence of the masked uncontrolled HT and white-coat controlled HT or treated normalized HT in RH was quite similar to the prevalence in general hypertensive subjects , 27. ButThe present study has several limitations. The generalizability can be limited because Kor-ABP registry data was driven by the tertiary referral center. But considering the RH is generally handled by the referral center, our data can be applied for referral center. And for all negative findings in this study such as the relation of MetS, CKD, or the relation of optimal dosage to the control status, it needs careful interpretation because the sample size seemed to be too small to exclude those associations. Secondly, in RH patient, it is crucial to make a differential diagnosis for secondary HT. But in our study, no standardized approach or reliable exclusion for secondary HT was performed. Thirdly, the information about the adherence as the behavioral factor which is important cause of RH was not available in the present study. Finally the relation of the clinical factors to the treatment resistance is not based on the causality because this study is a cross-sectional study.In conclusion, the prevalence itself was 11.9 % by daytime BP and it was significantly higher when using nighttime BP criteria. Control status of daytime BP was misclassified in 31 %. Smoking, drinking, coronary artery disease, calcium antagonist, and loop diuretics were associated with nighttime BP control status.


The objective of this study was to evaluate the prevalence of anemia in DM2 patients and its correlation with demographic and lifestyle and laboratory variables. This is a descriptive and analytical study of the type of case studies in the urban area of the Ijuí city, registered in programs of the Family Health Strategy, with a total sample of 146 patients with DM2. A semistructured questionnaire with sociodemographic and clinical variables and performed biochemical test was applied. Of the DM2 patients studied, 50 patients had anemia, and it was found that the body mass items and hypertension and hematological variables are significantly associated with anemia of chronic disease. So, the prevalence of anemia is high in patients with DM2. The set of observed changes characterizes the anemia of chronic disease, which affects quality of life of diabetic patients and is associated with disease progression, development, and comorbidities that contribute significantly to increasing the risk of cardiovascular diseases. Diabetes mellitus (DM) is a metabolic disorder of great impact worldwide. Epidemiological data showed that in 2010 there were 285 million people affected with the disease in the world, and it is estimated that in the year of 2030 we will have about 440 million diabetics [The increasing prevalence of type 2 diabetes mellitus (DM2) has become a major public health concern. The diabetic patients' number has been increasing due to population and urbanization growth, increase in the prevalence of obesity and sedentary lifestyle, and the longer survival of patients with DM . Diabeteβ-cells and the absence of endogenous insulin, and as DM2, insulin resistance characterized by a frame, generally associated with obesity. Both types are featured by hyperglycemia above. Insulin resistance reduces glucose tolerance especially in muscle cells and adipocytes, where glucose uptake is insulin dependent. This causes glucose accumulation in the circulation and consequently a hyperglycemic state, generating homeostatic and systemic imbalance [The disease can be classified into two predominant types, as type 1 DM (DM1), defined by the destruction of pancreatic mbalance .Diabetes is considered a major cause of premature death, because of the increased risk for developing cardiovascular diseases, which contribute to 50% to 80% of patients deaths due to increased levels of serum cholesterol and triglycerides. Cardiovascular diseases include diseases of the circulatory system, comprising a wide range of clinical syndromes, the main cause of atherosclerosis, which also increases the risk of acute coronary syndromes. The incidence of cardiovascular diseases reaches 20% in diabetics after a period of about 7 years .α, and NFκB. Thus, diabetes, as well as hyperglycemia due to its nature, is also an inflammatory disease character. Studies show that the longer the duration of the disease and/or loss of glycemic control, the higher the inflammatory process [Hyperglycemia has a direct relationship with the development of an inflammatory condition showed by the increased expression of proinflammatory cytokines such as IL-6, TNF- process , 8.The elevation of proinflammatory cytokines plays an essential role in insulin resistance and induces the appearance of cardiovascular complications diabetic micro- and macrovascular, kidney disease and anemia. By increasing especially IL-6, antierythropoietic effect occurs, since this cytokine changes the sensitivity of progenitors to erythropoietin (erythroid growth factor) and also promotes apoptosis of immature erythrocytes causing a decrease, further, in the number of circulating erythrocytes and consequently causing a reduction of circulating hemoglobin , 9.It should also be noted that, due to the development of diabetes mellitus, the nephropathy may arise, which further undermines the renal production of erythropoietin, positively contributing to an increased anemic framework , 10. AccThe National Kidney Foundation defines anemia in chronic kidney disease as Hb level < 13,5 g/dL in men and 12,0 g/dL in women . The aneAnemia in diabetic person has a significant adverse effect on quality of life and is associated with disease progression and the development of comorbidities , as obesThis is a descriptive and analytical study of the type of case studies in patients with DM2 and ages less than 75 years living in the urban area in the city of Ijuí RS, registered in programs of the Family Health Strategy (FHS) in this city. The study was conducted from January 2010 to January 2013, after agreement by the Research Ethics Committee of the Regional University of Rio Grande do Sul State Northwest (UNIJUÍ) (Opinion number 091/2010). All participants signed the informed consent in this research.The sample size was calculated by StatCalc application EpiInfo 3.5.3, considering the prevalence of nonspecific outcome of 50%, 5% error, and 95% level of reliability, which resulted in a sample of 269 patients. Foreseeing possible losings a percentage of 5% of this number was added, a total sample of 283 patients with DM2.The study excluded those patients who had difficulties to understand the proposed procedures, those who were bedridden, and those who had difficulty walking.The invitation to participate in the study was made to patients during home visits, with the monitoring of community health workers when possible. At the moment of visit, the research objectives were explained for the patient and the dates of the interviews were fixed with those who agreed to participate, in addition to scheduling the clinical and laboratory reviews, held, respectively, in Physiotherapy Clinic and the Laboratory of Clinical Analysis of UNIJUÍ (UNILAB).Sociodemographic characteristics:age (in years);sex .Health condition:time of diagnosis of type 2 diabetes (in years);advanced age (over 60 years).Comorbidities:presence of hypertension (yes/no);cardiac and/or respiratory (yes or no), analyzed according to the patient's report when asked about the presence of these diseases;dyslipidemia (yes/no), diagnosed by biochemical tests;2 for patients up to 59 years old and ≥27,0 kg/m2 for patients aged 60–75 [obesity (yes/no), when the value of body mass index was ≥30,0 kg/med 60–75 .Lifestyle:smoking (yes/no);alcohol consumption (yes/no);physical inactivity (yes/no);stress (yes/no).Eating habits, investigated through questioning a high salt diet (yes/no).The interviews and tests were conducted by trained health professionals. Data collection was performed by applying a semistructured instrument. The presence of anemia was considered as the dependent variable; the patient was considered anemic, according to the World Health Organization reference values . Thus, tEvery patient who declared himself a smoker at the moment of evaluation is considered smoker, regardless of the amount of cigarettes consumed; and alcoholic is the person who reported excessive consumption of alcohol during the study period, at any frequency. Excessive salt intake was measured by the question: Do you put much salt in your food? Stress was assessed by the question: Do you consider yourself a stressed person? There were classified physically inactive patients who reported not performing any type of regular exercise with the lowest frequency of three times a week.2.The evaluation of anthropometric data, including the measurement of body weight (in kilograms) on digital scale, was performed (Toledo); height (in meters) in stadiometer (Toledo) and waist circumference (WC) were measured at the midpoint between the last rib and the iliac crest using flexible standard tape and nonextensible, defining measure of 0,1 cm, according to techniques recommended . The bodAt the end of the clinical evaluation, an appointment was made with the date and the time of collection of blood from each patient. Patients personally received clarification on the procedures of collection and were instructed to fast for at least eight hours prior to the blood collection, in addition to writing instructions and containers for the collection of the first urine in the morning. Among the laboratory tests that were performed are the creatinine dosage and blood glucose by enzymatic Trinder method . In addiThe patient who presented two or more of the following criteria proposed by the National Cholesterol Education Program was classified as having metabolic syndrome:  increase2 estimated by the Cockroft-Gault equation [Renal function was assessed by the value of serum creatinine, obtained by biochemical tests. The glomerular filtration rate is estimated by the Cockcroft-Gault calculated using the formula available on the websites of the Brazilian Society of Nephrology (SBN) of the National Kidney Foundation . We consequation  represenequation . For theequation .t-test was used for normally distributed variables, and the Chi-square test and Fisher's exact Pearson were used to compare categorical variables in order to verify differences of variables between patients with and without anemia. The Spearman correlation coefficient was used to evaluate the correlation between clinical and biochemical parameters with the hemoglobin level. p < 0,05 was considered statistically significant. All tests were applied with a Confidence Interval (CI) of 95%.For processing the data, we used the Statistical Package for Social Science (SPSS) . In the statistical analysis, all variables were tested for normality using the Kolmogorov-Smirnov (KS) test. The qualitative variables are presented as frequencies and percentages and quantitative variables as average and standard deviation (average ± SD) ormedian (minimumand maximum). Mann-Whitney tests were used to compare two independent groups with abnormal distribution, Student's 283 patients with DM2 were suitable to the study inclusion criteria and were selected for home visits and invitation to participate in the study, according to data collected from health professionals in FHS or the medical records of the patients belonging to nine FHS in the city of Ijuí, RS. Of these, 64 patients were not included in the study for the following reasons: contact absence; refusal to participate; and not identifying the address informed and 73 individuals were not included due to insufficient data to evaluate the hematologic changes, since they did not undergo blood tests for hemoglobin count, a total sample of 146 type 2 diabetic patients in this study, of which 50 had anemia, corresponding to 34,2%.2, and a median of disease diagnosis time of 5,0 years .The study population had an average age of 60,9 ± 8,9 years, body mass index of 31,2 ± 5,8 kg/mp > 0,05). However, variables, body mass, and hypertension showed significance to the outcome studied . These data are presented in We analyzed the dependent variable “anemia” according to some characteristics of patients with DM2. For time of diagnosis of the disease, old age, metabolic syndrome, renal dysfunction by creatinine, and the Cockcroft-Gault equation, there was no difference between the presence and absence of anemia . The same is observed with respect to glucose, however, with higher values in the group without anemia. There was no statistically significant difference in creatinine variable . These data are presented in We observed statistically significant difference in hematological variables between groups with and without anemia , visceral fat mass, serum glucose levels, insulin sensitivity, and cholesterol levels –33.In addition, it was found in this study that the prevalence of hypertension in diabetic patients that were anemic was significantly higher when compared to nonanemic ones. This association is of concern considering that hypertension in diabetic increases the risk of cardiovascular complications such as heart failure, stroke, tissue inflammation, and atherosclerosis .According to Ximenes et al.  anemia iIt was observed in the present study that there are decreased values of hemoglobin, hematocrit, and red blood cells in anemic patients, which can be associated with a normocytic normochromic anemia, characteristic of an anemia of chronic disease (ACD). ACD is a light-to-moderate anemia shortening the survival of red blood cells . This phenomenon is attributed to hyperactivity state mononuclear phagocyte system, triggered by infectious, inflammatory, or neoplastic process, leading to early removal of circulating red blood cells. Inadequate bone marrow response observed is due basically to inappropriately low Secretion of Erythropoietin (EPO), decreased bone marrow response to EPO, and decreased erythropoiesis consequent to lower supply of iron to the bone marrow .One explanation for this bone marrow response is directly related to the activation of macrophages and the release of inflammatory cytokines, particularly IL-1, IL-6, tumor necrosis factor (TNF a), and interferon gamma (INF g) which act by inhibiting the proliferation of erythroid precursors and therefore inhibit erythropoiesis. Furthermore, the suppressive action of these cytokines on erythropoiesis stimulating overcomes the action of EPO resulting in decreased bone marrow response to EPO and erythropoiesis .Also it should be noted that there was no hemoglobin correlation with creatinine or statistical differences in creatinine values and glomerular filtration rate estimated between groups, indicating once again that anemia by chronic disease was inflammation triggered and the reduction renal function affects the production of EPO.The limitations in this study refer to the fact that the assessment of glycemic control in diabetic patients was performed by means of fasting glucose that is a momentary biochemical analysis, does not represent the average glucose of patients, and may also occur interfering in the examination, as the effect of hypoglycemic agents, promoting a reduction in glucose levels. In this sense, the gold standard for assessing glycemic control would be the achievement of HbA1c (glycated hemoglobin), which is one of the most important tools to assess glycemic control of patients with diabetes, as they express the average amount of glucose in the last three months, and this can infer the diabetes control efficiency and suggest the need for adjustments.Therefore, it is suggested that further studies should be conducted using test glycated hemoglobin, which currently is already considered an essential parameter in the DM control evaluation, in order to relate hyperglycemia, inflammation, and anemia.Patients with DM2 and anemia were those with high body mass, hypertension, increased waist circumference, and longer time of the disease. This set of changes characterizes the anemia as chronic disease, which has a significant adverse effect on quality of life of diabetic patients and is associated with the progression of the disease; the development of comorbidities significantly contributes to the increased risk of cardiovascular disease. However, against what was expected, the results of blood glucose were higher in nonanemic patients, which is contradictory due to the anemia of these patients being associated with an inflammatory condition, for being characterized as normocytic normochromic anemia. Deepening the study of the issues raised throughout this work provides knowledge for the establishment of new strategies for glycemic control, which can increase the research and correlate some analytical parameters, such as HbA1c, I1-6, VHS, and PCR.


P < 0.001), while C3a levels sharply increased from 427 ± 269 to 3501 ± 1638 ng/mL (P < 0.000). No changes were observed in augmentation index without ultrafiltration: 26.1 ± 11.1 versus 26.6 ± 12.4. Only aortic systolic blood pressure was lower at 15 minutes: 120.1 ± 17.7 versus 110.4 ± 25.8 mmHg (P = 0.009), in agreement with a reduction in brachial systolic blood pressure: 135.1 ± 18.1 versus 122.7 ± 27.4 mmHg (P = 0.01), without changes in aortic or brachial diastolic blood pressure. Important changes in pulse wave analysis were observed after a complete haemodialysis session: augmentation index 29.9 ± 10.1 versus 18.6 ± 15.0, aortic systolic blood pressure 139.8 ± 25.5 versus 119.4 ± 28.5 mmHg (P < 0.00), without changes in aortic diastolic blood pressure. In summary, haemodialysis with cellulose diacetate acutely induced a transient state of immunoactivation due to bioincompatibility, this phenomenon was nondetectable by pulse wave analysis. Complete haemodialysis session led to important changes in pulse wave analysis.Membrane bioincompatibility was demonstrated by successive white blood cell counts and C3a generation. Pulse wave analysis was obtained by applanation tonometry (SphygmoCor) in a sequential way: basal, after 30 minutes with nul ultrafiltration, and after a complete dialysis with ultrafiltration. At 15 minutes of haemodialysis, significant decrease in leukocyte count occurred: 6801 ± 1186 versus 4412 ± 1333 ( Cardiovascular (CV) disease is the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The increased risk is partly due to a higher prevalence of traditional CV risk factors. Nevertheless, these patients also present other nontraditional CV risk factors related with the setting of uremic background  that resAnother component that has been proposed to play a role in CV risk is the HD session per se. The dialysis procedure may induce acute functional alterations of the arterial wall through several mechanisms, the most remarkable being the intermittent immunoactivation state induced by dialysis –11, and As PWA measurements are being increasingly introduced in the clinical setting, the main objective of our study was to separately analyze the acute effects on PWA of bioincompatibility and ultrafiltration (UF) during the dialysis session.n = 11) and ultrafiltration  during the HD session. Patients were eligible for entry into the study when (1) they had been on HD for at least 3 months, (2) they were in a stable clinical situation, and (3) they did not suffer cardiovascular instability on dialysis. All selected patients agreed to participate in the study, which was approved by the Hospital Ethics Committee. We separately analyzed the acute effect on PWA of membrane bioincompatibility , subendocardial viability ratio (SEVR), ejection duration (ED), and aortic systolic and diastolic blood pressure. Measurements were taken by a single observer in triplicate and averaged.2 and dialysate calcium concentrations of 1.5 mM. In order to avoid the effects of intravascular volume changes on PWA, fluid removal was completely avoided (ultrafiltration = 0) during the 30 minutes of PWA monitoring.As a biological demonstration of membrane bioincompatibility, successive white blood cell counts in the ADVIA autoanalyzer and C3a generation (enzyme immunoassay Quidel) were obtained. The analysis was performed by leukocyte count and C3a levels monitored before, at 15, 30, 60 minutes, and at the end of the HD session. PWA was performed by SphygmoCor system before, at 15 and 30 minutes of starting HD session. All patients were dialyzed with the same cellulose diacetate membrane (Baxter) with surfaces of 170 or 210 mPWA was performed before and after a conventional HD session with the same cellulose diacetate membrane (Baxter) and dialysate calcium concentrations than in Study I. The procedure was carried out in normal conditions, with programmed UF as clinically needed based on their dry weight. A total of 19 patients were studied, and the mean ultrafiltration was 2.43 ± 1.12 Kg.t-test and repeated measures ANOVA. Univariate correlations between variables were assessed using the Pearson's coefficient of correlation test. P < 0.05 was considered statistically significant.Statistical analysis was performed using the computer software SPSS 17 for Windows. Data are expressed as mean ± SD. The effect of HD session on the measured variables was tested by means of the paired Eleven patients were included in Study I, with a mean age of 76.9 ± 10.5 years, 54.6% men, with a mean time on dialysis of 33.9 ± 37.9 months. Mean predialysis peripheral blood pressure measured in triplicate and averaged was 135.1 ± 18.1/61.7 ± 7.5 mmHg.P < 0.001), while C3a levels sharply increased from 427 ± 269 to 3501 ± 1638 ng/mL at 15 minutes (P < 0.000), both parameters being inversely correlated . No changes were demonstrated in any of the variables analysed in PWA: AI@75 (26.1 ± 11.1 versus 26.6 ± 12.4), ED (37.1 ± 5.9 versus 35.8 ± 5.1), and SEVR (129.1 ± 30.3 versus 141.1 ± 29.5). Only aortic systolic BP was lower at 15 minutes: 120.1 ± 17.7 versus 110.4 ± 25.8  mmHg (P = 0.009), in correlation with a reduction of brachial systolic BP: 135.1 ± 18.1 versus 122.7 ± 27.4 mmHg (P = 0.01), without changes in aortic or brachial diastolic BP.Membrane bioincompatibility results related with leukocyte count, C3a, peripheral and central blood pressure and stiffness parameters are displayed in Nineteen patients were included in Study II, with a mean age of 71.4 ± 12.2 years, 63.2% were men, and the mean time on dialysis was 36.2 ± 47.4 months. Mean predialysis brachial BP was 153.7 ± 26.7/74.7 ± 13.3 mmHg. Mean UF was 2.43 ± 1.12 Kg.P < 0.00), without changes in aortic diastolic BP 75.8 ± 13.9 versus 75.1 ± 17.9 mmHg (p : ns). However, there was no good correlation between the amount ultrafiltered and the changes in PWA parameters (r = 0.65), suggesting that arterial stiffness improvement was not caused by fluid removal alone.UF effects results are displayed in Arterial stiffness measurement in ESRD patients has gained importance in the last years, especially for its relationship with increased left ventricular hypertrophy and decreased coronary perfusion during diastole . NeverthWhen the dialysis procedure was performed with the normal pattern of UF, and PWA was measured at the end of the dialysis session (Study II), a significant effect on arterial stiffness parameters was shown. We observed a decrease in both aortic systolic BP and AI@75 at the end of the HD session. Contrary to expected, we found no correlation between changes in arterial stiffness parameters and the magnitude of fluid removal. Previous publications have analysed the effect of the HD session on arterial stiffness yielding different results. Some of them defend a lack of improvement of arterial stiffness arguing that vascular changes in ESRD are structural rather than functional , that oxThese discrepancies in the literature can be justified by two main reasons. On the one hand, the large number of variables that can influence during a HD session, not only immunoactivation and intravascular volume drop, but also BP changes, oxidative stress, activation of the rennin-angiotensin system, changes in calcium or magnesium levels during the session, or the differences between patients in intravascular refilling due to individual nutritional status, among others –26. It iWe can conclude that HD procedure with the diacetate cellulose membrane induces a clear immunoactivation effect easily demonstrable by leukocyte cell count and C3a generation that is not detectable by PWA. The improvement of arterial stiffness observed after the HD session assessed by PWA was not related with ultrafiltration nor with changes in BP.Further studies with control of the different variables should be carried out in order to determine how each of these factors affects arterial stiffness during the hemodialysis session.