Self-assessment of symptoms by patients with chronic conditions is an important element of disease management. A recent study in a commercially-insured population found that patients who received automated telephone calls for asthma self-assessment felt they benefitted from the calls. Few studies have evaluated the effectiveness of disease self-assessment in Medicaid populations. The goals of this study were to: (1) assess the feasibility of asthma self-assessment in a population predominantly insured by Medicaid, (2) study whether adding a gift card incentive increased completion of the self-assessment survey, and (3) evaluate how the self-assessment affected processes and outcomes of care.We studied adults and children aged 4 years and older who were insured by a Medicaid-focused managed care organization (MCO) in a pre- and post-intervention study. During the pre-incentive period, patients with computerized utilization data that met specific criteria for problematic asthma control were mailed the Asthma Control Test (ACT), a self-assessment survey, and asked to return it to the MCO. During the intervention period, patients were offered a $20 gift card for returning the completed ACT to the MCO. To evaluate clinical outcomes, we used computerized claims data to assess the number of hospitalization visits and emergency department visits experienced in the 3 months after receiving the ACT. To evaluate whether the self-management intervention improved processes of care, we conducted telephone interviews with patients who returned or did not return the ACT by mail.During the pre-incentive period, 1183 patients were identified as having problems with asthma control; 25 (2.0%) of these returned the ACT to the MCO. In contrast, during the incentive period, 1612 patients were identified as having problems with asthma control and 87 (5.4%) of these returned the ACT to the MCO (p < 0.0001). Of all 95 ACTs that were returned, 87% had a score of 19 or less, which suggested poor asthma control.During the 3 months after they received the ACT, patients who completed it had similar numbers of outpatient visits, emergency department visits, and hospitalizations for asthma as patients who did not complete the ACT. We completed interviews with 95 patients, including 28 who had completed the ACT and 67 who had not. Based on an ACT administered at the time of the interview, patients who had previously returned the ACT to the MCO had asthma control similar to those who had not . Patients had similar rates of contacting their providers within the past 2 months whether they had completed the mailed ACT or not .Mailing asthma self-assessment surveys to patients with poorly controlled asthma was not associated with better asthma-associated outcomes or processes of care in the Medicaid population studied. Adding a gift card incentive did not meaningfully increase response rates. Asthma disease management programs for Medicaid populations will most likely need to involve alternative strategies for engaging patients and their providers in managing their conditions. Patient self-assessment is a key element of the Chronic Care Model . Health . The ACT has been found reliable, valid, responsive, and efficacious in identifying patients with suboptimal asthma control [Patient self-assessment also holds promise to improve care for asthma, an important chronic condition that affects more than 16 million adults and 7 million children in the United States . Self-as control .Although patient self-assessment for asthma has shown promise in privately insured populations, scant information exists about its effectiveness in Medicaid populations. Medicaid-insured and low-income persons are at higher risk for poor asthma control , and praThe goals of this study were to (1) assess the feasibility of asthma self-assessment in a majority Medicaid population, (2) study whether adding a gift card incentive increased completion of the self-monitoring survey, and (3) evaluate how this self-assessment affected processes and outcomes of asthma care. We hypothesized that asthma self-monitoring in a Medicaid population would be feasible, that adding a gift card incentive would increase completion of the self-monitoring survey, and that self-monitoring would lead to processes of asthma care that result in fewer hospitalizations and ED visits.This study included adults and children aged 4 years and older insured by Neighborhood Health Plan (NHP), a community health center based Medicaid-focused managed care organization (MCO). NHP is contracted with MassHealth, the state Medicaid agency, to enroll members eligible for services, and MassHealth approved NHP's participation in the study. The study was also approved by the Human Studies Committee at Harvard Pilgrim Health Care. At the time of this study, the MCO insured more than 185,000 persons, including 125,000 who had Medicaid. Our study population consisted of patients with evidence of current problematic asthma control based on claims data. Criteria for inclusion in this population were developed by the medical director of the MCO with the goal of identifying patients who were certain to have problematic asthma control. Criteria included any one of the following: (1) high use of bronchodilators, defined as having at least one bronchodilator dispensing in the past 2 weeks and having had 3 or more dispensings of a bronchodilator in the past 4 months, (2) high use of systemic corticosteroids, defined as having at least one dispensing of a systemic corticosteroid in the past 2 weeks and having had 3 or more dispensings of a systemic in the past 4 months, or (3) an asthma-related ED visit within the past 6 weeks. As part of routine care, the MCO identified these patients with problematic asthma control and produced "asthma trigger reports." All trigger reports were distributed to the patients' primary care practice sites to alert providers that certain patients may have poorly controlled asthma. For a subset of patients, the MCO sent the patient's trigger report directly to the primary care provider with the GINA step chart for dose escalation .This study used a pre- and post-intervention design to evaluate the intervention, self-assessment with incentives. The overall schematic for the study is depicted in Figure This study involved two time periods: the pre-incentive and the incentive periods. During the pre-incentive (self-assessment without incentives) period, patients meeting the criteria for problematic asthma control were mailed the ACT with a cover letter from the MCO suggesting that it be completed in English or Spanish by each parent or guardian of each child ages 4 to 11 years or self-completed by children and adults ages 12 years and older. Responses used Likert-type rating scales and the sum yielded a score that suggested a range of control from poor to good. The cover letter informed the patients or parents that if the scores were 19 or less, their asthma was in poor control and they should contact their providers ,21. The Concurrent with our intervention, asthma case managers at the MCO contacted select patients appearing on the trigger report. Patients were selected for outreach on the basis of having appeared on the report at high frequency, indicative of long-standing problematic asthma control, based on the clinical expertise of the asthma case managers. The asthma care management process did not change between the pre-incentive and incentive periods.During the incentive period, all patients who were mailed the asthma self-assessment survey also were offered a $20 gift card to a local supermarket if the patient or parent returned the completed asthma self-assessment survey to the MCO.To evaluate clinical outcomes, we used computerized claims data to assess the number of hospitalizations and ED visits experienced in the 3 months after receiving the ACT. We also used computerized claims data to assess the number of fills of rescue and controller medications for asthma. We hypothesized that completion of the ACT would result in improved processes of care that would result in fewer hospitalizations and ED visits from asthma. In addition, we hypothesized that completion of the ACT would result in fewer numbers of fills of rescue medications and increased numbers of fills of controller medications.We conducted telephone interviews with pre-incentive and incentive period patients to assess the effectiveness of the patient self-assessment strategy. For each patient, we conducted the follow-up interview within 8 weeks after the ACT was mailed in order to conduct the interview while the patients could remember receiving the mailing.We conducted a second stage screening at the beginning of each telephone interview and excluded adults who reported (and children whose parents reported) that they had never been diagnosed with asthma. The structured telephone interview was conducted in English or Spanish and consisted of closed-ended questions. Parents who participated also received a $20 gift card for completing the telephone interview, independent of whether they had returned the ACT to the MCO. We attempted to conduct telephone interviews with all eligible patients.During the pre-incentive phase, of 390 patients who were identified as having high asthma utilization, 262 were ineligible for our telephone interviews. Reasons for ineligibility were: we did not have an accurate phone number or address (n = 241); the family did not speak English (n = 10); the patient denied having asthma during the initial screen (n = 6); or a family member had previously enrolled in the study (n = 5). Of the 125 patients who were eligible for the study during the pre-incentive phase, 35 subjects completed the telephone interviews.During the incentive phase, of 752 patients who were identified as having high asthma utilization, 538 were ineligible. Reasons for ineligibility were: we did not have an accurate phone number or address (n = 378); the patient or family member was already enrolled in the study (n = 113); the patient did not speak English (n = 35); the patient denied having asthma during the interview screen (n = 10), or the patient was unable to complete the survey due to cognitive or physical limitations (n = 2). Of the 214 patients who were eligible for the study during the incentive phase, 60 completed telephone interviews.The scripted telephone interview lasted approximately 20 minutes. After obtaining informed consent, questions were asked about baseline demographics including age, sex, race/ethnicity, highest grade completed in school, annual family household income, and whether the patient or parent was employed outside the home. We also assessed asthma medication use in the previous 12 months and administered the ACT.In order to assess the processes of care potentially affected by the intervention, we interviewed a small subsample of our larger population. We assessed the frequency of patient contact with their asthma providers in response to information gleaned from the ACT. For those making contact, we assessed whether it was by telephone, in-person appointment, or whether the provider directly contacted the patient, or whether the provider asked the patient to make an appointment. For patients who had visits with their providers, we assessed whether the provider communicated that asthma control needed improvement, whether the provider recommended alternative or additional medications, discontinued a medication, or adjusted dosing of current medications.In order to assess patient self-efficacy and perceived asthma control, our telephone interview included five questions that were adapted by RAND Corporation from a previous study . We hypoWe chose four questions on patient or parental expectations for symptoms (or asthma control) from a reliable and valid 8-item measure developed by Yoos et al . Each quFor patients who had visits with their asthma providers, we inquired whether the providers reported that their asthma control needed improvement, recommended medication changes, gave or reviewed a written asthma management plan, or suggested other interventions.We evaluated differences between the pre-incentive and incentive groups in rates of asthma outpatient visits, hospitalizations, ED visits, controller medications, and rescue medication using the t-test for continuous variables, Wilcoxon rank-sum test for non-parametrically distributed continuous variables or ordinal variables, and chi-square test for categorical variables. Analyses were conducted in R .During the pre-incentive period, 1183 patients were identified as having problems with asthma control; 25 (2.0%) returned the ACT to the MCO. During the incentive period, 1612 patients were identified and 87 (5.4%) returned the ACT to the MCO (p < 0.0001). Of all 112 ACTs returned, 87% had a score of 19 or less, consistent with poor asthma control. We completed telephone interviews with a total of 95 patients. Thirteen patients had returned the ACT to the MCO. In addition, 15 patients stated during their telephone interviews that they had completed the ACT but had not mailed it back to the health plan. Thus, a total of 28 patients had completed the ACT either based on receipt by the health plan or by self-report; we compared this group with the 67 patients who said they had not completed the ACT. In our analysis of telephone interview data, we grouped patients by whether they completed vs. did not complete the ACT, instead of returned vs. did not return the ACT. We felt that even if patients completed the ACT and forgot to mail the ACT to the MCO, completion of the ACT could result in changes in process and outcomes of care. In addition, it was possible that ACTs of patients could have been lost in the mail. Table For our analyses, we compared patients who completed the ACT vs. patients who did not complete the ACT. We combined the patients who completed the ACT in the pre- and post-incentive phases in order to study our primary hypothesis that completion of the ACT would result in changes in processes and outcomes of asthma care. We hypothesized that adding a monetary incentive would increase completion of the ACT; however, we expected that completion of the ACT whether in the pre-incentive or incentive groups would result in similar changes in processes and outcomes of asthma care.2-agonists, inhaled corticosteroids, long acting beta2-agonists, or leukotriene inhibitors in the three months after the ACT was mailed. In addition, no differences were found in any of these outcomes between patients who were surveyed during the pre-incentive versus the incentive period.Based on claims data analyzed for the 95 patients interviewed, 79% of patients who completed the ACT and 80% of patients who did not complete the ACT had 1 or more outpatient visits for asthma in the three months after receiving the ACT (p = 0.91). There were no differences in rates of outpatient visit, hospitalizations and ED visits in the 3 months after mailing ACT between the two groups Table . FurtherCompletion of the ACT did not have an effect on whether the patient made contact with the provider, how the contact was made, and whether medication changes resulted from the contact Table . As showOur study has three key findings. First, mailing asthma self-assessment surveys to patients with poorly controlled asthma in a predominantly Medicaid-insured population showed no evidence of having improved their health care use and medication use patterns. Secondly, response rates to the self-assessment surveys were low, and adding a monetary incentive did not improve response rates in a way that would justify this intervention. Third, health plan administrative data can identify patients with current problematic asthma control.In this study's population, mailing the ACT to patients with poorly controlled asthma was not associated with better outcomes or processes of care. A previous study found that self-assessment of asthma control with the Asthma Therapy Assessment Questionnaire (ATAQ) resulted in reduced numbers of hospitalizations and ED visits in a large urban medical group practice  and anotOur response rate was very low, most likely because we were attempting to outreach to a predominantly Medicaid population. Response rates to mailed surveys in the Medicaid population have been estimated to range 25–35% ,28, but Our approach to identifying patients with poor asthma control based on computerized utilization data for medication fills and ED visits appears to be a valid method in a population of predominantly Medicaid enrollees. Of the patients who we were able to contact via our telephone survey, most had ACT scores suggesting poor asthma control. Thus, using computerized data has good potential to identify patients with poor asthma control for further intervention. Higher-intensity interventions, such as engaging their primary care physicians or case managers within the patient's practice, may be beneficial.Despite the strengths of this study, a few caveats deserve mention. First, the response rate to our survey (28% during the pre-incentive and incentive phases) was relatively low. Nevertheless, we were able to conduct enough interviews for our objective of conducting a process evaluation of the intervention as a way to gain insight of potential barriers. Our goal was to identify patterns of experience rather than provide a systematic snapshot of the entire population. Furthermore, our power to identify an intervention effect on asthma-related health care use was limited, but no trends were identified. Furthermore, our utilization outcomes were limited to the three months after the ACTs were mailed; thus the follow up time period was relatively brief. Nevertheless, the medication fills were also similar whether patients completed or did not complete the ACT. We would expect that if completion of the ACT led to any changes in health care utilization, medication fills would change within three months of the mailings. As with other surveys, the ACT is prone to recall bias, however, studies have demonstrated the validity and reliability of this measure . The seaMailing asthma self-assessment surveys to patients with poorly controlled asthma yielded low completion rates and showed no evidence of improving asthma health services use or processes of care. Although health plans have the ability to reliably identify patients with problematic asthma control, additional interventions are needed to improve care for low income, multiethnic populations.The authors declare that they have no competing interests.ACW participated in the design and coordination of the study, supervised acquisition of data and statistical analysis, helped interpret the data, and drafted the manuscript. JW participated in the design and coordination of the study, helped with interpretation of the data, and helped to draft the manuscript. CG participated in the design and coordination of the study, participated in acquisition of data, and helped draft the manuscript. TAL participated in the design and coordination of the study, supervised the statistical analysis, participated in interpretation of the data, and helped draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


In recent years, there has been an increasing attention to thyroid function in paediatric obese patients. In the present study we aimed 1) to determine the prevalence of abnormally elevated thyroid-stimulating hormone (TSH) levels in Italian obese children and adolescents 2) to investigate whether hyperthyrotropinemia in obese children cardiovascular and metabolic risk factors 3) to verify if TSH elevation is reversible after weight loss.We examined 938 obese children and adolescents . Anthropometric, metabolic and hormonal variables were determined at baseline and, in a subgroup of children with hyperthyrotropinemia, after a six month weight loss program.Hyperthyrotropinemia (TSH ≥4.2 μUI/ml) was diagnosed in 120 patients . Body mass index (BMI) z-score (p = 0.02) and free T3 (fT3) levels (p = 0.03) were higher in patients with elevated TSH compared to the group with normal TSH. There were not significant differences in other metabolic parameters between the two groups.A positive correlation between baseline TSH and BMI z-score (p = 0.0045) and between Ft3 and BMI z-score (p = 0.0034) was observed, while there was no correlation between TSH and lipids. Twenty-three patients among those with hyperthyrotropinemia who participated to weight reduction intervention (64 patients), presented substantial weight loss and concomitantly a significant decrease in TSH and in fT3.These results suggest that: (1) a moderate elevation of TSH concentrations, is frequently found in obese children; (2) in obese children increase of TSH is not associated to metabolic risk factors, (3) hyperthyrotropinemia is reversible after weight loss and these data suggest that it should not be treated. Obesity is considered a worldwide health problem and its prevalence is increasing steadily and dramatically all over the world . PaediatIn recent years, there has been an increasing attention to thyroid function in paediatric obese patients . HypothyIn order to achieve a better understanding of this issue we aimed 1) to determine the prevalence of hyperthyrotropinemia in obese children and adolescents 2) to investigate whether hyperthyrotropinemia in childhood obesity is related to dyslipidemia and/or other metabolic complications 3) to verify whether hyperthyrotropinemia may reverse after weight loss program. Our series is the largest published till now.We examined 1010 children and adolescents, referred to our ward  for obesity between 1999 and 2008. Subjects with known presence of diabetes or using medications altering blood pressure, glucose or lipid metabolism, with goitre or known thyroid disease were excluded . The ethical committee of the Second University of Study of Naples approved the study. Informed consent was obtained by parents and, where appropriate, by children.th percentile for age and sex using the definition of the International Task Force for Obesity in Childhood and the charts for Italian population  .Thyroid hormones  and TPO-Ab and Tg-Ab were determined by high-specific solid-phase technique-chemiluminescenceimmunoassays .In a subgroup of 160 children we measured leptin plasma levels using double-antibody radioimmunoassay . The sensitivity cut-off for the leptin assay was 0.5 ng/ml; the intra and inter-assay variation coefficients were 10.8% and 7%, respectively.TPO-Ab and Tg-Ab levels higher than 60 UI/ml were considered positive, and autoimmune thyroiditis was diagnosed.th for our assay), with normal fT3 and fT4 and no signs or symptoms of hypothyroidism.Isolated hyperthyrotropinemia was diagnosed when TSH was higher than 4.2 μUI/ml  self-selected diet of common foods . All subjects underwent a lifestyle modification program. They followed a program based on physical exercise, and behavioral therapy, including individual psychological care of the child and his or her family. Thyroid hormones and lipids were reassessed after 6 months of the weight reduction program in patients with elevated TSH levels. Weight reduction was considered as at least a 0.5 decrease in BMI z-score .2 test.All values are expressed as mean ± SD. Skewness and kurtosis tests were used to evaluate the normal distribution of the variables. The significance of changes in discrete variables was analyzed by the XMean differences were analyzed with one-way ANOVA for variables with a normal distribution, and with the Kruskal-walis test for variables with non Gaussian distribution. Obese children with isolated hyperthyrotropinemia, were compared to the obese children with normal TSH concentrations with respect to peripheral hormones, lipids, HOMA-index, blood pressure and anthropometric measures, and in a subgroup to leptin.In the patients with hyperthyrotropinemia independent samples t-test for normal distribution and Mann-Whitney test for parameters with non-Gaussian distribution were used to compare the changes in the outcome variables between the group with decrease in BMI z-score >0.5 point, the one with decrease in BMI z-score between 0.2 and 0.5 points and the group with no changes in BMI z-score.Linear regression model has been performed to investigate the correlation between TSH and BMI z-score, waist, lipids, blood pressure and HOMA index (and leptin in the subgroup in which it was tested).Multiple linear regression analyses with lipids or blood pressure as dependent variables and age, gender, degree of overweight (BMI z-score) pubertal stage, HOMA index, and thyroid hormones as independent variables were performed.P < 0.05 was considered statistically significant. Stat-Graph 3.0 software for Windows was used for the statistical analysis.Gender and pubertal stage were used as classified variables. A The anthropometric and biochemical characteristics of patients are shown in Table Other 60 subjects had positive auto-antibodies, 8 of which with subclinical hypothyroidism, and were all excluded from the analysis; in total 72 patients (7%) had autoimmune thyroiditis confirmed by ultrasonography.Isolated hypethyrotropinemia (TSH≥4.2 μU/l) was diagnosed in 120 patients (62 girls) of the remaining 938 patients enrolled , 70% were prepubertal. There were no significant differences by sex and pubertal stage (p = 0.2 and p = 0.4 respectively) compared to those with normal TSH levels.Obese children with and without hyperthyrotropinemia had fT3 and fT4 concentrations within the normal range and did not differ significantly in their fT4, lipid concentrations, HOMA values and blood pressure compared to those with TSH in the normal range Table . All anaBMI z-score  and fT3 levels were significantly higher (p:0.03) in patients with elevated TSH, while their age was significantly lower .In all the 938 patients enrolled a positive correlation between baseline TSH and BMI z-score (p = 0.0045) and between Ft3 and BMI z-score (p = 0.0034), adjusted for age, gender and pubertal stage, was observed.In a multiple regression analysis adjusted for age, gender, pubertal age, degree of overweight and HOMA, there was no significant correlation between TSH and HDL , triglycerides , blood pressure  as well as between fT3 and HDL , triglycerides , blood pressure  as well as between fT4 and all the mentioned parameters.In a subgroup (160 patients), randomly selected, we measured plasma leptin. Among this subgroup 22 patients had isolated TSH elevation and their leptin levels were not different from those with normal TSH, adjusting for BMI z-score. Moreover in all 160 patients we did not find any correlation between leptin and TSH, also adjusting for gender, pubertal stage and degree of overweight (data not shown).A total of 64 patients with elevated TSH levels completed (53%) the weight reduction intervention. No difference in the baseline characteristics were found between patients who dropped out and those who did not. Among these 64 patients, 23 patients presented a substantial weight loss, defined as a decrease at least in 0.5 points of their BMI z-score . Twenty-Compared to their baseline parameters, patients who lost substantially weight presented a statistically significant decrease in TSH and in fT3 and improvement in lipid profile; such improvement did not significantly correlate to thyroid hormones after adjusting for changes in BMI , ,5-7,17; Thyroiditis appears to occur frequently in our sample of obese subjects (7%) compared to the reported prevalence of 1.2% in normal weight children . This coThe reason of the increase of TSH in obese subjects, both adults and children, is not clear.Patients with higher levels of TSH had a lower mean age, but the trend of TSH to decrease with age is well known and described . FurtherWe found a direct correlation between TSH and BMI-z-score and between fT3 and BMI-z-score; this relationship could suggest an association with leptin, which is regulated by body adiposity . FurtherIn some studies subclinical hypothyroidism has been shown to worsen metabolic profile, causing dyslipidemia or heart dysfunction ,30. HoweObese children are at increased metabolic risk, because they can present insulin resistance, hypertension or dyslipidemia .We show that obese children with isolated elevation of TSH do not have an increase in their metabolic risk factors and demonstrate no significant relationship between TSH levels and lipids, blood pressure and insulin resistance.These findings are in agreement with some other studies in adults and children ,31.After substantial weight reduction, TSH and fT3 lower significantly and normalize, in accordance with a previous study by Reinehr and in contrast with a recent study by Shalitin et al ,7. SlighObese patients have with hyperthyrotropinemia have fT3 levels significantly higher compared to obese children with normal TSH levels. This finding confirms the theory that the negative feedback between TSH and the peripheral hormones is decreased. Furthermore, fT3 levels diminish after weight loss. These findings can suggest another observation about pathogenesis. Thyroid hormones, especially fT3, regulate the resting energy expenditure (REE). In obese patients the moderate increase in fT3 and TSH lead to an increase of energy expenditure. As a consequence of this, the availability of accumulated energy for conversion into fat is diminished . The altIf this hypothesis is true, the possibility exists that, as weight loss is associated with a decrease of TSH and fT3, the resulting decrease in REE may contribute towards the difficulties of obese children in maintaining weight loss .In summary, a moderate elevation of TSH concentration is frequently found in obese children and is not associated to increased metabolic risk.This condition seems rather a consequence than a cause of obesity since weight loss leads to a normalization of elevated thyroid hormone levels.There is diffuse disagreement about the management of hyperthyrotropinemia both in adults and children. In particular we lack of large studies that demonstrate advantages to treat children showing TSH between 5 and 10 μU/ml .Considering our results we suggest that obese children with this condition should not be treated under the "diagnosis" of subclinical hypothyroidism because TSH alteration is more a consequence than a cause of obesity.(Tg-Ab): anti-tyreoglobulin anti-bodies; (TPO-Ab): anti-peroxidase anti-bodies; BMI: (body mass index); DPB: (diastolic blood pressure); (fT3): free T3; (fT4): free T4; (HDL): high density lipoprotein; HOMA: (homeostasis model assessment); (REE): resting energy expenditure; SBP: (systolic blood pressure); SD: (standard deviation); (TSH): thyroid-stimulating hormone.The authors declare that they have no competing interests.AG conceived of the study, participated in the design of the study and performed the statistical analysis. NS participated in the development of the protocol and analytic framework for the study, and contributed to the writing of the manuscript. FC participated in the development of the protocol, recruited patients and was responsible of clinical assessment of patients. PC was responsible for cardiovascular and leptin assessment. LP and EMDG supervised the design and execution of the study, performed the final data analyses, and contributed to the writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/10/8/prepub


Budesonide/formoterol is an effective treatment for both asthma and chronic obstructive pulmonary disease. This study compared the efficacy and safety of a novel hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI) formulation of budesonide/formoterol with that of budesonide pMDI and budesonide/formoterol dry-powder inhaler .This was a 12-week, multinational, randomised, double-blind, double-dummy study involving patients aged ≥ 12 years with asthma. All patients had a forced expiratory volume in 1 s of 50–90% predicted normal and were inadequately controlled on inhaled corticosteroids (500–1600 mu g/day) alone. Following a 2-week run-in, during which they received their usual medication, patients were randomised  to budesonide pMDI 200 mu g, budesonide/formoterol DPI 160/4.5 mu g or budesonide/formoterol pMDI 160/4.5 mu g. The primary efficacy end-point was change from baseline in morning peak expiratory flow (PEF).In total, 680 patients were randomised, of whom 668 were included in the primary analysis. Therapeutically equivalent increases in morning PEF were observed with budesonide/formoterol pMDI (29.3 l/min) and budesonide/formoterol DPI (32.0 l/min) . The increase in morning PEF with budesonide/formoterol pMDI was significantly higher than with budesonide pMDI . Similar improvements with budesonide/formoterol pMDI vs. budesonide pMDI were seen for all secondary efficacy end-points. Both combination treatments were similarly well tolerated.Budesonide/formoterol, administered via the HFA pMDI or DPI, is an effective and well-tolerated treatment for adult and adolescent patients with asthma, with both devices being therapeutically equivalent. The efficacy and safety of budesonide/formoterol administered via dry powder inhaler (DPI) are well established. However, pressurised metered-dose inhalers (pMDIs), the most commonly used inhalation devices in many countries worldwide, are currently being developed with hydrofluoroalkane (HFA)-based propellants to avoid the well-known ozone-depleting effects of chlorofluorocarbon propellants. Accordingly, budesonide/formoterol has also been reformulated as an HFA pMDI .The present study demonstrates that budesonide/formoterol administered via the novel HFA pMDI is an effective and well-tolerated treatment for adults and adolescents, and is therapeutically equivalent to budesonide/formoterol delivered via a DPI. These data provide further understanding of the use of the different budesonide/formoterol devices, and ultimately, will help provide clinicians and patients with greater freedom to select a delivery system that meets their needs and preferences.2-agonist (LABA) therapies are the recommended maintenance treatment option for adults with persistent asthma /long-acting bgr t asthma . One suct asthma .2-agonist (SABA) reliever medications, such as salbutamol  are the most commonly used inhalation devices in many countries worldwide . The majThe aim of this study was to compare the efficacy and safety of the new pMDI formulation of budesonide/formoterol with that of budesonide/formoterol DPI and budesonide  pMDI in adults and adolescents with asthma.1) ≥ 50% and ≤ 90% of predicted normal (prebronchodilator), reversibility of ≥ 12% FEV1 after inhalation of terbutaline 1 mg  and a history of daily ICS use (stable dose of 500–1600 mu g/day within 30 days prior to enrolment) for ≥ 3 months.Adult and adolescent outpatients (aged ≥ 12 years) with asthma  for ≥ 6 Before randomisation, all patients had to have a total asthma symptom score ≥ 1 on ≥ 4 of the last 7 days of run-in . The first patient was enrolled on 30th April 2002 and the last patient completed the study on 6th February 2003.This was a 12-week, phase III, randomised, double-blind, double-dummy, parallel-group study conducted in 62 centres across eight countries . The study complied with Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. An independent ethics committee or institutional review board approved the study protocol and patient consent form at each centre.2-agonists other than study reliever and reversibility test medication were not permitted.Patients were instructed to stop taking their LABA therapy for 3 days prior to the beginning of the run-in period (visit 1). Also, those using an ICS/LABA combination were requested to stop treatment with the combination 3 days before visit 1 and to continue with the same ICS alone. SABA use was restricted at 6 h prior to visit 1. During the study period [run-in and treatment period (visits 1–5)] any bgr Following a 10- to 14-day run-in, during which patients continued their prestudy ICS medication (stable dose), patients were randomised to treatment  with one of the following: budesonide pMDI 200 mu g (Pulmicort® pMDI); budesonide/formoterol DPI 160/4.5 mu g ; or budesonide/formoterol pMDI 160/4.5 mu g . The doses of budesonide in each group were comparable; differences are explained by labelling changes for new inhaled drugs that require the delivered dose to be reported rather than the metered dose.Patients were randomised sequentially in blocks of six using a computer-generated randomisation schedule. Eligible patients were consecutively allocated the lowest available randomisation code. The treatment code was only broken in the case of medical emergencies. The randomisation schedule was computer generated at AstraZeneca Research and Development, Charnwood, UK. To maintain blinding, each patient also received a placebo device. To reduce inconvenience, each patient received only two of the three devices: one active and one placebo device. An inhaled SABA  was available for all patients for symptom relief.The primary efficacy end-point was the change in morning peak expiratory flow (PEF) from baseline (mean of the last 10 days of run-in) to the mean value over the 12-week treatment period. Secondary efficacy end-points included: change from baseline (mean of the last 10 days of run-in) to the mean value over the treatment period in evening PEF; reliever medication use; reliever medication-free days; nighttime awakenings caused by asthma; asthma symptom score; symptom-free days (a night and day without asthma symptoms and no nighttime awakenings caused by asthma); and asthma-control days (a night and day without asthma symptoms or reliever medication use and no nighttime awakenings caused by asthma). All PEF measurements [taken prior to inhalation of study medication using a Mini-Wright® peak flow meter ], reliever medication use, nighttime awakenings caused by asthma and asthma symptom scores were recorded by patients in a daily diary.1 and change from baseline (week 0) to the end of treatment (week 12) in Asthma Quality of Life Questionnaire (standardised version) [AQLQ(S)] scores  to the mean of the treatment period (weeks 2–12) in FEV] scores  were alsndations , 25. Thendations . A changndations .Safety assessments included adverse events (assessed throughout), vital signs  and clinical laboratory parameters .All patients received instruction on how to use the pMDI and DPI devices and the peak flow metre before the start of the study at visit 1. Each participating study site was provided with a Turbuhaler/pMDI to be used with disposable mouthpieces/actuators, allowing patients to practise the inhalation technique.t-test with a 5% two-sided significance level).The intent-to-treat (ITT) population  was used for the main efficacy analyses. The primary objective of the study was to show that budesonide/formoterol pMDI was more efficacious than budesonide pMDI. The study was powered on this primary objective and approximately 600 evaluable patients (200 in each arm) were required for a 90% probability of detecting a true difference between budesonide/formoterol pMDI and budesonide pMDI of 13 l/min in mean change in morning PEF, assuming a standard deviation of 40 l/min  for the mean difference in morning PEF was within the prespecified equivalence limits of −15 and +15 l/min, as described previously . Assumin1 and AQLQ(S) were also analysed using an ANOVA model with treatment and country as fixed factors and the randomisation value as a covariate. Safety variables were analysed using descriptive statistics.Diary-card end-points, averaged over available data, were analysed using a validated analysis of variance (ANOVA) model with treatment and country as fixed factors and the run-in mean (last 10 days) as a covariate. FEVA total of 892 patients were enrolled and 680 were subsequently randomised to study treatment . The ITT and safety populations comprised 679 patients (one patient in the budesonide/formoterol pMDI group was lost to follow-up). For the primary analysis, 216, 223 and 229 patients in the budesonide pMDI, budesonide/formoterol DPI and budesonide/formoterol pMDI groups, respectively, had morning PEF data from both the run-in and the treatment period. Six hundred patients completed the study; discontinuations were comparable between the three treatment groups .Patients’ demographics and baseline characteristics were well balanced across the three treatment groups . In totaBudesonide/formoterol DPI and budesonide/formoterol pMDI improved morning PEF compared with budesonide pMDI (p < 0.001 for both) . Followi1 compared with budesonide pMDI  discontinued the study because of adverse events. The most frequently reported adverse event causing discontinuation was asthma aggravated . Other adverse events leading to discontinuation included nausea, tremor, palpitations and lower respiratory tract infection.Budesonide/formoterol, which is available as a DPI, has been reformulated as an HFA pMDI to enable delivery of this effective and well-tolerated therapy via two different devices that meet the needs and requirements of both patients and clinicians alike without detriment to the environment. This large-scale, international, double-blind, double-dummy study set out to compare the efficacy and safety of this novel pMDI formulation of budesonide/formoterol with that of the established DPI, budesonide/formoterol Turbuhaler®, and budesonide pMDI in adults and adolescents with inadequately controlled asthma.Analysis of the primary end-point – morning PEF – demonstrated that both budesonide/formoterol therapies are more effective than budesonide pMDI. The magnitude of improvement in morning PEF with both budesonide/formoterol therapies was within the range of that reported previously for budesonide/formoterol DPI , 28, 29,Analysis of other efficacy end-points relating to lung function, asthma symptoms, disease control and health-related quality of life supports the comparable efficacy of budesonide/formoterol pMDI with budesonide/formoterol DPI and the superiority of both formulations over budesonide pMDI. The only statistical differences between the two devices – which favoured budesonide/formoterol DPI – were in the composite end-points: symptom-free days and asthma-control days. In both cases, differences were driven by the additional improvement in daytime total asthma symptom score (data not shown). Previous studies report that the degree of lung deposition for the DPI device is approximately 2–3 times that of the corresponding pMDI device –32 and hIn the clinical setting, choice of inhaler device is less likely to depend on efficacy and tolerability and is more likely to be influenced by other factors, for example cost, the patient's ability to use the selected device correctly and personal preference . DPI devIn terms of safety, budesonide/formoterol pMDI, budesonide/formoterol DPI and budesonide pMDI were well tolerated, with a low overall incidence of adverse events across the three treatment groups. Adverse events were slightly more common in the budesonide pMDI group – although this was not thought to be clinically relevant – and the majority of patients who reported aggravated asthma as an adverse event were in this treatment group. Importantly, the tolerability profiles of both budesonide/formoterol therapies were similar to that reported previously for budesonide/formoterol DPI .In conclusion, this study demonstrates that budesonide/formoterol, administered via the HFA pMDI or DPI, is an effective and well-tolerated treatment for adult and adolescent patients with asthma, with both devices being therapeutically equivalent. The availability of both devices will give clinicians greater freedom to select a cost-effective therapy that suits the needs and preferences of individual patients and clinicians themselves.


Measurements were also made on an age- and sex-matched group of healthy controls (HC). In each case data were recorded for 30 min. In HC, the difference in absolute spectral amplitude of LDF oscillations between the two vasodilators manifests in the frequency interval 0.005–0.0095 Hz (p < 0.01); this difference is initially absent in patients with CHF, but appears following the β1-blocker treatment (p < 0.01). For HC, the difference between the two vasodilators also manifests in normalised spectral amplitude in 0.0095–0.021 Hz (p < 0.05). This latter difference is absent in CHF patients and is unchanged by treatment with β1-blockers. It is concluded that there are two oscillatory skin blood flow components associated with endothelial function. Both are reduced in CHF. Activity in the lower frequency interval is restored by β1-blocker treatment, confirming the association between CHF and endothelial dysfunction but suggesting the involvement of two distinct mechanisms.Laser Doppler flowmetry (LDF) of forearm skin blood flow, combined with iontophoretically-administered acetylcholine and sodium nitroprusside and wavelet spectral analysis, was used for noninvasive evaluation of endothelial function in 17 patients newly diagnosed with New York Heart Association class II–III congestive heart failure (CHF). After 20 ± 10 weeks' treatment with a β Congestive heart failure (CHF) is a complex clinical condition, in which the history of its management reflects the evolving understanding of its pathophysiology. CHF is associated with a typical neurohormonal response involving activation of both the renin–angiotensin system and the sympathetic nervous system. This activation is deleterious and current therapeutic strategies to block the effects of this activation e.g. with angiotensin converting enzyme inhibitors  and β-adThe endothelium plays a pivotal role in regulating blood flow by releasing relaxing and constricting factors, a role that has been shown to be impaired in CHF . One of Various techniques are available to evaluate endothelial function, including brachial arterial imaging , or pletdynamics  are coupled to the cardiac rhythm. Unlike many earlier studies, our interest therefore centres on blood flow dynamics , rather dynamics  and postdynamics . It was Patients for the CHF group were recruited either from cardiology clinics in the Royal Lancaster Infirmary or from patients referred directly for open access echocardiography. None of them exhibited significant edema. The severity of heart failure was established via echocardiography. Left ventricular diameter and left ventricular ejection fraction (LVEF) were determined. Inclusion criteria were that they had LVEF < 35% and symptoms between class II–III of the New York Heart Association (NYHA) classification. Exclusion criteria were recent myocardial infarction, or cerebrovascular accident (within 6 months), fibrillation, other life threatening co-morbidity, advanced frailty, current use of β-blocking drugs, or contra-indications to β-blocker therapy. All but one CHF patients remained on established treatment with angiotensin converting enzyme inhibitors and diuretics throughout the study; the exception was on an angiotensin-receptor antagonist and diuretics.1-antagonist). This was commenced in a dose of 1.25 mg under direct observation, and then increased, at intervals of a minimum of 1 week, through 2.5 mg, 3.75 mg and 5 mg. Finally it was increased at intervals of a minimum of 4 weeks from 7.5 mg to 10 mg. Upwards titration was stopped if symptomatic hypotension, or pulse rate < 50/min, or side-effects of the β-blocker, appeared. A second set of measurements was taken after 5 weeks of a stable dose (β-CHF subject group) and 20 ± 10 weeks after the first set of measurements. LVEF and NYHA were determined only before treatment. Patients' data are summarized in After the initial set of measurements all CHF patients were then treated with Bisoprolol  and sex (8 F and 13 M) matched control subjects were recruited from the local community. None of them was on medication or had a history of cardiovascular disease or problems related to the cardiovascular system, including hypertension or hypercholesterolemia. A single set of measurements, identical to that recorded for CHF patients, was taken from each of them.All participants gave their informed consent in writing. The investigation conformed with the principles outlined in the Declaration of Helsinki and was approved by the Local Ethics Committee of the Morecambe Bay Hospitals Trust.Subjects lay supine on a bed and relaxed for 15 min prior to the commencement of recording. Peripheral blood flow, heart rate, respiration, and skin temperature were simultaneously recorded for 30 min, based respectively on laser Doppler flowmetry (LDF), a conventional 3-lead ECG, a Biopac respiratory effort transducer placed around the thorax, and Thermilinear temperature sensors  placed on the arm and leg. The ECG, respiration and temperature signals were amplified using a specially designed signal conditioning unit . Signals were digitized at 400 Hz with 16-bit resolution by use of a National Instruments PCI-6035E A/D converter, and stored in a personal computer. The temperature of the room was maintained at 21 ± 2 °C.Skin blood flow signals were measured by the laser Doppler perfusion technique using a DRT4 LDF monitor . Two MPI–V2 probes were mounted within MIC1–IONlr chambers, where the vasoactive substances were inserted for iontophoretic administration in the same area as that where the blood flow was being recorded. Measurements were made on the volar aspect of the right forearm, choosing areas of skin that were free from blemishes. Both probes were positioned in areas with similar vasculature and without larger vessels in their vicinity. For each set of measurements the two chambers were placed 2 cm apart with random relative orientation. Near-infra-red light (wavelength 780 nm) was delivered to the probes via a nearly loss-free optical fibre. The back-scattered light was collected and returned to the monitor via another optical fibre, where it was converted to an analogue electrical signal. The cut-off frequency of the low-pass filter was 22.5 kHz, and an output time constant of 0.1 s was selected. The LDF probes were calibrated against a flux standard (Moor Instruments) and the blood flow was expressed in arbitrary units (AU).Two vasodilators were iontophoretically applied: ACh whose action is endothelium-dependent, and SNP an endothelium-independent direct NO donor. The difference in the blood flow enhancements that they produce in any oscillatory component is related to the responsiveness of the vascular endothelium . The 1% The time averages of the signals from the LDF probes were calculated, and the signals were then resampled at 10 Hz using a moving average technique. Trends were removed by giving the moving average a window length of 200 s, thereby eliminating frequencies below 0.005 Hz. Following this pre-processing, the wavelet transform (using the Morlet mother wavelet ) was comComputation of the wavelet transform of the blood flow signal yields the usual 3-dimensional structure above the time–frequency plane, exhibiting clearly resolved spectral peaks whose positions vary in time  as shownThese six spectral peaks have recently been confirmed in an independent study  based onFor convenience, the frequency intervals are labeled I–VI as specified in Two measures are used to quantify the contribution of the oscillations to the total blood flow: their absolute and normalised spectral amplitude. The word ‘spectral’ indicates they are both calculated from the coefficients of the wavelet transform. Absolute spectral amplitude is the mean value of the wavelet transform, and was calculated separately within each frequency interval. Absolute spectral amplitude over the whole frequency range from 0.005 to 2 Hz was also calculated. To differentiate it from absolute amplitudes within specific intervals, it was introduced as average spectral amplitude. The normalised spectral amplitudes are calculated from the absolute spectral amplitudes and are defined as the ratio between the absolute spectral amplitude within a given subinterval and the average spectral amplitude.R-peaks in ECG signals were automatically detected and manually checked, and the corresponding instantaneous heart rate (IHR) time series was generated, composed of inverse values of R–R periods. The mean heart rate (HR) for each subject was then obtained as a time-average of the IHR signal and the heart rate variability was defined as its standard deviation. In addition, maximal values in the respiration signals were automatically detected, manually checked, and analysed in a similar manner to yield the instantaneous respiration frequency (IRF) time series. The mean respiratory frequency (RF) was obtained as a time-average of IRF and the respiratory frequency (RF) variability was introduced as the standard deviation of IRF.The analysis was blinded, in that the relevant researcher had no connection with the experiments, but simply analyzed the anonymized time-series data with which he was provided.t-tests were used, a nonpaired one in comparing patients with controls and a paired one between patient groups. Paired and nonpaired Wilcoxon tests were used to produce the statistics in A nonpaired, nonparametric, Wilcoxon rank sum test was used to obtain the probability that two group distributions were equal .In all hypothesis tests a value of The demographic data in 1-blockers resulted in a significant reduction in both systolic and diastolic blood pressure. The systolic pressure decreased from 141 ± 16 to 124 ± 18 mm Hg (p = 0.003). The diastolic pressure decreased from 77 ± 12 to 62 ± 10 mm Hg (p = 0.002).Treatment with βp = 0.0003). Although HR variability is not relevant to the main findings of this study, we noted that it decreased very slightly, mainly on account of less ectopy. For the group, the number of ectopic beats dropped from 4.1 to 1.2 per minute. With ectopics included, HR variability was significantly greater in the CHF group than in the HCs; when the analysis was repeated with the extra-systoles removed (as shown), there was no significant difference between HR variability in the HC and CHF groups.The heart rate decreased significantly from 1.31 ± 0.27 to 0.95 ± 0.15 Hz . The change is smaller than the variation between individual patients and is statistically insignificant.There was a small decrease in patients' skin temperature as a result of the βEffect of ACh and SNP on mean value of the LDF signal and average spectral amplitude: a comparison of the HC and CHF groups' responses to ACh and SNP is presented in Effect of ACh and SNP on oscillatory flow components: In more detail, there is a distinction between the CHF and HC groups in their absolute spectral amplitudes in interval VI, which is significant in response to ACh a but notThe effect of Bisoprolol was evaluated in two different ways. First, the responses to ACh before and after the treatment were compared. Similarly, the comparison of responses to SNP before and after the treatment was performed. After treatment the response to ACh was slightly increased for each oscillatory component, but the increase was not statistically significant. The response to SNP did not change in any of the intervals.Secondly, the responses to ACh and SNP were compared. The comparison was performed before the treatment and after the treatment as well as for the HC group. A significant difference between the responses to the two substances was found only within the lowest two frequency intervals and this is shown in The figure compares absolute and normalized spectral amplitudes in response to ACh and SNP for all three subject groups. Parts (a) and (d) illustrate the differences in response to ACh and SNP in the HC group. The difference in normalized amplitude in interval V has been demonstrated in several earlier studies . Note th1-blockers, however, the CHF-β group exhibits differences in response to ACh and SNP in interval VI that are statistically significant, both in the absolute (6c) and in the normalised spectral amplitude (6f). The differences in response to ACh and SNP in interval V seen in the HC group are not, however, restored by the β1-blocker treatment.Parts (b) and (e) of 1 antagonist, partially reverses the endothelial dysfunction that is found in patients with CHF. Whilst the mechanisms for the improvement in endothelial function are not explored in the present study the differences between intervals V and VI help to shed some light on the complex effects seen at the level of endothelial regulation. The changes in CHF as compared to healthy controls, and the effect of β1-blockers on endothelial function in CHF patients, are now discussed.The major findings in this study are that patients with CHF have significant abnormalities in endothelial function compared with healthy controls, and that treatment with Bisoprolol, a selective βThe fact that the oscillatory amplitudes in intervals V and VI are differentially affected by ACh and SNP demonstrates that activity in both intervals is associated with the endothelium. This finding was first reported in the work by The reason for using iontophoresis for our administration of ACh and SNP was twofold. First, a comparison of responses to endothelium-dependent and endothelium-independent vasodilation provides a measure of endothelial activity. Secondly, vasodilator substances will, by mechanism of their action increase the mean value of the flow as well as all the oscillatory components. This is especially important in facilitating measurements of the low frequency oscillations which make a relatively low contribution to the flow in terms of energy.Detailed information about the oscillations in these two intervals and their origin can be found in the The results in The differing responses of the CHF and CHF-β groups  found inIn detail, the lack of ACh/SNP differentiation for CHF in interval VI can be explained by the fact that the response to ACh is significantly decreased in CHF compared to HC a while t1-blockers in CHF is still not wholly understood. Likely mechanisms involve reduction in sympathetic tone, increase in vagal tone, reduction of subendocardial ischaemia, reduction in rennin and endothelin release, increasing norepinephrine re-uptake, and reducing inflammatory cytokines (The mechanism of action of βytokines . It has ytokines . Whether1-blockers operate in many different ways, and it has yet to be determined which of them is/are responsible for the observed changes in low frequency blood flow spectra.We note that βWhat the present study has shown is that CHF patients exhibit blood flow abnormalities in frequency interval VI, that iontophoresis and wavelet analysis enable this abnormality to be detected, and that the medication partially restores normal function.As with all clinical studies involving patient follow up over time, it was not feasible to accommodate for the effects of disease progression. In addition all patients were on medication at the commencement of the study, and alteration of doses of other drugs e.g. diuretics was sometimes necessary at the discretion of the prescribing physician.The study was not performed in a placebo-controlled fashion because it would have been ethically unacceptable to withhold a life-prolonging treatment from 50% of the patients for 12 weeks.The main reason for the introduction of normalised spectral amplitudes is to reduce the inter-subject variability seen in the case of absolute amplitudes. However, an effect on normalised amplitude within a specific interval can then result from changes in the rest of the spectrum, not only from changes in the interval under consideration. For this reason special care should be taken when interpreting normalised data. In the present study, the main findings are based on comparison of responses to ACh and SNP within frequency intervals V and VI . AverageThe main conclusion is that, compared to healthy controls, CHF patients exhibit abnormally attenuated blood flow oscillations in frequency intervals V and VI, which represent different aspects of endothelial function. Treatment with Bisoprolol shifts the abnormality in spectral amplitude back towards the findings in healthy controls.1-blocker Bisoprolol moves the spectral amplitude of interval VI closer to that of the healthy controls. However, given that no significant change of activity in interval V is detected as a result of the treatment, whereas a highly significant change is observed in interval VI, it can be inferred that the effects of Bisoprolol on the endothelium are at least partly mediated through a non-NO mechanism.In more detail, iontophoretic administration of the endothelium-dependent and endothelium-independent vasodilators ACh and SNP has confirmed that the low-frequency spectral peaks in intervals V and VI of the LDF blood flow signal are associated with endothelial reactivity. Both peaks are significantly attenuated in patients with CHF. These spectral peaks are respectively governed by NO, and an as yet unknown factor. Treatment of CHF patients with the β


Repaired coarctation of the aorta is associated with premature atherosclerosis and an increased risk of cardiovascular events even in normotensive subjects. To date clinical risk stratification has focused on brachial blood pressures ignoring the complex pulsatility of the aortic wave form. The aim of this study was to assess components of this pulsatility in a clinical setting and to suggest possible techniques to improve risk stratification.This was a prospective study recruiting patients from a tertiary referral centre. Pulse wave morphology was assessed using applanation tonometry. B-mode ultrasound and cardiac magnetic resonance were used to assess carotid intimal–medial thickness and left ventricular mass.p = 0.0008) and central (34.5 mmHg (7.7) vs. 28.7 mmHg (4.7), p = 0.005) pulse pressures were elevated in the coarctation patients compared to controls. The reflected pressure wave returned to the ascending aorta earlier in the coarctation group (p = 0.007) and the tension time index (TTI) was increased (p = 0.03). The sub-endocardial viability index (SVI) was reduced in the coarctation subjects (159 (33) vs. 186 (31)%; p = 0.009) but there was no differences in central augmentation index (p = 0.35).Forty-six subjects with repaired coarctation of the aorta  and 20 matched controls were studied. Baseline brachial systolic and diastolic blood pressures were not statistically different between the 2 groups. Peripheral (62.5 mmHg (11.3) vs. 50.6 mmHg (15.0), This study demonstrates that there are patients with repaired coarctation who have an excellent mid-term outcome free from ventricular hypertrophy, carotid intima medial thickening and with relatively preserved vascular reactivity. However even in this “best outcome” cohort there were abnormal vascular characteristics that may predispose to increased cardiovascular risk. Simple non-invasive investigations can more extensively characterise these sub-clinical abnormalities and by utilised in long-term surveillance. What was previously perceived to be a simple localised abnormality of the descending aorta is now acknowledged to be a more complex lesion with life-long sequelae Despite this knowledge little has changed regarding the care of this patient group in adulthood. Late management remains “reactive” and there is only a patchy understanding of effective primary prevention. The foundation of long-term follow-up remains the assessment of baseline blood pressure in an outpatient or practice setting. Such measurements may however be a poor surrogate for the complex pulsatile nature of the aortic blood pressure which results from the interplay of vessel wall characteristics, flow dynamics and ventricular function The aim of this study was to assess a group of well and asymptomatic patients with repaired coarctation. The study endeavoured to apply simple non-invasive tests to assess if more detailed risk stratification could be performed in a manner applicable to routine clinical practise.22.1Adults with repaired coarctation were recruited prospectively from the Adult Congenital Heart Clinic at the Royal Brompton Hospital, London. Exclusion criteria included pregnancy, known systemic hypertension, other hemodynamically significant cardiac lesions, previous complex congenital heart disease, recoarctation awaiting intervention and the current use of vasoactive medication. A corresponding matched cohort of control subjects was recruited from hospital staff. The study protocol was approved by the institution's ethics committee.Patients were studied in a fasting state. Bloods were taken for routine biochemistry including serum lipids and blood glucose. A brief self-reported questionnaire assessed smoking habits and family history. Clinical examination was performed including three measurements of resting supine blood pressure in each limb using an automated calibrated blood pressure monitor .2.2Peripheral pressure waveforms were recorded from the right radial artery using applanation tonometry  The area under the systolic portion of the pressure waveform (tension time index — TTI) and the diastolic pressure–time integral (DPTI) were also determined. From these variables DPTI divided by TTI was calculated. This is a ratio between the diastolic portion of the aortic blood pressure waveform and the systolic component. This description of the perfusion pressure of the coronary arterial bed during diastole versus the systolic pressure load seen by the left ventricle is thought to be a marker of work-supply balance  Endothelial-dependent and independent vascular function was assessed using inhaled salbutamol (400 mcg) and sublingual glyceryl trinitrate (250 mcg) challenges 2.3Carotid scans were performed using an Acuson Sequioa ultrasound machine with an 8 MHz transducer. Following the acquisition of the scan the diastolic images which best demonstrated intimal medial thickening (IMT) were analysed. Both near and far walls of the common carotid artery were visualised on the same scan to ensure the transducer was transecting the artery at 90°. Scans were read by a single observer blinded to other results. Images were analysed using a quantitative analysis package (Siemens) giving an axial resolution of 0.001 mm. Measurements of IMT were made at 1 mm intervals over a 10 mm segment of vessel. The maximal and mean IMT measurements were determined for the near and far walls of the left and right common carotid arteries 2.4Left ventricular mass was calculated from a short axis cine stack. Gated cardiac magnetic resonance images were acquired using a Siemens 1.5 T scanner and analysed by an experienced imager who was blinded to the other study results. Volume and mass data was analysed from the short axis stack by manually delineating the endocardial boundary in systole and end-diastole 2.5t-test except for non-parametric variables, which were analysed using a Mann–Whitney test . Variables were compared using Pearson's correlation coefficients (r). A p value of less than 0.05 was taken to be statistically significant.Descriptive data for the cohort are presented as mean values and standard deviations. Non-parametric variables are described using medians. Differences between groups were compared using an unpaired 3n = 19); patch repair (n = 8); subclavian flap (n = 3); tube graft (n = 3); primary angioplasty (n = 4) and other/unknown (n = 9). Twenty-six percent of the cohort were repaired in the first 2 years of life and eleven subjects had undergone more than one coarctation repair procedure.Forty-six coarctation subjects  and 20 controls  were recruited over 14 months. The mean age of the patients was 31 years (range 16–62 years). Age at the time of first coarctation repair was 10.7 (10.1) years (range first day of life to 35 years). The intervention techniques employed were end-to-end anastomosis  of the coarctation group had a bicuspid aortic valve. No subject had hemodynamically significant valve disease. There was no evidence of significant recoarctation in any subject.3.2r = 0.41, p = 0.02) but the time to the aortic reflective wave (T2) was not.The tonometry-derived measures of pulsatility and central aortic pressures are presented in There was no difference between the coarctation subjects and the control population in terms of simple measurements of vascular reactivity . This wa3.3p = 0.26 (coarctation vs. control); mean far wall IMT left common carotid 0.59 vs. 0.54 mm, p = 0.27). The major determinants of carotid IMT were central systolic blood pressure  and central pulse pressure .In this cohort there was no significant difference in any of the intima media thickness parameters, a surrogate marker for coronary atheroma 3.4p = 0.21) but this was not statistically significant. There was no relationship between LV mass and IMT  in this cohort.There was a trend towards an increased left ventricular mass in this selected population of repaired coarctation subjects (76.5 (14.5) vs. 71.6 (9.7) g/m sq., 4Coarctation of the aorta is associated with late cardiovascular events with myocardial infarction and cerebrovascular disease accounting for the majority of deaths. This association is present even in individuals who had a successful repair. For the cardiologist caring for an adult with repaired coarctation a clinical difficulty is the early identification of those at increased risk of subsequent cardiovascular events and in the determination of effective primary prevention.Recently it has become clear that simple brachial systolic–diastolic blood pressure parameters may be inadequate to describe the variability of the aortic pressure wave — exemplified by the fact that in early systole cardiac output can be 6 times greater than mean flow with only a relatively narrow pulse pressure range The cohort investigated in this study represents the “best” end of the coarctation spectrum — repaired patients with no evidence of recoarctation or systemic hypertension. Our data reassuringly showed that even out to the age of 30 years (20 years post-repair) that increased intimal medial thickening and left ventricular hypertrophy are not inevitable in this population. In contrast to other less select cohorts significant endothelial dysfunction and smooth muscle vascular impairment were not ubiquitous In addition there is no excess of traditional cardiovascular risk factors and no change in Framingham risk scores.Despite these positive features this cohort still demonstrated abnormal central pulse pressures. In addition the reflected wave returned earlier either due to an increase in pulse wave velocity or a more proximal reflection point. This mirrors the finding from invasive assessment described by Murakami et al. In subjects with repaired coarctation vascular compliance has both structural and functional components Previous studies have demonstrated abnormalities in pulse wave velocity and flow-mediated dilatation following coarctation repair 4.1This study has the limitations of a cross-sectional design. Patients were clinically defined as being normotensive if not previously diagnosed and on no therapy. Patients may however have had mildly elevated blood pressure profiles on 24-hour testing. In addition subtle effects of different repair technique, minor residual repair site gradients or the presence of a bicuspid aortic valve on proximal hemodynamics cannot be excluded.The general transfer factor used to assess central hemodynamics has not been specifically validated in patients with coarctation repair and therefore small differenced in central pressures may be possible. In addition tonometry may under-estimate augmentation index and be more susceptible to error 5This study demonstrates that there are patients with repaired coarctation who have an excellent mid-term outcome free from ventricular hypertrophy, carotid intima medial thickening and with relatively preserved vascular reactivity. However even in this “best outcome” cohort there were abnormal vascular characteristics that may predispose to increased cardiovascular risk. Simple non-invasive investigations can more extensively characterise these sub-clinical abnormalities and thus more effectively target and monitor future preventative therapies.


Blood pressure (BP) variability has been associated with cardiovascular outcomes, but there is no consensus about the more effective method to measure it by ambulatory blood pressure monitoring (ABPM). We evaluated the association between three different methods to estimate BP variability by ABPM and the ankle brachial index (ABI).In a cross-sectional study of patients with hypertension, BP variability was estimated by the time rate index (the first derivative of SBP over time), standard deviation (SD) of 24-hour SBP; and coefficient of variability of 24-hour SBP. ABI was measured with a doppler probe. The sample included 425 patients with a mean age of 57 ± 12 years, being 69.2% women, 26.1% current smokers and 22.1% diabetics. Abnormal ABI (≤ 0.90 or ≥ 1.40) was present in 58 patients. The time rate index was 0.516 ± 0.146 mmHg/min in patients with abnormal ABI versus 0.476 ± 0.124 mmHg/min in patients with normal ABI (P = 0.007). In a logistic regression model the time rate index was associated with ABI, regardless of age . In a multiple linear regression model, adjusting for age, SBP and diabetes, the time rate index was strongly associated with ABI (P < 0.01). None of the other indexes of BP variability were associated with ABI in univariate and multivariate analyses.Time rate index is a sensible method to measure BP variability by ABPM. Its performance for risk stratification of patients with hypertension should be explored in longitudinal studies. The biomechanics of vascular damage induced by higher blood pressure include circumferential, axial and shear stresses . In addiDespite the growing interest in using these parameters for assessment of cardiovascular prognosis, it is still unclear if they add substantial information over blood pressure values and if there is superiority of any index in this regard. Guidelines still do not recommend the inclusion of measurements of blood pressure variability on the report of ABPM examinations ,15.The ankle brachial index (ABI) has been considered a marker of macrovascular atherosclerotic lesion -23, and This cross-sectional study was conducted in the Hypertension Clinic of the Division of Cardiology of Hospital de Clínicas de Porto Alegre . The study was approved by the Ethics Committee of our Institution, which is accredited by the Office of Human Research Protections as an Institutional Review Board, and all patients signed a written informed consent for participation.The study population was selected from a consecutive sample of patients screened for participation in randomized clinical trial of approaches to improve adherence in patients with hypertension (MONITOR study/NCT00921791). Patients were included in this analysis if they had:  absence Patients underwent to an extensive demographic and clinical baseline data collection, including the assessment of education, alcohol and tobacco consumption. Patients with a history of angioplasty or coronary revascularization, carotid endarterectomy, myocardial infarction, angina, heart failure, stroke, and transient ischemic attack were considered as having cardiovascular disease. The prevalence of peripheral arterial occlusive disease (PAD) was defined as presence of intermittent claudication or angioplasty of lower limb vessels. Diabetes mellitus was defined as fasting plasma glucose ≥ 126 mg/dl or use of antidiabetic drugs. BP was measured with an office aneroid sphygmomanometer and the mean values were estimated after an average of 6 measures in 3 different visits according to guidelines . PatientThe ABI was defined as the ratio between the highest systolic blood pressure of the ankle  and higher systolic pressure of the arm (right or left) . ABI wasAll individuals were submitted to ABPM in a normal working day . Readings were obtained at intervals of 15 minutes during the day and 20 minutes on the night of 24 hours throughout the period studied. Patients with less than 6 and 18 measures during the night and the day periods respectively were excluded from further analysis . Based oWhere r is the rate of BP variability over time  and N is the number of recordings.The groups for comparison were defined by the presence or absence of an abnormal ABI: values ≤ 0.9 or ≥ 1.4 in any lower limb. Comparisons were tested by Pearson's chi-square test, unpaired Student t test, and Mann-Whitney test. Logistic regression models and multiple linear regression were used to evaluate the association between parameters of variability of 24-hour SBP and ABI. Age, 24-hour SBP and diabetes were included in models. Three patients with ABI ≥ 1.4 in any leg were not included in the multiple linear models. All values are presented as mean and standard deviation, with their confidence intervals of 95% (CI). Values of P <0.05 were considered significant. The areas under (AUC) the Receiver-operating characteristic curve (ROC) of different 24-hour SPB variability indices were calculated to compare the performance of these parameters in the prediction of abnormal ABI .Data were analyzed using the program Statistical Package for Social Science .). Standard deviation and coefficient of variability calculated separately for the daytime and nighttime periods were not associated with abnormal ABI also.A total of 482 patients were evaluated, being 57 excluded because of lack of ABPM or ABI data, leading to the analysis of 425 patients (88% of those screened). The characteristics of the sample are presented in Table 1The independent association between the time rate index and abnormal ABI was assessed by logistic regression models and multiple linear regression (considering the right and left legs). The association was independent of age Table -model 1,Table In this large sample of patients with hypertension screened for a randomized clinical trial we identified that nearly 14% of participants had an abnormal ABI. This prevalence is similar to that reported in population-based studies ,17,19-21Individuals with abnormal ABI had higher blood pressure variability only if measured by the time rate index. This association was robust and independent of age when ABI was stratified in normal and abnormal. Systolic blood pressure and diabetes lowered the intensity of this association. On the other hand, when ABI was included as a dependent variable in a linear model, there was a strong and independent association with BP variability exclusively measured by the time rate index. In this regard, our findings are in agreement with those reported by Zakopoulos and colleagues, who demonstrated, in a cross-sectional study with 539 individuals, that only the time rate index was independently associated with the thickness of the carotid artery measured by ultrasound . Our finAbnormal ABI has been identified as a marker of vascular damage by atherosclerosis . Values The cross-sectional nature of our investigation precludes establishing temporal causality. Abnormal BP pressure variability could be responsible for the development of vascular abnormalities as well the vascular rigidity could lead to higher blood pressure variability. Longitudinal studies should be launched to identify if abnormalities in BP pressure variability precede the vascular damage detected by ABI. In face of the risks identified in cohort studies, with other indexes of blood pressure variability, it is expected that abnormalities in the ABI are favored by higher blood pressure variability. These findings can be explained by the association between the process of atherosclerosis and the hemodynamic changes that lead to vascular endothelial injury. In an elegant experiment, Cheng and colleagues demonstrated that the phenotype of endothelial injury is directly linked to the changes in blood flow . AtherosDespite that the precise assessment of blood pressure variability is only possible with beat-to-beat BP recording , our finIn conclusion, variability of systolic blood pressure over time derived from ABPM- the time rate index is associated with the ankle-brachial index. Blood pressure variability measured by the standard deviation of 24-hour SBP and by the coefficient of variability are not associated with the ankle-brachial index. The performance of the time rate index to identify cardiovascular risk over blood pressure values should be explored in longitudinal studies.The authors declare that they have no competing interests.EW: participated in the design of the study, elaboration of the protocol, data collection and draft preparation. SCF: planned the investigation, supervised data collection and database preparation, run the statistical analyses and helped to prepare the draft. FDF: participated in the design of the study and data analyses and interpretation, wrote the drafts and final version. LBM: participated in the design of the study and data analyses and helped to prepare the draft. EF: developed the software for time-rate measurement and helped in the statistical analyses. FTC, CMM, JN, MBM: were responsible for data collection, including all ABI measurements and patients' interviews and examinations. MG: conceived the hypothesis, proposed the methods of investigation, supervised data collection and participated in data analyses and draft preparation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/10/55/prepub


The gold standard for assessment of intraabdominal pressure (IAP) is via intravesicular pressure measurement (IVP). This accepted technique has some inherent problems, e.g. indirectness. Aim of this clinical study was to assess direct IAP measurement using an air-capsule method (ACM) regarding complications risks and agreement with IVP in patients undergoing abdominal surgery.®, Germany) was placed on the greater omentum. It was passed through the abdominal wall paralleling routine drainages. To compare ACM with IVP t-testing was performed and mean difference as well as limits of agreement were calculated.A prospective cohort study was performed in 30 patients undergoing elective colonic, hepatic, pancreatic and esophageal resection. For ACM a Probe 3 . 168 pairwise measurements were made. Mean ACM value was 7.9 ± 2.7 mmHg while mean IVP was 8.4 ± 3.0 mmHg (n.s). Mean difference was 0.4 mmHg ± 2.2 mmHg. Limits of agreement were -4.1 mmHg to 5.1 mmHg.Using ACM, direct IAP measurement is feasible and uncomplicated. Associated with relatively low pressure ranges (<17 mmHg), results are comparable to bladder pressure measurement. Intra-abdominal hypertension (IAH) is defined by a sustained or repeated pathological elevation of intra-abdominal pressure (IAP) to more than 12 mmHg. This condition has been shown to be an independent factor of organ dysfunction and -failure  and may Clinical examination of the abdomen in order to detect hypertension has been demonstrated to have an insufficient sensitivity . TherefoIn a porcine model an air-capsule-technique for the direct measurement was applied and this technique showed a high precision and a good agreement with bladder pressure measurement . AlthougWith approval of the local ethical committee (document-nr. EK-2024) a prospective cohort study was performed between January and August 2003 at the surgical intensive care unit (ICU) of the Department of Surgery, University Hospital of the RWTH Aachen, Germany. The study was conducted in accordance with the study protocol, the Declaration of Helsinki and applicable regulatory requirements.Included were patients scheduled for elective abdominal surgery: colon resection (35.4%), esophageal resection (18.7%), pancreaticoduodenectomy (12.5%), gastrectomy (10.5%) and liver resection (22.9%). Furthermore, patients were included if an abdominal drain was placed and if postoperative ICU surveillance as well as placement of a Foley-catheter was deemed necessary. The indication for these procedures was based on the standard preoperative assessment and surgical procedure but was not based on study reasons.Excluded were patients with an age < 18 years, coagulation dysfunction, intraabdominal inflammation, liver insufficiency (Child-Pugh-stage B or C), renal failure with necessity for dialysis and inclusion in other studies.A total of 30 patients were included  with a mean age of 57.5 years . The mean body weight was 75.4 kg with a mean body-mass-index (BMI) of 25.6.®-System, Probe 3, Hamburg, Germany) was placed during the operation on the greater omentum in midline position cranial of the umbilicus (figure ®) and was fixed to the skin with a suture. The system for air-capsule pressure measurement (ACM) consisted of the catheter with an air-inflatable capsule situated at the top  measurement was done as follows: The tubing system, Foley catheter, and bladder were first flushed with 50 ml sterile saline. This fluid was completely drained leaving no air in situ before another 50 ml saline was injected serving as measurement volume. Using a standpipe, pressure readings were obtained at the end of the exspiration. The level of the symphysis always served as reference and readings in cmH2O were converted into mmHg by multiplication with 0.74.Hydrostatic intravesicular pressure According to a protocol, IVP measurements were done every eight hours, while ACM was performed continuously. In this setting, ACM values were first to be recorded. Then, a reset was performed in order to initiate recalibration of the ACM monitoring system and bladder readings were taken. Simultaneous readings of ACM and IVP were recorded.2 for the induction of IAH [ACM value after recalibration was compared to the last ACM value before recalibration and to the corresponding IVP recordings. Comparison of ACM values was performed to assess a possible measurement drift over the period of 8 h. A measurement drift was observed in a previously performed porcine investigation using COn of IAH .The intraabdominal catheter was withdrawn whenever the urinary catheter war removed, patients left the intensive care unit (ICU) or after 5 day of ACM measurement. Patients were physically examined twice daily and assessed for dislocation or defect of ACM-catheter as well as for catheter related erosion and infection of adjacent tissue.After confirming normal distribution of the values with Shapiro-Wilk analysis, results are presented as mean ± SD.To compare readings derived from IVP and ACM Student's t-test was applied. Also, Pearson's coefficient of correlation (r) was calculated. Lastly, the mean difference and limits of agreement (mean difference ± 1.96 SD) were calculated according to the method of Bland and Altman .The use of the ACM did not lead to complications and postoperative course of all patients was uneventful. Particularly there were no signs of probe related organ lesion or surgical site infection.Except for one unintended dislocation of the measurement probe which occurred during a transport of the patient, we registered no catheter malfunction. Furthermore, withdrawal of the measurement probe at the end of the measurement period could be done uneventfully in all patients without any defect of material or complication.The mean insertion time of the intraabdominal measurement probe was 4.4 days (min-max: 1–5 days). The measurement drift was 0.9 ± 0.8 mmHg. Altogether 168 pairwise measurements of the intraabdominal and the intravesicular pressure were performed.A mean ACM value of 7.9 ± 2.7 mmHg (min – max: 1.5 – 15.0 mmHg) was recorded while mean IVP reading was 8.4 ± 3.0 mmHg (1.1 – 16.9 mmHg). There was no significant difference (p = 0.29). Pearson's coefficient of correlation was r = 0.69. The mean difference between IVP and ACM was 0.4 mmHg ± 2.2 mmHg. Limits of agreement were -4.1 mmHg to 5.1 mmHg for each device , agreement with standard IVP was acceptable in the underlaying study. Direct measurement could be indicated in patients after abdominal surgery who are at risk for the development of IAH e.g. after liver-transplantation, after decompression for ACS and prior to closure of abdominal walls after laparostomy. Although direct intraabdominal pressure measurement appears to be feasible in selected surgical patients, prospective clinical studies are needed to confirm IAP thresholds already known from bladder pressure measurement.AS is Scientific Manager for B. Braun Melsungen, Germany which does not manufacture a commercially available kit for intra-abdominal pressure monitoring. The remaining authors have no financial involvement with any organization or entity with a financial interest in or in financial competition with the subject matter or materials discussed in the manuscript.JO and AS have made substantial contributions to conception and design. DK and MJ have been involved in revising the manuscript critically for important intellectual content. AB and RD have made substantial contributions to acquisation of data. VS have given final approval of the version to be published.The pre-publication history for this paper can be accessed here: