While hypertension is a leading risk factor for an initial stroke, the role of blood pressure lowering to prevent subsequent stroke is less clear. The results of recent large clinical trials investigating effects of antihypertensive agents in patients with a history of stroke have not shown a significant benefit; findings that are at odds with previous data. Our meta-analysis systematically evaluates the available, relevant trials to examine the role of antihypertensive drugs in preventing recurrent stroke.MEDLINE, CENTRAL, and ClinicalTrials.gov were systematically searched and bibliographies from key reports were examined. All randomized, placebo-controlled trials that tested blood pressure lowering agents in patients with stroke or transient ischemic attack were identified. The results from these trials were combined and meta-analyses were performed.Ten studies were found to contain relevant endpoints and presented data allowing meta-analysis. Agents that lowered blood pressure reduced recurrent stroke  and cardiovascular events  in patients with a previous stroke or TIA. These agents did not affect the rate of myocardial infarction  or all-cause mortality  in this patient population.Despite recent large trials showing no significant effect, in patients that have experienced a TIA or stroke, blood pressure lowering agents reduced the occurrence of subsequent stroke and cardiovascular events. The rate of myocardial infarction and all-cause mortality was unchanged. Hypertension is the leading risk factor for cerebrovascular accident  and incrRashid and coauthors performed a systematic review of blood pressure and recurrent stroke in 2003  and concClinical trials were identified using MEDLINE/PubMed and CENTRAL  in April 2009. Literature searches were performed using the following search terms: "recurrence" OR "recurrent" OR "secondary prevention" AND "stroke." These search terms resulted in 7,046 primary articles from the PubMed database, including 1,702 review articles  version 5.0 . The Mantatistic . Putativstructed  to identTen randomized clinical trials were identified as having study participants with prior TIA, stroke or "reversible ischemic neurologic defect" who were chronically treated with a blood pressure lowering agent ,13,18-242 = 78%). Along the ten studies there were variations in study population. These variations included age, race, time of follow-up, antihypertensive medication used and degree of hypertension at trial start. Only one study, BPLPRS [All ten studies reported stroke recurrence as a primary or secondary endpoint. The total number of patients included in this analysis was 37,737 of which 18,903 received active treatment, 18,740 received placebo, and 94 received nothing. The Martí Massó study  was the , BPLPRS , lead toCardiovascular event is a composite endpoint which included death from any vascular cause, non-fatal stroke and non-fatal myocardial infarction. This composite was used in the HOPE trial  and has 2 = 24%; All-cause mortality, P = 0.21, I2 = 29%). As shown in Additional file The relative risks of myocardial infarction and all-cause mortality were determined from eight and seven of the ten trials, respectively. The SCOPE  and MartResults from recent large randomized clinical trials  have calThe findings of our analysis are in line with a previous meta-analysis of the subject done by Rashid and Bath in 2003 . They foAs shown in our analysis, blood pressure reduction in this patient population does not reduce all-cause mortality. It does, however, reduce cardiovascular events, and mortality from vascular causes is part of the composite endpoint. Information regarding cardiovascular mortality was only available for four out of the ten relevant trials and did not yield useful analysis.The TRANSCEND trial  is notabThere are always limitations to using data across trials, as opposed to data regarding individual patients. Indeed our meta-analysis does indicate inconsistencies in the data that extend beyond statistical heterogeneity, especially in the recurrent stroke and cardiovascular event groups. Some of this heterogeneity may be resolved if individual agents or drug classes were considered individually. Unfortunately due to the limited number of studies, generalizations about specific drug classes could be misleading. Studies that were excluded from our analysis because they did not include a control group could shed some light on this issue. For example, the MOSES trial  comparedBlood pressure control remains an important consideration for patients who have experienced previous TIA or stroke. Given the available data, blood pressure control does confer a benefit to stroke survivors by reducing risk of recurrent stroke and cardiovascular events. Optimal subacute and chronic treatment following stroke should be individualized to patient's needs but should include at least one blood pressure lowering agent.ARB: angiotensin II receptor blocker; BP: blood pressure; QUOROM: quality of reporting of meta-analyses; TIA: transient ischemic attack.The authors declare that they have no competing interests.All authors participated in the preparation of the manuscript, and read and approved the final manuscript.QUOROM statement checklist. A word document showing the QUOROM statement checklist.Click here for fileForest plot using a random effects model showing the effect of blood pressure lowering agents on the risk of recurrent stroke. A forest plot using a random effects model showing the effect of blood pressure lowering agents on the risk of recurrent stroke.Click here for fileForest plot using a random effects model showing the effect of blood pressure lowering agents on the risk of a cardiovascular event. A forest plot using a random effects model showing the effect of blood pressure lowering agents on the risk of a cardiovascular event.Click here for fileForest plot using a fixed effects model showing the effect of blood pressure lowering agents on the risk of a myocardial infarction. A forest plot using a fixed effects model showing the effect of blood pressure lowering agents on the risk of a myocardial infarction.Click here for fileForest plot using a fixed effects model showing the effect of blood pressure lowering agents on the risk of all-cause mortality. A forest plot using a fixed effects model showing the effect of blood pressure lowering agents on the risk of all-cause mortality.Click here for file


Adenosine is the most widely used vasodilator stress agent for Cardiovascular Magnetic Resonance (CMR) perfusion studies. With the standard dose of 140 mcg/kg/min some patients fail to demonstrate characteristic haemodynamic changes: a significant increase in heart rate (HR) and mild decrease in systolic blood pressure (SBP). Whether an increase in the rate of adenosine infusion would improve peripheral and, likely, coronary vasodilatation in those patients is unknown. The aim of the present study was to assess the tolerance and safety of a high-dose adenosine protocol in patients with inadequate haemodynamic response to the standard adenosine protocol when undergoing CMR perfusion imaging.98 consecutive patients with known or suspected coronary artery disease (CAD) underwent CMR perfusion imaging at 1.5 Tesla. Subjects were screened for contraindications to adenosine, and an electrocardiogram was performed prior to the scan. All patients initially received the standard adenosine protocol (140 mcg/kg/min for at least 3 minutes). If the haemodynamic response was inadequate (HR increase < 10 bpm or SBP decrease < 10 mmHg) then the infusion rate was increased up to a maximum of 210 mcg/kg/min .All patients successfully completed the CMR scan. Of a total of 98 patients, 18 (18%) did not demonstrate evidence of a significant increase in HR or decrease in SBP under the standard adenosine infusion rate. Following the increase in the rate of infusion, 16 out of those 18 patients showed an adequate haemodynamic response. One patient of the standard infusion group and two patients of the high-dose group developed transient advanced AV block. Significantly more patients complained of chest pain in the high-dose group . On multivariate analysis, age > 65 years and ejection fraction < 57% were the only independent predictors of blunted haemodynamic responsiveness to adenosine.A substantial number of patients do not show adequate peripheral haemodynamic response to standard-dose adenosine stress during perfusion CMR imaging. Age and reduced ejection fraction are predictors of inadequate response to standard dose adenosine. A high-dose adenosine protocol (up to 210 mcg/kg/min) is well tolerated and results in adequate haemodynamic response in nearly all patients. First pass perfusion cardiovascular magnetic resonance (CMR) is routinely performed under vasodilatory pharmacological stress with either adenosine or dipyridamole ,2. AdenoWith the standard adenosine dose of 140 mcg/kg/min most, but not all, patients develop maximal vasodilatation . In patind or 3rd degree atrioventricular (AV) block and bifascicular block. A 12-lead ECG was performed before the CMR scan. All patients were asked to abstain from caffeine for at least 12 hours prior to the scan. However, patients who reported caffeine intake within the last 12 hours were still included in the study. Prior to the CMR scan, a physician carefully explained the procedure to subjects, with emphasis on potential adenosine-related symptoms. Subjects were continuously monitored with peripheral oxygen saturation, heart rate and 2-lead ECG throughout the CMR scan. Systemic blood pressure was periodically checked at every minute during adenosine stress and 15 min after the end of the infusion. The monitor tracing during the CMR scan does not allow for identification of 1st or Wenckebach 2nd degree AV block and therefore only advanced degrees of AV block (Mobitz II 2nd degree and 3rd degree) were noted. Each subject was questioned during and immediately after termination of adenosine infusion, specifically for the occurrence of the following symptoms: shortness of breath or dyspnea, chest pain and other minor symptoms . At least two clinicians trained in cardiopulmonary resuscitation and CMR evacuation procedures were present during the adenosine infusion.The study population consisted of patients with known or suspected coronary artery disease (CAD) who underwent adenosine stress perfusion CMR imaging for clinical purposes. All patients gave informed consent before the CMR scan. All subjects were initially screened for the presence of contraindications to adenosine, which include asthma, unstable angina or acute myocardial infarction within two weeks of the study, 2®, Sanofi-Synthelabo) infusion dose of 140 mcg/kg/min for at least 3 minutes through an antecubital vein using a syringe pump (Graseby® 3500). If after 3 minutes of continuous infusion at the standard rate, the haemodynamic response to adenosine was inadequate  then the infusion rate was increased to 170 mcg/kg/min for a further 2 minutes. The absence or minimal presence of classical adenosine side effects was not a criterion to increase the dose if an adequate haemodynamic response was evidenced. If still patients failed to show evidence of peripheral vasodilatation then the infusion was increased to a maximum of 210 mcg/kg/min for a further 2 minutes. The infusion was discontinued if patients developed persistent or symptomatic 3rd degree AV block, severe hypotension (systolic blood pressure <90 mmHg) or bronchospasm. The attending physicians had aminophylline for adenosine receptor antagonism and nitroglycerine for persistent chest pain readily available, and a fully equipped resuscitation trolley with defibrillator was easily accessible.All patients initially had the standard adenosine  was administered intravenously at 0.075 mmol/kg body weight (injection rate 4 ml/s), followed by a 20 ml saline flush at the same rate. Perfusion imaging was performed every cardiac cycle during the first pass, using a T1-weighted fast (spoiled) gradient echo sequence . Three or four short-axis slices, positioned from the base to the apex of the left ventricle, were obtained. The same imaging sequence was repeated at least 10 minutes later without adenosine to obtain perfusion images at rest. For assessment of left ventricular function, steady-state free-precession cine images  were acquired in three long-axis views, and a short-axis stack to obtain coverage of the entire left ventricle. Analysis of left ventricular function was performed with Argus Syngo MR software  using the short-axis SSFP images as previously described [All CMR examinations were performed with subjects in a supine position on a 1.5 MR Tesla  with a 32-element phased-array coil. During the last minute of adenosine infusion a gadolinium-based contrast agent  and the SPSS Statistics software .Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as counts and percentages. All continuous variables were found to be normally distributed by the Kolmogorov-Smirnov test. Differences in continuous variables between the standard- and high-dose groups were assessed by independent student's t-test. One-way analysis of variance (ANOVA) followed by post-hoc Bonferroni analysis was used to compare the haemodynamic response to stress in the high-dose group at several time points . Comparisons of categorical variables between groups were performed by Data were collected from 98 consecutive subjects  of whom 66 (67%) were men. Of the 98 subjects enrolled, 53 (54%) had a coronary angiogram. Of these 53 patients undergoing coronary angiography, 26 (49%) were found to have significant CAD: 20 single-vessel and 6 multi-vessel disease. The majority of our patients had undergone coronary angiography before the CMR scan. Specifically, 36 patients (68%) had a coronary angiogram before the CMR scan and 17 after the scan (32%). Of those 53 patients who underwent coronary angiography, 13 (25%) had normal perfusion on CMR, 32 (60%) had perfusion defects at stress and 8 (15%) had defects at stress corresponding to LGE without evidence of peri-infarct ischaemia. Table Overall, 80 patients 82%) had an adequate response to the standard adenosine infusion rate of 140 mcg/kg/min with a significant increase in heart rate (p < 0.001) and rate pressure product (p < 0.001). There were minimal changes in systolic or diastolic blood pressure measurements. The mean duration of adenosine infusion was 246 ± 35 seconds (Table % had an Eighteen patients (18%) failed to show signs of adequate haemodynamic response during standard-dose adenosine infusion. Following an increase in the dose of adenosine  16 out of these 18 patients showed an improved haemodynamic response with greater rise in heart rate (p = 0.011) and a mild drop in systolic blood pressure (p = 0.57). There was a trend towards a significant increase to rate pressure product at maximum adenosine rate compared to baseline (p = 0.07). The mean duration of adenosine infusion was significantly longer for the high-dose group  compared to the standard dose group (246 ± 35 seconds). Table nd degree and 3rd degree) occurred in 3 subjects (8%), of whom 2 had the high-dose adenosine infusion and 1 the standard dose (p = 0.07). There were no sustained episodes of advanced AV block. More patients complained of chest pain/tightness in the high-dose group (p = 0.009), but these were short-lived, and sublingual nitrate administration was not required in any patients. There were no significant differences in the incidence of other common adenosine adverse effects such as shortness of breath, headache or flushing between the two groups. All these symptoms resolved shortly after termination of adenosine infusion and no aminophylline reversal was required. The adverse effects of adenosine in our cohort are summarised in Table There were no deaths, myocardial infarctions, or episodes of bronchospasm or pulmonary edema in our cohort as a result of the adenosine stress. Transient advanced AV block  do not show a sufficient haemodynamic response to adenosine stress. Independent predictors of an inadequate response to the standard adenosine dose of 140 mcg/kg/min were: age above 65 years and ejection fraction less than 57%. The attenuated response to adenosine can be surmounted by increasing adenosine dose up to 210 mcg/kg/min without significant adverse events. Our study has important clinical implications because a reduced peripheral haemodynamic response to standard dose intravenous administration of adenosine may reflect similarly inadequate effects on coronary vasodilatation, thereby affecting the diagnostic reliability of CMR perfusion imaging.2A and A2B adenosine receptors dilates the coronary and peripheral arterial beds , increases myocardial blood flow, and causes sympatho-excitation [Adenosine is a powerful vasoactive substance. Activation of cardiac Acitation . These ecitation ,9. The mcitation -6.In our study 18% of patients showed inadequate peripheral haemodynamic response to the standard infusion dose. Similarly, Wilson et al. measured coronary blood flow invasively using Doppler and found that 16% of their subjects who received adenosine at 140 mcg/kg/min did not achieve maximal coronary hyperaemia as compared to that produced with papaverine . ImpairmOur data suggest that there is a clear dose-response relation and when patients fail to show adequate vasomotor responsiveness, a further increase in adenosine dose can induce signs of improved peripheral hemodynamic effect. This dose-dependent vasodilator effect is also supported by previous studies using intravenous or intracoronary doses of adenosine -21. ReyePrevious studies looking into the relation between the peripheral hemodynamic actions of adenosine and its coronary vasodilator effect have shown that despite a lack of peripheral response to adenosine, coronary vasodilatation remains adequate for the purpose of myocardial perfusion imaging . This obThis study did not assess any potential advantage of high-dose adenosine perfusion CMR on the diagnostic performance of this technique in patients with reduced haemodynamic response to standard adenosine dose. To perform such a study the same cohort of patients with blunted vasodilatory response would need to undergo stress perfusion CMR twice using the standard- and the high-dose adenosine infusion with not only visual but also quantitative measurements of myocardial blood flow. Nevertheless, our aim was to show feasibility and initial safety data of the high-dose adenosine infusion protocol and not to assess the potential added clinical value of such an approach. Stress echocardiography using a high dose adenosine protocol has been shown to have incremental diagnostic value mainly by increasing sensitivity in patients with single-vessel disease . It is cAbout one fifth of patients undergoing stress perfusion CMR show inadequate haemodynamic response to adenosine infusion at the standard dose of 140 mcg/kg/min, for which age > 65 years and ejection fraction < 57% were independent predictors. A high-dose protocol (up to 210 mcg/kg/min) improves the peripheral haemodynamic response to adenosine, suggesting better coronary vasodilatation. Our initial experience with a high dose adenosine infusion suggests it is well tolerated and safe, although further confirmation is needed in larger scale studies which will test also the clinical utility of this protocol.All authors declare that they have no conflicts of interest related to the contents of this manuscript.TDK: conceived the study, performed and analysed CMR scans, drafted the manuscript, did statistical analysis. NN: performed and analysed CMR scans, helped with drafting the manuscript, data collection and analysis. JMF: performed CMR scans. CH: performed and analysed CMR scans, critically revised the manuscript. SGM: critically revised the manuscript. SN: critically revised the manuscript, guarantor of this work. All authors read and approved the final manuscript.


The Iraq war has vividly brought the problem of traumatic brain injury to the foreground. The costs of death and morbidity in lost wages, lost taxes, and rehabilitative costs, let alone the emotional costs, are enormous. Military personnel with traumatic brain injury and acute respiratory distress syndrome may represent a substantial problem. Each of these entities, in and of itself, may cause a massive inflammatory response. Both presenting in one patient can precipitate an overwhelming physiological scenario. Inhaled nitric oxide has recently been demonstrated to have anti-inflammatory effects beyond the pulmonary system, in addition to its ability to improve arterial oxygenation. Furthermore, it is virtually without side effects, and can easily be applied to combat casualties or to civilian casualties.Use of inhaled nitric oxide in patients with severe traumatic brain injury and acute respiratory distress syndrome will show a benefit through improved physiological parameters, a decrease in biochemical markers of inflammation and brain injury, thus leading to better outcomes.A prospective, randomized, non-blinded clinical trial may be performed in which patients meeting the case definition could be entered into the study. The hypothesis may be confirmed by: (1) demonstrating an improvement in physiologic parameters, intracranial pressure, and brain oxygenation with inhaled nitric oxide use in severely head injured patients, and (2) demonstrating a decrease in biochemical serum markers in such patients; specifically, glial fibrillary acidic protein, inflammatory cytokines, and biomarkers of the hypothalamic-pituitary-adrenal axis, and (3) documentation of outcomes.Inhaled nitric oxide therapy in traumatic brain injury patients with acute respiratory distress syndrome could result in increased numbers of lives saved, decreased patient morbidity, decreased hospital costs, decreased insurance carrier and government rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families could still have their loved ones among them. Traumatic brain injury (TBI) affects 1.4 million Americans annually, which includes 1.1 million emergency department visits, 235,000 hospitalizations, and 50,000 deaths . This isComplications occur frequently in TBI, and respiratory dysfunction represents a primary non-neurological system failure . These pIn severe TBI  it has been recommended that the partial pressure of oxygen in arterial blood be maintained at a minimum of 100 mm Hg , cerebraVery recent basic science and clinical research has brought into question the results of the above-mentioned ARDS trials, especially as they may relate to TBI. Mathru et al have demonstrated that INO attenuates ischemia-reperfusion injury in the lower extremities of humans , and GazThus, use of INO in patients with severe TBI and ARDS will show a benefit through improved physiological parameters and a decrease in biochemical markers of inflammation and brain injury, leading to better outcomes.While INO is a potent pulmonary vasodilator, and has been thought to remain only in the pulmonary system, recent work has demonstrated that INO may go downstream to improve other organs  in the fINO and glucocorticoid regulation may be important, not only in sepsis, but also in TBI. Da et al have demonstrated that glucocorticoid receptor (GR) up-regulation decreased the inflammatory response in a porcine model of sepsis using INO in combination with glucocorticoids  . In contIn view of new findings on its downstream effects and lack of side effects , INO mayThe hypothesis may be confirmed by achieving the following aims: (1) demonstrating an improvement in physiologic parameters, ICP, and brain oxygenation with INO use in patients with severe TBI, and (2) demonstrating a decrease in biochemical serum markers of TBI with INO use. Specifically, glial fibrillary acidic protein , infA prospective, randomized, non-blinded clinical trial may be performed in which patients meeting the following case definition could be entered into the study: a subject whose GCS is ≥ 8, who has clinically qualified for intracranial pressure monitoring, whose trachea is intubated, whose oxygenation and ventilation is being supported by a ventilator, and in whom the ratio of partial pressure of oxygen in arterial blood to inspired oxygen is less than 200 with radiographic evidence of lung injury. The subjects should be randomized into two groups, those that will receive treatment without INO, and those who will receive INO. Invasive monitoring of CNS, renal, and cardiopulmonary parameters will be necessary. Follow-up at 28 days and 6 months can be through hospital records, an information-gathering tool, and the social security death index.® Brain Oxygen tissue monitor , cerebral oximetry, pulse oximetry, and transcranial doppler monitor for middle cerebral artery velocities. Also arterial blood gases, cerebral perfusion pressure, lactate, and methemoglobin will be monitored.Biochemical markers will be evaluated by enzyme-linked immunosorbent assays (ELISA). Physiologic monitors shall include: pulmonary artery catheter for cardio-pulmonary-vascular indices (cardiac output (CO), cardiac index (CI), mixed venous oxygenation (SVO2), central venous pressure (CVP), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), stroke volume index (SVI), right ventricular ejection fraction (RVEF), right ventricular end diastolic volume (RVEDV), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI), oxygen delivery (DO2), oxygen uptake (VO2), and oxygen extraction ratio (O2ER)), arterial line for blood pressure, foley catheter with abdominal pressure monitor, LICOXThe subjects' entire physiologic/biochemical/hematologic profiles will be available for analysis, such as hemoglobin, hematocrit, electrolytes, etc., as will the injury severity score (ISS) and Apache II score.Inhaled nitric oxide in humans with TBI and ARDS has been used successfully on two occasions to improve outcomes. It has also been shown to be effective in hippocampal preservation in animals. Positive results could immediately affect treatment of military and civilian TBI patients worldwide. A decreased inflammatory response and increased arterial oxygen tension in TBI patients with ARDS, through the use of INO, could potentially lead to decreased ICP and better brain oxygenation. This would result in increased numbers of lives saved, decreased patient morbidity, decreased hospital costs, decreased insurance carrier and government rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families could stay intact.The author(s) declare that they have no competing interests.


The reduction of blood pressure alone does not eliminate the increased risk of arterial hypertension. Whilst concomitant metabolic risk factors have been shown to be responsible, the available pharmacotherapy has differential effects on these metabolic risk factors. For example, diuretics and betablockers worsen glucose metabolism, hence the starting point of the current subanalysis of the CHILI (Candesartan in patients with HIgher cardiovascuLar rIsk) study was the assumption that an angiotensin receptor blocker may counterbalance the metabolic effects of a low dose diuretic in patients with several metabolic risk factors.The present study was performed as a non-interventional observational study in Germany. Patients with previously uncontrolled hypertension with at least one further risk factor in which physicians deemed a treatment with 16 mg Candesartan/12.5 mg HCTZ to be necessary were included. The risk factors were calculated in patient subgroups with diabetes, the metabolic syndrome (MetSyn) and neither condition (control). The risk of cardiovascular mortality within the next 10 years was calculated using the SCORE algorithm of the ESC.Between August 2006 and February 2007 a total of 3,787 patients were included into the non-interventional trial. Patients were 62.2 ± 11.3 years old, 48.1% were female, 97.5% had at least one additional risk factor. Blood pressure was reduced by -27.2/-13.4 mmHg with only minor non significant variations between patient groups. Waist circumference was reduced (P < 0.0001) and HDL-C elevated (P < 0.05) in every subgroup except the control subgroup. Fasting blood glucose was reduced by -5.6 ± 21.6% (P < 0.0001 vs. baseline and vs. control) as well as triglycerides . The SCORE value was reduced substantially .The present study demonstrates that a 16 mg candesartan/12.5 mg HCTZ based treatment results in a pronounced blood pressure reduction and was associated with a favourable change in metabolic risk factors such as HDL cholesterol, triglycerides and blood glucose. These data indicate that metabolic effects observed in clinical trials like ALPINE, SCOPE or CHARM can also be observed in an unselected patient population in primary care. Arterial hypertension is one of the most prevalent risk factors for cardiovascular disease -3 and anHypertension is frequently found together with other metabolic risk factors . The HOT study for example found that each of the risk factors considered was an important cause of residual risk, despite good blood pressure control . It therIn a recent meta-analysis Elliott and colleagues  showed tOf particular interest within this context is a combination of candesartan with a low dose diuretic  and to test whether the properties of both agents combine to create a beneficial outcome for patients. It was therefore the aim of the present analysis of the non interventional CHILI (Candesartan in patients with HIgher cardiovascuLar rIsk) study to investigate the influence of candesartan in fixed combination with HCTZ on a number of metabolic parameters and cardiovascular risk factors in more detail. The study was conducted in a primary care setting in order to acquire the broadest possible spectrum of patients in clinical practice. Three core questions were to be answered: 1) reduction in blood pressure; 2) reduction of cardiovascular risk factors like fasting glucose, waist circumference, triglycerides, HDL-Cholesterol after 8 week treatment and differential effects in patients with diabetes, the metabolic syndrome and neither disease state; 3) change in the absolute 10 year risk of cardiovascular morbidity (using the SCORE method) and the contribution of a) blood pressure and b) metabolic effects to this effect.The present non-interventional study was conducted between August 2006 and February 2007 with the help of 893 primary care physicians all over Germany. Therefore a sample of general practitioners, internists, cardiologists and practical physicians was drawn from all segments of the Institute for Medical Statistics . The study was duly notified according to local laws and regulations (§ 67 (6) Arzneimittelgesetz, AMG) to the higher authorities  and the federal panel doctors' association . Approval was obtained by the Technical University Dresden ethical committee. Due to regulations for this kind of study no patient informed consent had to be obtained. Methods of this study have been published previously .Patients were at least 18 years old, had essential arterial hypertension with blood pressure values beyond 140/90 mmHg (> 130/85 mmHg in diabetic patients) and previous antihypertensive therapy of at least 8 weeks duration had proven unsuccessful. In addition to this one of the following risk factors had to be present: Diabetes mellitus, dyslipidemia, abdominal obesity, hs-CRP ≥ 2 mg/l or confirmation of microalbuminaria (MAU). Patients who fulfilled these criteria and who's treating physician deemed a treatment with 16 mg Candesartan/12.5 mg HCTZ to be necessary were documented.The AHA/NHLBI 2004 definition was used to determine the presence of the metabolic syndrome . It requThe following parameters were used for the calculation of the score : sex, agPhysicians were asked to document at least 3 patients with arterial hypertension and concomitant cardiovascular risk factors. The observational period was 8 weeks and patients had a voluntary additional visit at 4 weeks and the case report forms were retrieved by the CRO Christine Franzen Consulting,  and screened routinely for plausibility and completeness. Source data verification was however not performed. Confidentiality: Patient data were recorded anonymously (age and gender only). Electronic data processing was conducted in accordance with local laws and regulations and the participating GPs received remuneration for the documentation of each patient which was in accordance with the "Gebührenordnung für Ärzte" (GOÄ).Regarding safety, the trial was adequately sized  to identify rare AEs, i.e. those that may not have been detected in previous clinical studies,  with a probability of > 99%. These data have been published previously . The sta2. 97.5% had at least one cardiovascular risk factor, 29.8% existing cardiovascular disease. 13.0% of patients had angina pectoris, 12.5% heart failure, 8.4% myocardial infarction, 6.2% kidney failure and 4.9% previous stroke.3,787 patients were included into the present study. The patients had a mean age of 62.2 ± 11.3 years, 48.1% were female and BMI was 29.5 ± 4.7 kg/mThe risk factors making up the metabolic syndrome were elevated throughout all patient subgroups  with hypertension (inclusion criterion), dyslipidemia 78.2%) and abdominal obesity (65.4%) being the most frequent. Tables % and abdFigure Finally absolute cardiovascular risk was calculated according to the SCORE method. The baseline risk differed substantially in the three patient subgroups (Diabetes 19.8 > MetSyn 7.4 > Neither 6.4%) as did the absolute risk reduction (Diabetes -8.7 > MetSyn -3.2 > Neither -2.7%). For details see table Antihypertensive drugs have been shown to have differential effects on metabolic parameters in clinical trials and recent meta analyses . TreatmeIn the present study a blood pressure reduction of -27.2/-13.4 mmHg was documented. Baseline blood pressure values were comparable throughout the subgroups as was the reduction in blood pressure induced by 16 mg candesartan/12.5 mg HCT. In a previous study patients with previously untreated severe hypertension (mean blood pressure 178/117 mmHg) who received 16 mg candesartan/12.5 mg HCTZ experienced a rapid blood pressure reduction that peaked at -38/-29 mmHg . The bloThroughout the study a reduction of cardiovascular risk factors was observed. However one should consider the short time frame  in which the changes were observed and its relative magnitude Figure . While aThe underlying mechanism for the eumetabolic effects of Candesartan are largely speculative. While there currently is great attention to the PPARγ activating properties of some ARBs  candesarPrevious studies in primary care, similar in design as the present study, have shown comparable results to the ones reported here ,27. ThesCardiovascular risk scores have been developed to estimate the cardiovascular risk of a given patient. They reflect findings from epidemiological studies like Framingham and PROCAM that a particular set of risk factors makes up the largest proportion of risk. The SCORE method has been developed under the auspices of the European Society of Cardiology (ESC) and has been adapted to fit particular countries in Europe  and specThe documented baseline risk of in the present was well beyond the intervention threshold of 5% disregarding that most of these patients were eligible for intervention based on a diagnosis of diabetes mellitus or concomitant cardiovascular disease. Treating patients with the fixed dose combination of 16 mg candesartan/12.5 mg HCTZ resulted in a substantial risk reduction. Similar analyses have been conducted in the primary care setting in a previous study. Bramlage et al. showed that Irbesartan treatment (with or without HCTZ) led to a reduction of cardiovascular risk in hypertensive type-2 diabetic patients . The effThe present results have to be considered against the background of potential limitations. The study was not controlled and therefore the role of a placebo effect or the withdrawal of antihypertensive agents is unknown. Second, in the absence of a randomization procedure and not consecutive inclusion the influence of unknown biases, e.g. through patient selection, cannot be ruled out. Third, changes in concomitant medication influencing the metabolic profile  have not been documented in the present study. Fourth, randomly high values for blood pressure readings or metabolic changes may have resulted in artificially large reductions consistent with the phenomenon "regression to the mean", the extent of which is difficult to determine. Among the strengths of the study was the choice of the setting. Observational studies in primary care, which include typical patient groups and reflect current treatment approaches, are useful for complementing the findings of randomized controlled trials .The present study confirms prior results from randomized controlled trials that a candesartan 16 mg/HCTZ 12.5 mg based treatment resulted in a good population blood pressure control in actual practice. It further shows that despite concerns about the metabolic effects of diuretics, improvements in metabolic parameters may be seen in patients who receive a low-dose diuretic with candesartan as part of their overall medical care.Takeda Pharma GmbH, Aachen, Germany has financed the study. PB has received research support from Takeda for the statistical exploration, analysis and the preparation of the manuscript. PO and ES declare that they have no competing interests.PB has explored the data, requested statistical analyses from the CRO and wrote the manuscript. PO and ES have revised the manuscript for important intellectual content and have participated in the study conduct. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Objective To determine levels of blood pressure monitoring and control in primary care and to determine the effect of social deprivation on these levels.Design Retrospective longitudinal survey, 2005 to 2007.Setting General practices in England.Participants Data obtained from 8515 practices  in year 1, 8264 (98.3%) in year 2, and 8192 (97.8%) in year 3.Main outcome measures Blood pressure indicators and chronic disease prevalence estimates contained within the UK quality and outcomes framework; social deprivation scores for each practice, ethnicity data obtained from the 2001 national census; general practice characteristics.Results In 2005, 82.3% of adults (n=52.8m) had an up to date blood pressure recording; by 2007, this proportion had risen to 88.3% (n=53.2m). Initially, there was a 1.7% gap between mean blood pressure recording levels in practices located in the least deprived fifth of communities compared with the most deprived fifth, but, three years later, this gap had narrowed to 0.2%. Achievement of target blood pressure levels in 2005 for practices located in the least deprived communities ranged from 71.0% (95% CI 70.4% to 71.6%) for diabetes to 85.1% (84.7% to 85.6%) for coronary heart disease; practices in the most deprived communities achieved 68.9% (68.4% to 69.5%) and 81.8 % (81.3% to 82.3%) respectively. Three years later, target achievement in the least deprived practices had risen to 78.6% (78.1% to 79.1%) and 89.4% (89.1% to 89.7%) respectively. Target achievement in the most deprived practices rose similarly, to 79.2% (78.8% to 79.6%) and 88.4% (88.2% to 88.7%) respectively. Similar changes were observed for the achievement of blood pressure targets in hypertension, cerebrovascular disease, and chronic kidney disease.Conclusions Since the reporting of performance indicators for primary care and the incorporation of pay for performance in 2004, blood pressure monitoring and control have improved substantially. Improvements in achievement have been accompanied by the near disappearance of the achievement gap between least and most deprived areas. High blood pressure is the single most important risk factor worldwide for the development of cardiovascular disease, being responsible for about half of all cases of strokes, ischaemic heart disease, and heart failure.Over the past two decades, several countries have conducted community surveys on blood pressure detection and control. Based on national surveys, 12-25% of the population of five European countries had blood pressure above 160 mm Hg systolic or 90 mm Hg diastolic compared with 7.4% in Canada and 5.3% in the United States.In England the most recent detailed national population survey data are from the health survey for England conducted in 2003. A total of 8834 adults aged ≥16 years were surveyed with blood pressure readings taken on three occasions. Their mean blood pressure was 131/75 mm Hg. Of those with hypertension (blood pressure ≥140/90 mm Hg or taking antihypertensive drugs), 61.7% were aware of their diagnosis, 47.7% were receiving antihypertensive treatment, and 21.8% had adequate blood pressure control (blood pressure ≤140/90 mm Hg).5In 2004 the contract for all UK general practitioners was revised to include a pay for performance system accounting for up to a quarter of total annual income. This system, termed the quality and outcomes framework (QOF), has provided new performance data aggregated at practice level.The linkage of financial incentives to performance targets was intended to drive up the standards of primary care. It has also been observed that health inequalities between different population groups may be diminished as overall collective achievement increases. For example, the introduction of cervical smear targets for UK general practices in 1990 resulted in practices in affluent areas rapidly achieving the highest targets, initially widening the health inequality gap. Within a few years, however, practices in deprived areas had caught up, resulting in an eventual reduction in inequality based on social deprivation.We decided to use the data available through the QOF to provide a current perspective on two measures—national rates of blood pressure monitoring in primary care patients and the achievement of blood pressure control targets in patients with chronic conditions. We aimed to describe changes in these two measures over the three years since QOF data have been available. In addition, we describe the effect of any changes over time on health inequalities between general practices in deprived and less deprived communities.We obtained QOF data covering the three years from April 2004 to March 2007 for all general practices in England. Data for the preceding year were collected in February  and March (performance indicator data) of years 2005, 2006, and 2007.The proportion of all registered patients aged ≥45 years who had had their blood pressure taken within the preceding five yearsThe prevalence of five chronic conditions  and the achievement of blood pressure targets for each of these conditions.The denominator for the analysis of all QOF data was the total population of patients on the respective disease registers for each practice. This method of analysis precludes the process of “exception reporting,” whereby general practitioners are permitted to omit certain patients from their performance data on the grounds of unsuitability . For a pay for performance scheme, exception reporting is an important means to avoid penalising a general practitioner when patient-dependent factors, beyond the control of the general practitioner, diminish the achievement of clinical indicators. For research purposes, exception reporting introduces bias, since different general practitioners have different exception reporting thresholds.We obtained a detailed summary of practice characteristics.We obtained data from the 2001 national UK census based on the lower layer “super output area” (SOA) for each practice.Like most commonly used deprivation indices, the index of multiple deprivation does not include a measure of ethnicity. These data are available from the 2001 national census, and we added them to our own dataset, again aggregated at the level of super output area.We constructed a dataset for all general practices in England containing data from the QOF, the practice, and census data for the surrounding super output area. We removed from the dataset practices that were no longer independent at the end of the study year or had a list size of <750 patients or <500 per full time general practitioner, on the grounds that these practices were likely to be newly formed or about to be closed. On this basis, we removed 61 practices in year 1, 145 in year 2, and 180 in year 3. Postcode and super output area anomalies meant that we were unable to match deprivation and ethnicity data for 35 practices in year 1, none in year 2, and 361 in year 3. The final dataset consisted of 8515 practices  in year 1, with 8480 of these practices linked to the 2004 index of multiple deprivation; 8264 practices  in year 2, all linked to the deprivation index; and 8192  in year 3, with 7831 linked to the deprivation index.Firstly, we explored the relationship between social deprivation and the achievement of the six QOF indicators related to blood pressure that we included in our study. We conducted this analysis by comparing the achievement of practices located in the most deprived fifth of super output areas in the country with the achievement of practices in the least deprived fifth. We calculated mean values for each of the blood pressure related variables in all practices and then recalculated them as weighted means (based on the number of registered patients) in order to adjust for the effect of practice size. To enable comparison of mean values in the most deprived and least deprived areas, we estimated the 95% confidence intervals of the means. We then searched for possible confounding variables using multivariate analysis and a forward stepwise method; variables were entered into the equation if the significance of the association on univariate analysis, P, was <0.1.Table 1Table 2When we analysed data for all practices in England, the mean number of patients with an up to date blood pressure recording in 2007 (year 3 of the QOF) was 88.3% (n=53.21 million); after weighting for practice list size, the mean was 87.9%. Comparable values for 2005 were 81.6% and 82.3% (n=52.78 million), respectively.Table 3Table 4We constructed a series of regression models to explore the role of possible confounding variables. For each of the five chronic conditions in our study, none of the models explained more than 2.5% of the variation in achievement of target blood pressures (results available from the authors). However, 6.5% of the variation in the proportion of adult patients with up to date blood pressure monitoring was explained by four factors  registered at general practices in England have risen by 5% over the three years during which QOF data have been available such that, by 2007, 88% of the adult population have had their blood pressure measured in the preceding five years. The weighted mean, which gives a more accurate indication of the proportion of the national population who have had blood pressure screening, produced an almost identical value.When blood pressure monitoring data first became available through the QOF dataset, there was a difference in blood pressure monitoring between most and least deprived areas. However, as overall blood pressure monitoring levels increased, this inequality has narrowed over the three years such that, by 2007, the difference was negligible (0.2%).There are marked differences between practices in least and most deprived areas. For example, deprived areas have more singlehanded practices and less training practices. Regression analysis suggested that neither of these two factors had acted as confounding variables. However, on multivariate analysis (in 2007), practices found to be performing less well in terms of blood pressure monitoring were those with higher proportions of black or black British residents in the local population, were situated in less deprived areas, had larger numbers of general practitioners, and had larger list sizes per general practitioner. Hence, in the third year of QOF, social deprivation was no longer having a negative effect on blood pressure monitoring and, once corrected for confounding, had a weakly positive effect. The strongest confounding effect (based on the standardised regression coefficients) was the proportion of black or black British people in the local community.We also found high levels of blood pressure control for the five chronic conditions included in our study. For all five conditions, the achievement of target blood pressure targets had improved substantially over the three year study period. The greatest increase over time was observed for blood pressure control in diabetics in the most deprived practices, which improved by over 10%, with 79% achieving target blood pressure levels by 2007.Just as for overall blood pressure screening in the adult population, the improvements in achievement of blood pressure targets in chronic conditions have resulted in almost complete disappearance of the differences between least and most deprived areas. In 2005, the shortfall in the achievement of blood pressure targets in most deprived areas compared with the least deprived ranged from 2.1% to 4.3%. By 2007, the differences in achievement ranged from 1.3 to −0.6 (mean blood pressure control was slightly better in diabetic patients in deprived areas). We conducted multivariate analysis and constructed models for each of the diseases, but these had low predictive power and added little to the univariate findings. In particular, ethnicity did not emerge as a significant confounding covariable for blood pressure control. This suggests that ethnicity played a role in determining the level of blood pressure monitoring by general practitioners but not in the control of high blood pressure.Data from the health survey for England have shown steady improvements in population blood pressure control over the decade 1994-2003.15The inverse equity hypothesis describes trends in health inequalities during a period of rapid overall improvement in standards.Based on a national study, we have presented the first report of rapidly rising achievement of blood pressure monitoring and control in primary care over recent years and the narrowing of the small but real initial differences based on social deprivation, in terms of these blood pressure variables. Although no comparable national data are available that predate the QOF era, it is likely that pay for performance incentives have contributed to these overall improvements.This study, although based on aggregated data, provides a summary of recorded blood pressure variables for 53 million people. As such, it offers a far more comprehensive survey than data obtained from population surveys of volunteers.Recent calls for the introduction of five-yearly cardiovascular screening for all adults in the UK aged 45-74 years have highlighted the national importance of preventing cardiovascular disease, which is now seen as a government priority.The values for successful blood pressure control obtained in our study are much higher than previously reported from population surveys in the UK.11Our results may have overestimated success because the practice disease register is not validated. Indeed, prevalence figures reported by general practices are lower than predicted by community surveys. For example, the 2003 health survey for England found a national crude prevalence for coronary heart disease of 7.4% in men and 4.5% in women,21Black patients are often not well engaged with primary care in the UK, but this is the first report that blood pressure screening might be reduced in this patient group.24Several general limitations affect the interpretation of QOF data. QOF was not designed as a research tool, and the data are not validated externally. QOF data may be presented in a more favourable light in order to maximise practice income. For example, patients with poorly controlled blood pressure may not appear on the disease register or may have their blood pressure recorded in “free text” rather than in a coded format and thus be invisible to QOF; they may be defined as “unsuitable” and thus excluded by exception reporting; or they may be included but recorded with an optimistic blood pressure reading based on non-standard procedures. In spite of these temptations, and in the knowledge that QOF data are subject to annual scrutiny by health service managers, Doran et al concluded that the overall level of gaming was low with a median exception reporting rate of 6%, although a small number of practices were characterised by high exception reporting, and some aspects of gaming remain hard to quantify.The level of scrutiny by health service managers may itself introduce bias into the recording of QOF achievement (including blood pressure targets) since data verification methods differ between localities, some practices will be the subject of far greater scrutiny than others, and new audit procedures have been introduced since the early years of QOF. Prevalence data available in the QOF database are not standardised for age and sex. Individual patient data are not available through QOF, and many patients appear on more than one of the disease registers at the same time.General practice postcodes were used as a proxy for the postcodes of registered patients at each practice. Although this makes our data susceptible to the ecological fallacy, a primary care study in Rotherham concluded that deprivation scores linked to practice postcodes did provide a valid proxy for patient-level deprivation measures and may even underestimate the association between deprivation and all cause mortality.25Finally, our survey was not able to obtain consultation data. We therefore have no information about how the blood pressure recordings of adult patients were interpreted or how effectively they were used in the diagnosis and treatment of hypertension. Moreover, the blood pressure readings presented by practices for QOF may not be representative of the average blood pressure readings taken over the preceding year, since only the final blood pressure reading recorded during the QOF year is included in the QOF dataset. Similarly, the lack of consultation data means that blood pressure recording can be analysed only according to the timeframes of QOF itself. This results in inconsistencies such that well controlled blood pressure is defined as within the previous 15 months for patients with coronary heart disease but within the previous nine months for hypertensive patients. Blood pressure monitoring of the adult population aged ≥45 years can be analysed only to determine if one or more blood pressure readings have been recorded over the preceding five years, and detailed analysis of more recent data is not possible.Performance indicators relating to the detection and control of blood pressure were introduced into primary care in England in 2004. Since then, blood pressure monitoring and control have improved substantially. Improvements in achievement have been accompanied by the near disappearance of the achievement gap between least and most deprived areas.High blood pressure is the single most powerful risk factor for the development of cardiovascular diseaseSuccessful control of blood pressure has the potential to reduce greatly the incidence of cardiovascular disease but is less likely to be achieved in more socially deprived areasLevels of blood pressure monitoring and control in England have increased substantially over the years 2005 to 2007This increase has been accompanied by narrowing of the small but real social gradients in blood pressure monitoring and control, which were found to have improved more rapidly in more deprived areasThe introduction of a series of primary care performance indicators related to blood pressure control may have contributed to this success


Various factors may be responsible for hypertension during the perioperative period, including pain and sympathetic responses during surgical stimulation. Critical times, when stimulation may be maximal and hypertension is present, include laryngoscopy for endotracheal intubation and emergence from anesthesia with the added stimulation from the presence of an endotracheal tube. In addition to blood pressure changes related to perioperative issues, patients with previously unrecognized hypertension or those who are noncompliant with their current medication regimen may present for operative procedures. These issues are further confounded by the current recommendations to hold certain antihypertensive medications (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) for 12-24 hours prior to surgery, given their association with profound and refractory hypotension during anesthetic care.[1Various complications may be related to perioperative hypertension, including myocardial ischemia, cerebrovascular insults, bleeding, and renal failure. The potential association between perioperative hypertension and an increased risk of complications and mortality was first noted by Smithwick and Thompson in 1953, when they reported that the mortality of hypertensive patients undergoing sympathectomy was six-fold higher than that of normotensive patients undergoing similar operations.–8 A cohoAlthough elective cases may be delayed until appropriate therapy is instituted and the blood pressure is controlled, the anesthesia provider may be confronted with a hypertensive patient requiring an urgent or emergent surgical procedure. Additionally, overzealous requirements for blood pressure control may result in the unnecessary cancellation or delay of surgical cases. Therefore, rapidly acting and titratable intravenous medications are needed to allow for the perioperative control of blood pressure. Depending on the scenario encountered and the anticipated duration of blood pressure control that is required, anesthesia providers generally use short-acting vasodilators (sodium nitroprusside or nitroglycerin) by continuous infusion or the intermittent administration of longer acting β-adrenergic antagonists, such as, labetolol.in vitro studies, activation of the sympathetic nervous system with reflex tachycardia, rebound hypertension with discontinuation of its administration, tachyphylaxis with prolonged use, cyanide and thiocyanate toxicity, and cardiovascular effects , which may shift the myocardial oxygen delivery/demand ratio.[Sodium nitroprusside (SNP) remains one of the most commonly used agents for the acute management of perioperative hypertension. It is a direct-acting, nonselective, peripheral vasodilator that dilates resistance and capacitance vessels to decrease systemic vascular resistance and preload. Its popularity in the perioperative period relates to its rapid onset of action (approximately 30 seconds), rapid peak hypotensive effect (within two minutes), and rapid offset. SNP's physiological effects result from the release of nitric oxide , which activates guanylate cyclase, leading to an increase in the intracellular concentration of cyclic guanosine monophosphate (GMP). Cyclic GMP decreases the availability of intracellular calcium by decreasing its release from the sarcoplasmic reticulum into the intracellular space of smooth muscle cells. Despite its efficacy in controlling perioperative blood pressure, SNP's adverse effect profile remains worrisome to many clinicians. Adverse effects may include cerebral vasodilation and an increase in intracranial pressure (ICP) in patients with altered intracranial compliance and light sensitivity, mandating shielding of the bag and infusion tubing from ambient light, increased intrapulmonary shunt due to ablation of hypoxic pulmonary vasoconstriction, evidence of platelet dysfunction from nd ratio.–11 Furthnd ratio.131, β1, and β2 adrenergic receptors. Blood pressure control results from the blockade of α1 and β1 adrenergic receptors, with a decrease in both cardiac contractility and heart rate as well as peripheral vasodilatation. This is clinically seen as a decrease in both cardiac output and systemic vascular resistance. Myocardial oxygen consumption decreases as a result of a decrease in afterload, heart rate, and contractility. With intravenous administration, the onset of action is in 5-10 minutes, with the duration of action of 2-4 hours. In addition to its use by intermittent bolus dosing, it may be used in a continuous infusion of 0.5-2 mg/min. Advantages of labetolol include limited effects on intracranial pressure, cerebral blood flow, and cerebral oxygenation, thereby making it a favorite agent in the areas of neuroanesthesia and neurocritical care. Orlowski et al. demonstrated a decrease in intracranial pressure after substituting labetolol for SNP.[Given the issues with both SNP and NTG, many anesthesia providers choose intermittent dosing of a β-adrenergic antagonist to treat perioperative hypertension. In many cases, as the stimulus causing hypertension is short-lived, intermittent dosing provides an effective alternative for the treatment of alterations in blood pressure. Labetolol is a competitive antagonist at α for SNP. It has lDespite its advantageous properties, there are specific adverse effects and contraindications that may limit the widespread intraoperative use of labetolol. These adverse effects, which are primarily related to its β-adrenergic antagonistic properties, include heart block, heart failure, and bronchospasm. Its potential deleterious effects on airway reactivity may limit its use in patients with asthma or chronic obstructive pulmonary disease. Additionally, unlike many of the other agents that are available for the perioperative control of blood pressure, the half-life of labetolol is significantly longer, thereby occasionally resulting in prolonged hypotension.The calcium channel antagonists are a structurally diverse group of compounds with a common cellular mechanism of action. Although they have been used most commonly to treat cardiovascular disturbances, such as, angina and essential hypertension, specific agents in this class, such as nicardipine, have also been used via continuous intravenous infusion to control blood pressure in the Operating Room and in the Intensive Care Unit. The calcium channel antagonists interfere with the transmembrane movement of calcium by interacting with either the inner or outer gate of the calcium channel. Although the exact physiological effects may differ from agent to agent, their general physiological actions include vasodilatation and a decrease in the force of cardiac contractility. Verapamil and diltiazem have negative chronotropic and dromotropic effects, while nifedipine and nicardipine predominantly affect the resistance vessels, resulting in vasodilatation.et al. compared the efficacy of SNP and nicardipine in 20 adult patients during isoflurane anesthesia for spinal surgery.[Nicardipine is a 1, 4 dihydropyridine derivative that vasodilates the systemic, cerebral, and coronary vasculature, with limited effects on myocardial contractility and stroke volume. As nicar16Saudi Journal of Anasthesia, we present an anecdotal experience with the use of clevidipine to control blood pressure during general anesthesia, for an aneurysm coiling in a cohort of three adult patients. We found that clevidipine effectively controlled blood pressure intraoperatively and during emergence from general anesthesia, with only a modest reflex increase in heart rate of 8-10 beats/minute. Clevidipine was recently released by the United States Food and Drug Administration for blood pressure control in adults. It is an ultra-short-acting, calcium channel antagonist of the dihydropyridine group, which provides selective arteriolar vasodilatation.[In this issue of the latation.19 Similalatation. Clevidiplatation.–23 In thlatation. In additClevidipine is supplied in a concentration of 0.5 mg/mL in 50 or 100 mL vials. On account of solubility issues, it is provided in a lipid solution and is contraindicated in patients with allergy to eggs, egg products, soy beans or soy products, as well as, disorders of lipid metabolism. To date, no issues with lipid emulsion have been noted during short-term infusions. Although pricing varies according to region and supplier, the 100 mL vial is approximately $80-100 in the United States. Given its efficacy in the adult cardiac population, future trials in various patient populations, both in the Operating Room and the Intensive Care Unit appear warranted.


Although congestive heart failure (CHF) patients typically present with abnormal auscultatory findings on lung examination, respiratory sounds are not normally subjected to additional analysis. The aim of this pilot study was to examine respiratory sound patterns of CHF patients using acoustic-based imaging technology. Lung vibration energy was examined during acute exacerbation and after clinical improvement.Respiratory sounds throughout the respiratory cycle were captured using an acoustic-based imaging technique. Twenty-three consecutive CHF patients were imaged at the time of presentation to the emergency department and after clinical improvement. Digital images were created (a larger image represents more homogeneously distributed vibration energy of respiratory sound). Geographical area of the images and respiratory sound patterns were quantitatively analyzed. Data from the CHF patients were also compared to healthy volunteers.p < 0.05). After clinical improvement, the geographical area of the vibration energy image of CHF patients without and with radiographically evident pulmonary edema were increased by 18 ± 15% (p < 0.05) and 25 ± 16% (p < 0.05), respectively.The median (interquartile range) geographical areas of the vibration energy image of acute CHF patients without and with radiographically evident pulmonary edema were 66.9 (9.0) and 64.1(9.0) kilo-pixels, respectively (With clinical improvement of acute CHF exacerbations, there was more homogenous distribution of lung vibration energy, as demonstrated by the increased geographical area of the vibration energy image. Congestive heart failure (CHF) is one of the leading causes of frequent visits to the emergency department (ED) with a prevalence of 1-2% in the general population and a five year mortality rate after diagnosis reported at 60% in males and 45% in females . The theComputerized vibration imaging technology is able to record lung vibrations (energy) and convert the signals to a dynamic image of the lung in near real time. This technology has been studied recently for the detection of pleural effusion, and graft function in single lung transplant recipients ,5. To ouThe aim of this pilot study is to document in detail the differences in respiratory sound patterns between normal individuals, CHF patients during acute exacerbations, and those same patients after clinical improvement.The study protocol was approved by the Institutional Review Board, and informed consent was obtained from all participants. There were three groups of participants in this investigation. The first group consisted of acute CHF patients: Consecutive patients aged 18-85 years, who presented to the ED with acute shortness of breath and were diagnosed with CHF were eligible for inclusion in this study. All CHF patients were diagnosed by the attending emergency physician based on some combination of presenting complaint and symptoms, past medical history, physical examination findings, echocardiograph, BNP level and chest radiograph .For the CHF patients, respiratory sound data was acquired on the day of presentation to the ED and again on the day of discharge. For the mechanically ventilated CHF patients, respiratory sound data was acquired when chest radiographs showed pulmonary edema and again before extubation when radiographs demonstrated an improvement in pulmonary edema. All recordings were obtained with the subjects in the seated position. The tidal volumes of the non-ventilated patients in this study were not measured; patients were instructed to take comfortable deep breaths for all recordings. All measurements were performed by one individual who followed a standardized protocol to obtain vibrational images. This individual was also blinded to the clinical and radiologic information of subjects.Respiratory sounds were captured using a vibration response imaging device . This is a non-invasive computerized acoustic-based imaging technique that displays the geographic distribution of vibration energy of respiratory sounds throughout the respiratory cycle ,5. With Image J, a public domain Java image processing program inspired by National Institute of Health Image which traces the edge of the vibration energy image and objectively provides a digital measurement of the number of pixels in the traced image [Image J divides the image into visual signal (shade of grey to black) and background (white) and provides a numerical readout of area of the visual signal. In addition to image analysis of the maximal vibration energy frame, numerical maximal inspiratory vibration energy analysis was performed [The area of the maximal energy frame image during inspiration was measured using the software ed image . The auterformed . This anRespiratory sound generated vibration signals have very high signal intensity when compared to usual background noise and combined with the orientation of the sensor, allow pulmonary airflow to be the dominant signal in the gray-scale distribution. High energy artifacts from background noise due to patient movement against matrix framework or from sudden loud noises in the environment are occasionally encountered and easily identified in the image. These images were excluded from the analysis.p value less than 0.05 was considered statistically significant.Wilcoxon signed rank test for paired and unpaired data  was used to analyze the data. Median and interquartile range (IQR) and mean ± standard deviation (SD) are reported. A pre-study power calculation was not possible due to unknown size of effect of pulmonary edema and treatment on amount and distribution of vibration energy. A A total of 23 consecutive CHF patients with shortness of breath at rest were enrolled in the study. Follow-up studies were obtained on the day of discharge following clinical improvement of CHF symptoms (no shortness of breath) and were not obtained for 4 patients due to timing of their discharge. In addition to the improvement of CHF symptoms such as shortness of breath, physical examination findings documented by the physicians were also used as objective measures of clinical improvement. All patients were discharged on the recommendation of the treating physician. The average hospital stay for CHF patients without and with REPE was 2.9 ± 1.6 days and 3.4 ± 1.4 days respectively (p > 0.05). CHF patients without and with REPE had a negative fluid balance during treatment of 1736 ± 945 ml/day and 1871 ± 763 ml/day, respectively (P > 0.05).Chest radiographs and vibration energy images for healthy volunteers and CHF patients on admission and after clinical improvement are shown in Figure p < 0.05) . After clinical improvement, the geographic area increased to 71.9 (12.0) and 73.4 (12.0) kilo-pixels in patients without REPE and with pulmonary edema, respectively  and 25 ± 16% (p < 0.01), in the without REPE and with REPE patients, respectively. The total vibration energy values were calculated in each group on admission and were found to be significantly higher in CHF patients with REPE compared to those without REPE and healthy volunteers . Total vibration energy decreased in CHF patients with REPE following clinical improvement by an average of 90 ± 11% (p < 0.01) but remained unchanged in CHF patients without REPE  geographical area of the vibration energy image was 76.2 (6.0) kilo-pixels. On admission, areas for CHF patients without REPE and those with REPE were66.9 (9.0) and 64.1(9.0), respectively  Figure . On admip < 0.01). This increase in size of the image was seen with tidal volume held constant. As in non-mechanically ventilated patients with REPE, total vibration energy also decreased following therapy .For mechanically ventilated CHF patients, all with REPE, the geographical area of the vibration energy images were smaller in size bilaterally and became larger after clinical improvement Figure  in a simy Figure  . The vibration energy image represents the relative distribution of vibration energy, not the absolute energy. A larger image indicates a more homogeneous distribution of vibration intensity throughout the lung and a smaller image a more focal distribution. Because of how the vibration energy image is created, an increase in the size of the image after clinical improvement reflects a more homogeneous distribution of vibration intensity with decrease in lung water. The lack of homogeneity of lung vibration intensity throughout the chest in the presence of acute CHF might be explained by several mechanisms. Gravity-driven maldistribution of pulmonary edema may play a role -13 and hThe reason for the decreased area (distribution of vibration) seen peripherally in CHF patients is likely due to decreased transmission of breath sounds to peripheral lung tissue in the presence of pulmonary edema. This would in turn result in a smaller image due to decreased homogeneity of vibration intensity  ,5. LowerThe increase in total vibration energy in patients with REPE is likely caused by more significant airflow obstruction resulting in narrowed airways and more turbulence. Although airflow obstruction in the setting of pulmonary edema has long been acknowledged by clinicians , the mecThe edema may additionally cause smaller airways to close and reopen during inspiration; thereby, increasing noise ,21-23. TAnother manifestation of CHF is cardiomegaly. Since the pulmonary system and the heart share one thoracic space, an enlarged heart would decrease the space available for the lungs to expand -26. ThisIn healthy volunteers, it has been shown that total vibration energy increases with increasing tidal volume . AlthougNevertheless, to remove the confounding effects of tidal volume changes before and after clinical improvements, mechanically ventilated CHF patients were studied as a control group for same tidal volumes , when REPE was present and again when the CHF had improved and REPE was reduced. In these patients, the geographical areas of the vibration energy images were also diminished, and increased with clinical improvements. The total vibration energy of respiratory sound was high and decreased following therapy. This group of patients had the same tidal volumes, ventilation modes and settings before and after clinically improvements. Therefore, these changes were not due to alterations in tidal volumes.There were several limitations to this investigation. Because this was a preliminary study our sample size was small and we may not have been adequately powered for all of our analyses. We did not objectively measure pulmonary edema (e.g. via a pulmonary catheter). In a trial of critically ill patients, the use of a pulmonary artery catheter (PAC) was associated with increased mortality rates in patients with a lower severity of illness score while reducing mortality in the most severely ill . A recenIn conclusion, with clinical improvement of acute exacerbation of CHF, there is a more homogenous distribution of vibration energy of respiratory sound. Respiratory sound analysis is non-invasive and also does not expose the patient to ionizing radiation. It can be conducted at the bedside and repeat measures are easily obtained. Based on our preliminary findings, this modality may be a useful adjunct to current methods in assessing improvement in acute CHF exacerbations.CHF: congestive heart failure; ED: emergency department; IQR: interquartile range; PAC: pulmonary artery catheter; REPE: radiographically evident pulmonary edema; SD: standard deviation; VRI: vibration response imaging.The authors declare that they have no competing interests.ZW and SJ carried out the VRI recordings. ZW, SJ and BB worked on the calculations of recordings and data analysis. ZW and SJ drafted the manuscript. BB, KS and KNG revised the manuscript critically for important intellectual content. All authors edited and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-227X/10/1/prepub


Total cholesterol (TC) and blood pressure (BP) are likely to take a dynamic course over time in patients with systemic lupus erythematosus (SLE). This would have important implications in terms of using single-point-in-time measurements of these variables to assess coronary artery disease (CAD) risk. The objective of this study was to describe and quantify variability over time of TC and BP among patients with SLE and to determine their correlates.or DBP ≥ 90 mm Hg), and also in terms of within- and between-patient variance quantified by using analysis of variance modeling. Generalized estimating equations (GEEs) were used to determine independent correlates of each of TC, SBP, and DBP, treated as continuous outcome variables.Patients in the Toronto lupus cohort who had two or more serial measurements of TC and systolic and diastolic BP (SBP and DBP) were included in the analysis. Variability over time was described in terms of the proportion of patients whose TC and BP profile fluctuated between normal and elevated .In total, 1,260 patients, comprising 26,267 measurements of each of TC, SBP, and DBP, were included. Mean ± SD number of measurements per patient was 20.8 ± 20. Mean ± SD time interval between measurements was 5.4 ± 9.7 months. Mean ± SD time interval from the start to the end of the study was 9.3 ± 8.5 years. Over time, 64.7% of patients varied between having normal and elevated cholesterol levels, whereas the status of 46.4% of patients varied between normotensive and hypertensive. By using analysis of variance (ANOVA), the TC and BP vary markedly over time in patients with SLE. This variability is due not only to lipid-lowering and antihypertensive medications, but also to disease- and treatment-related factors such as disease activity, corticosteroids, and antimalarials. The dynamic nature of TC and BP in SLE makes a compelling case for deriving summary measures that better capture cumulative exposure to these risk factors. Systemic lupus erythematosus (SLE) is strongly associated with premature atherosclerotic CAD ,2. IndeeHypercholesterolemia and hypertension are two traditional cardiac risk factors that have been shown to be independently predictive of coronary events in patients with SLE when measured at the first available visit ('baseline') or defined as 'abnormal ever' during follow-up ,4,7. Howand as continuous variables. Generalized estimating equations (GEEs) were used to determine independent correlates of TC, SBP, and DBP over time.Evidence suggests that in the first 3 years of disease, one third of patients with SLE have 'variable hypercholesterolemia', with cholesterol levels that fluctuate between 'normal' and 'abnormal', which, in this case, is defined as total serum cholesterol > 5.2 mmol/L . Similarserial measurements of TC, SBP, and DBP were included in the analysis. Patients attending the University of Toronto lupus clinic are followed up at 2- to 6-month intervals, and clinical and laboratory data obtained at each visit are stored in a dedicated database. All patients fulfill four or more of the ACR classification criteria for SLE, or have three criteria and a typical lesion of SLE on renal or skin biopsy [Among the University of Toronto lupus cohort, patients who had two or more n biopsy ,13. CollIn addition to TC, SBP, and DBP, data on patients' demographic profiles , disease duration, disease activity, medications, intercurrent infections, smoking, and diabetes were routinely collected according to a set protocol. The data were stored and tracked in the lupus database at each clinic visit for the period from entry into the clinic up to the most recent visit as of August 2008. Each measurement of TC, SBP, and DBP was therefore tied to a clinic visit. We used only visits wherein all of three of TC, SBP, and DBP had been measured and recorded.Age and disease duration at the time of each visit were reported in years. Disease duration was calculated from the date of physician diagnosis of SLE to the date of each visit. Disease activity at each visit was reported by using the SLE Disease Activity Index 2000 (SLEDAI-2K), wherein scores range from 0 to 105, with higher scores indicating more-active disease . CorticoHypercholesterolemia was defined as total plasma cholesterol > 5.2 mmol/L ,16. SBP continuous variable.Characteristics of patients in the study as well as the total number, frequency, and values of TC, SBP, and DBP measurements are described. The proportion of patients with 'normal' or 'elevated' TC, SBP, and DBP at study entry and during follow-up was determined. 'Method of moments' analysis of variance (ANOVA) modeling was used to quantify total, within-, and between-patient variance in TC, SBP, and DBP, each treated as a Linear regression modeling with analysis of repeated measures was performed by using GEE to determine the independent correlates of each of TC, SBP, and DBP ('outcome' variables). Predictor/independent variables ('covariates') included sex, age, disease duration, SLEDAI-2K score, infection, diabetes, smoking, and treatment with corticosteroids, antimalarials, immunosuppressives, antihypertensives, and lipid-lowering medications. For each covariate, the measurements used were those recorded at the time of  with each measurement of SBP or DBP.In the model used to determine correlates of TC, hypertension was also included as a covariate, whereas in the models used to determine correlates of SBP and DBP, hypercholesterolemia was also included as a covariate. Modeling was repeated by using only female patients. In these models, in addition to the aforementioned independent variables, menopausal status and hormone-replacement therapy were also included as covariates.All statistical analyses were performed by using SAS version 9.1 .In total, 1,260 patients were included in the analysis, comprising 26,267 measurements of each of TC, SBP, and DBP. The characteristics of these patients are summarized in Table The total number, frequency, and values of TC, SBP, and DBP measurements are reported in Table The proportion of patients with normal (or elevated) TC or BP at the start of the study and during follow-up is reported in Table The total and the within- and between-patient variance in TC, SBP, and DBP determined by using method of moments ANOVA is reported in Table P = 0.0005), coincident SLEDAI-2K score ; coincident corticosteroid use ; coincident use of immunosuppressives ; coincident use of antihypertensives ; and coincident hypertension . Coincident use of antimalarials was negatively correlated with TC . When the model was run with only female patients (Table P < 0.0001). A trend toward a significant association with menopausal status was noted (P = 0.089). Disease duration  and coincident lipid-lowering therapy  were negatively correlated with TC.Linear-regression modeling with repeated measures analysis using GEE revealed several independent correlates of TC Table : coincidP < 0.0001), SLEDAI-2K score , use of antihypertensives , and hypercholesterolemia . When the model was run using only female patients (Table P = 0.0002) and coincident smoking . A trend was noted toward a significant association with menopausal status (P = 0.0927). Coincident use of antimalarials , immunosuppressives  and lipid-lowering therapy  were negatively correlated with SBP.Independent correlates of SBP determined by using GEE are listed in Table P = 0.0001), SLEDAI-2K score , coincident use of antihypertensives  and coincident hypercholesterolemia . When the model was run using only female patients, in addition to these variables, coincident disease duration  also was independently correlated with DBP. Coincident use of antimalarials , immunosuppressives , and lipid-lowering therapy  were negatively correlated with DBP.Independent correlates of DBP determined by using GEE overall mirrored those of SBP. DBP was independently correlated with coincident age  and frequent  measurements of these variables in 1,260 patients with SLE, followed up on average for 9.3 years. In total, a large dataset of 26,267 individual data points was used in analysis of variability and correlates for TC, SBP, and DBP.We chose to report 'variability' in serial measurements taken over time in two ways. First, TC, SBP, and DBP each were dichotomized into 'normal' and 'elevated' values based on conventional cut points, and over time, the proportion of patients in whom values fluctuated from one category to another was determined. Second, with TC, SBP, and DBP treated as continuous variables, total variance in each variable was quantified and dissected into within- and between-patient variance by using ANOVA modeling. The latter approach eliminates the need to dichotomize TC and BP values according to cut points, which, although based on evidence, are somewhat arbitrary. Common to both methods is the assessment of change in mean or average values over time. However, it must be borne in mind that this approach does not capture the trajectory taken by each variable measured serially in each patient.In this study, over a mean and median follow-up period of 9.3 and 6.5 years, respectively, 8.8% of patients had persistent hypercholesterolemia, whereas almost two thirds (64.7%) had variable hypercholesterolemia. This is even greater variability over time than previously reported in SLE patients in the first 3 years of disease, wherein one third of patients had persistent hypercholesterolemia, whereas one third had variable hypercholesterolemia ,19.Likewise, almost half (46.4%) of all patients in this study had varying hypertension over the duration of the study, whereas only 1.7% had persistent hypertension. Although no previous studies exist with which to compare the proportion of SLE patients who have persistent and variable hypertension, the findings of this study support our original hypothesis that BP likely takes a variable course in patients with SLE.The absolute total variance in TC and BP is reported in Table Previous studies evaluated the role of TC and BP as predictors of atherosclerotic coronary events in SLE; this is the first study to look at these risk factors as 'outcome' variables and to seek to determine their independent correlates. The importance of this approach is twofold. First, this type of analysis provides insight into the reasons for the pronounced variability over time of these cardiac risk factors in SLE. Second, identifying correlates of TC and BP in SLE aids in the selection of covariates and interaction terms for inclusion in multivariate models when the outcome of interest is atherosclerotic coronary events.et al. [In our analyses, we used GEE to allow adjustment for the expected correlation between repeated measures over time within individuals ('fixed effects'). These models have shown significant associations between increasing age and each of TC, SBP, and DBP. The association between older age and elevation in lipid levels and blood pressure is well described in the general population ,22. Our et al.  previousAlthough we found that use of immunosuppressives was significantly and independently associated with elevated TC, it is unlikely that hypercholesterolemia is a direct effect of treatment with these agents. Rather, immunosuppressive use is likely a surrogate for persistent low-grade disease activity that may not be adequately captured by the SLEDAI-2K scoring system. Notably, coincident use of immunosuppressives was negatively associated with both SBP and DBP, indicating that although greater disease activity is associated with higher BP, control of disease activity is associated with a reduction in BP.The findings of this study support the long-suspected independent association between hypercholesterolemia and hypertension in SLE . In thisAs shown in previous studies, concomitant use of antimalarials was associated with lower levels of TC. Reduction in plasma cholesterol level is one of the direct pharmacologic effects of antimalarials in patients with SLE -27. In tAmong women with SLE, other independent correlates of TC and BP were current smoking and hormone-replacement therapy. However, our analyses were limited by lack of data on pack-years of smoking . The assThe link between longer disease duration and higher TC and DBP suggests that the accrual of cardiac risk factors occurs over the course of disease and is consistent with the concept that chronic inflammation contributes to cardiac risk through association with traditional risk factors and other as-yet-undefined mechanisms.Finally, this study has confirmed the well-known association between corticosteroid use and hypercholesterolemia ,35. ThisFuture studies must be done to quantify the CAD risk associated with corticosteroid dose. Future studies will also need to determine the relation between various lipids and lipoproteins, such as high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) over time in SLE. Lack of a large number of serial measurements of these lipid and lipoprotein fractions among our patients precluded us from doing such an analysis in the present study.The contributions of this study to the field of SLE-related CAD are both conceptual and practical. First, this study has illustrated a very important concept: the marked variability of TC and BP over time in patients with SLE. The dynamic nature of these variables, in patients with SLE, makes a strong case for deriving summary measures that better capture cumulative exposure to these risk factors over time, than a single-point-in-time or 'snap-shot' measurement. Use of such cumulative measures would allow more-accurate quantification of risk for CAD in SLE. Second, this study has provided some insights into the complex relation between various risk factors for CAD in SLE. However, these interactions merit further investigation in longitudinal studies.This study has shown that TC, SBP, and DBP take a dynamic course in SLE, with more than half of the total variance over time seen within individual patients. Here we have shown that these risk factors fluctuate because of changes in disease activity, medications, and the accrual of other cardiovascular risk factors. The variable nature of cholesterol and blood pressure in patients with SLE makes a compelling case for deriving summary measures that better capture cumulative exposure to these risk factors over time.ACR: American College of Rheumatology; ANOVA: analysis of variance; BP: blood pressure; CAD: coronary artery disease; CI: confidence interval; DBP: diastolic blood pressure; GEE: generalized estimating equation; HDL-C: high-density lipoprotein cholesterol; HRT: hormone-replacement therapy; LDL-C: low-density lipoprotein cholesterol; Max: maximum; Min: minimum; mm Hg: millimeters of mercury; mmol/L: millimoles per liter; SD: standard deviation; SLE: systemic lupus erythematosus; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; TC: total cholesterol.The authors declare that they have no competing interests.MN participated in the study design, collection and analysis of data, interpretation of results, and preparation of manuscript; DDG, in the study design, collection of data, interpretation of results, and preparation of manuscript; DI, in the study design, analysis of data, interpretation of results, and preparation of manuscript; PJH, in the study design, interpretation of results, and preparation of manuscript; and MBU, in the study design, collection of data, interpretation of results, and preparation of manuscript.