Paracetamol’s solubility is achieved by adding to the excipient sodium salts, either as bicarbonate, carbonate or citrate. As the relationship between salt and hypertension is well known, due to the sodium content it has raised a hypothesis that may interfere with the control of that risk factor.Therefore, the objective of this study is to evaluate the effect on blood pressure of effervescent paracetamol compared to non-effervescent, in hypertensive patients.This is the protocol of a phase IV multicenter clinical trial, randomized, controlled, crossover, open, which will compare the effect of two different formulations of paracetamol (effervescent or non-effervescent) in the blood pressure of hypertensive patients, with a seven weeks follow up.49 controlled hypertensive patients will be included  and mild to moderate pain .The study was approved by the ethics committee of the Fundació Jordi Gol i Gurina and following standards of good clinical practice.The primary endpoint will be the variations in systolic BP in 24 h Ambulatory Blood Pressure Monitoring, considering significant differences 2 or more mmHg among those treated with non-effervescent and effervescent formulations.Intention-to-treat and per-protocol analysis will be held.Despite the broad recommendation not to use effervescent drugs in patients with hypertension, there are relatively little studies that show exactly this pressor effect due to sodium in salt that gives the effervescence of the product.This is the first clinical trial designed to study the effect of effervescence compared to the non-effervescent, in well-controlled hypertensive patients with mild to moderate pain, performed in routine clinical practiceNCT 02514538 Hypertension control has become a prime target because of its significant relationship to cardiovascular disease –3. At thIt is known that the continued use of nonsteroidal anti-inflammatory drugs (NSAIDs) carries a high risk of side effects, including difficulty in controlling hypertension –7. ThereHowever, in some studies it has been observed that paracetamol can also be associated with an increase in BP, increasing the risk of hypertension or hindering its control, although there is no consensus on this issue –13.Moreover, one of the most common forms of presentation of paracetamol is soluble, which appears to increase the absorption rate, reduce the time of onset of action and facilitates its administration when there are intake difficulties.Solubility of paracetamol is achieved by adding to the excipient salts containing sodium, either as bicarbonate, carbonate or citrate. As the relationship between salt and hypertension is well known, due to the sodium content it has raised a hypothesis about whether these presentations could interfere in the control of hypertensive patients or favor the emergence of new cases of hypertension. There are some observational studies, although few patients included, which seem to support this relationship between consumption of effervescent formulations and the difficulty of hypertension control , 15Such small samples, the potential confounders not included in the studies such as patients’ pain, the possible phenomenon of regression to the mean, and data from other studies that contradict this hypothesis –21 make The overall aim of the study is to evaluate the pressor effect of effervescent paracetamol formulation compared to the formulation of non-effervescent paracetamol in hypertensive patients.The effervescent preparations normally don’t contain sodium chloride , but contain other salts. So, we hypothesize that hypertensive patients treated with effervescent paracetamol should not present BP higher than those taking formulations non-effervescent.This is a multicenter, randomized, controlled, crossover, open, phase IV clinical trial, which compares the effect of two different formulations of paracetamol (effervescent or non-effervescent tablets) in the blood pressure of hypertensive patients after 3 weeks treatment (coded EUDRACT 2010-023485-53). The washout period between the two treatment periods is approximately 1 week (minimum 3 days).The study will be conducted in Primary Care, with the participation of 13 primary care centers in Catalonia and Euskadi. The study protocol was approved by the Ethics Committee of IDIAP Jordi Gol and the rules of good clinical research practice will be followed.be hypertensive patients over 18 yearswith chronic osteoarticular diseasewhich regularly need analgesic treatment.Patients included in the study must meet the following criteria:They must submit BP in the consultation lower than 150 and 95 mmHg or lower than 135 and 85 mmHg if they have associated cardiovascular disease  or diabetes mellitus.Antihypertensive treatment must be stable and unchanged in the last month, or patients should be controlled without drugs. In relation to chronic osteoarticular disease, they should have a degree of mild to moderate pain, with a score between 1 and 4 on a VAS.Patients with allergy, intolerance or contraindication to paracetamol or tramadol will be excluded, as those who have taken NSAIDs orally or parenterally in the last week, or have a high degree of pain (VAS > 4) or poorly controlled hypertension (office BP > 150/95 mmHg or daytime ambulatory mean BP > 140/90 mmHg).Patients with heart failure due to systolic and / or diastolic dysfunction will also be excluded, those who have suffered a cardiovascular event  in the last 6 months, presenting sleep apnea or any form of secondary hypertension, elevated transaminases , or a glomerular filtration rate <30 ml/min, over a maximum period of three months before starting the study; patients with dementia or judicial disability, with alcoholism or other addictions; pregnant patients; patients treated with oral anticoagulants or subcutaneous heparin. Patients in which changes are foreseen in usual dose drugs with effects on BP throughout the study  or those who will initiate major changes in lifestyles ; those who do not give their informed consent and that in the opinion of the investigator, have poor adherence or may become lost to follow-up.Patients meeting the inclusion criteria will be identified using the electronic medical record systems, OSABIDE in Osakidetza and the SISAP in the Catalan Health Service. Considering the information in the medical record, each doctor will check the list of candidate patients, rejecting those that a priori meet any of the exclusion criteria, that is, cases in which inappropriate patients have been identified by the electronic selection’ process.Participating physicians may also include patients who met inclusion criteria, but for some reason were not selected by the selection system.Once elected, it will be proposed to patients to participate in the trial, giving writing information and requesting written informed consent, after a first visit for confirmation of all the inclusion criteria and none of exclusion.In addition, a blood test assessing complete blood count, kidney and liver function will be performed to all patients who do not have one including all these parameters in the previous 3 months.A 3 to 7 days washout period for paracetamol will precede randomization. During this washout period, the analgesic treatment will be tramadol when necessary.A: Effervescent Paracetamol  at doses of 1000 mg / 8 hB: Paracetamol in non-effervescent tablets (Kern pharma ® Paracetamol 1 g), at doses of 1000 mg / 8 h.Patients who met all inclusion criteria and none of the exclusion will be assigned through centralized, automatic and masked randomization, for successive scrambling. Patients will be allocated through an electronic case report form (CRF) to the first of two treatment sequences to follow: AB or BA.The initial paracetamol dose is 1000 mg every 8 h. If the pain is not controlled (VAS > 3), tramadol will be administered at doses between 50 i 150 mg / day, at the discretion of the investigator.Rescue analgesia chosen is tramadol, following the NICE Osteoarthritis Guide recommendations, which ranks in the second therapeutic step .The medications in this trial are marketed and will be procured in Spain and conditioned  according to the standards of Good Manufacturing Practice for medicinal products.To assess compliance, counting tablets or sachets dispensed will be held in each subsequent visit to dispensing medication. It will be considered adequate if it is between 80 and 110 %.BP must be measured in both arms at first visit, subsequent blood pressures measures will be performed in the arm with the higher reading. These measures must be done with the person seated and standing, and using an appropriate cuff size for the person’s arm. For ambulatory blood pressure monitoring (ABPM) validated SpaceLabs 90207  or MicroFigures The primary endpoint is the change in mean daytime, night-time (sleep) and 24-h systolic BP, measured by ABPM, from baseline at 3 weeks of treatment in both periods.Changes in systolic BP measured in the clinic at the end of 3-week follow-up respect baseline in both periods.24-h, daytime and night-time (sleep) diastolic BP measured by ABPM: change from baseline at 3 weeks of treatment in both periodsChanges in diastolic BP measured in the clinic at the end of 3-week follow-up respect baseline in both periods.Percentage of patients maintaining clinical BP under 140 and 90 mmHg at the end of each periodDegree of pain assessed by visual analog scaleConsumption of rescue medicationTherapeutic complianceMild adverse events occurring during the study will be collected in the case report form, indicating the likelihood that may be related to drugs; if serious adverse reactions occur they will be immediately notified to the responsible for pharmacovigilance.49 patients are required to detect a difference in systolic BP equal to or greater than 2 mmHg in 24-h systolic BP detected by ABPM , with a standard deviation of the mean difference of 4.5 mmHg , and forThe analysis will be carried out on an intention-to-treat basis, comparing the mean blood pressure at the end of the period with that observed at initial time, adjusting for the baseline blood pressure at the start of each period in all patients which at least have received one dose of treatment. Moreover, we will perform a per protocol analysis with only the patients who have not changed their treatment within the 7-weeks of the trial and have not been withdrawn.Categorical variables will be presented using frequencies and percentages whereas that continuous variables will be presented using the mean, median, standard deviation, minimum, maximum, interquartile range and number of subjects under observation. All statistical tests are going to be two-tailed tests with an α level of 0.05, obtaining confidence intervals of 95 %.To analyze the differences between drugs in BP change between the beginning and the end of treatment, an ANOVA model will be used with the period, sequence, treatment and subject factors, declaring random factor subject nested within sequence. From this model estimators of the difference between the two formulations with confidence intervals to 95 % will be obtained.t-test. If not met the assumptions of applicability, nonparametric methods (Wilcoxon test) will be used.For all other variables the following strategy is to be used: to compare categorical variables intragroup McNemar’s test will be used, for continuous variables dependent Student’s We will adjust for potential confounding or modifying variables: age, sex, comorbidity as diagnosis of dyslipidemia, diabetes, stroke, Peripheral artery disease or myocardial infarction.In the mixed-effect analysis, all the data available from each of the subjects included in the study will be considered, regardless of whether there is missing data. Values of missing data will not be imputed, except in the case of the baseline values for the second period, in which case they will be assigned the same value as the baseline measurements at the start of the study. It has been shown that this is more robust than other approaches to dealing with missing data.The study will be subject to regular monitoring by the Clinical Research Associate (CRA), personnel specially trained in Good Clinical Practice standards. The CRA will monitor the patient recruitment and ethical issues; furthermore, he will guarantee the quality of data and ensure the patient safety. In addition to this, the CRA will revise the incidence of adverse events and concomitant medication. Data will be evaluated following the protocol and in concordance with source documents.This clinical trial will comply with the following regulations: the 2008 version of the Declaration of Helsinki, the Spanish Royal Decree 223/2004 of 6th February and the recommendations of the Council of Europe . The protocol of the clinical trial has been agreed on by the primary care research committee, approved by the Clinical Research Ethics Committee of Jordi Gol i Gurina, which is the reference committee, and authorized by the Spanish Agency for Medicaments and Health Products.Only the researchers involved in the study will have access to patient codes. In relation to this, we will comply with the Spanish Act 14/2007 of Biomedical Research and Royal Decree 1720/2007 of 21st December that approves the regulations on the Development of the Organic Act 15/1999 of 13th December on Personal Data Protection.The main limitation of the study is that it is an open trial, since it is not possible to have an effervescent placebo, but this has been attempted to solve by the blinding of data analysis.Another limitation is the inability to adjust the results for dietary salt intake, or exercise, a fact that has been attempted to solve by explaining and emphasizing the need not to change lifestyle habits during the study period.Among the non-pharmacological measures for hypertension treatment, in all existing clinical practice guidelines it is recommended to reduce salt intake –28, refeAlthough there is a case–control study that evaluates the effect of effervescent drugs in the risk of developing cardiovascular events, which results are in favor of increased risk , this woAs it is executed in routine clinical practice, this will help to extrapolate the results to include the general population.The only drugs not allowed are those who already have a recognized pressor effect as NSAIDs or oral corticosteroids. Besides, there is no increase in BP due to changes in antihypertensive medication because this is an exclusion criterion.The results will have high validity due to performing BP measurements not only in consultation, but also through ABPM, thereby minimizing the possible white coat effect which could appear with measurements taken by medical personnel. This is also a relevant difference with studies already existing.At this time, patient recruitment is proceeding to complete.


Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved.Here, we describe a novel, highly specific and sensitive biomarker for Niemann-Pick Type C disease type 1 (NPC1), lyso-sphingomyelin-509. We cross-validate this biomarker with cholestane-3β,5α,6β-triol and relative lysosomal volume. The primary cohort for establishment of the biomarker contained 135 NPC1 patients, 66 NPC1 carriers, 241 patients with other LSDs and 46 healthy controls.With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3β,5α,6β-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3β,5α,6β-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity.In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment.The online version of this article (doi:10.1186/s13023-015-0274-1) contains supplementary material, which is available to authorized users. Lysosomal storage disorders (LSDs) are a group of over 70 different inborn errors of metabolism with a combined incidence around 1 in 5,000 live births . Niemann24H49N2O7P), though so far we were not able to elucidate the exact structure of lyso-SM-509. In keeping with this finding, lyso-SM-509 is also highly elevated in patients with NP-A/B, though the disease is easier to diagnose due to availability of enzyme activity assays for sphingomyelinase.Here, we report the establishment of a novel biomarker for NPC1 and cross-validate our findings with published cholestane-3β,5α,6β-triol and MEFL data analyzing the same plasma data . As a fiIn a second line assessment we compared lyso-SM-509 measurements with those published for cholestane-3β,5α,6β-triol and MEFL. Here, we report on the result of the establishment of lyso-SM-509 as a biomarker and the cross-validation with the previously published biomarkers.Blood samples were obtained from patients enrolled in the “Biomarker for Niemann-Pick Type C Disease (BioNPC)” trial  and underwent biochemical analysis or genetic testing for verification of a suspected metabolic disease by the Albrecht-Kossel-Institute for Neuroregeneration (AKos). Additionally, blood plasma samples collected in the scope of the investigation of relative acidic compartment volume in NPC have been analysed for retrospectively for lyso-sphingomyelin-509 levels [11].Standard analysis of the NPC1 gene was performed according to standard protocols . All meaScreening for potential biomarkers was carried out using HPLC-MS/MS of blood plasma samples of 10 healthy subjects and 10 NPC1 patients with accurate mass MS-systems (Orbitrap XL) and tandem MS systems. Differences between NPC1 patients and healthy controls were carefully assessed with regards to substances strongly increased only in patients. Molecular weight and structure of such substances were determined carefully. Peaks were identified by accurate mass MS-system and measured by tandem MS/MS systems using already known internal standards as reference. After validating the robustness of lyso-SM-509, measurements in healthy controls, NPC1 carriers, NPC1 patients and in patients with other LSDs ensued ) working solution (in EtOH) and were then mixed subsequently using a DVX-2500 Multi-tube vortex device at 2500 rpm for about 30 seconds. After centrifugation at 4000 rpm for 2 minutes the clear supernatant was transferred into auto-sampler vials and injected into the HPLC-MS/MS system. Mobile phase used for gradient elution was 50 mM formic acid in water and 50 mM formic acid in acetonitrile/acetone . HPLC flow was set at 0.9 mL/min on an ACE 3 C8 column (50 × 2.1 mm) at 60°C, the injection volume used was 5 μL. Retention time for the analytes were approximately 3.2 minutes for lyso-SM and 3.6 minutes for lyso-SM-509, and for the internal standard ) approximately 3.2 minutes. Lyso-Gb2 was checked in regards to native concentrations in plasma and was found to be at very low levels only, a sufficient amount was added therefore during sample preparation. The MS/MS system used was an API 4000 using electrospray ionization in MRM mode in positive mode at 500°C for determination of free Lyso-Sphingomyelin in plasma. Quadrupole resolution was set at unit /unit, MRM transitions used were 465 → 184 m/z for the analyte, 509 → 184 m/z for 509, and 624 → 282 for the internal standard. Calibration was done from 2 ng/mL to 200 ng/mL in aqueous/methanolic solution; QC samples were spiked in plasma at levels of 15 and 150 ng/mL.www.spss.com).Data were aggregated by taking the first measured value according to genotype . Data is given in median and interquartile range where indicated. In order to analyze the diagnostic value of lyso-sphingomyelin-509 a receiver operating characteristic (ROC) curve was employed and the area under the curve (AUC) with 95%CI was calculated. Descriptive statistics and ROC curve analysis were done using SPSS Release Version 22 . Graphs with error bars represent mean ± SD. A p-value smaller than 0.05 was considered significant.Logistic regression models were fitted to compare proportions, Wilcoxon-Mann-Whitney and Kruskal-Wallis tests were used to compare medians, and ANOVA was used to compare means where appropriate. Linear regression models were fitted with maximum likelihood. A locally adaptive super smoother was used to extract the data structure without a regression model . These cThe protocol of the BioNPC trial has been approved by the Research Ethics Committee of the University Rostock . Patients undergoing therapy were treated according to standard protocols. Written informed consent was obtained from all participants or their legal guardians.The recently emerging novel treatment approaches for treating NPC including cyclodextrin , HSP70 aSince then the perception of lysoglycosphingolipids has changed dramatically. For example several lysosphingolipid biomarkers having been established recently, e.g. lyso-Globotriaosylceramide (lyso-Gb3) in Fabry disease , Glucosy24H49N2O7P as the molecular formula for lyso-SM-509  NPC1 carriers  NP-A/B patients  NP-A/B carriers , and (5) healthy controls  NPC1 patients  ,11. In tρ denotes Spearman’s correlation coefficient . In addition, lyso-SM-509 levels correlate very well with cholestane-3β,5α,6β-triol  , we measured its values in 240 samples from 125 subjects  that were previously collected and analyzed by FM Platt and colleagues in the scope of a 5-year international prospective study investigating lysosomal volume in B cells from NPC patients . Data foρ = 0.031, p = 0.794). However, as NPC1 is a progressive neurodegenerative disorder, and patients continue to progress over a number of years the annual severity increment score (ASIS) [p = 0.003), as were cholestane-3β,5α,6β-triol (slope p < 0.001) and MEFL (slope p = 0.039)  so a larger study will be needed to address this.A randomly selected subgroup of 73 samples with measurements from 36 NPC1 patients for cholestane-3β,5α,6β-triol and lyso-SM-509 (median age: 12.76 (IQR: 9.83-17.28)) and MEFL with 57 measurements in 30 patients (median age: 13.00 IQR: 10.38-18.49)) were analyzed for correlations with the total severity score of the patients (excluding hearing). In agreement with previous studies on the cholestane-3β,5α,6β-triol and MEFL there were no significant correlations with any of these biomarkers (data not shown) .38-18.49. We alsoe (ASIS)  was calce (ASIS) , hearingIn summary, we have established a novel, sensitive and specific biomarker for the primary diagnosis of NPC1. The major advantage of lyso-SM-509 is that it is quick and easy to measure and standardize. As a consequence, lyso-SM-509 is definitely a useful biomarker for simple diagnostic in blood plasma, future investigations will analyze the sensitivity and specificity of lyso-SM-509 on dried blood spot samples, which would further simplify the diagnostic process.


Microvascular obstruction (MVO) following primary percutaneous coronary intervention (PPCI) treatment of ST-segment elevation myocardial infarction (STEMI) contributes to infarct expansion, left ventricular (LV) remodelling, and worse clinical outcomes. The REFLO-STEMI trial tested whether intra-coronary (IC) high-dose adenosine or sodium nitroprusside (SNP) reduce infarct size and/or MVO determined by cardiac magnetic resonance (CMR).n = 197). Clinical follow-up was to 6 months. There was no significant difference in infarct size  between adenosine , SNP , and control , P = 0.062 and P = 0.160, respectively, vs. control. MVO  was similar across groups . On per-protocol analysis, infarct size , major adverse cardiac events  at 30 days and 6 months  were increased and ejection fraction reduced  in adenosine-treated patients compared with control.REFLO-STEMI, a prospective, open-label, multi-centre trial with blinded endpoints, randomized (1:1:1) 247 STEMI patients with single vessel disease presenting within 6 h of symptom onset to IC adenosine  or SNP  immediately following thrombectomy and again following stenting, or to standard PPCI. The primary endpoint was infarct size % LV mass (%LVM) on CMR undertaken 24–96 h after PPCI (High-dose IC adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR. Furthermore, adenosine may adversely affect mid-term clinical outcome.https://clinicaltrials.gov/ct2/show/NCT01747174ClinicalTrials.gov Identifier: NCT01747174;  See page 1920 for the editorial comment on this article (doi:10.1093/eurheartj/ehw186)1 However, residual mortality (up to 12% at 6 months1) and morbidity may be partially attributable to sub-optimal microvascular perfusion.3 Microvascular obstruction (MVO) can occur in up to 70% patients when detected with cardiovascular magnetic resonance (CMR) imaging.5 Microvascular obstruction may contribute to infarct expansion, adverse left ventricular (LV) remodelling and adverse clinical outcomes, independent of infarct size.5Primary percutaneous coronary intervention (PPCI) is the default reperfusion therapy for ST-segment elevation myocardial infarction (STEMI).6 and have included calcium channel blockers, nicorandil, atrial natriuretic peptide, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, thrombolytics, and, perhaps most studied, vaso-active agents such as sodium nitroprusside (SNP)8 and adenosine.8–12 Adenosine inhibits neutrophil-related processes central to the evolution of MVO and in a canine model, reduced ischaemia-reperfusion injury (IRI), limited infarct size, and improved ventricular function.13 Sodium nitroprusside is a direct nitric oxide donor that mediates potent arteriolar vasodilation, inhibits platelet adhesion and promotes anti-inflammatory processes,14 which effectively reduce MVO in animal IRI models.15 Previous clinical trials with these agents varied in their design and they mostly lacked a sensitive method to detect MVO, which may have contributed to the multiple conflicting results seen.17 Uncertainty remains regarding the potential therapeutic impact of these agents.1Various strategies have been proposed to attenuate MVOWe hypothesized that, in patients undergoing PPCI for STEMI, appropriate doses of intra-coronary (IC) adenosine or SNP delivered distally to the coronary bed, and again after stent deployment, was the optimal administration that would reduce infarct size and MVO as determined by the sensitive measure of in-patient CMR.16 Briefly, REFLO-STEMI was a multi-centre, prospective, randomized, open-label, controlled trial, with blinded endpoint analysis, conducted in accordance with the Helsinki Declaration. Ethical approval for the study (reference 11/H0405/10) was obtained from the National Research Ethics Service (UK). ST-segment elevation myocardial infarction patients with single vessel disease and thrombolysis in myocardial infarction (TIMI) flow grades 0–1 in the IRA were enrolled between October 2011 and April 2014 in four regional cardiac centres in the UK. All patients >18 years age, presenting within 6 h of symptom onset, with ST-segment elevation ≥2 mm in ≥2 contiguous leads and with a baseline corrected QT interval (QTc) <450 ms on admission electrocardiogram (ECG) were eligible and assented.16 Full eligibility criteria are shown in The trial design and methods have been published previously.1 as well as bivalirudin 0.75 mg/kg bolus plus infusion of 1.75 mg/kg/h until completion of PPCI or continued for 4 h if clinically indicated. Bivalirudin, recommended in all patients, was standard of care in the enrolling centres at the time of trial initiation. Allocation was 1:1:1 to adenosine, SNP, or control  with stratification by ‘symptoms to balloon either less than or ≥3 h’ and ‘anterior infarction or not’. Manual thrombectomy was mandated in all patients and the thrombectomy catheter then used to deliver the first drug bolus (adenosine 1 mg or SNP 250 μg) IC distal in the coronary bed, after thorough flushing of the catheter. Immediately following stent deployment, and providing a repeat QTc was <450 ms , the second dose (adenosine 1 mg if IRA was the right coronary artery otherwise 2 mg or SNP 250 μg) was delivered over 1 min via the guide catheter .Patients were randomized using a 24-h interactive voice recognition service with concealed allocation. All patients were pre-treated with aspirin 300 mg and prasugrel 60 mg or ticagrelor 180 mgFigure 1) to determine infarct size (primary endpoint).16 Secondary outcomes included: MVO extent assessed on early- and late-gadolinium enhanced  images and the presence of intra-myocardial haemorrhage (IMH) on CMR; ST-segment resolution (STR) on ECG performed 90 min post-PPCI; major adverse cardiovascular events  within 6 months. Important adverse events and study outcome measures are defined online  using cmr42 . Early-gadolinium enhanced and LGE images were acquired after 1–3 and 10–15 min, respectively, following 0.15 mmol/kg gadolinium-DTPA  administration using a single-shot or segmented inversion-recovery gradient-echo sequence. Early- and late-MVO  were defined as hypoenhancement within the infarct territory on EGE and LGE imaging, respectively. Left ventricular volumes, infarct size, myocardial oedema , intra-myocardial haemorrhage (IMH), and MSI were determined as described previously.16Cardiac magnetic resonance was performed as previously described18–22α of 0.05 and two tailed, with 80% power, a total of 192 patients were required. Allowing for a drop-out rate of 20% between PPCI and CMR resulted in a final sample size requirement of 240 patients.To detect a reduction in infarct size from 20 to 15% of LV mass, assuming a standard deviation of 10%,t-tests and analysis of variance (ANOVA). Non-normally distributed data were presented as median (25th–75th quartiles) and compared using non-parametric methods . Comparison between groups for categorical outcomes was undertaken using χ2 tests. Potential significant confounders of infarct size  were assessed using a forward selection procedure . Multivariable analysis using linear regression was used to adjust for significant confounders. Time-to-event Cox proportional hazards regression models were used to assess predictors of first MACE (both at 30 days and at the study end) and to obtain unadjusted and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for adenosine/SNP vs. control. In addition, actuarial event rates of MACE by 1 and 6 months for each intervention were reported with 95% CIs. The assumption of proportional hazards was assessed by a global hypothesis test.24 No formal adjustment for multiple hypothesis testing was used, but P-values were interpreted cautiously. All statistical analyses were performed using SPSS  and R .Primary analysis was by intention-to-treat with a secondary per-protocol analysis in those patients who received both doses of the investigational drugs. Continuous variables, including infarct size, were investigated for normality and were log-transformed when found to be non-normally distributed. Normally distributed continuous variables were expressed as mean ± standard deviation and compared using Figure 2. Two hundred and forty-seven patients were randomized with 207 (84%) undergoing CMR. Ten patients did not complete the CMR  so that the primary outcome of infarct size was assessed in 197 patients (80% of those randomized).Patient recruitment is outlined in Table 1 (see Baseline characteristics for randomized patients are presented in Table 2). Intra-procedural complications were similar across all groups. However, the incidence of transient atrio-ventricular (AV) block not requiring pacing was greater in the control arm. There was a low incidence of AV block requiring pacing with the study drugs (adenosine 2.4% vs. SNP 1.3% vs. 0% in control arm). The rate of transient hypotension  was almost three-fold greater  in the SNP group compared with control.Radial access, thrombectomy, and drug-eluting stent use were uniformly high  and 53/79 (67%) patients . The commonest reasons for withholding the second dose were QTc prolongation in 30  and hypotension in 3  patients. Failure to cross the lesion or deploy a stent and prohibiting intra-procedural complications accounted for the remainder.Table 2). Likewise ECG (STR>70%) assessment of microvascular tissue perfusion was similar across the groups. There was no statistically significant difference between groups in peak creatine kinase levels.There was no difference in the occurrence of post-PPCI TIMI flow grade <3 between groups (Table 3). On multivariable regression analysis, adjusting for significant confounders, mean infarct size was increased in the adenosine group  when compared with controls. This was not seen in the SNP group.There was no statistically significant difference in the primary outcome measure of unadjusted infarct size between groups (P = 0.029). However, the extent of L-MVO was small and not significantly different between any groups. Other CMR parameters of microvascular injury (E-MVO and IMH) were also similar between groups and none of the potential confounders were identified as being of statistical importance by the forward selection procedure. Diagnostic quality T2-weighted (oedema) imaging was only obtainable in 109 patients (55%). There were no significant differences in AAR or MSI between groups.Late-MVO was present in 67% patients and was significantly more prevalent in the SNP arm vs. control .Left ventricular end-diastolic and end-systolic volumes indexed to BSA  were significantly increased with adenosine compared with control and this was accompanied by a non-significant reduction in ejection fraction (EF). Left ventricular volumes and function were similar in the SNP and standard PPCI arms (P = 0.004) in the adenosine-treated group compared with control  driven by incidence of heart failure ; HR 6.53 (95% CIs 1.46–29.2), P = 0.01. When adjusted for potential confounders, the observed MACE difference remained with similar hazard ratios with P-values: P = 0.018 at 30 days and P = 0.01 at 6 months (see Table 4).Two hundred and thirty-three (94%) patients completed follow-up (12 patients withdrew consent/refused follow-up and 2 patients were lost to follow-up). There was a significant increase in MACE at 6 months  and LV volumes  and EF (%) was reduced . Major adverse cardiac events was increased in per-protocol adenosine-treated patients compared with control at 30 days  and 6 months . There was no increase in MACE in those who actually received SNP compared with controls  and extent of L-MVO %LVM  compared with controls (see P = 0.025) compared with controls.In patients with anterior STEMI, those who received adenosine had significantly greater IS %LVM . Furthermore, in REOPEN-AMI, the enzymatic infarct size was 30% lower in the adenosine compared with the saline group but this is a greater effect size than would be expected by the attenuation of MVO alone, which makes interpretation difficult. However, in the absence of corroborative AAR or infarct size data from robust imaging such as CMR, this may imply that the adenosine group were destined to have smaller infarcts compared with control , potentially over-estimating the benefit of adenosine in that study.The proportion of patients achieving STR >70%, as an ECG surrogate marker of coronary vascular flow, was relatively high and similar across groups compared with previous studies.8 and an earlier double-blind, placebo-controlled RCT.7In our REFLO-STEMI trial, a positive impact of IC SNP on MVO assessed by ECG or CMR was not seen. This is consistent with the REOPEN-AMI study26 of failure of reduction in MVO or infarct size using adjunctive therapies, despite an extensive body of positive experimental data, raises the question of trial design or even whether IRI is a distinct entity clinically and whether it represents exclusively ischaemic injury.27The demonstration in our study, and in those of others,post hoc analysis of AMISTAD-II, which reported that a 3 h adenosine infusion decreased 1-month  and 6-month mortality  compared with placebo, and reduced the composite clinical endpoint of death or heart failure at 6 months .28 However, there were several methodological weaknesses with that study including: (i) adenosine was infused intravenously after the PCI, (ii) infarct size was measured in only 11% of patients and by technetium-99m sestamibi single-photon emission computed tomography, which may underestimate infarct size compared with CMR; and (iii) no measure of myocardial salvage was obtained. Furthermore, the adverse MACE signal seen with adenosine in our study is consistent whether assessed as intention-to-treat or per-protocol analysis, at 1 and 6 months follow-up and remains despite adjustment for potential confounding variables. This suggests that high-dose IC adenosine, delivered as we have indicated in this study, may lead to significantly worse clinical outcomes.There were significantly worse outcomes for the adenosine group compared with control, largely driven by increased early heart failure events. This is a novel finding. Whilst this may have occurred by chance, the hazard ratio is high and cannot be discounted. Our results, including definitive and significantly worse clinical outcome particularly in those with anterior STEMI receiving adenosine, contradicts the Table 1) and there were no significant differences in the primary endpoint or MVO for the patients receiving ticagrelor  and probably should not be used to prevent MVO, in the circumstances of this trial.The finding of an adverse effect of high-dose adenosine remains difficult to explain. It could be that high-dose adenosine tends to activate other receptors, which lead to adverse events; adenosine has been speculated to be responsible for excess dyspnoea observed with ticagrelor in the PLATO study. However, any effect of ticagrelor on circulating adenosine levels is likely to be small compared with the relatively high doses of adenosine administered in our study. Furthermore, the distribution of ticagrelor and prasugrel across the treatment arms was comparable  this was not overwhelming, and our results were further supported by actuarial estimates of the absolute MACE event rate by 6 months.2-AR; 30 We utilized a slow-bolus dosing regimen and it could be that, owing to the short-half life of adenosine, concentrations of adenosine were insufficient in the microvascular bed to augment the benefits of reperfusion. A1-AR activation at lower adenosine doses may exacerbate MVO by promoting neutrophil chemotaxis.30 As such, delivering adenosine as a continuous infusion, to ensure more prolonged availability of adenosine in the microvasculature, may be superior to boli injections in antagonizing MVO-related processes. It should be noted that one might still consider low-dose (50–100 μg) adenosine, as is common in clinical practice, to reverse established slow-flow or no-reflow when it occurs.It is possible that the dose of adenosine used in our study was insufficient to achieve sustained activation of AIntra-coronary adenosine and SNP did not reduce infarct size nor MVO during PPCI for STEMI. Furthermore, high-dose adenosine appeared to be associated with adverse clinical outcomes, increased infarct size, and reduced EF compared with control. These data suggest that neither agent is effective for sub-clinical no-reflow and should not be used routinely and prophylactically in the setting of PPCI to prevent reperfusion injury.S.N., K.A. performed statistical analysis; A.G., G.M., J.G., D.B., I.M., L.S., K.A., S.N. handled funding and supervision; S.N., J.K., G.M., J.G., D.B., V.K., M.B., A.G. acquired the data; A.G., G.M., J. G., D.B., I.M., L.S., S.N. conceived and designed the research; S.N., A.G. drafted the manuscript; G.M., J.G., D.B., V.K., J.K., I.M., M.B., R.W., A.A.J.A. made critical revision of the manuscript for key intellectual content.REFLO-STEMI was funded by the Medical Research Council (MRC) through the Efficacy and Mechanism Evaluation (EME) Board (project number 09/150/28) and managed by the NIHR on behalf of the MRC-NIHR partnership. Funding to pay the Open Access publication charges for this article was provided by The University of Leicester.Conflict of interest: none declared.Supplementary DataClick here for additional data file.


P < 0.05). In multivariate analysis, BP reverse dipping remained significantly associated with the prevalence of sCAD . Furthermore, the circadian decline rate of SBP was independently associated with sCAD . The hypertensive patients with reverse BP dipping were found to be more frequently suffering from sCAD. BP reverse dipping examined with 24-hour ABPM may indicate sCAD.The dipping variations of circadian blood pressure (BP) correlate closely with target-organ damages and cardiovascular events. The aim of this study was to investigate the relationship between BP reverse dipping and the prevalence of stable coronary artery disease (sCAD) in hypertensive patients. Clinical data and the results of 24-hour ambulatory BP monitoring (ABPM) were obtained from 718 hypertensive patients  in a single centre in Northern China. Reverse dipping pattern was defined as nocturnal systolic BP (SBP) was higher than daytime SBP. A logistic regression model was applied to explore the independent risk factors of sCAD. The patients with BP reverse dipping accounted for 31.5% in sCAD group and 19.5% in control group ( Blood pressure (BP) presents a reproducible circadian pattern, which is normally lower at night than during the day by approximately 10–20%, mostly due to endogenous neuroendocrine rhythms and other variables23678Our previous studies have demonstrated that BP reverse dipping was exposed to higher risks for lacuna infarction and carotid plaque formation, which was shown to be able to predict coronary artery disease (CAD) accurately10116There are published evidences indicating carotid plaque could predict ischemic stroke and CAD accurately in clinical practice1116The age of all hypertensive patients (257 sCAD and 461 non-sCAD) is 59.6 ± 13.8 years (range: 21 to 87) in average, 54.3% of the participates were males, 29.9% were current smokers, 26.3% had diabetes mellitus and 24-hour SBP were 134.6 ± 14.0 mmHg. Hypertensive patients with sCAD (31.5%) had higher percentage of BP reverse dipping pattern than control group (19.5%) (p = 0.004). In the meanwhile, the proportion of dipping pattern was 18.3% in sCAD group and 28.2% in non-sCAD group. Moreover, the ratio of nondipping pattern was similar between sCAD (50.2%) and non-sCAD (52.3%). Other clinical characteristics of the participates are shown in p = 0.031), dipping and reverse dipping (p < 0.001), non-dipping and reverse dipping (p = 0.004) were statistically significant. Patients with reverse dipping pattern had a lowest prevalence of non-sCAD while had a highest prevalence of sCAD (p < 0.01).The distribution of hypertensive patients with sCAD in dipping, nondipping and reverse dipping group was 26.6%, 34.9% and 47.4%, respectively. After using chi-squared test, the difference between dipping and non-dipping (P = 0.027), age  and total cholesterol  were significantly correlated with sCAD (P = 0.043) was significantly related to sCAD  and age  were significantly associated with reverse dipping .Our previous study revealed that diabetes and reverse dipping were interrelated risk factor for each other. This study also found that diabetes  and “non-dipper”2315242526p < 0.05), not non-dipper pattern, was directly associated with lacunar infarctionWe have previously found “non-dippers” had significant heterogeneity in complications among a small population of hypertensive patients. To further clarify the impact of different circadian BP patterns, we divided the patients into normal dipping (night-to-day SBP ratio ≤ 0.9 and >0.8), extreme dipping (night-to-day SBP ratio ≤ 0.8), nondipping (night-to-day SBP ratio ≤ 1.0 and >0.9) and reverse dipping (night-to-day SBP ratio >1.0) according to previous literatureAs a particular portion of non-dipper pattern, reverse dipper pattern has been shown to correlate with the highest incidence of cardiovascular events and worst prognosis in hypertensive patients, comparing with the dippers and non-dippersAlthough the relationship may be present between reverse dipper pattern of BP and CAD, the pathophysiological mechanism is far more to be investigated. We would like to propose that the higher risk of atherosclerosis associated with reverse dipper pattern of BP may relate to relatively higher blood mechanical forces on endothelial cells, leading to the damage of vascular integrity. It has been revealed that BP variability may correlate with aortic wall remodeling and reduced aortic compliance in the animal experiment33et al.Ultrasound assessment of carotid plaque is a non-invasive imaging test to evaluate the cardiovascular complications of patientTo our knowledge, this is the first study to report the association between reverse dipper pattern of BP and the incidence of sCAD in individuals with hypertension. Therefore, the development of antihypertensive medicine with an effect on decreased fall of nocturnal BP may influence the development of sCAD. Further studies are needed to address the differing impact of extreme-dipper pattern on CAD in hypertensive patients. In addition, multiple ABPM over a longer period of time may provide more information.Hypertensive patient selection and data retrieval were extracted from ABPM database from April 2012 to June 2013 (n = 1740) in the Second Affiliated Hospital, Xi’an Jiaotong University School of Medicine, Northern China. Hypertensive patients were defined as office BP ≥ 140/90 mmHg or 24-hour ABPM ≥ 135/85 mmHg20Ambulatory BP was monitored over a 24-hour period using an oscillometric device . All the participants were asked to record their activities, sleep times and sleep quality during the monitoring session. Strenuous physical activity was discouraged during the monitoring period. The BP recording was made every 30 min from 7:00 AM till 11:00 PM and every 60 min from 11:00 PM till 7:00 AM. The parameters evaluated were mean 24-hour systolic and diastolic BP (SBP and DBP), SBP- and DBP-awakening, SBP- and DBP-bedtime. We divided the patient according to nocturnal BP reduction as follow: normal dipping (night-to-day SBP ratio ≤ 0.9 and >0.8), extreme dipping (night-to-day SBP ratio ≤ 0.8), nondipping (night-to-day SBP ratio ≤ 1.0 and >0.9) and reverse dipping (night-to-day SBP ratio >1.0)The initial diagnostic approach for CAD encompasses syndrome, identifying significant dyslipidaemia, hyperglycaemia or other biochemical risk factors, chest radiography, echocardiography and an electrocardiogram. Once this initial evaluation is performed stress testing, CT angiography and a coronary angiogram may be necessary to obtain further diagnostic insightt-test (continuous variables) and by χ2-test , respectively. A logistic regression model was utilized to analyze the relationship between sCAD and age, gender, smoking, diabetes, cholesterol, triglycerides, circadian blood pressure variation and ABPM results. Variables with statistical significance in univariate models were then included in the multivariate analyses. A two-tailed P value of less than 0.05 was considered statistically significant.All the data was analyzed using SPSS version 18.0 . Bivariate comparisons between patients with and without sCAD were performed by unpaired How to cite this article: Yan, B. et al. Blood pressure reverse dipping may associate with stable coronary artery disease in patients with essential hypertension: a cross-sectional study. Sci. Rep.6, 25410; doi: 10.1038/srep25410 (2016).


Vascular insufficiency has been reported to be a cause of normal tension glaucoma (NTG). The aim of this study was to compare ocular perfusion pressure (OPP) and ophthalmic artery flow (OAF) between patients with NTG and those without glaucoma.χ2, ANOVA and Pearson Correlation tests were performed, with p < 0.05 considered statistically significant.We considered one eye each from 31 NTG and 15 non-glaucoma control patients. Blood pressure and intraocular pressure (IOP) were measured in the sitting position, for calculation of OPP. Humphrey visual field (HVF) assessment was then carried out on NTG patients. All patients then underwent Transcranial Doppler ultrasound measurements of OAF parameters, including mean flow velocity (MFV), end diastolic velocity (EDV), peak systolic velocity (PSV) and resistive index (RI). We looked at differences in OPP and OAF parameters between the two groups, and their correlations in NTG patients. T-tests, p = 0.393), and also no statistically significant differences in MFV, EDV, PSV and RI . In the NTG group, there were positive correlations between OPP and both MFV  and EDV . There were no statistically significant correlations between HVF mean deviation and OPP or OAF parameters .There were no statistically significant differences in OPP between the NTG and control groups (60.5+/-8.7 mmHg and 62.9+/-10.2 mmHg respectively, There is no difference in OPP and OAF parameters between patients with NTG and non-glaucoma controls, suggesting that vascular insufficiency or dysregulation by themselves may not account for the pathogenesis of NTG. Normal tension glaucoma (NTG) is a variant of primary open angle glaucoma (POAG). It is characterized by glaucomatous optic disc damage and visual field loss; intraocular pressure (IOP) of ≤21 mmHg; open drainage angles on gonioscopy; and absence of secondary causes for the glaucomatous optic disc damage. The pathogenesis of NTG has not been conclusively determined, although vascular insufficiency and decreased optic disc resistance have been postulated .Ocular perfusion pressure (OPP) is the calculated difference between mean arterial blood pressure and IOP. It is an important parameter which determines the perfusion of the optic nerve head. OPP has been linked with glaucoma in many epidemiologic studies –8. In pawhere DBP is diastolic blood pressure and SBP is systolic blood pressure.The ophthalmic artery is the first branch of the internal carotid artery distal to the cavernous sinus. Branches of the ophthalmic artery supply all the structures in the orbit. The ophthalmic artery can be detected by Transcranial Doppler (TCD) ultrasound. This modality measures the velocity of blood flow through the blood vessels in the brain. The velocities follow the cardiac cycle, and measurements of the peak systolic velocity (PSV) and mean flow velocity (MFV) are usually taken. End diastolic velocity (EDV) is usually calculated fromThe Resistive Index (RI) is a ratio used to relate the systolic and diastolic velocities to each other. It is relatively operator independent, and is a good method to quantify the vascular resistance of the circulation . RI reflThe main objectives in this study were to look for differences in OAF and OPP between NTG and non-glaucomatous patient, and to determine the correlation between OPP and OAF in NTG patients. We also aimed to identify if OAF and OPP parameters changed with increasing severity of glaucoma in NTG patients.This was a cross-sectional, non-interventional study at the Ophthalmology clinic and Neurology laboratory of the University Malaya Medical Centre, Kuala Lumpur. Data was collected from August till December 2014. This study complied with the tenets of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the University Malaya Medical Centre. Informed consent was given by every subject prior to their enrolment.NTG patients were defined as those having glaucomatous visual field defects corresponding to optic disc changes; IOP of ≤21 mmHg on 24-h phasing; open iridocorneal angles on gonioscopy; and no evidence of secondary glaucoma such as pseudoexfoliation or pigment dispersion. Exclusion criteria included presence of diabetic or hypertensive retinopathy, past history of cerebrovascular accidents which could contribute to visual field defects, and eyes which had undergone any kind of glaucoma filtration or drainage device surgery. Controls were selected from patients attending the Ophthalmology clinic for various conditions, including cataract and diabetic retinopathy screening. These patients had cup-disc ratios within normal limits and IOP of ≤21 mmHg.All subjects underwent full eye examinations including visual acuity, slit lamp examination, and IOP measurement. IOP measurements were taken using a Goldmann applanation tonometer . Two readings were taken and the average recorded. Gonioscopy was carried out if a prior examination had not been done in the last 6 months. Dilated fundoscopy was done, and the cup-disc ratios assessed clinically. Following this, blood pressure measurements were taken in the sitting position using an automated blood pressure monitor . SITA-standard, central 24-2 Humphrey visual field assessment was then carried out for the NTG patients. Reliable results were defined as false positive and false negative values of <33 %, and the Mean Deviation (MD) value was taken as a measure of glaucoma severity. Finally, all subjects had Transcranial Colour Doppler imaging of the OAF at the Neurology laboratory, using a SONARA Transcranial Doppler system . One experienced technician performed all the examinations. The technique was standardised; with the patient lying supine and head resting on one pillow, the transducer was placed on the closed eyelid, with coupling gel in between. No overt force was used during placement of the transducer. Measurements took about 5 min to obtain per eye. MFV, PSV and RI were measured while EDV was calculated based on the formula mentioned previously. All these procedures were performed between 11 am and 1 pm on the same day.χ2 tests and ANOVA were performed to test differences between the groups. Pearson correlation tests were performed to study the correlation between variables in the NTG group. P < 0.05 was considered statistically significant.We analysed the right eyes of the patients and controls, except in one patient who had previously undergone a filtration procedure in that eye. In this patient, the left eye was analysed. Data analysis was performed using SPSS version 14 . T-tests, The study group consisted of 31 NTG patients and 15 normal patients. There were no statistically significant differences in demographics, OPP parameters, and OAF parameters between the NTG and control groups  between the groups. Plange et al. found that patients with NTG had lower PSV and EDV when compared to healthy controls . Kaiser We found moderate positive correlations between OPP and both MFV and EDV in the NTG patients. In our literature search, we found only one other study which looked into this relationship. Gherghel et al. found a positive correlation between OPP and EDV in patients with progressive POAG and NTG . HoweverNo statistically significant correlation was found between severity of glaucoma, as evidenced by MD values, and either OPP or OAF parameters. We believe that this may have been contributed by the fact that our study had more patients with mild glaucoma  than those with moderate  or severe  glaucoma. In a study conducted by Kondo et al., they noted that NTG patients with less severe glaucoma had significantly better retrobulbar haemodynamics compared to those with more severe glaucoma . In our There are a few limitations to this study. We measured blood flow velocity in the ophthalmic artery as an indicator of the optic nerve microcirculation. As the artery supplies all structures in the orbit, the non-statistically significant changes and correlations observed in this study do not rule out changes in arteries directly supplying the optic nerve such as the posterior ciliary arteries. Next, there was no washout of the patients’ anti-glaucoma medications. Some of the patients had advanced glaucoma and it was deemed unsuitable to stop treatment for this group. Had we found any differences between the groups, it would be difficult to attribute them to the glaucoma, or to the anti-glaucoma medication. We also did not exclude patients with underlying diabetes mellitus or hypertension. Although it was assumed that these patients did not have severe microvascular changes based on the fact that they did not have diabetic or hypertensive retinopathy, there may have been underlying milder microvascular damage in the eyes of both groups of subjects, which could have influenced the outcome of this study. Finally, the sample size was also relatively small, and thus had limited power to detect differences between the groups. In future studies, a larger sample size may find differences between NTG patients and healthy controls that were not discovered in this study.There is no difference in OPP and OAF parameters between patients with NTG and non-glaucoma controls, suggesting that vascular insufficiency or dysregulation by themselves may not account for the pathogenesis of NTG.This study complied with the tenets of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the University Malaya Medical Centre. Informed consent was given by every subject prior to their enrolment.Not applicable.The first author has full access to all the data. This will be shared upon request.


Although there are no prevalence studies on hypertension in Botswana, this condition is thought to be common and the quality of care to be poor.The aim of this project was to assess and improve the quality of primary care for hypertension.Moshupa clinic and catchment area, Botswana.Quality improvement cycle.p < 0.05) was shown in 10 criteria although the target standard was not always met. In the re-audit, the target of achieving blood pressure control (< 140/90) in 70% of patients was achieved.Two hundred participants were included in the audit. Sixty-eight per cent were women with a mean age of 55 years. In the baseline audit none of the target standards were met. During the re-audit six months later, six out of nine structural target standards, five out of 11 process target standards and one out of two outcome target standards were achieved. Statistically-significant improvement in performance (The quality of care for hypertension was suboptimal in our setting. Simple interventions were designed and implemented to improve the quality of care. These interventions led to significant improvement in structural and process criteria. A corresponding significant improvement in the control of blood pressure was also seen. This imposes more financial constraints on the health system, which is already burdened by the HIV pandemic. Based on the available evidence, the current US guidelines, published in the Seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC 7), recommend maintaining blood pressure at less than 140/90 mmHg for most patients and less than 130/85 mmHg for patients with diabetes mellitus and renal disease.7 A reduction of 5–6 mmHg in diastolic blood pressure (DBP) has been shown to reduce the incidence of stroke by 40%, coronary events by 15% and heart failure by 50%.5 Non-pharmacological measures as well as medication can contribute to blood pressure reduction. For example, the Dietary Approaches to Stop Hypertension (DASH) low sodium diet reduces the systolic blood pressure (SBP) by 2–8 mmHg and weight reduction of 10 kg can contribute to a reduction of 5–20 mmHg.5There is evidence that treatment to specific targets can reduce morbidity and mortality.5 A study conducted on veterans in the USA from 1990 to 1995 showed that more than 65% had blood pressure measurements of 140/90 mmHg or higher and 40% had measurements of 160/90 mmHg or higher.5 Only 24% had their blood pressure controlled to less than 140/90 mmHg in a study conducted at five Department of Veterans Affairs sites in the USA.8Despite this evidence, treatment in many settings is not very successful at achieving blood pressure control and meeting these targets. Control may remain poor as a result of limited resources, poor adherence to medication as well as inappropriate choice of medication. The National Health and Nutrition Examination Survey (NHANES III), conducted in the United States of America (USA) from 1988 to 1991, showed that 76% of known hypertensive patients had blood pressure measurements of 140/90 mmHg or higher.4It is likely that the control of blood pressure and quality of care in Botswana is also problematic, although few studies exist to verify this. One study performed in Gaborone demonstrated that health workers frequently measure the patients’ blood pressure incorrectly.9 Both guidelines address the processes of care for hypertensive patients.There are guidelines that have been developed locally to improve the care of hypertensive patients. The South African Hypertension Society guideline was published in 2011 and a Botswana guideline in 2007.The aim of this study was to improve the quality of care for hypertension at Moshupa clinic in Botswana. The specific objectives were to assess the current quality of care for hypertension; to plan and implement changes to improve the quality of care; to assess whether these changes were associated with a measurable improvement in the quality of care; and to make recommendations to the local Department of Health on how to improve the quality of care in primary care clinics.Ethical approval for the study was obtained from Stellenbosch University, reference N11/06/188.Establishing an audit team.Setting up of criteria and target standards.Data collection.Data analysis.Data interpretation.Planning of changes in the facility and the implementation of the changes.10Re-audit to detect changes in the quality of care.This project was a quality improvement cycle comprising the following steps:11 There is no hospital in Moshupa and the district relies on a mission hospital in Kanye for referral. Laboratory, radiograph facilities and ECG machines are non-existent in the district and all health facilities refer to the mission hospital for these investigations.Moshupa district is situated in the southern part of Botswana. It has an estimated population of 22 811 which is served by 26 health facilities .Clinics are staffed with an average of six health workers whilst health posts have an average of three health workers. Moshupa clinic (the main clinic in Moshupa) offers 24-hour services. It is staffed with 10 nurses working in shifts, a lay counsellor, one health auxiliary, two cleaners and two ambulance drivers.There are six doctors in the district. They are involved in consultation of adults and children in primary care, maternity and emergency care. Each doctor is allocated a number of health facilities that they visit on a monthly basis, but they visit clinics more regularly than health posts.A dedicated hypertension clinic does not exist in the district and hypertensive patients are seen daily, together with other general patients, by doctors and nurses with different levels of expertise. Antihypertensive drugs are refilled monthly at the local clinics. The following antihypertensive classes are available: thiazide diuretics, loop diuretics (furosemide), calcium-channel blockers (nifedipine), beta blockers , angiotensin-converting enzyme inhibitors . Health education is organised in each health facility in the morning and covers a variety of topics, with talks delivered by the health workers. At times, patients are also asked to deliver a health talk under the supervision of a nurse or health education assistant.The present study focused on the Moshupa council clinic and the three health posts that were in its catchment area: Lothlakane West health post, Moshupa health post and Ralekgetho health post.The audit team was headed by the main researcher and included two doctors, one health auxiliary and four nurses. The team members felt motivated to participate in the quality improvement cycle as this would serve as a basis to audit other health programmes in which they had any active involvement. Prior to the audit, members had training on blood pressure measurement, which was not assessed in the study.7 which are the latest regional guideline based on internationally-accepted evidence. These guidelines also address the process of care in more detail and stratify the cardiovascular risk. The performance levels were set to be achievable targets and were based on the opinion of the audit team.The audit team opted to use the South African Society of Hypertension guidelines,7to assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatmentto reveal identifiable causes of high blood pressureto assess the presence or absence of target organ damage and cardiovascular disease (CVD).The South African Hypertension Society has established steps to follow to control BP. The first step is to evaluate the hypertensive patients with the following three objectives:5 Further decisions with regard to the introduction of antihypertensive medications depend on the current blood pressure and the level of risk as described by the first step of evaluation of all hypertensive patients.In a nutshell, lifestyle modifications reduce blood pressure, prevent or delay the incidence of hypertension, enhance antihypertensive drug efficacy and decrease cardiovascular risk.The choice of antihypertensive medications is also influenced by the presence of other co-morbid conditions, such as ischaemic heart disease, gout or asthma. In patients without such co-morbid conditions, the first antihypertensive medications are usually the thiazide or thiazide-like diuretics.SBP 120–129 mmHg or DBP 80–84 mmHgNormal:SBP 130–139 mmHg or DBP 85–89 mmHgHigh normal:SBP 140–159 mmHg or DBP 90–99 mmHgStage 1 (mild hypertension):SBP 160–179 mmHg or DBP 100–109 mmHgStage 2 (moderate hypertension):SBP >180 mmHg or DBP >110 mmHgStage3 (severe hypertension):The guidelines classify hypertension as follows:Body weight at every visit.Height at first visit.Body mass index at every visit.Abdominal obesity (waist circumference or waist-to-hip ratio) at every visit.Urinalysis at first visit and then yearly if normal. Repeated at the next visit if abnormal. If 2+ protein or 1+ haematuria, refer for or perform further investigations.Blood tests for creatinine, potassium, total cholesterol and fasting blood glucose should be done yearly.ECG should be done yearly.Furthermore, the guidelines recommend the following routine investigations:Additional investigations are to be performed if secondary causes are suspected at the first visit or if refractory hypertension exists.Treatment of hypertension should aim to achieve a target blood pressure of ≤140/90 mmHg for most patients; and a target blood pressure of ≤130/80 mmHg for patients with diabetes mellitus or chronic kidney disease.The criteria were discussed during a meeting with the members of the audit team that agreed upon the performance levels. Performance levels were set for the structures relevant to hypertension management, the process of managing hypertensive patients and the outcome of the management of hypertension.one functional anaeroid sphygmomanometer (blood pressure machine) at each facilitya small, medium and large blood pressure cuff at each facilityone functional weighing scale at each facilityone functional height scale at each facilitythe hypertension guidelines (2011 Southern African Hypertension Society) at each facilityinvestigation request forms (laboratory and ECG) at each facilityspecimen tubes for blood tests at each facilityan ECG machine at each facilityspecimen bottles for urine at each facility.One would expect certain items to be available at each facility. A score of two was assigned for full compliance, a score of one for partial compliance and zero for non-compliance. Partial compliance meant that items were present, but not in good working condition or in insufficient quantities or expired. Target standards for the structure were the presence of:90% of records have the height recorded once90% of records contain a weight measurement at each visit in the last year90% of records have a classification of hypertension control in last year70% of records demonstrate appropriate drug management as per the guidelines at each visit60% of records have a serum creatinine recorded once yearly60% of records have a fasting blood glucose recorded once yearly60% of records have a record of urinalysis for protein, blood and glucose once yearly90% of records have a random total cholesterol recorded once yearly60% of records have an ECG recorded once yearly80% of records have health education documented  at each visit90% of records have a body mass index recorded at each visit.Target standards for the process were the following:70% of records have a blood pressure < 140/90 mmHg70% of records have a blood pressure < 130/80 mmHg for high risk patients.Target standards for outcomes were:p value of 0.05 recommended that 233 participants be included in the audit. Exclusion criteria were defined as pregnant women, patients from outside the Moshupa clinic catchment area and hypertensive patients aged less than 18 years.Our study population included all adult hypertensive patients aged 18 years and above, who visited the facilities with a documented diagnosis of hypertension over at least a six-month period. A sample-size calculation based on an 80% ability to detect a before–after difference with a Clients were selected systematically by taking every second patient with hypertension who walked into the consulting room for their usual review during November 2011. The folders were then put aside and retrospective data collected from the patient's file using a data collection tool in order to measure the defined criteria. This was done by the doctors and nurses in charge at each of the selected sites. The structural criteria were evaluated by an inspection of the facility by the audit team.p < 0.05).Data were captured using a Microsoft Excel spread sheet and analysed by the Centre for Statistical Consultation at Stellenbosch University. Data analysis included frequency tables and comparison for significant change between the baseline audit and re-audit. Data were categorical in nature and a Chi-square test was used to detect significant differences , Moshupa health post , Lotlhakane health post  and Ralekgetho health post . Moshupa had a larger population and the facilities there were busier than the smaller health posts. The participants’ mean age was 55 years and their age distribution is shown in There were 200 participants recruited from the four different sites: Moshupa clinic (The performance levels for structural criteria in both audits are compared in The performance level for process criteria are compared in Recommendations were formulated by the audit team to address the poor performance seen in the baseline audit. Implementation of changes involved doctors, nurses and the pharmacist. The changes are summarised in The baseline audit demonstrated a poor quality of care for patients with hypertension and achieved none of the target standards. During the re-audit the structural criteria were the most improved, with six targets out of nine achieved. The process criteria showed five targets were achieved out of 11 and the outcome criteria met one target out of two. Significant improvement in performance was shown in 10 criteria although the target standard was not always met. Significant improvement in performance was the more important finding as the levels set were somewhat arbitrary and may have been too high and ambitious in many cases. It was possible to implement changes with simple interventions designed by the audit team and with regular follow up.15Improving the use of investigations was limited by the performance of the hospital-based laboratory, which often lacked reagents or had broken equipment. At the clinic level, the use of incorrect specimen bottles and forms resulted in some specimens being rejected.Our study showed improved blood pressure control with 70% of records recording a blood pressure of less than 140/80 mmHg in the re-audit. These results are supported by a number of other studies where improving the technical quality of care was an effective strategy for improving blood pressure control and was achieved by relatively simple interventions within quality improvement cycles.5 This study demonstrated that the frequency of health education improved, although the audit cannot assess the content or quality of the counselling.Furthermore, JNC7 suggests that healthcare providers give insufficient attention to health education.5 Primary care in Botswana has not been organised for the adequate management of non-communicable diseases, such as hypertension, and yet this audit shows that significant improvement can easily be made when attention is given to the requirements. At the end of the study, however, none of the clinics had easy access to an ECG machine.Routine laboratory tests recommended in the South African guidelines included a 12-lead ECG, urinalysis, blood glucose, creatinine and total cholesterol. These laboratory tests were seldom carried out in the baseline audit, although this improved following the planning and implementation of change to clinical practice. This shows a lack of adherence on the part of the healthcare providers as suggested by the JNC 7 report.Thirty-three patients were lost to follow up and the sample size with paired data was reduced to 200. The sample, however, appeared to be powered adequately to detect significant differences in the re-audit. Poor record keeping meant that not all activities were recorded in the notes and some patients kept their own records, which could not be traced at subsequent visits, resulting in missing data. The anaeroid sphygmomanometers were not calibrated regularly and thus the blood pressure measurements used in the audit were not taken under ideal conditions. The adherence of staff to the rules for blood pressure measurement was also not observed or assessed, although training on this was given prior to the audit.Improvement in performance should be seen as an ongoing process so that improvements are maintained and further improvements targeted. Such a commitment must involve the local facility staff and the district management. Realistic performance targets should be set from the baseline findings and the audit extended to other facilities and health programmes run in the district.The process criteria need additional interventions with regards to access to investigations and essential equipment. ECG machines, glucometers and urine dipsticks need to be procured. The district still relies on the mission hospital for most of the investigations. The audit team advocated for procurement of basic equipment for the main clinic as well as a laboratory facility for the district.The quality of care for hypertension was suboptimal in our setting as highlighted by the baseline audit. Simple interventions were designed and implemented to improve the quality of care of hypertensive patients. These interventions led to significant improvement in structural and process criteria. A corresponding significant improvement in the control of blood pressure was also seen. It is recommended that the quality improvement process be continued, expanded to other clinics and to other chronic conditions.


Aims. The purpose of the present study was to evaluate predictors of outcome in primary supratentorial cerebral haemorrhage. Furthermore, we aimed to develop a prognostic model to predict 30-day fatality. Methods. We retrospectively analyzed a database of 156 patients with spontaneous supratentorial haemorrhage to explore the relationship between clinical and CT characteristics and fatal outcome within 30 days using multiple logistic regression analysis. The analyzed factors included volumetric data assessed by neuropathological and CT volumetry. A second CT scan in survivors or neuropathological ABC/2 volumetry in nonsurvivors was used along with the baseline CT to assess the growth index of haematoma. Results. Systolic blood pressure, serum potassium and glucose levels, platelet count, absolute and relative haematoma volumes, and presence and size of intraventricular haemorrhage statistically significantly predicted the fatal outcome within 30 days. Based on our results we formulated a six-factor scoring algorithm named SUSPEKT to predict outcome. Conclusions. After validation the SUSPEKT score may be applicable in general clinical practice for early patient selection to optimize individual management or for assessment of eligibility for treatment trials. Spontaneous intracerebral haemorrhage (ICH) accounts for 8% to 14% of all strokes and carries the highest mortality rate of major stroke subtypes . Half ofPredictors of mortality and functional outcome have been studied widely –7, but nThe autopsy rate of our department is more than 90%; therefore we could incorporate also the results of brain autopsies into our analysis. This is a unique opportunity (compared with similar studies) in the era of declining brain autopsy rates . Althoug in vivo (image-based) volumetric evaluations with the measurements performed on the same formalin-fixed brain slices after the death of patients. Taking advantage of this opportunity, the ABC/2 method was also applied, using the initial CT as a point of reference, to assess the growth index of the haematoma in the nonsurvivor group as a novel approach. To the best of our knowledge, no remarkable previous attempts have been made to use this method on cadaver brains with ICH.Numerous pathological events might occur in the brain of ICH patients  between the first and second imaging  or betweFurthermore, we developed a new scoring system to predict the risk of death within 30 days after primary supratentorial ICH using variables found to be independently and significantly associated with outcome by multiple logistic regression analysis. All of these variables can practically be reported within the first few hours after admission. After validation, this scoring system has the potential to be useful for early classification of patients.Ethical permission for these investigations was granted by the Regional and Institutional Ethics Committee, University of Debrecen, Medical and Health Science Center. We retrospectively reviewed the data of 156 Caucasian patients (71 nonsurvivors and 85 survivors) with primary supratentorial ICH admitted to our Intensive Care Unit (ICU) in a 53-month period. The outcome was defined as 30-day fatality for any reason. All patients were older than 18 years of age and were transported to our ICU within 24 hours of stroke onset. If this point of time could not be ascertained, we used the last time when the patient was known to be well. All patients routinely underwent a baseline nonenhanced CT within 30 minutes of arrival, and the CT confirmed the ICH. A second CT was obtained on average on the 10th day after admission or when symptoms deteriorated. Exclusion criteria were traumatic ICH, subarachnoid haemorrhage (SAH), vascular malformation, tumour, haemorrhagic transformation of ischaemic stroke (on admission or any CT performed later), postthrombolytic haemorrhage in ischaemic stroke, infratentorial ICH, and primary intraventricular bleeding. We did not include subjects who had undergone neurosurgical evacuation or drainage. All patients were treated on specialized stroke units with multiparametric monitoring.The following data were collected retrospectively from patients' clinical notes partly based on the Debrecen Stroke Database , 12: sex3. Additionally, relative volumes were defined as the ratio of total, intraparenchymal, and intraventricular haematoma volumes to intracranial volume yielding variables (without unit).Image analysis was carried out retrospectively by two consultant neuroradiologists of our Department of Biomedical Laboratory and Imaging Science, who were blinded to the outcome. CT scans were performed on two 16-slice MDCT (multidetector computed tomography) scanners . Slice thickness was 5 to 10 mms for supratentorial and 2.5 to 4 mms for infratentorial regions. Images were transferred to an offline image processing workstation as DICOM  files. Haemorrhage segmentation was carried out using the 3D Slicer software package developed by Brigham and Women's Hospital Surgical Planning Laboratory and MIT  . This pr in vivo diagnostic the ABC/2 method was used to estimate haematoma volumes [3 to cm3. In these cases the relative haematoma volume was calculated using the initial CT intracranial volumetry data (for methods see above).Autopsies were performed within 48 hours after death. In our Neuropathology Laboratory, brains fixed in 10% formalin were cut into coronal slices. During the examination we verified the clinical diagnosis. Similarly to the volumes , 15 base volumes . ConsecuL = log(hpb2/(1 − hpb2)) − log(hpb1/(1 − hpb1)), and growth  index = exp(L)/(1 + exp(L)) − 0.5, where hpb is haematoma per brain; hpb2 is ratio of total haematoma volume obtained by the second volumetry  to intracranial volume based on the follow-up CT (survivors) or the first CT (nonsurvivors); hpb1 is ratio of total haematoma volume to intracranial volume based on the first CT volumetry (survivors and nonsurvivors). Negative growth indices denote reduction of haematoma; positive growth indices denote haematoma expansion.The growth index of haematomas was calculated in two steps according to the following logistic formulas : P = 0.05. To create the scoring system, model-predicted probabilities of outcome were generated for all subjects, and statistics for the minimum, the 10th, 20th,…, 90th percentage points, and the maximum were derived from the resulting set of values. The coefficients of the final model were built into a spreadsheet-based calculation interface which places any patient, with given input data, in terms of probability-of-death percentage range, given the percentage points observed on our sample of patients. All analyses were performed using Stata Statistical Software (StataCorp. 2009).Variables were described using mean and SD (continuous variables) or category percentages  stratified for survivors and nonsurvivors. Associations between explanatory factors and the outcome of death within 30 days were evaluated using logistic regression. Curvatures in relationships were assessed and allowed for by transformation or by adding a squared term if this substantially improved model fit. Variables showing remarkable associations in unadjusted models were selected for multiple regression modeling unless they are collinear with each other, in which case elimination was carried out on grounds of clinical practicability. Left-out variables were assessed for their potential contribution by adding to the prefinal multiple model one by one and left in if found clinically remarkable or statistically significant. The final multiple logistic regression model was checked for goodness of fit using the Hosmer-Lemeshow test. The level of significance was set at Of the 81 survivor patients, eight were excluded because they did not have a second CT. Of the 75 nonsurvivor patients we excluded two based on brain autopsy results: ruptured aneurysm of the middle cerebral artery and a metastatic tumour, respectively, had been confirmed. Twelve brains were unsuitable for volumetry due to fragmented, multilobar haematomas or having been damaged during removal from the skull, cases in which the ABC/2 method fails to accurately estimate haemorrhage volumes . In addiThe relationship between fatal outcome within 30 days and some selected discrete or continuous clinical variables is presented in There was no statistical significance regarding sex, current smoking, excessive alcohol consumption, diastolic arterial blood pressure, and pulse rate at arrival. Laboratory parameters were collected from the initial blood sampling: serum sodium, potassium, glucose levels, sedimentation rate, haemoglobin, white blood cell (WBC) and platelet counts, liver and kidney function tests, and coagulation parameters. Of these, serum potassium concentration was significantly associated with fatal outcome: high and low levels outside the normal range both represented elevated odds of death. We identified higher serum glucose concentration and lower platelet count as further predictors of fatal outcome.Tables Sugar); total haematoma volume (Size); systolic blood Pressure; presence of intraventricular haemorrhage (Extension to the ventricular system); and serum potassium level . Using these and adding age (lifeTime) which was of borderline significance we developed the six-factor scoring system SUSPEKT. The SUSPEKT scoring system in use to make predictions after primary supratentorial ICH is demonstrated in Tables x represent means observed in the present study, hence the decimal fraction for intraventricular haemorrhage; e denotes Euler's number.The final multiple logistic regression model showed statistically significant associations between 30-day case fatality and a number of variables: serum glucose  level on admission to be significantly associated with lethal outcome and this result is also supported by previous studies [Of the laboratory parameters, we found serum glucose , haematoma growth index, and presence and size of intraventricular haemorrhage are predictors of death within 30 days after ICH. We recommend the use of absolute haematoma volume since it is easier to calculate and its predictive value is similar to relative volume. Haematoma volume is a well-known essential predictor of outcome in patients with ICH [We also found that absolute and relative haematoma volumes  on admission are associated with outcome, and admission diastolic blood pressure is associated with larger ICH volume [According to previous findings, high systolic  and meanH volume . We founE” for expansion) are also strongly associated with outcome in both overall and supratentorial cerebral haemorrhages [Presence and size of intraventricular haemorrhage  level and 30-day lethal outcome, which was related to both high and low levels outside the normal range, although others found that higher dietary potassium intake is associated with lower rates of stroke [We observed a previously unreported, very strongly significant association between serum potassium  had a borderline predictive P value of 0.054 consistent with previous observations that the role of age in outcome after ICH is controversial. Some prior studies reported that age was significantly and independently correlated with fatal outcome, while others did not find this association [Age  orders. Thus, deliberated guideline-concordant therapy is essential for all ICH patients . Early pOur findings are limited by some shortcomings. Prehospital deaths, exclusion of large, multilobar haematomas, and missing second CT in the survivor group may have led to possible selection bias.We have demonstrated that systolic blood pressure, serum potassium and glucose levels, platelet count, absolute and relative haematoma volumes, haematoma growth index, and presence and size of intraventricular haemorrhage independently predict 30-day fatal outcome in primary supratentorial ICH. We developed the SUSPEKT score which after validation on large independent datasets may be applicable in clinical practice for patient selection to optimize individual management and for assessment of eligibility for clinical trials.


Proximal end of tourniquet regulators was used in case of 39 patients and Fogarty catheter for volume dosing of shunt was used in case of 42 patients. Clinical examination: EchoCG (with detection of velocity of blood flowing through the subclavian-pulmonary regulated anastomosis), ECG, chest X-rays ; cardiac monitoring: heart rate, blood pressure, central venous pressure, gas exchange parameters and deep oxygen status , increase of SpO2 to 90,1 ± 1,2 together with poor values of deep oxygen status . Restriction of anastomosis functioning allowed to achieve stabilization of hemodynamic (blood pressure 90 - 100 mm Hg), deep oxygen status , which were accompanied by disappearance of rales, improvement of echocardiographic data in dynamics with reduced duration of mechanical ventilation and time of staying in the ICU. Approximate initial date MLV: Vt = 7-9 ml/kg, f = 15-17, I:E = 1:2, PEEP = 5 sm H2O, FiO2 = 40-50%, trigger = 3-3,5L/min or 2,5-3 sm H2O. On reaching satisfactory performance of gases of blood, stable haemodynamics, good functioning SPA and good X-ray picture patients expose to extubation.From overall patients 14 patients had hyperfunction of anastomosis: the picture of pulmonary preedema was noted in 6 cases, and 9 patients had “managed” hypervolemia of the pulmonary circulation that manifested as: hemodynamic instability (MABP 75-80 mm Hg, HR-120-140 bpm, CVP - 100-140 mm HThe proposed tactics of intensive care in the early postoperative period after controlled subclavian-pulmonary anastomosis in patients with Fallot's tetralogy allows monitoring and active controlling of the volume of shunted through the anastomosis blood, thus helping to avoid development of hyperfunctioning of anastomosis and pulmonary edema.