Background. Acupuncture is frequently advocated as an adjunct treatment for essential hypertension. The aim of this review was to assess its adjunct effectiveness in treating hypertension. Methods. We searched PubMed, the Cochrane Library, EMBASE, and the Chinese databases Sino-Med, CNKI, WanFang, and VIP through November, 2012, for eligible randomized controlled trials that compared acupuncture with sham acupuncture. Outcome measures were changes in diastolic (DBP) and systolic blood pressure (SBP). Results. A total of 4 randomized controlled trials were included. We found no evidence of an improvement with the fact that acupuncture relative to sham acupuncture in SBP change , and an insignificant improvement in DBP change  mmHg; I2 = 97%). In subgroup analyses, acupuncture significantly improved both SBP and DBP in patients taking antihypertensive medications. Only minor acupuncture-related adverse events were reported. Conclusions. Our results are consistent with acupuncture significantly lowers blood pressure in patients taking antihypertensive medications. We did not find that acupuncture without antihypertensive medications significantly improves blood pressure in those hypertensive patients. Essential hypertension is the most common cardiovascular disease (CVD), affecting about one billion individuals worldwide. The prevalence and incidence of hypertension tend to rise with age. Hypertension correlates closely with vascular morbidity and is a significant independent and well-characterized risk factor for other CVD, such as stroke and kidney disease. If the rise in blood pressure (BP) with age could be diminished, then the prevalence of hypertension, CVD, and cerebrovascular diseases could be greatly reduced. However, hypertension continues to be either untreated or uncontrolled in most individuals. Several classes of drugs can lower BP, but their availability, cost, and unwanted side effects have limited the effective control of hypertension to only about 50% of patients. Lifestyle interventions, such as exercise, weight loss, and salt intake restriction, can also lower BP, but these practices can be difficult to achieve and maintain. Therefore, there has been a growing interest in acupuncture as a treatment for hypertension.Acupuncture is an ancient treatment technique anchored in traditional Chinese medicine (TCM) that has been used to treat symptoms related to hypertension for centuries . PhysiciThe efficacy of acupuncture for lowering BP was suggested by many published case reports and uncontrolled trials that have shown significant associated reductions . HoweverA systematic search of the Cochrane Library, EMBASE, and PubMed was conducted without any language restriction. We also searched Chinese databases, including Sino-Med, Wanfang, CNKI, and VIP. Publications available from the inception of each database through November 2012 were reviewed to identify available randomized sham-controlled trials of acupuncture for hypertension. The following keywords were used in English digital databases: “Blood pressure,” “Hypertension,” “Acupuncture,” “Electroacupuncture,” and “Auricular acupuncture.” The following terms were used in the Chinese database searches: “ZHEN” (which means “Acupuncture”) and “Gao Xue Ya” (which means “Hypertension”). We also carefully scanned the references of relevant publications to identify further publications. When questions arose related to either the design or outcomes of trials, corresponding authors were contacted to confirm the information that we extracted from their trials or to clarify any ambiguity.Inclusion criteria included the following: (1) randomized sham-controlled clinical trials; (2) patients were diagnosed with hypertension, according to a systolic blood pressure (SBP) ≥140 mmHg and/or a diastolic blood pressure (DBP) ≥90 mmHg, or use antihypertensive drugs; (3) patients in the experimental group were treated with acupuncture, electroacupuncture, or auricular acupuncture more than once either with or without antihypertensive drugs; (4) placebo (sham) procedures were used; (5) the study included an available clinical database.Exclusion criteria included the following: (1) nonrandomized studies; (2) studies involving other forms of acupuncture, such as transcutaneous electrical nerve stimulation or laser acupuncture; (3) duplicate reporting with same results; (4) a lack of follow-up outcome data about BP; (5) if controls were given complementary or alternative therapies of which the efficacy is not yet established .Following data were extracted independently by two of the authors (D. Li and Y. Zhou): (1) details of participants ; (2) trial design, sample size, blinding, intervention procedures, withdrawals, and dropouts; (3) net changes in SBP and DBP and/or mean BP before and after acupuncture treatment as available. Any disagreements about either inclusions or analyses were resolved by consensus or arbitration by a third reviewer (Y. Yang). We contacted corresponding authors via e-mail to request further information when necessary.The methodological quality of each included study was assessed by using the 5-point Jadad quality scale . The JadP < 0.10. Publication bias was explored via a funnel-plot analysis. In case of heterogeneity, we attempted to identify and explain it by using subgroup analysis.The meta-analysis and statistical analyses were performed by using Stata software v12.0  and RevMan software v5.1 . In the absence of clinical heterogeneity, we synthesized the results in a meta-analysis and compared the mean BP change in outcome measures with baseline values to assess differences between the intervention and control groups. Weighted mean differences and 95% confidence intervals (CIs) were calculated. The mean effect size was calculated by using a random effects model as we assumed that each study assessed different acupuncture treatments and thus represented different effects. A fixed effect model was used when there was no significant heterogeneity . DiffereAn initial search of RCTs yielded 2407 potential literature citations. After screening titles and abstracts of all studies, 48 potentially relevant articles were selected and retrieved for a full-text assessment. Further screening for eligibility was performed by two independent reviewers by using inclusion and exclusion criteria. Finally, 4 RCTs were included, all being published in English .The 4 RCTs included a total of 386 patients with essential hypertension –11: 223 Individualized acupuncture and/or standardized acupuncture were used 2-3 times a week for 6–10 weeks in the active acupuncture group in all 4 RCTs. All studies used sham acupuncture: 1 trial used superficial acupuncture in the control procedure; 2 used nonpenetrating acupuncture on either nonacupuncture points or real acupuncture points; and 1 used penetrating acupuncture on points irrelevant for lowering BP. No trials used sham electrostimulation on acupoints.Studies were generally of good quality with a mean Jadad score of 4.75 , of whicn = 386; mean difference = −3.80 mmHg, 95% CI = −10.03–2.44 mmHg; I2 = 99%)  mmHg; I2 = 97%)   or DBP (2 = 97%) .Pheterogeneity < 0.00001; I2 = 99%) and for DBP change . In subgroup analyses, a significant benefit in both SBP  mmHg; I2 = 17%)  mmHg; I2 = 0%)   (Studies were significantly heterogeneous for SBP change (2 = 17%)  and DBP 2 = 0%)  was foun2 = 63%) , but not2 = 44%) .Four trials reported occurrences of adverse events. One study reported that 2 of their standardized acupuncture participants experienced hypertensive urgencies and 1 of their control participants experienced congestive heart failure . Minor aversus sham acupuncture for essential hypertension. In our review, we found that acupuncture according to TCM practices significantly lowered SBP and DBP in patients taking antihypertensive medications. For its part, acupuncture significantly lowered DBP, but not SBP, in patients who were not taking antihypertensive medications.To the best of our knowledge, this is the first meta-analysis of acupuncture In TCM, hypertension is conceptualized as being caused by emotional factors, constitutional weaknesses which render to individuals susceptible to disease, and poor diet and overexertion which lead to imbalances between yin and yang in the liver, spleen, and kidney. Mechanisms by which acupuncture are theorized to be therapeutic for hypertension according to Chinese medicine are by regulating yin and yang, reinforcing healthy qi, and expelling pathogenic factors . PractitFor its part, according to Western medicine, therapeutic mechanisms of acupuncture are unclear, but some evidence suggests that acupuncture can affect the intrarenal renin-angiotensin system and sympathetic nervous and endocrine systems . AcupuncAs early as the 1950s, results from many clinical studies have suggested beneficial effects of acupuncture for lowering BP in patients with essential hypertension . In 1975In our meta-analysis, we found that acupuncture was able to lower DBP only and to help antihypertensive medications to lower BP. Therefore, acupuncture alone would be unlikely to bring significant benefits to patients with essential hypertension. Results from many studies in China suggested that acupuncture is a safe and effective treatment for essential hypertension, lowering SBP about 10–20 mmHg) and DBP (about 6–10 mmHg) with few adverse events  mmHg and. TherefoOur study provided evidence that acupuncture helped (lowered) BP in patients taking antihypertensive medications but had no effect for the patients without antihypertensive medications. According to the four RCTs , 9–11, YThe duration and frequency of acupuncture treatment are not enough so that only acupuncture could not lower blood pressure. Chen et al.'s study  proved tAlthough our review was thorough, we cannot be absolutely certain that all relevant RCTs were found. The number of studies included in our meta-analysis (4) was small with each study also having a relatively small sample size, which ranged from 30 to 192 patients. Only grades I and II hypertensive patients were included in studies, so conclusions regarding grade III hypertension could not be drawn from our results.In future RCTs of acupuncture it would be beneficial if all acupuncture procedures were performed according to TCM theory, based upon diagnoses made by four diagnostic methods , and performed according to syndrome differentiation.Results from this meta-analysis of randomized sham-controlled trials provide evidence that acupuncture helped (lowered) BP in patients taking antihypertensive medications. Our results did not provide support that acupuncture alone significantly lowers BP in patients with hypertension. Larger RCTs with longer follow-up periods would help clarify the potential efficacy and safety of acupuncture for treating hypertension.


Blood contact with artificial surfaces of the extracorporeal circuit and ischemia-reperfusion injury in CABG with CPB, may lead to a systemic inflammatory response. Hypertonic saline have been recently investigated as a fluid in order to decrease inflammatory response and cytokines generation in patients undergo cardiac operations. Our purpose is to study the prophylactic effect of HS 5% infusion versus NS on serum IL-6 as an inflammatory & IL-10 as an anti-inflammatory biomarker in CABG patients.The present study is a randomized double-blinded clinical trial. 40 patients undergoing CABG were randomized to receive HS 5% or NS before operation. Blood samples were obtained after receiving HS or NS, just before operation, 24 and 48 hours post-operatively. Plasma levels of IL-6 and IL-10 were measured by ELISA.Patients received HS had lower levels of IL-6 and higher level of IL-10 compared with NS group, however these differences were not statistically significant. Results of this study suggest that pre-treatment with small volume hypertonic saline 5% may have beneficial effects on inflammatory response following CABG operation. Infusion of Hypertonic saline (HS) solution increases serum osmolarity and markedly intravascular and interstitial fluid volume expansion, which causes improving hemodynamic status. Fluid rRecent studies demonstrated immunomodulatory effects of hypertonic saline by blunting neutrophil activation and reducing cytokine production,5.Cardiac surgery with cardiopulmonary bypass (CPB) leads to acute changes in the composition and volume of body fluid compartments. CPB dilutes serum proteins, decreases the plasma colloid osmotic pressure and reduces endothelial integrity. This caIn this study it was hypothesized that administration of HS just before coronary artery bypass surgery (CABG) was be helpful in decreasing of generated inflammatory cytokines because of increasing in intravascular volume and tissue perfusion.Study design & Patient population: The present study is a randomized double-blinded clinical trial. 40 patients <70 years old, undergoing elective CABG surgery admitted in Tehran Heart Center, Tehran University of Medical Sciences, between December 2010 & March 2011, entered into the study. Patients were randomly assigned to control (A) and intervention (B) groups, based on a computerized randomization sequence form. All patients had undergo necessary clinical and paraclinical examinations including: CBC, Diff, Electrolytes, PFT, LFT, renal function tests, chest X ray, ECG, Cardiac Enzyme Assay, PT, PTT, INR, thyroid tests, blood group and matching, Carotid Doppler,…, patient educations, consultations, and preparing processes before surgery.All the perioperative cares and also surgeries were carried out by the same (single) surgeon and intensivist who were blinded to the treatment groups. Patients also were blinded to the choice of fluids.2) > 45 mmHg and Oxygen Pressure (PO2) < 60 mmHg, Forced Expiratory Volume in 1 second (FEV1) < 60% or Forced Vital Capacity (FEV1/ FVC) < 60% and Vital Capacity (VC) <50%].All patients had ejection fraction (EF) >35% and their serum creatinine were between 0.5-1.5 mg/dl pre-operatively. Our research was approved by Pharmaceutical Sciences Research Center ethics committee by ethical code of 89-7-7:15–1 according to the declaration of Helsinki and written informed consent was obtained from the legal guardian of each patient before enrollment. Exclusion criteria included any concomitant operation, recent myocardial infarction (during 6 months), emergent surgery, urgent or elective intubation before surgery, unstable hemodynamic status, recent cerebral vascular accident, neurological complications or consciousness disorder or significant neuralgic defect, head trauma, uncontrolled diabetes mellitus, congenital heart disorder, blood transfusion before operation, pre-operative infection, serum creatinine >1.5 mg/dl or GFR < 50, Na > 150 mmole/dl, BMI > 40 and Chronic Obstructive Pulmonary Disease (COPD) or abnormal pulmonary function test [respiratory distress, Carbon Dioxide Pressure  + 400 ml normal saline (0.9%) equivalent to 155 mmole NaCl (group B) or 500 ml normal saline (0.9%) equivalent to 77 mmole NaCl (group A); in a uniform packages from a peripheral venous line in upper arm during 6 hour before surgery.All preparation and treatment measurements were performed in a unique manner based on the attending hospital protocols. Patients received oxazepam 10 mg/po at the night before surgery, promethazine 25 mg/ po 1 hour before surgery, and clonidine 0.1 mg/po before surgery as premedication. Patients were NPO (except medication) for 8 hour before surgery.During surgery all patients had standard continuously monitoring of ECG, pulse oximetery, invasive blood pressure monitoring, non- invasive blood pressure monitoring, central venous pressure, end tidal capnometery, central and peripheral temperature monitoring, bipectoral index, and also intermittent monitoring of arterial blood gas, Na, K, BS, CBC, ACT test for heparin loading & reversal. All patients received the same anesthetic regimen and routine CPB management. Anesthesia was induced by midazolam (0.05 mg/kg), fentanyl (5 mcg/kg), propofol 2 mg/kg and pancuronium (0.1 mg/kg), and was maintained with propofol infusion (10 mg/kg/h) and additional doses of fentanyl & pancuronium.2O, PSV = 5 cmH2O above PEEP , pressure support = 10 cmH2O, oxygen flow = 60 lit/min and FiO2 =50% at first, then adjusted based on PaO2. Subsequently ventilation was adjusted based on ABG, and other laboratory and clinical parameters. Furthermore, RSBI , which is the proportion of respiratory rate/ tidal volume, has been considered as a criteria for the extubation; if this proportion was >105, patients could not stand the extubation. The recruitment maneuver was done for all of patients before extubation.Just after ICU admission, cuff pressure was controlled and it has monitored every 8 hrs. The ventilator machine was set on SIMV-PSV mode , based on tidal volume = 8 cc/kg of ideal body weight, F (IMV) = 10/min, F (IMV + PSV) = 15/min, I/E (Inspiratory/Expiratory) = 1/2, PEEP (Positive End-Expiratory Pressure) = 5 cmHSpecimen collection: A 5 ml sample of blood was obtained from each patient after receiving HS or NS, just before operation and 24 and 48 hrs post-operatively, and anonymously referred to local laboratory to be centrifuged and the serum stored at −70°C. Plasma IL-6 & IL-10 levels were measured. We also monitored heart rate, systolic and diastolic blood pressure, central venous pressure, arterial pH, PaO2, FIO2, blood sugar, Na, K, Mg, hemoglobin, white blood cell, hematocrit and platelet for each patient before and after surgery.Marker measurements: Enzyme-Linked Immunosorbent Assay (ELISA) technique was used to measure IL-6 (BMS213/2CE) and IL-10 (BMS215/2CE)  samples plasma level according to manufacturer’s instructions.Statistical Analysis: Data were analyzed using the statistical software SPSS version 15.0 for windows . Continuous variables are presented as mean ± standard deviation (SD) or mean ± standard error of mean (SEM), while categorical variables are summarized by absolute frequencies and percentages. Continuous variables were compared using the Student's t-test or nonparametric Mann–Whitney U test, whenever the data did not appear to have normal distributions; and categorical variables were compared using Chi-Square test, as required. Repeated measure ANOVA was used to evaluate inter-group differences and intra-group changes. All p values <0.05 were considered statistically significant.An equal number of patients received NS or HS. There were no differences in demographic data Table . DetaileOf the 40 patients included, 4 in HS group versus 2 in NS group had received inotropic drug within the first 24 hrs after surgery, however the different was not statistically significant (0.336) (Table The plasma levels of pro-inflammatory (IL-6) and anti-inflammatory IL-10) cytokines were significantly changed during 48 hrs post-operatively in two groups (p < 0.001 & p < 0.005 respectively) ; acute rHS solutions have been examined in numerous studies as plasma volume expanders for resuscitation in various hypovolemic situations but there is little attention to their immunomodulatory effects. Basic science studies have demonstrated that HS has marked effects on the immune system. More investigations have confirmed that HS blunted neutrophil (PMNs) activation and diminished the monocytes production profile in patients with traumatic hemorrhagic shock. HS soluIL-6 is produced by monocytes, lymphocytes, and endothelial cells. IL-6 induces the adhesive neutrophil-cardiac myocyte interaction and myocardial damage following CPB surgery. Highest plasma level of IL-6 significantly correlated with the duration of SIRS and alsoIn the state of ischemia (duration of aortic cross clamp) endothelial surface layer thickness and glycocalyx structure have impaired, and dimension of glycocalyx degradation was proportional to the duration of ischemia, therefoAfter declamping aorta and reestablishing the microvascular perfusion, the ischemic process has been stopped by supplying the oxygen and nutrients, but at the same time a cascade of events has similar characteristics to inflammatory response is rapidly initiated. This inflammatory-like response to ischemia-reperfusion, mediated largely by neutrophils. StimulaIL-10 is a prototypical endogenous anti-inflammatory and immunosuppressive cytokine, which iHigher levels of IL-10 in HS group of our study may indicate its ability to evoke host anti-inflammatory cytokines to reduce reperfusion damage.HS solutions have benefits on cardiac outputs, because of the increasing preload (venous return and volume expanding effect) and decreasing afterload (vasodilation and reduction in pulmonary and systemic vascular resistance),35. WhetLimited number of eligible candidate for intervention with hypertonic saline before CABG, uni-center nature of the study, high cost of cytokine evaluation and ethical concern regarding the safety of hyperoncotic fluids on subject with venerable hemodynamic profiles were mean parts of our study’s limitations.Pre-treatment with small volume hypertonic saline may have beneficial effects on inflammatory response following CABG operation.The authors declare that they have no competing interests.MM was responsible for data gathering and manuscript preparation. FY was responsible for study design, patient selection, data gathering, manuscript preparation, MA in-charged for statistical analysis, cytokine bio-assays. HH was responsible for manuscript preparation. KB was responsible for patients’ selection. MAB was responsible for sample preparation and Laboratory tests. AJ was responsible for statistical analysis. AA was in-charged for study design and proposal preparation. SM was involved in study design. MB was involved in data gathering. MM was mean main scientific manager of the study, and was involved in design of the study and proposal preparation, responsible for mean main idea, and discussion for finding of study. All authors read and approved the final manuscript.


Reactive oxygen species are implicated in the physiopathogenesis of salt-induced hypertension and the C242T polymorphism of the p22-phox gene has been associated with higher superoxide production. This study investigated the impact of this polymorphism on the relationship between urinary sodium excretion (USE) and blood pressure levels in an urban Brazilian population.We cross-sectionally evaluated 1,298 subjects from the city of Vitoria-ES, located in the Southeast region of Brazil, by clinical history, physical examination, anthropometry, analysis of laboratory parameters, USE measurement and p22-phox C242T polymorphism genotyping.No significant differences in studied parameters were detected between the studied genotype groups (CC vs. CT+TT). Systolic blood pressure exhibited significant correlation with USE only in T allele carriers , while diastolic blood pressure and hypertension status correlated with USE in both genotypes albeit more weakly in subjects with CC genotype  than in T carriers . Regression analyses adjusted for confounding factors showed that USE remained independently associated with systolic (p<0.001) and diastolic blood pressure (p<0.001) and hypertension status (p = 0.004) only in T allele carriers. Finally, higher diastolic and systolic blood pressure levels were detected in T allele carriers than in CC genotype individuals in the highest tertile of USE.The p22-phox 242T allele is associated with higher blood pressure levels among subjects with higher USE in an urban Brazilian population. Oxidative stress, exerted by intracellular accumulation of reactive oxygen species, has been implicated in the physiopathogenesis of salt-induced hypertension To date, several polymorphisms of the p22-phox (CYBA) gene have been identified Urinary sodium excretion is usually used as the standard method for evaluation of sodium intake in clinical and epidemiological studies The study was conducted in accordance with the Declaration of Helsinki and the protocol was approved by the Institutional Review Board of the Espírito Santo Federal University. All participants read and signed informed consent.A cross-sectional study of risk factors for cardiovascular diseases was performed in the urban population of Vitoria, Brazil, using the WHO-MONICA project guidelines 2). Height was measured in centimeters and weight in kilograms using a calibrated balance.Blood pressure was measured using a standard mercury sphygmomanometer on the left arm after 5 min rest, in the sitting position. Systolic and diastolic blood pressures were calculated from three readings with a minimal interval of 5 min. Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Glucose, total cholesterol, lipoprotein fractions, triglycerides, uric acid and creatinine were assayed by standard techniques in 12-h fasting blood sample. Diabetes mellitus was defined as a fasting glucose ≥126 mg/dL and/or use of hypoglycemic drugs Urine was collected from participants during a 12-h period (from 7∶00 PM to 7∶00 AM) during the night before the clinic visit. Sodium and potassium concentrations were measured in the 12-h urine by flame photometry. All measurements were performed in the same laboratory and the same commercial kits were used in all investigations. Previous data have shown that 12-h urine collected at night can be used as a reliable tool to estimate 24-h excretion of sodium and potassium Genomic DNA was extracted from leukocytes in samples of whole blood, following a standard salting-out procedure Data were analyzed using SPSS 15.0™. Descriptive statistical results are given as means ± SEM. All continuous variables presented normal distribution as assessed by the Kolmogorov–Smirnov test. A chi-square test was used to compare categorical variables and to test for Hardy–Weinberg disequilibrium. Unpaired t-test was used to compare continuous variables. Bivariate correlations between variables were examined by using Pearson correlation coefficient for normally distributed data and Spearman rank correlation coefficient for non-normally distributed data. Fisheŕs z-test was used to compare correlation coefficients. Linear and logistic regression analyses were used to evaluate the independent predictors of blood pressure levels and hypertension, respectively. Variables that exhibited significant correlation at bivariate analysis and urinary sodium excretion were included as independent variables in regression analyses. Significance was accepted if p<0.05.2 = 0.78). The clinical, anthropometric and laboratory characteristics of studied subjects according to C242T genotypes are shown in Genotypic frequencies of the C242T polymorphism  were in accordance with the Hardy-Weinberg equilibrium , while diastolic blood pressure correlated with urinary sodium excretion in both genotype groups, albeit more weakly in CC genotype than in T carriers . In addition, significant correlation coefficients between hypertension status and urinary sodium excretion were detected in both genotype groups albeit also more weakly in CC genotype than in T carriers . Further correlation analysis between clinical/laboratory variables and blood pressure measurements/hypertension was performed in order to determine potential confounding factors in the relationship between blood pressure/hypertension status and urinary sodium excretion in both genotype groups .To confirm whether the p22-phox C242T polymorphism influenced the relationship between urinary sodium excretion and blood pressure and hypertension status, linear and logistic regression analysis were performed. Noticeably, urinary sodium excretion remained independently associated with systolic and diastolic blood pressure  and hypeThe next step was to evaluate the frequencies of the p22-phox C242T polymorphism and the clinical and laboratory features of all studied subjects according to the tertiles of urinary sodium excretion . IncreasIn the present report, we found that the p22-phox C242T polymorphism modulated the relationship between urinary sodium excretion and blood pressure levels in Brazilian general population. Remarkably, only in presence of the T allele, urinary sodium excretion showed an independent association with systolic blood pressure, diastolic blood pressure and hypertension status. In addition, higher diastolic and systolic blood pressure levels were detected in T allele carriers than in CC genotype individuals in the highest tertile of urinary sodium excretion. Overall, these findings indicate that the p22-phox 242T allele might be a potential marker of increased blood pressure under higher salt intake.Although the reasons by which the 242T influenced the interaction between sodium intake and blood pressure levels were not apparent in the present study, some explanations can be proposed. High daily salt intake impairs vasodilatation and enhances vasoconstriction, resulting in reduction of regional blood flow and elevation of blood pressure in healthy and hypertensive individuals et alet al  presented a remarkable smaller sample size than that of the present paper , which strengthens the validity of our data. Despite the differences, these data indicate that the p22-phox C242T polymorphism might be a potential marker of susceptibility to blood pressure response to high sodium intake.Our study did not measure salt sensibility, but our main findings are in the same line of those reported by Castejon Some limitations to our study need to be addressed. First, we only performed a single measure of urinary sodium excretion, which might not be fully representative of sodium intake. Nevertheless, a previous study evaluating the urban population of Vitória showed that urinary sodium excretion estimated by a single 12-h urine collection had a good correlation with sodium intake assessed by questionnaires In conclusion, the present study provided novel evidence that the p22-phox 242T allele is associated with higher blood pressure levels among subjects with higher USE in an urban Brazilian population. However, further studies in other populations are warranted to confirm the current evidence.Table S1Bivariate correlation coefficients between blood pressure/hypertension status and clinical/laboratory variables.(DOC)Click here for additional data file.


Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with elevated office blood pressure vs. self-measured home blood pressure.Please see later in the article for the Editors' Summary The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).This meta-analysis included 5,008 individuals randomly recruited from five populations . All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant  is the leading risk factor for cardiovascular disease and is responsible for 9.4 million deaths annually from heart attacks, stroke, and other cardiovascular diseases. Hypertension, which rarely has any symptoms, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure) and lowest when the heart is refilling (diastolic blood pressure). European guidelines define optimal blood pressure as a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) and a diastolic blood pressure of less than 80 mm Hg (a blood pressure of less than 120/80 mm Hg). Normal blood pressure, high-normal blood pressure, and mild hypertension are defined as blood pressures in the ranges 120–129/80–84 mm Hg, 130–139/85–89 mm Hg, and 140–159/90–99 mm Hg, respectively. A blood pressure of more than 160 mm Hg systolic or 100 mm Hg diastolic indicates severe hypertension. Many factors affect blood pressure; overweight people and individuals who eat salty or fatty food are at high risk of developing hypertension. Lifestyle changes and/or antihypertensive drugs can be used to control hypertension.The current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure . However, self-measured home blood pressure (HBP) more accurately predicts outcomes because multiple HBP readings are taken and because HBP measurement avoids the “white-coat effect”—some individuals have a raised blood pressure in a clinical setting but not at home. Could risk stratification across increasing categories of CBP be refined through the use of self-measured HBP, particularly at CBP levels assumed to be associated with no or only mildly increased risk? Here, the researchers undertake a participant-level meta-analysis  to answer this question.The researchers included 5,008 individuals recruited from five populations and enrolled in the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome (IDHOCO) in their meta-analysis. CBP readings were available for all the participants, who measured their HBP using an oscillometric device (an electronic device for measuring blood pressure). The researchers used information on fatal and nonfatal cardiovascular, cardiac, and cerebrovascular (stroke) events to calculate the hazard ratios  associated with a 10-mm Hg increase in systolic HBP across standard CBP categories. In participants with optimal CBP, an increase in systolic HBP of 10-mm Hg increased the risk of any cardiovascular event by nearly 30% (an HR of 1.28). Similar HRs were associated with a 10-mm Hg increase in systolic HBP for all cardiovascular events among people with normal and high-normal CBP and with mild hypertension, but for people with severe hypertension, systolic HBP did not significantly add to the prediction of any end point. Among people with optimal, normal, and high-normal CBP, 5%, 18.4%, and 30.4%, respectively, had a HBP of 130/85 or higher . Finally, compared to individuals with optimal CBP without masked hypertension, individuals with masked hypertension had more than double the risk of cardiovascular disease.These findings indicate that HBP measurements, particularly in individuals with masked hypertension, refine risk stratification at CBP levels assumed to be associated with no or mildly elevated risk of cardiovascular disease. That is, HBP measurements can improve the prediction of cardiovascular complications or death among individuals with optimal, normal, and high-normal CBP but not among individuals with severe hypertension. Clinical trials are needed to test whether the identification and treatment of masked hypertension leads to a reduction of cardiovascular complications and is cost-effective compared to the current standard of care, which does not include HBP measurements and does not treat people with normal or high-normal CBP. Until then, these findings provide support for including HBP monitoring in primary prevention strategies for cardiovascular disease among individuals at risk for masked hypertension , and for carrying out HBP monitoring in people with a normal CBP but unexplained signs of hypertensive target organ damage.http://dx.doi.org/10.1371/journal.pmed.1001591.Please access these websites via the online version of this summary at PLOS MedicinePerspective by Mark CaulfieldThis study is further discussed in a high blood pressure (in English and Spanish) and a guide to lowering high blood pressure that includes personal storiesThe US National Heart, Lung, and Blood Institute has patient information about American Heart Association provides information on high blood pressure and on cardiovascular diseases ; it also provides personal stories about dealing with high blood pressureThe hypertension  and about cardiovascular diseaseThe UK National Health Service Choices website provides detailed information for patients about cardiovascular disease and controlling blood pressure; its A Global Brief on Hypertension was published on World Health Day 2013The World Health Organization provides information on Blood Pressure UK provides information about white-coat hypertension and about home blood pressure monitoringThe UK charity high blood pressure, heart disease, and stroke (in English and Spanish)MedlinePlus provides links to further information about  Current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure, i.e., blood pressure measured in a medical environment The Global Burden of Diseases Study 2010 reported that high blood pressure is the leading risk factor for global disease burden, and is estimated to cause 9.4 million deaths every year—more than half of the estimated 17 million deaths a year caused by total cardiovascular disease All studies included in IDHOCO received ethical approval. They have been described in detail in peer-reviewed publications. All participants gave informed written consent.n = 34), HBP was not self-measured (n = 4), the study included patients instead of a population sample (n = 7), or cardiovascular outcome was not collected (n = 12). J. A. S. and K. A. assessed nine studies in detail n = 1,465), because fewer than two measurements of their CBP or HBP were on record (n = 270), or because information on current smoking or cardiovascular disease history was unavailable (n = 10). Thus, the number of participants analyzed totaled 5,008. Analyzed participants were 1,605 Finns representing a nationwide population sample (the Finn-Home study) At the time of writing this report, IDHOCO included six eligible population cohorts IDHOCO was constructed and maintained at the Studies Coordinating Centre in Leuven, Belgium, in accordance with Belgian legislation on the protection of privacy CBP was measured with a standard mercury sphygmomanometer .For database management and statistical analysis, we used SAS software, version 9.3 (SAS Institute). We compared means and proportions using the standard normal We used Cox proportional hazards models to compute hazard ratios (HRs), while adjusting for cohort as a random effect and for sex, age, body mass index, smoking, total cholesterol, and history of cardiovascular disease and diabetes mellitus as fixed effects. We checked the proportional hazards assumption and the functional forms of the covariables using the Kolmogorov-type supremum test, as implemented in the PROC PHREG procedure of the SAS package. In multivariable-adjusted Cox proportional hazards models, we explored whether, within each category of CBP, HBP analyzed as continuous variable refined risk stratification. We derived HRs that expressed the change in risk associated with increases in the systolic and diastolic HBP of 10 and 5 mm Hg, respectively. In sensitivity analyses, we computed the differences in the HRs between subgroups by introducing the appropriate interaction term in the Cox proportional hazards models. Finally, we computed multivariable-adjusted HRs comparing the risk of masked hypertension in participants with optimal, normal, or high-normal CBP with the risk incurred by participants with optimal CBP without masked hypertension. We tested heterogeneity in the HRs among the three subgroups with masked hypertension by testing an ordinal variable coding for these subgroups among participants with masked hypertension.p<0.0001) and 3.0 mm Hg  lower than mean CBP. 2 statistic p-values for differences across the five categories were significant (p≤0.015) except for the prevalence of smoking (p = 0.083).Of 5,008 participants, 2,834 (56.6%) were female, 2,115 (42.2%) were 60 y or older, 1,148 (22.9%) were current smokers, 317 (6.3%) had diabetes mellitus, and 327 (6.5%) had a history of cardiovascular disease. Age averaged 57.1 y . Across all participants, CBP averaged 130.9  mm Hg systolic and 77.9  mm Hg diastolic. The corresponding means for HBP were 123.9  mm Hg and 74.9  mm Hg. The mean self-measured HBP was therefore 7.0 mm Hg  and ranged by study from 5.5 y (2.3 to 5.6) in Tsurugaya to 11.9 y (3.8 to 16.9) in Ohasama . During p<0.0001). Similarly, incidence rates standardized by the direct method for sex and age  increased across the categories of CBP (p≤0.0009). The multivariable-adjusted HRs, expressing the risk compared with optimal blood pressure (p = 0.011) as well as for fatal combined with nonfatal outcomes (p≤0.0004).pressure , increasp≥0.20). The home diastolic blood pressure was a weak and inconsistent predictor across the categories of CBP  and 1.28  for total mortality and cardiovascular events. The corresponding HRs among participants with normal CBP were 1.18  and 1.22 , respectively. The home systolic blood pressure also predicted the composite cardiovascular end point and stroke  in partis of CBP .Excluding one cohort at a time or stratifying participants by sex, ethnicity, or age (<60 versus ≥60 y) confirmed the main analyses of home systolic blood pressure, as reported in p<0.0001), to smoke , to have diabetes mellitus  or a history of cardiovascular disease , and to be older  and more obese .Participants with masked hypertension according to the 130/85-mm Hg threshold, compared with participants with true optimal, normal, or high-normal blood pressure , were mop<0.0001), to smoke , to have diabetes mellitus  or a history of cardiovascular disease , and to be older  and more obese .Participants with masked hypertension according to the 135/85-mm Hg threshold, compared with participants with true optimal, normal, or high-normal blood pressure , were moUsing 130/85 mm Hg as threshold for HBP to define masked hypertension ; Table 9Using 135/85 mm Hg as the HBP threshold to define masked hypertension , the numCurrent guidelines for the diagnosis and management of hypertension n = 120) or without (n = 471) masked hypertension. The participants were hospital staff, patients referred for reasons other than cardiovascular disease or hypertension, and volunteers. During 6.6 y of follow-up, 29 fatal and nonfatal cardiovascular events occurred. In prehypertensive patients without and with masked hypertension, the event rates per 100 patient-years were 0.57 and 1.51, respectively. With adjustments applied for covariables, including CBP, cardiovascular risk was significantly higher in masked hypertensive patients than in true prehypertension .To the best of our knowledge, only one previous prospective study addressed risk stratification by out-of-the-office blood pressure measurement in prehypertensive patients, but applied ambulatory monitoring instead of self-measurement. Pierdomenico and coworkers p = 0.032).According to the European Society of Hypertension guidelines Our current findings have important implications for clinical practice. The relation between cardiovascular complications and blood pressure is continuous at least down to a CBP level of 115 mm Hg systolic or 75 mm Hg diastolic Using HBP measurement to screen for masked hypertension is probably cost-effective. Fukunaga and coworkers studied the cost-effectiveness of HBP measurement from the perspective of the Japanese health care system, using simulations based on the Ohasama population study Our individual-participant meta-analysis is clearly an advance over previous publications in the research field of risk stratification based on blood pressure. To our knowledge, our study is the first to assess the risk associated with self-measured HBP across increasing categories of CBP. It raises the issue that the economic analysis of HBP monitoring should be based on cost-savings not only via the avoidance of unnecessary treatment On the other hand, our study also has some potential limitations. First, we did not determine the reproducibility of masked hypertension in the context of our current study. However, Viera and colleagues reported prevalence rates of masked hypertension among patients not being treated with hypertension but with borderline elevated CBP to be 54% and 53% on first and repeat assessment, with an agreement of 73% In conclusion, HBP monitoring substantially refines risk stratification in people with levels of CBP assumed to carry no or only mildly elevated risk, in particular in the presence of masked hypertension. Properly designed randomized clinical trials are required to determine whether identification and treatment of masked hypertension versus the current standard of care, i.e., not to perform HBP measurement and not to treat people with normal blood pressure on conventional measurement, leads to a reduction of cardiovascular complications and is cost-effective. Such trials might be mounted worldwide in developed and developing countries, including remote areas and even in low-resource settings Text S1PRISMA statement.(DOC)Click here for additional data file.


Controversy exists in predicting costly hospitalization in patients with chronic kidney disease and co-morbid conditions. We therefore tested associations between serum chemistry values and the occurrence of in-patient hospital costs over a thirteen month study period. Secondarily, we derived a linear combination of variables to estimate probability of such occurrences in any patient.We calculated parsimonious values for select variables associated with in-patient hospitalization and compared sensitivity and specificity of these models to ordinal staging of renal disease.Data from 1104 de-identified patients which included 18 blood chemistry observations along with complete claims data for all medical expenses.We employed multivariable logistic regression for serum chemistry values significantly associated with in-patient hospital costs exceeding $3,000 in any single month and contrasted those results to other models by ROC area curves.The linear combination of weighted Z scores for parathyroid hormone, phosphorus, and albumin correlated with in-patient hospital care at p < 0.005. ROC curves derived from weighted variables of age, eGFR, hemoglobin, albumin, creatinine, and alanine aminotransferase demonstrated significance over models based on non-weighted Z scores for those same variables or CKD stage alone. In contrast, the linear combination of weighted PTH, PO4 and albumin demonstrated better prediction, but not significance over non-weighted Z scores for PTH alone.Further study is justified to explore indices that predict costly hospitalization. Such metrics could assist Accountable Care Organizations in evaluating risk adjusted compensation for providers. Patients with chronic kidney disease (CKD) are at risk for complications requiring costly hospital care. However predicting which patients are at risk for high cost hospitalization has been a difficult endeavor. Cardiovascular disease (CVD) is a co-morbidity that drives many costs -3. In adSome investigators have suggested that serum PTH levels can predict cardiovascular events -9. NumerDisorders in mineral metabolism have become a focal point for predicting costly hospitalization. Covic et al in a comprehensive review of the literature reported a significant rise in all-cause mortality associated with serum mineral disturbances . Their rOn the other hand, other investigators have demonstrated that elevated alkaline phosphatase predicted mortality and hospitalization in hemodialysis patients independent of calcium, phosphorus, and PTH levels .Serum albumin associated with calcium binding is another factor linked with increased morbidity in CKD patients. Since low serum albumin is frequently seen with protein energy malnutrition, it has been suggested as a predictor for increased mortality in CKD patients -23.In summary, chronic kidney disease is clearly associated with multiple organ dysfunctions that impact cost, diminish health and work productivity -29. HoweWe analyzed the association of each blood chemistry variable on the probability of hospitalization, and did so under the assumption that the influence of each variable is through its impact on a linear predictor. The result provides an association of each variable to the probability for an adverse outcome.The objective of this study was to investigate the relationship between select serum chemistry values and the occurrence of in-patient hospital payments exceeding $3,000 in any single month for a range of CKD patients. Next, we compared those results to other predictive models based on non-weighted Z scores of the same serum values or to ordinal stages of CKD in the same patients.Our data set included 1104 de-identified patients from the kidney disease registry of a local managed care organization (MCO), who had received treatment from November 2007 through November 2008. This data was obtained after review of the study protocol by the university's school of medicine Institutional Review Board (IRB) and permission from the regional MCO.Since our goal was to study the relationship between a select series of blood chemistry values and high hospital cost in CKD patients, we employed the definition of CKD as two or more recordings of eGFR at or below 60 ml/min over a three month period. In the dataset supplied to us, CKD was confirmed in 888 patients. The remaining 216 excluded patients had no eGFR values recorded at any time over the 13 month study period. In addition within this excluded group, 212 patients had one or more serum glucose recordings, and 139 had one or more abnormal serum creatinine values with no other blood tests recorded at any time. These excluded patients appeared on the renal registry because their primary-care physician assigned a diagnostic code (ICD-9) indicating acute or chronic renal disease or a family history of CKD with diabetes.A total of eighteen blood tests were requested from the MCO for analysis in this study by a consulting group of university nephrologists. The test choices were made based on each variable's perceived importance in monitoring the health of CKD patients. The 18 blood tests were: serum urate, phosphorus (PO4), parathyroid hormone (PTH), glucose, glycolated hemoglobin (HbA1c), hemoglobin (HGB), bicarbonate, albumin, creatinine, urea nitrogen (BUN), potassium, calcium, sodium, alkaline phosphatase, alanine aminotransferase (ALT), bilirubin, leukocytes, and eGFR (by MDRD4). The data set also included the complete financial profile for all medical claims that were paid for these patients over the same time period. These costs were linked to lab records using SQL queries written to join lab and claims data by unique patient identifiers within each dataset and allowed reimbursements to be studied.Since tests ordered by physicians showed marked variation in selection and repetition, we sorted the remaining pool of 888 patients into two data sets for two separate sets of modeling analyses based on the following criterion: (1), 267 patients with no missing observations for serum parathyroid hormone (PTH) in order to focus on mineral metabolism disorders; and (2) 792 patients with no missing observations for serum creatinine in order to focus on serum values associated with renal function. Several models with various sets of explanatory variables were fitted using each of these data sets. Each model was fitted to the data for the subset of all patients in the respective data sets with non-missing values for every variable in the model.The blood tests for all patients were performed by the same laboratory. Thus, the units of measurement and normal range for each test were common to all observations. Summary measures over the 13-month observation period were calculated for each lab test by averaging the tests results over all times of observation. Except for HbA1c and eGFR, the mid-point of the normal range for each test was taken as the mean, and the range divided by four as the standard deviation for a non-diseased normal population. Each lab test was standardized using this mean and standard deviation to obtain a Z-score for each variable for each patient.Costs were totaled within each month and used, along with the codes for service provider type  to define cost allocation. The frequency distribution for all hospital reimbursements displayed a bimodal curve with $3000 as the best dividing point between the two modes. We therefore selected this value as a cutoff point. This decision was further justified by the fact that total payments which exceeded $3000 were primarily for in-patient hospital care. That variable was defined as outcome 1. We chose to name this outcome as "High-Cost Hospitalization" or HCH to allow for the possibility that hospital care could be associated with reimbursements less than $3000. Other patients not meeting this criterion were assigned an outcome value of 0, or non-HCH.The primary purpose of our study was to test the associations between a CKD patient's serum chemistry values and the occurrence of HCH in any single month over the thirteen-month study period. Secondarily, we derived a linear combination of blood tests to estimate the probability of HCH for any given patient. Next, we tested the association of a patient's CKD stage to the occurrence of HCH under the same criterion. Next the sensitivity and specificity for predicting HCH was calculated for a sequence of cut-points on each linear predictor scale by comparing predicted values of HCH to the occurrence of true positive and true negative HCH. Finally, the predictive models were compared through calculation of areas under receiver operating characteristic (ROC) curves.As discussed previously, some investigators conclude that measurement of PTH, phosphorus, calcium, alkaline phosphatase, albumin and eGFR predict illness severity and hospitalization in renal patients. To test for this association, we modeled the probability of HCH as a multivariable logistic function of average age, eGFR, and the Z-scores calculated from the average measures of PTH, phosphorus, bicarbonate, albumin, potassium, calcium, sodium, alkaline phosphatase and eGFR, over the 13 month period. A backward selection model building strategy was employed to derive a parsimonious model containing only significant predictors. At each step, the explanatory variable with the highest p-value greater than 0.10 was deleted. If its deletion resulted in another variable that had been significant (p < 0.10) previously becoming non-significant, then the deleted variable was added back into the model and the variable with the next largest p-value greater than 0.10 was deleted. These steps were repeated until only significant variables (p < 0.10) remained in the model.i.e., the weighted sum of predictor variables with weights that are the estimated coefficients from the logistic regression) to the probability of HCH.These analyses produced a regression table with an estimated constant and regression coefficients for each explanatory variable in the final model, along with calculated p-values. The Hosmer-Lemeshow Goodness-of-Fit test was calculated to test for a lack of fit of the final model. Probability curves were created relating the linear predictor . As above, the goodness of fit of the final model was tested using the Hosmer-Lemeshow test.For the logistic regressions described above, the number of observations used to fit each model was the number with non-missing values of all variables in the model. All computations were done using the Minitab package of statistical software.http://www.jrocfit.org.We calculated the sensitivity and specificity for each model based on a series of cut-points on the linear predictor scale for the final multivariable logistic regression models. We then compared resulting predicted values to the occurrence of true positive and true false values for HCH and calculated sensitivity and specificity for each cut-point. The same calculations were made for cut-points on the linear predictor obtained from the CKD stage model for predicting HCH. Similarly, calculations were made for a series of cut-points on the linear predictors defined by the sum of non-weighted Z scores in both the mineral metabolism and renal models for the occurrence of HCH. Lastly, ROC curves were calculated for each model along with an area under each respective curve in order to compare models for accuracy in predicting HCH. ROC curves and areas under the curves were calculated using the software application by Eng J. ROC analysis: web-based calculator for ROC curves. Baltimore: Johns Hopkins University [updated 2006 May 17.] Available from: For the total pool of CKD patients in this study, analysis of the claims data revealed that 435 patients had at least one HCH  month. The remaining 453 patients had no HCH during the 13 study-months (HCH = 0).The average annual payment per patient for the group designated non-HCH (outcome 0) was $3,167 with a range of $264 to $17,197. The average monthly payment per patient in this group was $313.In contrast, the HCH (outcome 1) group had average annual payments of $35,892 with a range of $4,276 to $314,533. Their average monthly per patient payment was $3,136.Figure On the other hand in the non-HCH (outcome 0) group, payments for hospital only services averaged $830 per patient with a range of $0 to $5,865. For other medical services, that average total payment per patient was $2,652 with a range of $264 to $16,572.For the 267 patients with repeated PTH and serum phosphate testing, logistic regression analysis demonstrated a significant association between increasing PTH levels and HCH at p < 0.005. The Hosmer-Lemeshow Goodness-of-Fit test p-value was calculated at 0.06 with 66.5% concordant pairs between the response variable and the predicted probabilities.For those variables associated in the literature with mineral metabolism disorders  their overall p-value for correlation with HCH was significant at p < 0.005, nonetheless, a number of variables had p-values that were not significant. After a step-wise elimination of the least significant variable, the regression calculation for the most parsimonious model demonstrated that PTH, phosphorus and albumin had significance at p < 0.005 with a Chi-Square Goodness of Fit test that was not significant (p = 0.83). In addition, there was an association of 74.3% concordant pairs between the response variables and predicted probabilities.lp/(1+elp), whereUsing the calculated regression coefficients for the linear predictor's constant and PTH, phosphate, and albumin coefficients, we calculated a probability curve for HCH as a function of the linear predictor, using the following formula for probability of HCH given elp/(1+elp) for each patient and plotting versus the linear predictor (lp) we produced the curve shown in Figure By calculating eThe probability for HCH increased sharply to 50% as the linear predictor for serum PTH, phosphorous and albumin increased from 0.0 to 1.0. With an increase of the linear predictor to 2.0, the probability for HCH rose to 65%. As the linear predictor increased to 4.0, the probability for HCH reached 80%. And as the linear predictor doubled from 4.0 to 8.0, the probability of HCH increased to 90%.In order to tabulate the impact of individual variables on the outcome of HCH, we calculated individual probability curves for PTH, phosphorus and albumin. By holding each of the non-selected variables at Z-score = 0, we recalculated logistic regression values and subsequent probability values. For Z-scores of PTH at 20, 40 and 70, the probability of HCH was 34%, 50% and 72% respectfully. For Z-scores of phosphorus at 2, 4, 6, the probability of HCH was 36%, 55%, and 70% respectively. For Z-scores of albumin at -2.0, -3.0 and -4.0, the probability of HCH was 42%, 55%, and 69% respectively.Since the reference range for normal can vary in different laboratories, practicing clinicians can calculate the Z-scores for their patient's test values and substitute those values within the above formulas in order to calculate patient specific probabilities.Since the data pool for renal patients with serum testing other than PTH and phosphorous was considerable larger (792), we calculated logistic regression coefficients for the variables of age, glucose, hemoglobin, bicarbonate, albumin, creatinine, BUN, potassium, calcium, sodium, alkaline phosphatase, ALT, leukocytes, eGFR and to achieve the most parsimonious model each variable with the least significant value was eliminated in a step wise fashion and the logistic regression recalculated. The final list consisted of age, hemoglobin, albumin, creatinine, ALT, and eGFR.This calculation had p < 0.005 and a Chi-Square Goodness of Fit test by the Hosmer-Lemeshow method that was not significant at the 0.40 level. In addition, the association between the response variable and the predicted probabilities had 69.9% concordant pairs.Calculation of a probability curve for the outcome of HCH over the study period versus the linear predictor for those variables is displayed in Figure Figure Figure The Area under the Curve (AUC) shown in Figure For the cohort of 792 patients, the AUC derived from the linear combination of predictor values for age, serum hemoglobin, albumin, creatinine, ALT and eGFR compared to the true positive occurrence for HCH had an area of 0.699.In contrast, Figure In a similar manner, The ROC area curves based on the sum of the non-weighted Z scores for hemoglobin, creatinine, albumin and ALT was calculated at 0.472, and when compared to AUC for Figure #4 demonstrated significance at p < 0.0005. Similarly, the AUC derived from comparison of the average eGFR to the true positive and true negative occurrence of HCH was calculated at 0.414 and when compared to Figure #4 demonstrated a significance at p < 0.0005.Our study suggests a linear combination of select serum values correlates with prediction of in-patient hospital care (HCH) for CKD patients defined as payments in excess of $3,000 in one or more months over a one year study period.Although there is controversy in the literature over which mineral metabolites are most significantly related to morbidity and mortality, our investigation found that the sum of a linear combination of beta weighted Z scores for PTH, phosphorous and albumin correlated significantly with the outcome of HCH.Given the limited pool of 267 patients with regular testing for serum parathyroid hormone and phosphorus, our findings justify further exploration of this promising relationship. Initially we questioned whether patients with tests for PTH and phosphorus had more advanced renal disease than our second cohort of 792 patients without such testing. However the average CKD stage for patients in the first and second cohorts was: 3.8 and 3.6 respectively.The area under the ROC curve for the linear combination of weighted values for PTH, PO4 and albumin was greater, but not significantly different, than the areas under ROC curves for the non-weighted sum of Z scores for PTH, PO4 and albumin or for the Z score of PTH alone. The association of true positive HCH with the Z score for PTH alone was intriguing to us. The Z scores for average PTH within our patient pool ranged from -2.1 to 79.7, with a mean value of 5.9. This wide variation was not observed in the average Z scores for PO4 or albumin which ranged from -3.6 to 8.1 (mean 0.9), and from -4.9 to 1.2 (mean -1.0) respectively. The wide variation for PTH and its strong correlation with HCH is consistent with other researchers . But thiOur second cohort of 792 patients with more complete observations and weighted Z scores displayed better correlation to the true positive occurrence of HCH. That model differed significantly from the model based on non-weighted Z scores of the same blood tests or for stages of CKD.As public policy supports sizable investments in electronic health records, along with regional health information exchanges, there is rapid movement towards Accountable Care Organizations within the United States. Since ACOs intend to shift provider focus from procedure pricing to better health outcomes, the incentive for achieving this goal is financial compensation based on individual patient outcome. Such a shift will require metrics to predict expected outcomes for patients in various stages of illness. Currently most payers rely on claims data for prediction. Such analysis is population based and does not recognize individual patient complexity.In order to tailor prevention for better health, improved disease modeling is necessary. Accurate forecasts based on objective data will also enhance delivery of value-based outcomes.We believe that further investigation is warranted to evaluate additional linear combinations of diagnostic measures for select chronic illnesses in order to achieve these goals.The primary limitations of our study deal with population size, blood test selection by both primary care physicians and specialists, as well as lack of data residing on the medical record such as: micro-albuminuria, systolic and diastolic blood pressure, along with BMI (Body Mass Index). We are engaged in follow on studies, which intend to address these concerns by expansion of our data pool to additional MCO's. With the advent of significant federal and state investments in electronic health records and the establishment of regional health information organizations (RHIO), we have undertaken the necessary consent procedures to acquire more complete physical and laboratory data on confirmed CKD patients.In conclusion, our study demonstrates that:1: A linear combination of blood tests based on Z scores for PTH, PO4, and albumin derived from a multivariate logistic regression model correlates significantly with in-patient hospital payments (HCH) exceeding $3,000 in one or more months over a 13 month study period at p < 0.005.2: Summing the exponential values for the regression coefficients derived from the logistic regression for those variables divided by one plus the exponential linear progression for those same variables produced a probability curve predicting HCH.3: Calculation of a probability curve for the occurrence of HCH in one or more months during the study period based on the linear progression of the variables for age, serum hemoglobin, albumin, creatinine, ALT and eGFR demonstrated significance at p < 0.005.4: Calculation of receiver operating characteristic (ROC) curves for the models predicting HCH based on the linear combination of age, hemoglobin, albumin, creatinine, ALT, and eGFR demonstrated significance at p < 0.005 when compared to ROC area calculations for models based on the non- weighted Z scores for those same variables or CKD stage alone.5: In contrast, ROC area curves derived from a linear combination of values derived from weighted variables for PTH, PO4, and albumin demonstrated prediction that was better, but not significantly different, than ROC area curves calculated for the non-weighted Z scores for those same variables as well as PTH alone.6: Our findings suggest that multivariate logistic regression calculations based on blood chemistry values related to illness severity and reimbursement may have value to future accountable care organizations in creating risk adjusted compensation models for providers. In addition, these predictive models may have value in earlier identification of patients for targeted prevention therapy.The authors declare that they have no competing interests.RWB conceived the study design, carried out data analysis, participated in statistical analysis and drafted the manuscript. RLC assisted in data analysis, participated and verified the statistical analysis, participated in drafting the manuscript.All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/12/65/prepub


Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function , with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing's protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure  (P < 0.05), but not with heart rate variability (HRV) tests . Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated. Neuropathy is a common complication in diabetes mellitus (DM), with 60%–70% of patients affected over lifetime. Symptoms of neuropathy are very common, and subclinical neuropathy is more common than clinical neuropathy . NeuropaSweat glands are innervated by thin and unmyelinated sympathetic C fibers that could be affected early in the course of diabetes, as demonstrated in patients with prediabetes . The conWe compared SUDOSCAN findings with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes, in a proof of principle study to investigate the usefulness of this measure in clinical practice.The study was conducted in Diabetes Unit, King Edward Memorial (KEM) Hospital Research Centre, Pune, India from September 2009 to February 2010. KEM Hospital Research Centre ethics committee approved the study, and informed consent was obtained from each subject.Type 2 diabetes patients between 21 and 75 yrs of age, with or without symptoms of neuropathy, were enrolled in the study. Exclusion criteria included treatment with drugs that would have an effect on the sympathetic system such as beta blockers (to avoid interference in CAN testing), amputation of arms or legs, implantation of electrical implantable devices (pacemaker/defibrillator), sensitivity to nickel or any other standard electrodes, history of seizures or epilepsy, presence of proliferative retinopathy, myocardial infarction (MI) and/or stroke in the past 6 months, arrhythmia's, treatment with anti-arrhythmic drugs, and any advanced systemic condition.A medical officer examined the patients. Height, weight, waist, and hip circumference were measured using standardised methods and used to calculate body mass index (BMI) and waist hip ratio (WHR). Blood pressure was recorded in supine position after 5 minutes rest using oscillometry. Medication history  was noted.We used the MNSI questionnaire to record neuropathic symptoms (MNSI A) . ClinicaVPT was measured on both sides (left and right) using a biothesiometer on the plantar side of the great toe on a continuous scale. We used mean of the two sides for analysis.R-R intervals during inhalation and exhalation are calculated. The longest R-R interval is determined during expiration (R-R max) and the shortest interval during inspiration (R-R min). The ratio of the longest to shortest R-R is called as E/I ratio. Normal values ≥ 1.21.HRV during deep breathing (E/I Ratio): R-R interval is measured after standing which is around the 15th beat. This is followed by bradycardia which is indicated by the longest R-R interval around 30th beat. The ratio of longest to shortest R-R is calculated which is called as 30/15 ratio. Normal values ≥ 1.03.HRV to standing (30/15 Ratio): shortest R-R interval after maneuver to shortest R-R interval during the maneuver is calculated. Normal values ≥ 1.20.HRV during Valsalva maneuver: in this test the ratio of longest Blood pressure response to standing (orthostatic blood pressure response): the postural fall in the blood pressure is taken as the difference between the systolic blood pressure lying and standing. Normal fall is ≤20 mmHg.International Diabetes Federation (IDF) (2005) recommends the use of resting heart rate and heart rate response to provocation tests , and lying and standing blood pressure difference for diagnosis of CAN . ADA hasμS) for the hands, and the feet (right and left sides). We used mean of left and right readings for the analysis.SUDOSCAN device  consists1c was measured using HPLC method  calibrated against  NGSP. Urine albumin was measured using an immunoprecipitation assay, and albumin-creatinine ratio (UACR) was calculated.Nonfasting blood sample was collected in EDTA vacutainer and processed to obtain plasma. Plasma aliquots were stored (−70°C) until further analysis. Hemoglobin was measured on whole blood on a Beckman Coulter Analyzer . Plasma glucose, uric acid, and creatinine, were measured on an automated biochemistry analyzer , using standard enzymatic methods. HbAData are presented as mean (sd). Normality of the variables was checked, and appropriate transformations were done before analysis. following variables needed transformation: log transformation for VPT and HRV tests including 30/15 standing ratio and the Valsalva maneuver, log-log transformation for E/I Ratio, and square root transformation for MNSI A score. Agreement between left and right readings (VPT and ESC) was investigated using mean percent difference and coefficient of variation (CV). Simple linear regression analysis and Chi-square proportional trend test were used to study the association of ESC with continuous and categorical measurements of biological determinants  and conventional measures of peripheral and cardiac neuropathy . Agreement between MNSI, biothesiometer readings, and ESC values was studied using simple linear regression analysis. In this we express results as prediction interval by calculating percentage of observation outside the prediction limit. Low percentage indicates good agreement. Association between ESC and biological determinants was also tested using multiple linear regression analysis. Area under the curve (AUC) of the ROC curve was calculated to measure the efficiency of ESC in diagnosing patients with and without neuropathy against VPT . StatistWe studied 265 type 2 diabetic patients  who were found eligible for the study and gave informed consent. Clinical and biochemical characteristics of the subjects are described in 2, of whom 6 (2.2%) had eGFR < 60 mL/min/1.73 m2. Sixty patients (22.5%) had nonproliferative diabetic retinopathy (NPDR). Seventy-four patients had low levels of plasma vitamin B12 (<150 pmol/L) or were on vitamin B12 supplements, and they had similar nerve function  compared to those who had higher levels of vitamin B12 and are included in the analysis.Thirty six patients (13%) showed microalbuminuria, 7 (2.6%) had macroalbuminuria. None had serum creatinine > 1.5 mg%, 53 (20%) had eGFR < 90 mL/min/1.73 mTwo hundred and thirty (86.8%) patients had at least one symptom of neuropathy. One hundred and forty-nine patients (56.2%) had abnormal appearance on foot inspection, 57 (21.5%) had reduced ankle reflex, 41 (15.5%) showed reduced vibration sensation using tuning fork, and 15 (5.7%) showed reduced touch sensation using SWME on at least one foot. One hundred and forty-four patients (54.3%) showed MNSI B score >2 “Clinical neuropathy”. Patients with neuropathy were older, had longer duration of diabetes, and had higher VPT (biothesiometer) and lower ESC (SUDOSCAN)  Table 2Table 2.P < 0.001, both), higher HbA1c concentration (P < 0.05), higher serum creatinine and lower eGFR, and with decreasing ESC .On biothesiometry, 90 (34.0%) patients had a VPT reading of ≤10 V which is considered normal, 93 (35.1%) patients had a reading between >10 and ≤15 V, 60 (22.6%) had a reading between >15 and ≤25 V, and 22 (8.3%) had a reading >25 V. Increasing VPT was associated with higher age and longer duration of diabetes  had abnormal E/I ratio (<1.21), 84 (32%) had abnormal 30/15 ratio (<1.03), and 21 (8%) had orthostatic hypotension (>20 mmHg). Valsalva test was performed satisfactorily by only 171 patients, out of which only 1 was abnormal (<1.20). Of 171 on whom all test results were available, in 102 all tests were normal, 46 had one test abnormal, and 23 had two or more tests abnormal.Conductance measurements were normally distributed in hands and feet. Mean percent difference between measurements on right and left side was 9.5% for hands and 6.0% for feet while it was 14.2% for VPT measurements . The CV For further analysis, only the feet ESC results are used, and similar results were observed for hands ESC.1c, and lower hemoglobin concentrations, but were not related to gender, BMI, WHR, non-fasting plasma glucose, uric acid, creatinine concentrations and eGFR. On multiple linear regression analysis, lower ESC was independently associated with higher age and higher HbA1c , but not with gender, anthropometric and other biochemical parameters.r = −0.12, P < 0.05), increasing score on physical abnormalities, suggestive of peripheral neuropathy (MNSI B) , and increasing score on VPT . Compared to patients with ESC ≥ 40 μS, patients with ESC < 40 μS were more than two times likely to have MNSI B score > 2, (OR = 2.3 (1.28–4.14)), more than three times likely to have VPT > 25 V (OR = 3.97 (1.61–9.99)), and more than 4 times likely to have 2 or more CAN tests abnormal (OR = 4.41 (1.72–11.29)). Of the four CAN tests, only postural fall in blood pressure was associated with lower ESC .Lower ESC was significantly associated with both increasing symptoms (MNSI A)  and VPT on ESC and calculated the predicted VPT and MNSI measurements for any observed value of ESC. Percentage of observations outside prediction interval was 2.6% for MNSI A, 1.5% for MNSI B, and 4.5% for VPT, which indicates good agreement.μS which indicates that 73% of neuropathy patients and 62% of without neuropathy patients were correctly diagnosed by SUDOSCAN.Efficiency of sweat function measurement in diagnosing patients with and without neuropathy was checked using ROC curve. The AUC of ESC, calculated against continuous scale of VPT, was 71% at VPT = 21 V. The sensitivity and specificity, calculated on the continuous scale of ESC, were 73% and 62%, respectively, at ESC = 52 In this proof of principle study in diabetic patients, we found that lower ESC on SUDOSCAN (reflecting sweat gland dysfunction) was significantly associated with symptoms of peripheral neuropathy and conventional clinical tests of vibration perception and monofilament touch. The association of ESC with vibration perception (biothesiometer) was continuous and graded, similar to the findings of a previous study performed in France . Lower E1c) predict low ESC, indirectly supporting that it is a reliable measure of diabetic neuropathy.SUDOSCAN evaluates sudomotor function by measuring ESC resulting from an electrochemical reaction between sweat chloride and nickel electrodes after a low DC stimulation. Importance of sweat chloride in this reaction was well demonstrated in a study performed with cystic fibrosis (CF) patients who had significantly higher conductance compared with healthy subjects . Sweat gTuning fork and monofilament tests are easy to perform but qualitative. Biothesiometry is quantitative. But all these tests are subjective, requiring patient's attention and cooperation , and theAdmittedly, this proof of principle study has some limitations in applicability because of the design and methodology. The need to compare the results with conventional HRV tests (Ewing's protocol) necessitated exclusion of patients who were on medications which could affect HRV. It is also true that Ewing's protocol is somewhat outdated though it remains the “standard” method for autonomic testing. The use of a DC in the testing required exclusion of patients who suffered from seizures or were carrying an electrical medical device. Patients with foot ulcers or amputation had to be excluded because of the technical requirement of the test. Comparison of vibration perception (biothesiometer) and sudomotor function meant that we compared affection of large, myelinated type A fibers with that of small, unmyelinated type C fibres. However, this comparison allowed us to test the performance of a novel method with established clinical methods. It would be informative to compare SUDOSCAN with other methods of sweat gland function like QSART   or NeuroFurther clinical application of sudomotor testing in a diabetic clinic will depend on conducting larger unbiased studies in representative patient populations and relating the findings to varied clinical outcomes including foot ulceration, amputations, cardiovascular events, and sudden death, in all of which autonomic neuropathy is thought to play a significant role.Assessment of sudomotor function using SUDOSCAN, a quick and noninvasive test, could be considered as an additional screening test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic to identify patients with small fibre neuropathy who may be at higher risk of foot problems or cardiac neuropathy.


Cerebral perfusion pressure (CPP) is defined as the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP). However, since patients with traumatic brain injury (TBI) are usually treated with head elevation, the recorded CPP values depends on the zero level used for calibration of the arterial blood pressure. Although international guidelines suggest that target values of optimal CPP are within the range of 50 – 70 mmHg in patients with TBI, the calibration of blood pressure, which directly influences CPP, is not described in the guidelines.The aim of this study was to review the literature used to support the CPP recommendations from the Brain Trauma Foundation, and to survey common clinical practice with respect to MAP, CPP targets and head elevation in European centres treating TBI patients.A review of the literature behind CPP threshold recommendations was performed. Authors were contacted if the publications did not report how MAP or CPP was measured. A short questionnaire related to measurement and treatment targets of MAP and CPP was sent to European neurosurgical centres treating patients with TBI.Assessment methods for CPP measurement were only retrieved from 6 of the 11 studies cited in the TBI guidelines. Routines for assessment of CPP varied between these 6 publications. The 58 neurosurgical centres that answered our survey reported diverging routines on how to measure MAP and target CPP values. Higher CPP threshold were not observed if blood pressure was calibrated at the heart level (p = 0.51).The evidence behind the recommended CPP thresholds shows no consistency on how blood pressure is calibrated and clinical practice for MAP measurements and CPP target values seems to be highly variable. Until a consensus is reached on how to measure CPP, confusion will prevail. Maintaining an adequate cerebral perfusion pressure (CPP) is crucial in patients with traumatic brain injury (TBI). CPP is defined as the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP). Aggressive attempts to keep the CPP above 70 mmHg have been reported to be detrimental,2, as haCuriously, how to measure MAP and consequently also CPP in the first place, has not been given much attention. Since most patients with TBI are managed with head elevation, the level of zero calibration of the arterial blood pressure will affect the MAP, and hence CPP levels, significantly. Simple trigonometry reveals that in a person with 30 degrees elevation head and 30 cm distance between heart and the head, the difference in measured MAP/CPP levels will be 11 mmHg depending on if the blood pressure transducer is calibrated in the heart or head level ). In February 2013 a short questionnaire  V.21. A Pearson Chi-square test was used to investigate the relationship between desired CPP-thresholds and level of arterial line calibration.The Brain Trauma Foundation has published recommendations regarding CPP thresholds. The list of evidence supporting this recommendation is presented in Table The main conclusions regarding CPP-levels from the available evidence is presented in Table The questionnaire was sent to the head of the neurosurgical department in 309 European hospitals. If the respondent was unable to answer the questions, they were instructed to forward the e-mail to the person in charge of neuro-intensive care at their centre (neurosurgeon or anaesthesiologist). After two reminder e-mails to the non-respondents, a total of 58(19%) centres responded to the survey.Clinical practice for target CPP values, degree of head elevation and MAP calibration levels varied between European neurosurgical centres Table . 56% repThere was no significant correlation between the desired CPP targets and routines for MAP calibration levels among the respondents, p = 0,51 Table .Measurements of and interventions to obtain optimal CPP is a cornerstone in neuro-intensive care. However, routines on how to measure MAP will affect observed CPP levels profoundly. Unfortunately, we find that studies behind the recommended CPP thresholds often do not elaborate on how MAP and CPP are measured. Additionally, methods of MAP and CPP measurements vary considerably in the studies where this information was available. The only level II evidence study cited in respect to CPP in the TBI guidelines measured MAP and ICP at the same level. This raA limitation of the study was the low response rate in the survey, but it was somewhat as expected when comparing to other internet based surveys. This raIn conclusion, the methods for CPP measurements in studies used for development of TBI guidelines are often not reported. Studies that report how CPP is obtained use various methods. Clinical practice related to the measurement and treatment of CPP varies between neurosurgical centres. Until a consensus is reached on how to measure CPP, confusion will prevail.TBI: Traumatic brain injury; MAP: Mean arterieal pressure; ICP: Intracranial pressure; CPP: Cerebral perfusion pressure.None of the authors have any competing interest or financial disclosures to declare.VR participated in the design of the study, the review of literature, data collection/processing/interpretation and drafting the manuscript. PK contributed in the design of the study, interpretation of data and drafting the manuscript. OKL participated in the design of the study, creation of figures, interpretation of data and drafting the manuscript. OS participated in the conception and design of the study, the review of literature, data processing/interpretation and drafting the manuscript. All authors read and approved the final manuscript.


Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).In response to empagliflozin during clamped euglycaemia, systolic blood pressure  and augmentation indices at the radial , carotid  and aortic positions  declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia . HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.NCT01392560Clinical trial registration:  In type 2 diabetes mellitus (T2D), approximately 40% of patients are hypertensive at the time of diagnosis, and in type 1 DM (T1D), the prevalence of hypertension increases with longer duration of disease . TogetheAside from effects of RAAS and SNS activation on vascular function, arterial stiffness increases under the influence of ambient hyperglycaemia and can be improved through tight glycemic control -11. InteAlternatively, glucose lowering may be achieved with novel sodium glucose co-transport 2 (SGLT2) inhibitors in patients with T2D ,21. SincIn a trial designed with the primary objective of investigating renal hemodynamic effects of SGLT2 inhibition, we examined systemic hemodynamic effects of empagliflozin , a new and highly selective SGLT2 inhibitor. We hypothesized that empagliflozin would decrease arterial stiffness, including augmentation index and pulse wave velocity, leading to declines in systemic blood pressure. In addition, due to the stimulatory effect of hyperglycaemia on the SNS , we hypohttp://www.clinicaltrials.gov/ct2/show/NCT01392560). In brief, men and women ≥18 years with T1D ≥ 12 months with estimated GFR ≥60 ml/min/1.73 m2 and no hypertension or macroalbuminuria were included. Patients taking medication known to interfere with RAAS activity and/or renal function based on investigator judgment were excluded [In this 8-week, open-label, prospective clinical trial, 42 participants with T1D were treated with empagliflozin 25 mg once daily (NCT01392560). Inclusion and exclusion criteria at screening have been described elsewhere  . Augmentation index, an estimate of systemic arterial stiffness was calculated as the difference between the second systolic peak and inflection point, expressed as a percentage of the central pulse pressure corrected to an average heart rate of 75 beats per minute. The aortic pulse wave velocity (PWV) was measured using the same device by sequentially recording ECG-gated right carotid and radial artery waveforms. Two vascular measurements were obtained for each parameter and the average value reported. The use of the SphygmoCor device to assess arterial stiffness parameters has been previously published by our group . AutomatAfter completion of arterial stiffness testing, HRV testing was performed using AtCor software . In brief, two 10-minute segments were recorded. Vagal tone (Root Mean Square Successive Difference - RMSSD) and sympathetic activity  measures were obtained at each of the two periods and the results were then averaged. Plasma noradrenalin and adrenaline concentrations were obtained on each of the study days according to standard, previously described methods .The primary endpoint of this study was change in GFR after treatment with empagliflozin for 8 weeks . Sample The baseline characteristics of this T1D study cohort are described in Table During clamped euglycaemia, empagliflozin significantly reduced systolic blood pressure, radial augmentation index, carotid augmentation index and aortic augmentation index Table . CarotidDuring clamped hyperglycemic conditions, treatment with empagliflozin did not reduce blood pressure significantly, despite significant effects on radial augmentation index, carotid augmentation index and aortic augmentation index Table . EmpagliDespite optimal medical therapy including RAAS inhibitors, many patients continue to develop hypertension, chronic kidney disease and cardiovascular diseases . MoreovePrevious studies in T2D have suggested that oral hypoglycemic agents such as metformin reduce blood pressure, primarily through improving glycemic control -14,43. IArterial stiffness is influenced by a variety of factors, including neurohormonal mediators and changes in arterial structure . We haveWhile neither RAAS, NO nor SNS activity can explain our results, we postulate that changes in arterial stiffness with empagliflozin are due to several other factors Figure . First, Due to their insulin-independent mechanism of action and as shown in animal models , SGLT2 iThis trial has some limitations. First, the duration of therapy was limited to 8 weeks. Therefore, conclusions regarding longer term clinical benefits cannot be made from this study. Second, further work is needed to explore the interdependence among beneficial effects on arterial stiffness, including weight loss, glycemic control and blood pressure seen with empagliflozin. In particular, we could not determine if changes in blood pressure were based on declines in arterial stiffness, or whether reduced arterial stiffness was responsible for the fall in systolic blood pressure. Nevertheless, consistent changes in these vascular parameters are encouraging and support the rationale for ongoing long-term cardiovascular outcome trials. Third, these results in young patients with uncomplicated T1D cannot be generalized to older T1D patients, T1D patients with hypertension or to those with T2D. Given the important relationship between age and arterial stiffness, future work should determine if SGLT2 inhibition exerts similar effects in older individuals. Finally, measures of arterial stiffness have a high variability. As a consequence, our results should be viewed as exploratory and should be confirmed in future studies.In summary, empagliflozin reduces arterial stiffness in patients with T1D. Longer-term studies are warranted to assess the safety and clinical effects of these agents in T1D. Moreover, since arterial stiffness is a surrogate marker for renal and cardiovascular clinical outcomes, future trials should assess the effect of empagliflozin on cardiorenal protection in patients with diabetes.The results presented in this paper have not been published previously in whole or in part. Some of the results presented in this paper were presented at the American Society of Nephrology Kidney Week in November 2013. D.Z.I.C. has received speaker honoraria from Boehringer Ingelheim and B.A.P received operational funding with D.Z.I.C. for this work. N.S., N.F., H.J.W. O.E.J., U.C.B., M.v E. are employees of Boehringer Ingelheim.DZIC, BAP, RH, researched data, wrote the manuscript. NF, HJW, NS, OEJ, UCB, MvE contributed to discussion, reviewed/edited manuscript. All authors have approved the final version of this manuscript.David ZI Cherney, Bruce A Perkins and Nima Soleymanlou are co-primary first authors and Maximilian von Eynatten and Uli C Broedl contributed equally as co-senior authors.