Diabetes is associated closely with an increased risk of cardiovascular events, including diastolic dysfunction and heart failure that leads to a shortening of life expectancy. It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function. However, the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern. We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub-analysis of the PROLOGUE study.Patients in the PROLOGUE study were assigned randomly to either add-on sitagliptin treatment or conventional antidiabetic treatment. Of the 463 patients in the overall study, 115 patients  who had complete echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e′) at baseline and after 12 and 24 months were included in this study. The primary endpoint of this post hoc sub-analysis was a comparison of the changes in the ratio of E to e′ (E/e′) between the two groups from baseline to 24 months.The baseline-adjusted change in E/e′ during 24 months was significantly lower in the sitagliptin group than in the conventional group , irrespective of a higher E/e′ value at baseline in the sitagliptin group. In analysis of covariance, sitagliptin treatment was significantly associated with change in E/e′ over 24 months , independent of other clinical variables at baseline such as blood pressure, HbA1c, and medications for diabetes. Changes in other clinical variables including blood pressure and glycemic parameters, and echocardiographic parameters, such as cardiac structure and systolic function, were comparable between the two groups. There was also no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive C-reactive protein between the two groups during the study period.Adding sitagliptin to conventional antidiabetic regimens in patients with T2DM for 24 months attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction (E/e′) independent of other clinical variables such as blood pressure and glycemic control.Trial registration UMIN000004490 . https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005356; registered November 1, 2010The online version of this article (doi:10.1186/s12933-017-0546-2) contains supplementary material, which is available to authorized users. Type 2 diabetes mellitus (T2DM) is associated closely with an increased risk of cardiovascular (CV) events including heart failure , 2. The To date, three randomized controlled trials that focused on major CV outcomes in patients with T2DM treated with either dipeptidyl peptidase-4 (DPP-4) inhibitors or placebo have been reported. Alogliptin in the EXAMIN , saxagliThe PROLOGUE study  was a prospective multicenter study conducted in Japan to evaluate the inhibitory effect of sitagliptin on the progression of atherosclerosis based on carotid-artery intima-media thickness (IMT) assessed by ultrasonography over a 2-year follow-up period , 18. In The details of the PROLOGUE study design have been published elsewhere . BrieflyOf the 436 participants in the PROLOGUE study, an echocardiographic examination was performed at baseline in 152 patients in the sitagliptin group and 148 patients in the conventional group. The present study analyzed the data of 115 patients  who had echocardiographic data of the ratio of peak early diastolic transmitral flow (TMF) velocity (E) to peak early diastolic mitral annular velocity (e′) at baseline and at both 12 and 24 months .Data were expressed as mean ± standard deviation for normally distributed variables, median and interquartile range for variables with a skewed distribution, and frequencies (%) for categorical variables. All reported probability values were two-sided with a p value <0.05 considered statistically significant. The percentage changes in the variables during the study period were calculated as /baseline value. The differences between the two groups were assessed, where appropriate, by either the Student’s Table The levels of fasting plasma glucose, HbA1c, and 1, 5 AG were similar at baseline in the two groups and there were no significant changes in these parameters during the 24 months of treatment between the groups , relative to conventional treatment alone. On the other hand, changes in other parameters such as LV size and LVEF did not differ between the two groups. We also found no significant differences in the biomarkers measured during the study. It is known that metabolic disturbances and diabetes are associated closely with cardiac diastolic dysfunction such as diabetic cardiomyopathy, and there is also evidence that patients with diabetes and an increased E/e′ have higher mortality , 23. GivRecently we demonstrated a possible effect of sitagliptin on carotid atherosclerosis , endotheDPP-4 inhibitors promote glucose-dependent insulin secretion and suppress glucagon secretion by inhibiting the activity of an enzyme which inactivates endogenous incretin like glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide. This leads to improved postprandial hyperglycemia similar to that seen with the normal physiological response. DPP-4 inhibitors do not cause weight gain and a single administration is unlikely to induce hypoglycemia. It is therefore relatively easy to use DPP-4 inhibitors safely in the elderly and patients with renal dysfunction. To date, the three randomized clinical trials mentioned above have reported non-inferiority, relative to placebo, for CV outcomes in patients with T2DM with high cardiovascular risk or established CV disease –13. In pAccumulated evidence suggests that patients with TD2M often exhibit LV diastolic dysfunction and heart failure due to underlying metabolic derangement, such as insulin resistance, independent of hypertension and coronary artery disease (CAD) –30. ReceIn the present study, adding sitagliptin to usual diabetes treatment significantly attenuated the annual increase in E/e′, suggesting a preventive effect on LV compliance and diastolic dysfunction. However, sitagliptin treatment did not affect other echocardiographic parameters of systolic function and cardiac structures or other clinical variables, such as NT-proBNP, blood pressure, and glycemic control. Comparison with a previous study in which sitagliptin did not improve diastolic dysfunction  showed tThe present study was a sub-analysis of the PROLOGUE study. Because echocardiography was a voluntary measurement in the PROLOGUE study and not performed in all participants, the number of patients in this study was small and included only Japanese subjects. Whether or not echocardiography was performed was left to the judgment of each researcher and therefore selection bias could not be fully excluded. The sample size may therefore be underpowered and accordingly the clinical implications may be limited. In addition, the PROLOGUE study recruited patients with and without history of heart failure at baseline, with patients with a NYHA functional classification of III and IV being excluded. Because most patients had no history of heart failure evident at baseline, we did not determine whether there were differences in the effects of sitagliptin on diastolic function between patients with or without heart failure. Further studies on a larger number of subjects are needed to assess whether longer-term DPP-4 inhibitor treatment is safe and has beneficial effect on cardiac function in T2DM patients with or without overt heart failure.Our present sub-group analysis from the PROLOGUE study demonstrated that adding sitagliptin to conventional antidiabetic regimens for 24 months in patients with T2DM attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction, E/e′, independent of other clinical variables such as blood pressure and glycemic control. These results suggest that sitagliptin is potentially a beneficial agent for diastolic function in patients with T2DM.


Oxidative stress is thought to be involved in the pathogenesis of microalbuminuria in Sickle cell anemia (SCA). Antioxidant enzymes such as glutathione peroxidase (GPx) and Cu-Zn superoxide dismutase (SOD) may play an important protective role. This study aimed to evaluate the association between albuminuria and these two antioxidant enzymes.We consecutively recruited Steady state children aged between 2 and 18 years old with established diagnosis of homozygous SCA in two hospitals of Kinshasa/DR Congo. The relationship between Urinary Albumin Creatinine Ratio (UACR) and other variables of interest , percentage of fetal hemoglobin, serum iron, ferritin, CRP) was analyzed by Bivariate correlation (Pearson’s correlation coefficient). Microalbuminuria was defined by urine albumin/creatinine ratio between 30 and 299 mg/g.r = 0.260; p = 0.033) and WBC count  were positively correlated with UACR whereas GPx  and Cu-Zn SOD  were negatively correlated with UACR.Seventy Steady state Black African children with SCA  were selected. Prevalence of microalbuminuria was 11.8%. LDH (Albuminuria is associated with decreased antioxidant capacity and increased levels of markers of hemolysis and inflammation. Therefore, strategies targeting the reduction of sickling and subsequent hemolysis, oxidative stress and inflammation could help preventing or at least delaying the progression of kidney disease in SCA children. Sickle cell anemia (SCA) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced patient’s quality of life and life expectancy . OxidatiThe design of this cross sectional study has been described elsewhere . The stuFor each patient, anthropometric parameters, past medical history especially current medication were obtained and physical examination performed.A venous blood sample was collected for the determination of the level of GPx and Cu-Zn SOD as well as other biochemical parameters of interest including Fetal hemoglobin (HbF), blood count, serum creatinine, total bilirubin and its fractions, lactate dehydrogenase (LDH), iron, ferritin, C reactive protein (CRP), plasma free Hb.Cu-Zn SOD and GPx were assayed by double-sandwich Elisa method using biotin-streptavidin system . For GPxSingle spot morning urine specimens were collected and urine samples containing blood (1+ or greater), white blood cells (1+ or greater) and/or nitrites were excluded. Both urine dipstick test and UACR measurement were performed. UACR was performed using an immunoassay method with DCA Bayer 2000 reagent . Normal albuminuria, microalbuminuria and macroalbuminuria were defined as UACR < 30 mg/g, 30 to 299 mg/g and ≥ 300 mg/g, respectively .Ethical approval for the study was granted by the institutional review boards of the Monkole hospital (006 CEFA-MONKOLE/2014) in line with the principles of the Declaration of Helsinki, second revision. The aim and study procedures were explained to the parents or legal guardians and they provided written consent before any of the subjects were included.t-test or Mann Whitney U test were used to assess numerical data as appropriate. Statistical significance was defined as p value of < 0.05.Statistical analyses were performed using SPSS . The primary focus in the data analysis was to assess the relationship between UACR and the antioxidant status. For this purpose, bivariate correlation (Pearson’s correlation coefficient) analyses were performed to analyze the relationships between UACR and other numerical data. Analyses were carried out with Pearson’s correlation, simple and multiple linear regressions. Step-wise multivariate regression analysis was performed to determine the independent variables for UACR. For other results, numerical variables are presented as mean ± standard deviation (SD) for normally distributed values or as median with interquartile (IQ) range for nonparametric values and categorical variables are presented as percentage. Pearson chi-square or Fisher’s exact test were used to assess differences in categorical data between groups and Student p = 0.293.Table In the study group, 37 patients (53%) received hydroxyurea (HU). Compared with the untreated patients, those who received HU had higher rates of GPx and Cu-SOD. They also had lower levels of UACR but the difference was not statistically significant Table .Table 2Cr = 0.260; p = 0.033) and leucocytes levels  were positively correlated with UACR whereas GPx  and Cu-Zn SOD  were negatively correlated with UACR. There was no statistically correlation between UACR and age, systolic blood pressure, diastolic blood pressure, creatinine, glomerular filtration, fetal hemoglobin, plasma free hemoglobin, serum iron, ferritin, indirect bilirubin and CRP.Table The results related to the linear regression are reported in Table The main findings of the present cross-sectional study of Steady state SCA children can be summarized as follows. First, albuminuria was inversely correlated with antioxidant enzyme levels and positively to absolute white blood cell (WBC) count and LDH enzyme levels. Second, antioxidant enzyme glutathione peroxidase (GPx) and LDH levels emerged as the main independent multivariate determinants of albuminuria but the model explained only 14% of the variations of albuminuria. Third, patients receiving hydroxyurea appear to have improved antioxidant capacity and low UACR.202). This finding may suggest that the overabundance of oxidative stress leads to consumption or inactivation this protective cofactor [In our cohort, we found an inverse correlation between albuminuria and antioxidant enzyme GPx and Cu-Zn SOD. This observation is similar to previous reports from Nigeria , Egypt  and Qatacofactor , 14. Oxicofactor , 15. Oxicofactor .A Previous study reported the relationship between albuminuria and inflammation, and hemolysis . This reThe LDH is known to be a marker of hemolysis. The positive association between albuminuria and LDH suggest the central role of hemolysis as the starting point for many of the subsequent complications of SCA, including kidney damage , 18. A PIn multivariate analysis, GPx and LDH levels were independent determinants of albuminuria but the model explained only 14% of the variation in albuminuria levels suggesting the non-inclusion in the model of other variables susceptible to influence this variation. Although an association between markers of oxidative stress and common secondary diseases in SCA have been reported, other factors such as diet, physical activity, and other comorbid diseases associated with SCA may interfere with the variations in albuminuria levels [For decades, many studies worldwide have shown the benefit of HU in SCA , 22. AltOur results should be interpreted within the limitations of the present work. First, the cross-sectional design of the study precludes the establishment of temporal relationships between study variables. Secondly, the small sample does not confer much power to statistics tests to identify additional associations between the study variables. Third, given the limited financial resources, we did not measure the cofactors of antioxidant enzymes and trace elements to better explain the alterations in enzymes levels. The assay of transferrin also was not done. However, we can mention that both ferritin  and transferrin prevent the iron to react with its immediate environment. Indeed, in healthy cells, the iron ions are chelated by transport proteins (transferrin) or storage proteins (ferritin). Fourth, in medical human literature, there are few data on reference values of each antioxidant or oxidative stress markers. It is known that, initially, the body will react in a moderate oxidative stress by overexpressing antioxidant enzymes (eg when exercise). If the stress persists and produces massively free radicals, SOD and GPx will be destroyed and its concentration drops. Paradoxically, a too high concentration of SOD can be dangerous because, in this case, it is the basis of a hydrogen peroxide overproduction  .In the present study, albuminuria was associated with decreased antioxidant capacity and increased levels of markers of hemolysis and inflammation. Therefore, strategies targeting the reduction of Sickling and subsequent hemolysis and oxidative stress and inflammation could help preventing or at least delaying the progression of cardiovascular and kidney disease in SCA children.


Septic patients often require sedation in intensive care unit, and midazolam is one of the most frequently used sedatives among them. But the interaction between midazolam and septic shock is not known. The aim of this study is to investigate the effects of midazolam on preload dependency in an endotoxic shock model by evaluating systemic vascular tone and cardiac function.−1 h−1 (MID1) and 3 mg kg−1 h−1 (MID2) (T2). Rabbits received another round of fluid challenge and norepinephrine infusion to return the MAP to normal (T3).Eighteen rabbits were randomly divided into three groups: Control group, MID1 group and MID2 group. Rabbits underwent ketamine anaesthesia and mechanical ventilation, and haemodynamic assessments were recorded in three groups (T0). Endotoxic shock was induced by lipopolysaccharide intravenously, and fluid resuscitation and norepinephrine were administered to obtain the baseline mean arterial pressure (MAP) (T1). Rabbits received equivalent normal saline (Control) and two consecutive dosages of midazolam: 0.3 mg kgNo significant differences in haemodynamic parameters were observed in three groups at T0, T1 or T3. Midazolam infusion significantly increased pulse pressure variation (PPV) and stroke volume variation (SVV) compared to the values in Control group, and MAP, central venous pressure (CVP), mean systemic filling pressure (Pmsf) and cardiac output (CO) decreased at T2. Same effects were observed with increasing doses of midazolam, and resistance for venous return (Rvr) decreased (MID1 vs. MID2) at T2. PPV and SVV increased significantly at T2 compared to the values at T1. MAP, CVP, Pmsf and CO decreased in MID1 and MID2 groups. Rvr also decreased in MID2 group (T2 vs. T1). Midazolam did not affect cardiac function index, systemic vascular resistance or artery resistance (T2 vs. T1).Midazolam administration promoted preload dependency in septic shock models via decreased venous vascular tone without affecting cardiac function. Septic shock is a deleterious systemic host response to infection characterized by hypotension that is not reversed with fluids alone. Septic shock is a common reason for admission to the intensive care unit (ICU) . The resPatients with septic shock generally require mechanical ventilation, which makes the use of sedative drugs almost imperative to reduce anxiety and agitation and facilitate care. Benzodiazepines (e.g. midazolam) are commonly used to sedate patients in the ICU, and a recent survey demonstrated that midazolam remains widely used . BenzodiNorepinephrine, an α1-agonist drug, is recommended as a first-line vasopressor . NorepinIn the present experimental, randomized study, we investigated the effects of midazolam on preload dependency in rabbits subjected to endotoxic shock with norepinephrine infusion by evaluating the systemic vascular system and cardiac function.New Zealand white rabbits (3.26 ± 0.14 kg body weight) were obtained from the animal centre of Southeast University and housed in a pathogen-free environment on a 12-h light/dark cycle with free food and water access for at least 5 days prior to experimentation. All animals received care according to the Helsinki convention for the use and care of animals, the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” by the China National Academy of Sciences. The Academic Ethical Committee of Southeast University Medical School, Nanjing, China, approved the study protocol, which has been described previously .−1) and atropine (0.15 mg kg−1), which was used to reduce mucosal secretion in the airways. A marginal ear vein was cannulated to guarantee intravenous anaesthesia using ketamine (3 mg kg−1 h−1) during the entire study protocol, as previously described [−1 h−1) was administered for neuromuscular block, and an adjunctive bolus of 0.5–1 mg was added to optimize the animal curarization if needed.Rabbits received an intramuscular injection of ketamine  and an inspired fraction of oxygen of 60%. Arterial blood was sampled for gas analysis to adjust the ventilator setting in case of respiratory acidosis prior to endotoxic shock induction. The right internal jugular vein and femoral artery were surgically isolated, and a central vein catheter was placed to infuse fluids and drugs. A dedicated arterial thermodilution catheter  was inserted to acquire the haemodynamic measurements [−1 h−1) was infused in the central vein catheter, and 2 mL h−1 of normal saline with 4 IU mL−1 of heparin was infused through the arterial line. Blood temperature was monitored and maintained between 38 and 39 °C via a warming lamp.Rabbits were ventilated via volume control ventilation with the following settings: zero end-expiratory pressure, a tidal volume equal to 8 mL kgurements . Lactate−1E. coli LPS  was used to induce endotoxic shock, which was confirmed by a 25% decrease in mean arterial pressure (MAP) [−1 fluid was injected for another 2 h to maintain blood pressure. Norepinephrine infusion was initiated, and the dose was titrated to maintain MAP at baseline values and remain constant throughout the entire protocol. The haemodynamic variables were allowed to stabilize, which was assessed as a variation of MAP < 10% over a 30-min period [An intravenous infusion over 30 s of 0.5 mg kgre (MAP) . Fluid rn period .n = 6 in each group): Control group, MID1 group and MID2 group. Figure −1 h−1 (MID1 group) and 3 mg kg−1 h−1 (MID2 group). Rabbits in the Control group received equivalent doses of normal saline. Haemodynamic measurements were performed at the end of the 30 min trial, and the data were recorded (T2). Rabbits received another round of fluid challenge and norepinephrine infusion to return the MAP to normal (T3).Rabbits were randomly divided into three groups (Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP and central vein pressure (CVP) were continuously monitored and recorded. Haemodynamic measurements were performed using a dedicated indwelling arterial catheter for the PiCCO Plus device .Proper calibration of the PiCCO Plus for pulse contour analysis was performed at each measurement time point using two 3-mL bolus injections of 4 °C normal saline. A third calibrating injection was performed if the first two values differed by more than 10%.Stroke volume (SV), cardiac output (CO) and global end-diastolic volume (GEDV) were acquired via transpulmonary dilution , 15. PulY-axis) and CVP (X-axis), and the regression line was computed using the least-squares method in Microsoft Excel. Pmsf was estimated as the pressure that corresponded to the X-intercept of the regression line, and resistance to the venous return was calculated as the inverse of the slope of the line. Rsys was calculated as (MAP-CVP)/CI. Ra was estimated as (MAP-Pmsf)/CI, and Rvr was calculated as (Pmsf-CVP)/CI.Systemic vascular resistance (Rsys), mean systemic filling pressure (Pmsf), resistance to venous return (Rvr) and arterial resistance (Ra) were calculated as previously described , 16. BriThe Cardiac Function Index (CFI) was calculated as the ratio of CO × 1000 to GEDV, and it was recorded as an estimate of ventricular systolic function , 14, 17.2), the ratio of alveolar oxygen partial pressure to the fraction of inspiration O2 (P/F), lactic acid (Lac), haemoglobin (Hb), bicarbonate (HCO3−) and oxygen saturation of mixed venous blood (SvO2).Blood gas measurements were obtained from the arterial and venous catheters at T0, T1, T2 and T3 to measure pH, the partial pressure of carbon dioxide  and GraphPad Prism 7 for Windows . We computed the descriptive statistics for all study variables. We used the Kolmogorov–Smirnov test and stratified the distribution plots to verify the distribution normality of the continuous variables. Data that were normally distributed are presented as the mean ± standard deviation (SD), and non-normally distributed data are presented as medians . We assessed differences in the distribution normality of the continuous variables using one-way analyses of variances followed by Bonferroni corrections for multiple comparisons. We used the Mann–Whitney p > 0.05) or the volume of administered fluid during T0–T1 and T1–T2. The volume of administered fluid increased from T2 to T3 between the Control, MID1 and MID2 groups . No differences were detected between the Control, MID1 and MID2 groups with respect to the norepinephrine infusion rate . Blood gases confirmed normal baseline status, and there were no significant differences between T0, T1, T2 or T3 among all three groups .Table p < 0.05), and it significantly increased SVV in the MID1 and MID2 groups (p < 0.05) compared to that in the Control group  .Table p < 0.05) but increased significantly in the MID1 and MID2 groups at T2 compared to the values at T1 (p < 0.05). PPV and SVV decreased in the MID1 and MID2 groups from T2 to T3 (p < 0.05), but no differences were detected in the Control group , and CVP and CO decreased in the MID2 group compared to the values in the Control group at T2 (p < 0.05) (Table p < 0.05) (Table As shown in Table 5) Table . MAP, CV5) Table .p < 0.05) .Midazolam dosage did not affect Rsys or Ra at T2 or T3, but Rvr deceased significantly in the MID2 group compared to that in the Control group at T2 and T3 (p < 0.05). Rsys, Ra, Rvr, HR and CFI decreased significantly from T0 to T1 (p < 0.05) (Table p < 0.05), and the opposite results occurred at T3 compared to the values at T2 (Table p < 0.05). No differences were detected in Rvr from T2 to T3 .MAP, CVP, Pmsf, CO and SV increased from T0 to T1 and T2 to T3 in all three groups  midazolam increased the preload dependency, reduced Pmsf, CVP, GEDI and Pvr and affected the SV and CO despite the increase in HR; (2) no effects on cardiac contractile function as expressed by the CFI were observed. Thus, midazolam primarily affects the heart by increasing venous capacitance.To better elucidate the mechanism, the venous return curve of one representative rabbit was constructed from the average values obtained for right atrial pressure  and cardiac output Fig. , as prevAugmented vascular capacitance and lower Pmsf reduced the venous return and therefore the SV and CO, despite attempts at compensation by increasing the HR. The CFI was not affected. The preload (i.e. GEDV) decreased significantly because of the reduced venous return, and the preload dependency (PPV) increased significantly. The Rvr decreased significantly from T0 to T2, which confirmed midazolam-induced venous dilatation and resulted in reduced preload and increased preload dependency.Our study demonstrates that midazolam increases preload dependency in an endotoxic shock rabbit model. This result is inconsistent with a prior clinical observational study also conducted by our work team in which midazolam use did not increase the preload dependency in septic shock patients . The folWe recorded no differences in cardiac function as expressed by the CFI, i.e. the ratio of cardiac output to global end-diastolic volume. CFI correlates with left ventricular global systolic function , 22, andSome limitations of the present study must be mentioned. First, we used SVV and PVV to reflect volume responsiveness. Previous studies demonstrated that SVV (directly measured using different pulse contour techniques or Doppler ultrasounds) or PPV reliably predicts the response to fluids when several prerequisites are met  , 24. TheSecond, we used the end-inspiratory occlusion technique to draw the venous return curve for Pmsf computation . PersichIn conclusion, midazolam affected the preload dependency at increasing doses in endotoxic shock rabbits undergoing norepinephrine infusion without affecting heart contractile function. These results suggest no major effects of midazolam on cardiac function in septic shock and that the haemodynamic fluctuations at large doses of midazolam were due to venous dilation. These data were derived from animal models, and further studies must be performed in humans to understand the possible interference of benzodiazepine in septic shocked patients.In conclusion, a high dose of midazolam administration in a septic shock model after fluid resuscitation and norepinephrine infusion increased the preload dependency via modification of vascular resistance. No effects on cardiac function were observed. Further studies must be performed in humans to understand the possible interference of sedative drugs on haemodynamics during septic shock.


This review will examine the implications for perioperative management of new hypertension guidelines and place these in the context of findings from recent large observational studies.Recent hypertension guidelines highlight the role of ambulatory blood pressure measurement with the implication that isolated preoperative blood pressure measurements are of limited value. There is emerging evidence from large observational studies that both preoperative and intraoperative hypotension are associated with increased risk. It is not clear if this is a particular concern for hypertensive patients.Assessment of the hypertensive surgical patient should include blood pressure measurements taken using the correct technique. Preoperative blood pressures of less than 180/100 mmHg are not grounds for deferring surgery in the absence of active comorbid disease. Evidence to guide the perioperative management of patients with higher pressures is scanty and decisions should be made on a case-by-case basis. Hypertension is common. In 2011, 31% of men and 28% of women in the UK were classified as hypertensive, defined as having a blood pressure greater than 140/90 mmHg [Threshold blood pressures for the diagnosis of hypertension are based on the association between a given blood pressure and comorbid disease such as ischaemic heart disease or renal failure. There is a continuum of risk, higher blood pressures being associated with a higher incidence of complications. Severe hypertension, for example a systolic blood pressure of greater than 180 mmHg is uncommon but carries very considerable risks for the patient. Lesser degrees of raised blood pressure such as a blood pressure of 140–150 mmHg systolic are much more common and, whilst they carry less risk for the individual patient, are responsible for a great deal of the population burden of cardiovascular disease. The definition and categorisation of hypertension rests on striking a balance between the prevention of such cardiovascular disease and the requirement to treat a large proportion the population with antihypertensive medications . VariousWhichever guidelines are being applied, it is essential that appropriate technique is used when measuring the blood pressure. The patient should be sitting quietly with the arm supported at heart level. The patient should not be engaging in conversation. An appropriate size cuff should be used. If an automated device is used, it should conform to the appropriate national standards . The pulBlood pressures recorded in patients coming to hospital for elective surgery are often elevated. It would not be appropriate to diagnose new or poorly controlled hypertension on the basis of blood pressure recordings from the preassessment clinic. However, the effect of the medical setting is related to the true blood pressure with “white-coat” hypertension being seen in 55% of people with grade 1 hypertension but only about 10% of people with severe hypertension . PatientHypertension is of concern because of the extensive damage that it can cause throughout the body. Target organ damage in the heart may be manifest as left ventricular hypertrophy, diastolic dysfunction, heart failure, microvascular disease, and atherosclerotic coronary artery disease . The braBlood pressure is regulated by a number of integrated cardiovascular control systems. The immediate control of blood pressure over the course of 10 to 20 s is through changes in heart rate and vascular tone in response to blood pressure changes sensed by the carotid and aortic baroreceptors. Control of blood pressure over minutes to hours is through the regulation of circulating volume. Low-pressure receptors in the atria and great veins regulate the release of antidiuretic hormone and atrial natriuretic factor. The long-term control of the “set-point” around which an individual’s blood pressure is regulated is through the renin-angiotensin-aldosterone system (RAAS) which controls natriuresis and through this, diuresis . The RAAIn primary hypertension, the set point for blood pressure is elevated. Primary hypertension was previously known as essential hypertension and has been renamed to better reflect our incomplete understanding of the mechanisms of this change. It is thought that primary hypertension is due to the interaction of genetic and environmental factors . Genetic−1/h−1) should be treated with an “anti-volume” drug such as a diuretic whereas those with high-renin vasoconstriction hypertension (PRA > 0.65 ng ml−1 h−1) should be managed with an antagonist of the renin-angiotensin system such as an ACE inhibitor [It has been proposed plasma renin activity (PRA) may be useful to guide the treatment of hypertensive patients. This approach suggests that patients with low-renin, volume-dependant hypertension  act by reducing the conversion of angiotensin I to angiotensin II in the lungs. This class of drugs includes the oral drugs captopril, enalapril, ramipril, perindopril, and lisinopril. Enalaprilat is the active form of enalapril and is administered intravenously. ACEI are first-line agents for the treatment of primary hypertension in patients aged less than 55 years.1 receptors and antagonise the action of angiotensin II. Losartan and valsartan are competitive antagonists whilst candesartan and telmisartan bind irreversibly with the AT1 receptor. The ARAs do not inhibit bradykinin metabolism and because of this, ARAs are less likely than ACEI to cause a chronic cough. They also have the potential merit of blocking the action of angiotensin II produced by pathways other than angiotensin-converting enzyme such as that are produced by the action of chymase in the kidney.The angiotensin receptor antagonist (ARA) drugs act on ATBoth ACEI and ARAs can produce relative hypovolaemia and there are reports of an increased incidence of hypotension with induction of anaesthesia with both these classes of drug. This is said to be particularly marked with a combination of ARAs and diuretics •, 17. MaAliskiren is a direct renin inhibitor which is administered orally and has a place in the treatment of hypertension refractory to management with other medications. It has a long elimination half-life of 24 to 40 h and there are concerns that it may be associated with refractory hypotension following induction of anaesthesia. However, the data to support this are limited .Beta-blockers are no longer considered to be first-line antihypertensive agents unless also being administered for other indications such as secondary prevention following myocardial infarction. They act to inhibit catecholamines at G protein-coupled β-adenoreceptors and reduce blood pressure through multiple mechanisms. The blockade of cardiac β-1 receptors reduces heart rate and beta-blockade also reduces myocardial contractility. Blockade of β-receptors in the juxtaglomerular apparatus reduces renin secretion and thus salt and water retention.Calcium channel blockers (CCBs) are first-line treatment for primary hypertension in patients aged over 55 years and in black patients of African or Caribbean origin. CCBs act on L-type calcium channels in vascular smooth muscle and the heart. Those with a greater affinity for the myocardium, for example verapamil and diltiazem, have a role in the management of tachyarrhythmias and angina. CCBs with a particular affinity for vascular smooth muscle, such as nifedipine, produce vasodilatation and are favoured for the management of hypertension. It should be noted that nifedipine can cause significant vasodilatation with a reflex tachycardia. There has long been the concern that sublingual nifedipine can produce dramatic reductions in blood pressure and myocardial ischaemia in elderly patients . CCBs arq protein-coupled receptors causing smooth muscle relaxation and vasodilatation. Selective alpha-1 blockers such as doxazosin are used in the management of hypertension that is refractory to treatment with first-line drugs alone. Nonselective alpha blockers act at both α-1 and α-2 receptors. Blockade of presynaptic alpha-2 receptors increases norepinephrine release and may cause tachycardia. However, nonselective alpha blockers such as phenoxybenzamine and phentolamine have a place in the management of pheochromocytoma. Labetalol acts as an antagonist at α-1 receptors and is also a nonselective β-receptor antagonist; thus, it lowers blood pressure by causing vasodilatation and can counteract the reflex tachycardia that may result from a fall in blood pressure produced by α-1 receptor blockade and vasodilation.Alpha-1 blockers act at post-ganglionic α-1 GThiazide  and thiazide-like diuretics  are used to treat hypertension in patients intolerant of CCBs and in those who have or are at risk of heart failure. They also are widely prescribed as second-line drugs in patients who have not responded to initial pharmacological treatment. They inhibit sodium and chloride reabsorption in the proximal part of the distal tubular and so produce diuresis. They also act directly on vascular smooth muscle opening calcium-activated potassium channels and reducing systemic vascular resistance. The side effects of thiazide diuretics are well known and have direct relevance to perioperative management. Patients taking these drugs may suffer from hypokalaemia, hyponatraemia, hypercalcaemia, hypomagnesaemia, hyperuricaemia, hypercholesterolaemia, hypoglycaemia, and hypokalaemia alkalosis.Aldosterone antagonists such as spironolactone are used as fourth-line agents in the treatment of hypertension. The loop diuretics have a place in the management of resistant hypertension in patients with heart failure or chronic kidney disease.Direct acting vasodilators include hydralazine and minoxidil. Vasodilator drugs cause side effects including headache, fluid retention, and oedema and are generally poorly tolerated. However, hydralazine has a place in the management of pre-eclampsia.Centrally acting drugs such as clonidine, methyldopa, and monondinine are associated with significant adverse effects and are reserved for refractory hypertension. Again, methyldopa has a specific place for the management of hypertension in pregnancy.Historically, concerns about the care of the hypertensive patient have focused on the perceived risks of anaesthesia and surgery and the appropriateness of deferring surgery to allow the blood pressure to be treated and reduced.The risks of anaesthesia and surgery in hypertensive patients were highlighted in a case series published in 1929 which described the outcomes of a series of patients with cardiac disease who underwent anaesthesia and surgery at the Massachusetts General Hospital between 1917 and 1927 . Twenty-Studies conducted over the past 20 years suggest that mild-to-moderate preoperative hypertension is not a major risk factor for complications –29. WhilEvidence is scanty regarding the management of patients who are present for surgery and are found to have markedly raised blood pressure on repeated measurement. Patients presenting in primary care with severe hypertension would be considered for the immediate initiation of antihypertensive treatment without further clinic visits. The European guidelines suggest that delaying surgery for further assessment may be considered in patients who are found to have blood pressure readings consistently greater than 180 mmHg systolic or 110 mmHg diastolic.  This decData are now emerging from large databases that may be relevant to this discussion. A recent analysis of a large UK primary care database of over quarter of a million patients found an association between postoperative mortality and elevated diastolic pressure ••. ElevaWhilst the primary focus of this review is the preoperative management of the hypertensive surgical patient, this inevitably has a bearing on intraoperative care. It has been noted above and is highlighted in the most recent European guidelines that hypertensive patients may display greater cardiovascular lability during surgery with increases in blood pressure of 20 to 30 mmHg and heart rate of 15 to 20 bpm at induction of anaesthesia and a risk of hypotension in the intraoperative period . A numbeThese findings are striking especially when set in the context of the report referenced above an association between preoperative diastolic hypotension and adverse outcome. The concept of autoregulation of organ perfusion is a well-established tenant of physiology . Put simThe reader will have gathered from this review that much of the advice and guidance around the pre-and perioperative management of the hypertensive patient are based on epidemiological data rather than randomised controlled trials and that the care of hypertensive individuals requires the combination of an understanding of the evidence including its strengths and limitations and pragmatic clinical judgement on the part of the anaesthetist. It is important to remember that outside of the surgical setting, the evidence for treating raised blood pressure is robust and that doing so can spare the patient the life-changing crisis of a stroke or myocardial infarction. Thus, whilst it may not be appropriate to defer anaesthesia and surgery in a patient with mild or moderate hypertension, the anaesthetist shares a responsibility with other doctors to ensure that the patient found to have persistently elevated blood pressure during preassessment is referred for further blood pressure readings and appropriate management either before or after surgery as appropriate.


Pulmonary hypertension due to left ventricular heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly medical problem. The aim of the study was to evaluate the clinical efficacy of fasudil on PH-HFpEF elderly patients and to figure out the subtype of PH-HFpEF which may be the therapeutic object of fasudil.  58 PH-HFpEF elderly patients were enrolled. Patients were diagnosed with passive pulmonary hypertension (PPH) or reactive pulmonary hypertension (RPH) by right heart catheterization and all receiving Rho kinase inhibitor fasudil for 2 weeks. The endpoint includes changes in SpO2, NT-pro BNP, cardiac functional classification, and echocardiography measurements after 2 weeks treatment. p < 0.05). Cardiac output was found to be worse in the RPH group than the PPH group (p < 0.01). Besides, the RPH group demonstrated a greater transpulmonary pressure gradient (TPG) and pulmonary vascular resistance (PVR) than the PPH group (p < 0.01 for both) as well as pulmonary arterial systolic pressure (PASP) and mean pulmonary arterial pressure (mPAP) (p < 0.01 for both), which fits the feature of RPH. After treatment of fasudil, in RPH group, PASP significantly decreased (p < 0.01) with decreased E/E′ and increased E/A (p < 0.05 for both), indicating that pulmonary haemodynamics and cardiac diastolic function were ameliorated, but the measurements in the PPH group had no significant changes. NT-pro BNP and 6 MWD of both groups were improved (p < 0.05). The total effective rate of the RPH group was 74.29%, which was higher than 47.83% of the PPH group (p < 0.05).  The course of disease in the RPH group was longer than the PPH group (ChiCTR-INR-16009511. The Rho kinase inhibitor fasudil can improve pulmonary and left ventricular haemodynamics in patients with PH-HFpEF. The total effective rate was higher in the RPH group. Fasudil may be a promising targeted drug for the RPH in PH-HFpEF patients. This trial is registered with  Despite the increasing number of patients with heart failure with preserved ejection fraction (HFpEF), currently there is no proven therapy for HFpEF . The lonBased on transpulmonary pressure gradient (TPG = mPAP − PAWP), pulmonary hypertension due to left heart disease (PH-LHD) could be classified into two groups: passive PH  and reactive PH . The 2015 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of PH further separated PH-LHD into isolated postcapillary PH and mixed pre- and postcapillary PH. This classification was based on whether the diastolic pressure gradient (DPG = DPAP − PAWP) is lower or higher than 7 , which iFasudil is a Rho-kinase inhibitor that blocks the activity of Rho kinase by competing the ATP binding site of the Rho-kinase catalytic domain with ATP and thus plays an important role in relaxing pulmonary vasculature. A variety of clinical studies suggested that the Rho-kinase pathway is involved in many cellular functions including proliferation, migration, and contraction of the vascular smooth muscle cell –10, and To date, few clinical trials of Rho kinase inhibitors have been reported in PH associated with left ventricular HFpEF. The goal of this study is to investigate the effects of fasudil on PH-HFpEF and determine the response differences to treatment between RPH and PPH.The study population was prospectively recruited from patients with heart failure (HF) symptoms from August 2014 to February 2017 in Zhoupu Hospital and Shanghai Renji Hospital. According to the 2016 ESC guidelines for heart failure, all symptomatic HF patients who underwent echocardiography with left ventricular ejection fraction (LVEF) ≥50%  were diaAs proposed by the ASE , linear E) and peak A-wave velocity (A) were obtained in the apical four-chamber view with color flow imaging for optimal alignment of pulsed-wave (PW) Doppler with blood flow. And mitral annular lateral E velocity (E′) was obtained in the apical four-chamber view with proper alignment to acquire septal and lateral mitral annular velocity using tissue Doppler [E′, E/A, and E/E′.Mitral valve peak E-wave velocity  and/or interventional therapies . Following the above initial treatment of primary cardiac diseases, right heart catheterization (RHC) was performed, and the patients with mPAP ≥25 mmHg and PAWP >15 mmHg were confirmed as PH-HFpEF .Right atrial pressure, right ventricular pressure, pulmonary artery pressure including PASP, mean pulmonary artery pressure (mPAP), diastolic pulmonary arterial pressure (DPAP), and pulmonary artery wedge pressure (PAWP) were measured by RHC using a 6-lumen Edward catheter. We replaced PAWP by LVEDP when there was PAWP measurement error caused by incomplete balloon incarceration. Cardiac output (CO) was measured in triplicate by the thermodilution technique. TPG was calculated as mPAP minus PAWP, and PVR was calculated using the following formula: (mPAP − PAWP)/CO. Among these PH-HFpEF patients, those TPG ≤12 mmHg were considered as PPH, whereas TPG >12 mmHg were classified as RPH.The PH-HFpEF patients aged 60–80 years with HFpEF secondary to coronary disease, hypertension, degenerative valvular heart disease , cardiomyopathy, and New York Heart Association (NYHA) functional class II–IV were enrolled.Severe liver or kidney diseases, malignant tumor, and cerebrovascular diseaseRestrictive cardiomyopathy, hypertrophic obstructive cardiomyopathy, constrictive pericarditis, moderate-to-severe mitral stenosis, or aortic stenosisPH caused by congenital heart disease, rheumatic heart disease, autoimmune disease, chronic obstructive pulmonary disease, chronic thromboembolism, pulmonary vascular abnormalities, and idiopathic PAH (IPAH)Patients who are treated with calcium blockers, prostacyclin, or endothelin receptor antagonistsPatients with incomplete dataThe exclusion criteria include the following:A total of 58 PH-HFpEF patients were enrolled, of which 35 were diagnosed with RPH while 23 patients were confirmed as PPH.These enrolled patients were treated with fasudil , 30 mg intravenous drip twice a day for 2 weeks. During the treatment, the heart rate, blood pressure, liver function, renal function, and electrolytes were closely monitored in case adverse events or background therapy remained unchanged.2.Data collection was undertaken and compared pre- and posttreatment results in all patients, including Doppler echocardiography, measurement of 6MWD, NYHA heart failure functional classification, and laboratory tests results, such as NT-pro-BNP and SvOWe evaluated the cardiac function of patients based on NYHA classification and 6-minute walking distance (6MWD). The efficacy of fasudil was determined according to the changes of NYHA classification: (1) markedly effective: heart failure is basically controlled or cardiac functional classification increased by 2 and above; (2) effective: cardiac functional classification increases by 1, but less than 2; (3) ineffective: cardiac function is better than before, but its classification did not change; and (4) deterioration: cardiac functional classification decreases by 1 or more.t-test for normally distributed data, and the differences of examination data between pre- and posttreatment were evaluated using the paired t-test. The Wilcoxon test was used for continuous nonnormally distributed variables. Enumeration data were presented in terms of the rate and test by χ2 or exact probability method, and the rank sum test was used for ranked data.Continuous variables are expressed as mean ± SEM unless otherwise stated. The differences of baseline and baseline changes between RPH and PPH were compared using Student's p value < 0.05 was considered to indicate statistically significant. Statistical analyses were performed using SAS and SPSS version 17.0.Two-sided The patients' demographic and etiological data and pulmonary hemodynamic measurements, as well as the medication used for basic diseases and heart failure treatment, are summarized in p < 0.05), and the TPG and PVR in the RPH group were higher than those in the PPH group , which are the characteristics of patients with RPH. Meanwhile, compared to the PPH group, PASP and mPAP in RPH patients were also higher  while CO was lower , suggesting that pulmonary hypertension in RPH patients is more severe than that in PPH and leads to CO decrease.The disease course in the RPH group was longer than that in the PPH group .As shown in E/E′ and increased E/A, was improved , and PASP in the RPH group significantly decreased from 64.37 ± 13.82 mmHg to 63.51 ± 13.79 mmHg (p < 0.05). However, there was no change in E/E′, E/A, and PASP in the PPH group.After 2 weeks of therapy with fasudil, the left ventricular diastolic function in RPH group, as indicated by decreased 2, NT-pro-BNP, 6MWD, and NYHA classification.At baseline, there were no statistical differences between the study groups in SvOp < 0.05).In both groups, NT-pro-BNP and 6MWD were improved after treatment as summarized in During the 2-week treatment, no adverse event was observed in either group; patient's liver function, renal function, electrolyte, blood, urine, and stool routine tests were all normal. Two patients in the PPH group and 3 patients in the RPH group reported some mild side effects including slightly decreased heart rate and blood pressure, dizziness, and fatigue, which were all reported tolerable to the patients and thus fasudil treatment was not discontinued.Heart failure with preserved ejection fraction originates from left ventricular diastolic dysfunction secondary to impaired relaxation and stiffened myocardium. The increased load of left ventricle exposes the lung vasculature to pressure-induced challenges. In the long term, the sustained pulmonary hemodynamic change not only leads to pulmonary hypertension but also increases the pulsatile loading on the right ventricle , which dThe management of pulmonary hypertension due to left heart disease (PH-LHD) focuses on treating the primary left heart disease and improves left ventricular function, thereby alleviating PH. However, even with optimal treatment, the clinical symptoms and mortality of this disease cannot be improved. Aronson et al.  performeRecently, whether PH caused by pulmonary vascular remodeling in late PH-LHD can be treated with targeted drugs has drawn much attention. FIRST  and ENABThe results of our current prospective controlled trial show that fasudil can reduce pulmonary artery pressure and improve cardiac function more significantly in RPH-HFpEF than in PPH-HFpEF patients. We found that RPH patients had a longer course of heart failure, higher levels of PASP, mPAP, TPG, and PVR than those of PPH patients. These findings may be explained by the hypothesis that RPH and PPH have different pathophysiology, and PPH and RPH may be two different stages of PH-HFpEF. PPH is the early stage due to passive transduction of the increased pulmonary venous pressure, whereas RPH is the advanced stage characterized by vascular constriction and proliferation caused by chronic progressive increase of pulmonary artery wedged pressure and pulmonary artery pressure, which leads to the elevation of TPG and PVR, as well as pulmonary vasculopathy. In contrast, there was no significant difference between RPH and PPH in NT-pro-BNP, 6MWD, NYHA, and other cardiac functional indexes suggesting that the cardiac functional impairment of RPH might not be proportional to the increase of pulmonary artery pressure.Fasudil is a potent selective inhibitor of Rho kinase. Several trials studying the acute- or long-term effects of fasudil on PAH have demonstrated that fasudil improves pulmonary hemodynamics –24, whicα) [In animal studies, fasudil was reported to decrease the mean pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary arteriolar medial thickness and augment pulmonary expression of endothelial nitric oxide synthase (eNOS) in rats with PH secondary to left ventricular dysfunction . Furtherα)  in monocE/A ratio and decrease in E/E′. Several lines of evidence have revealed that Rho/ROCK inhibitors not only increase eNOS expression both in vivo and in vitro but also regulate the activity of myosin phosphatase activity by inducing the phosphorylation of its myosin-binding subunit [With regard to the left heart, Guo et al.  reported subunit , 29, whiIn terms of study limitations, the main limitations of the current study include the relatively small number of trial size, the lack of RHC reexamination, and the data of RV function improvement, which limit the precision for estimation of the magnitude of effects. In addition, there is no placebo control group in this study which restricts the accuracy of the efficacy estimation of fasudil. Lastly, the long-term effect of fasudil on RPH or PPH-HFpEF is still unknown.In summary, Newman et al. had proposed that redefining pulmonary hypertension through pulmonary vascular disease phenomics and resolving the heterogeneity of the PH syndrome will allow for more targeted therapeutics . PH-LHD


Appropriate mechanical ventilation and prevention of alveolar collaps is mainly dependent on transpulmonary pressure TPP. TPP is assessed by measurement of esophageal pressure EP, largely influenced by pleural and intraabdominal pressure IAP. Consecutively, TPP-guided ventilation might be particularly useful in patients with high IAP.This study investigates the impact of large volume paracentesis LVP on TPP, EP, IAP as well as on hemodynamic and respiratory function in patients with liver cirrhosis and tense ascites.We analysed 23 LVP-procedures in 11 cirrhotic patients ventilated with the AVEA Viasys respirator  which is capable to measure EP via an esophageal tube.2O; p<0.001) as well as expiratory TPP . In parallel, the inspiratory  and expiratory EP  significantly decreased. The effects were most pronounced for the release of the first 500 mL of ascites. LVP evoked substantial decreases in IAP and central venous pressure CVP. By contrast, mean arterial pressure, cardiac index, global end-diastolic volume index, extravascular lung water index and systemic vascular resistance index did not change.LVP of a mean volume of 4826±1276 mL of ascites resulted in marked increases in inspiratory  and a decrease in Oxygenation Index OI . Tidal volume  and dynamic respiratory system compliance Cdyn  increased, whereas paCO2  and the respiratory rate decreased .Among the respiratory parameters we observed an increase in pIn mechanically ventilated patients with decompensated cirrhosis, intraabdominal hypertension resulted in a substantially decreased TPP despite PEEP-setting according to the ARDSNet.In these patients LVP markedly increased TPP and improved respiratory function in parallel with a decline of EP. Furthermore, LVP induced a decrease in IAP and CVP, while other hemodynamic parameters did not change. However, sufficient ventilation depends not only on intrapulmonary pressures, but to a great extent on the extrapulmonary pressure level. The latter largely varies in critically ill patients, and it is highly dependent on both pleural and intraabdominal pressures [Extrapulmonary” or pleural pressure usually is estimated by measurement of the esophageal pressure (EP) using esophageal catheters [Mechanical ventilation (MV) in acute respiratory distress syndrome (ARDS) is guided by a number of standard recommendations for key parameters such as positive end-expiratory pressure (PEEP) and tidal volume (TV) , 2. In aressures , 6. “Extatheters , 8 whichatheters . Consequatheters . In patiatheters .Ventilator setting in patients with liver cirrhosis is particularly challenging due to several reasons: Previous studies demonstrated that the need for mechanical ventilation is independently associated with the ICU mortality of patients with decompensated liver cirrhosis –14. The Therefore, TPP-guided ventilator setting might be of particular importance in patients with tense ascites and increased IAP. A number of studies in ventilated patients with cirrhosis suggest that large volume paracentesis LVP –20 improDespite their unquestioned merits none of these studies investigated the impact of LVP on TPP. Therefore, our study aimed to investigate the effect of LVP on inspiratory and expiratory TPP (primary endpoint), IAP and hemodynamics in patients with decompensated liver cirrhosis equipped with monitoring of EP as well as with TPTD.This prospective observational study was approved by the institutional review board . Informed consent was obtained by all patients or their legal representatives.Between January 2012 and July 2014 all patients of an eight-bed university hospital general ICU with decompensated liver cirrhosis under mechanical ventilation were screened for the feasibility of EP measurements, if LVP had to be performed irrespective of the study and based on the indication made by the treating ICU physician. EP-analysis was considered to be feasible in patients without high-grade esophageal varices (grad III or IV and/or risk signs like cherry red spots or “varix on varix phenomenon”) and without a history of gastrointestinal bleeding within last 6 months.Finally, a total of 23 LVP-procedures in 11 patients with decompensated cirrhosis and tense ascites were analyzed.In general, eligible patients were transferred from the routine ventilator device EVITA XL of our ICU  to the AVEA Viasys ventilator . Key ventilation parameters were set according to ARDSNet recommendations for PEEP and low tidal volume , 2. Thisdyn and fraction of inspired oxygen FiO2 were recorded at baseline, during and at the end of paracentesis. PaO2 and paCO2 were measured using a fully-automatic blood gas analysis device . Blood gas analysis and ventilatory parameters were used for calculation of PaO2/FiO2 as well as Oxygenation Index (OI = FiO2*mean airway pressure*100/PaO2) [Routine parameters of ventilator setting such as PEEP, tidal volume TV, mean airway pressure, dynamic respiratory system compliance C00/PaO2) .intra-peritoneal measurement (IAP_P) connecting the puncture needle with a pressure transducer and in addition by measurement of the intra-vesical (IAP-V) pressure [LVP was performed in supine position and guided by ultrasound . Two tecpressure , 29. Subpressure .All patients were under hemodynamic monitoring with the PiCCO-2-device  irrespective of the study. Hemodynamic monitoring using TPTD was performed as previously described , 32: A 5Clinical and laboratory parameters for the calculation of APACHE II-, SOFA-, MELD- and Child-Pugh-scores were recorded on the day of paracentesis. Ventilatory parameters including TPP and EP as well as IAP were documented immediately before as well as after the release of 500, 1000, 1500, 3000, 4500 and up to a maximum volume of 6000 mL ascites. Parameters of hemodynamic and respiratory function were documented immediately before and after paracentesis.For primary outcome analysis we investigated expiratory TPP at the end of LVP compared to baseline. Assuming a decrease in at least 80% of 20 LVPs resulted in a statistical power of at least 80% with a p-value < 0.05 (two-tail-test).All analyses were performed using IPM SPSS Statistics 23 ; graphs were generated using GraphPad Prism 6.0 . Correlations were calculated using Spearman`s correlation coefficient. Continuous variables are expressed as mean±standard deviation. Categorical variables are expressed as percentages. To compare continuous variables we used Wilcoxon-test for paired samples. Significance was assumed at a p-value < 0.05.Patients´ baseline characteristics are presented in 20 and mean FiO2 42.0±11.1 (30–70) %. Both parameters were maintained constant during LVP.23 LVP-procedures in 11 patients  with decompensated liver cirrhosis and tense ascites were performed. The etiology of cirrhosis was predominantly alcoholic. APACHE, SOFA, MELD and Child-Pugh scores were in line with critical illness and advanced hepatic impairment. Patients were mechanically ventilated due to respiratory insufficiency (n = 8) or hepatic encephalopathy (n = 3). Ventilation was performed as pressure-controlled  or pressure-supported ventilation . Mean PEEP-level was 7.7±2.0 (6–14) cmHiO2 according to the local standard: As shown in iO2 were in line with combinations of both parameters suggested by the ARDSNet.For all patients the PEEP was set according to the ARDSNet recommendations for the individual F2O  were analyzed. LVP resulted in a marked increase of mean TPP: At the end of LVP, inspiratory TPP increased from 5.4±13.3 to 17.9±8.9 cmHp<0.001; . Expiratp<0.001; . Despite2O  and EP (ΔEP) were highest after the release of the Furthermore, LVP resulted in a marked decrease of IAP: At the end of paracentesis, levels of IAP_P had lowered from 11.7±2.0 to 5.2±2.3 mmHg p<0.001; . IAP_V hfirst 500 mL volume during stepwise paracentesis , global end-diastolic volume index GEDVI , extravascular lung water index EVLWI  and systemic vascular resistance index SVRI  did not change significantly . The substantial decrease in CVP by about 30% was in contrast to unchanged values for all hemodynamic parameters assessed by TPTD or pulse contour analysis: Mean arterial pressure MAP , cardiac Index CI (5.3±1.5 vs 5.6±1.2 L/min/mficantly .aO2/FiO2 from 208.3±46.8 to 247.7±60.9 mmHg (p<0.001) as well as of Oxygenation index OI from 5.8±3.1 to 4.8±2.0 cmH2O/mmHg (p = 0.002).All parameters and indicators of respiratory function significantly improved during LVP without changes of the ventilator setting: We registered an improvement of paO2/FiO2 before all LVP procedures was in line with ARDS according to the Berlin-criteria [aO2/FiO2 had substantially improved in four measurements to values above 300mmHg, which is outside the range defining ARDS (see Pcriteria . After LARDS see .dyn from 35.1±14.6 to 46.8±15.9 mL/cmH20 (p<0.001). LVP also induced a decrease in paCO2 from 51.3±12.2 to 47.3±10.7 (p = 0.046). Based on the high ratio of patients with pressure-supported ventilation in this analysis, we also found a decrease of the respiratory rate from 19.6±7.8 to 17.1±7.3 min-1 (p = 0.010). Improvement of respiratory function is outlined in Furthermore, LVP induced an increase of tidal volume TV from 452±113 to 510±100 mL (p = 0.008) and of compliance CIn this study LVP induced an immediate improvement of several parameters of lung function in patients with decompensated liver cirrhosis, tense ascites and high intraabdominal pressure IAP. According to our data this respiratory enhancement is largely referable to changes in transpulmonary pressure TPP.negative expiratory levels for TPP, indicating repeated alveolar collapse and lung atelectasis [Optimization of TPP seems to play a key role in critically ill patients with elevated IAP. Adapted levels of TPP improve oxygenation and limit alveolar damage , 10. TPPlectasis . LVP prodyn [aO2/FiO2, Cdyn and tidal volume. Moreover, the Oxygenation index OI improved after LVP. OI combines mean airway pressure level with paO2/FiO2 in a single and easily provided parameter. In several studies OI better predicted outcome of ARDS-patients compared to ARDS definitions predominantly based on paO2/FiO2 [These findings are supported by previous data underlining the impact of LVP on oxygenation. The benefit of LVP is particularly due to decreases in IAP and consecutive improvement of respiratory mechanics , 38, 39.dyn , 25. OuraO2/FiO2 –42. Withfirst 500 mL of evacuated volume. This observation is supported by previous findings that in case of high baseline IAP even a low-volume paracentesis might considerably decrease the pressure level [Furthermore, LVP induced a substantial decrease of IAP in our study. Elevations of IAP are common in decompensated liver cirrhosis , 15. Incre level .extra-thoracic pressure level [In contrast to the beneficial effects on TPP, respiratory function and IAP, there were no changes in hemodynamic function after LVP. Previous studies yielded contradictory statements regarding cardiocirculatory parameters: Some of them described mechanisms of paracentesis-induced circulatory dysfunction –49, whilre level , 52–54. Altogether, the study emphasizes the importance of individualized and optimized ventilator setting in certain patient populations. We used a baseline ventilator setting in accordance with the current Acute Respiratory Distress Syndrome Network (ARDSNet) recommendations , 36. ParNevertheless, a ventilator setting restricted exclusively to optimized TPP might be difficult to guide in case of high-grade esophageal varices which preclude the measurement of esophageal pressure. Since high-grade varices are frequent in end-stage liver disease, other strategies including continuous or repeated measurements of IAP should be considered in these patients.To the best of our knowledge this is the first study analyzing the effects of LVP on TPP, respiratory and ventilatory parameters as well as advanced hemodynamic monitoring data in cirrhotic patients with tense ascites.Although our results are conclusive with high levels of statistical significance, this is a single centre study with a limited number of patients and datasets.In mechanically ventilated patients with decompensated cirrhosis, tense ascites with increased IAP resulted in a substantially decreased TPP despite PEEP-setting according to the ARDSNet.aO2/FiO2, paCO2, OI, TV and Cdyn. CVP decreased in parallel with IAP, while all other hemodynamic parameters remained unchanged by LVP.LVP induced a substantial improvement of TPP, p


C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD.Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity.p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters . The association of CNP with HRV persisted after adjustment for potential covariates.Mean (±standard deviation) age of the patients were 59.9 (±14.9) years and 56.6% were male. Average plasma CNP level was 790.8 ± 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction  contains supplementary material, which is available to authorized users. Chronic kidney disease (CKD) is a well-known potent risk factor for developing cardiovascular disease , 2. IndiNppc gene on chromosome 2 and is most widely expressed in the brain and endothelial cells [C-type natriuretic peptide (CNP) is a cardiovascular bioactive hormone of the natriuretic peptide family and shares structure homology with the other two cardiac peptide, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) . It is eal cells . It is sal cells . Previoual cells , 8. It cal cells , 10. To al cells , 12 and al cells . These dAlthough ANP and BNP have been extensively studied in patients with kidney disease, there is a paucity of data regarding CNP and its relationship to cardiovascular alteration in CKD. Questions remain to be answered include: (1) is plasma CNP accumulated as renal function declines? (2) is there any association of circulating bioactive CNP-22 with cardiovascular alteration in CKD patients? To answer the questions, we conducted the current cross-sectional study. We measured plasma CNP-22 in a group of non-dialysis-dependent CKD patients and explore its association with (1) estimated glomerular filtration rate (eGFR) and (2) several cardiovascular measures which were chosen based on prior experimental evidence, including blood pressure, endothelial function, arterial elasticity and heart rate variability (HRV).All participants were recruited from the Center for Kidney disease of the Second Affiliated Hospital of Nanjing Medical University. Patients aged over 18 years with a clinical diagnosis of CKD referring to our center were invited to participate in the study. The diagnoses of CKD were made by clinical physicians conforming to the definition of K/DOQI guideline and had been confirmed by study staffs at enrollment. Exclusion criteria were: (1) previous history of renal transplantation; (2) malignancy; (3) acute infection or any other unstable condition. All subjects provided written informed consents. The study protocol was approved by the Institutional Ethical Committee of the Second Affiliated Hospital of Nanjing Medical University.All cardiovascular evaluations were performed in the morning with the patients on an empty stomach. Antihypertensive medications and nitrates were not allowed within 2 h, and long-acting nitrates were not permitted for 12 h before measurement. Test room temperature was set at 22-25 °C.Patients rested for 10 min in a seated position and then underwent three consecutive blood pressure measurements using an automated oscillometric device . Each measurement was separated by 1 min interval. The three measurements were averaged to calculate blood pressure for final analysis.Carotid–femoral pulse wave velocity (cfPWV) and carotid–radial pulse wave velocity (crPWV) were determined after blood pressure measurement. An experienced technician performed the measurement for all participants using the Complior Analyzer device . Three probes were placed in a place of palpable pulse of the carotid, femoral and radial artery, respectively. The transit time was averaged over ten consecutive recordings using the intersecting tangent algorithm as recommended . CarotidEndothelial function and HRV were measured via peripheral arterial tonometry using the EndoPAT 2000 . Patients underwent the test in seated position with two finger probes placed on the index finger of each hand. After 6 min of baseline measurement, pulsatile arterial flow was occluded through inflation of a blood pressure cuff on the test arm for 5 min. The cuff was inflated starting at a pressure of 250 mmHg and increased until a complete occlusion was achieved as judged by the PAT signal or to a maximum of 300 mmHg. After occlusion, PAT signal was recorded for another 5 min. Reactive hyperemia index (RHI) were calculated automatically by the system . EndotheFasting blood were drawn into a EDTA tube to separate plasma. All sample were aliquoted and stored at − 80 °C until measurement. Plasma CNP was detected by an enzyme immunoassay kit . This assay detected the bioactive form of CNP (i.e CNP-22) with a range from 0 to 100 ng/ml. The coefficient of variation at the level of 100 pg/ml was 16.6%.Demographic and medical information  were acquired by a combination of patient interview and review of medical records. Previous history of cardiovascular disease refers to any history of acute myocardial infarction, ischemic or hemorrhagic stroke, coronary heart disease other than myocardial infarction, chronic heart failure, atrial fibrillation and other types confirmed by the research staff. All routine laboratory tests were performed in the local Laboratory Department using fasting blood or first voided morning urine. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. CKD stage classification were determined as recommended by the K/DOQI guideline .p value < 0.05 was considered statistically significant.Data were presented as the mean ± standard deviation or the median (interquartile range) for numerical variables, and as counts (%) for categorical variables. Comparisons of CNP levels between groups were performed using Student’s t test or the chi-square test as appropriate. To evaluate the relationship of plasma CNP with cardiovascular measures, Pearson’s correlation analysis was used. Due to the skewed distribution of HRV parameters, there were logarithm transformed in these analyses. To confirm the association of CNP with HRV, multiple linear regression analyses were conducted with adjustment for several potential covariates, including age, sex, eGFR, diabetes mellitus, body mass index, current smoker, previous history of cardiovascular diseases, hemoglobin and systolic blood pressure. For the selection of covariates, we first checked the associations of all available factors with HRV parameters and found none of them has a consistent association with HRVs (“consistent” defined as significantly associated with at least two HRV parameters) except for sex. Considering the small sample size, our choices of covariates were then mainly determined by whether there is known or expected association with the outcome variable (HRV) which is justified on the basis of previous evidence . All ana2 and 42.1% patients had a previous history of cardiovascular disease. Average plasma CNP level was 790.8 ± 309.1 pg/ml. To evaluate whether renal dysfunction is associated with altered circulating CNP level, we compared plasma CNP concentration in different CKD stages as shown in Fig. p = 0.84).A total of 76 patients participated in the current study. General characteristics of the study patients are presented in Table p = 0.14).Endothelial cells are the primary source of circulating CNP in humans. We therefore explored whether patients with endothelial dysfunction exhibit reduced plasma CNP level Fig. . The resr = 0.23, p = 0.04) and negatively with SDNN , RMSSD  and triangular index  .Cardiovascular evaluation results are presented in Table p = 0.003; RMSSD: ß = − 0.11, p = 0.02; Triangular index: ß = − 0.08, p = 0.004; all ß were calculated per SD increment of CNP). In a sensitivity analysis excluding patients with coronary artery disease (n = 9), the associations remained essentially unchanged  Increased plasma CNP was associated with reduced HRV; (2) Decreased renal function was not associated with elevated plasma CNP level; (3) Circulating CNP was not reduced in patients with endothelial dysfunction compared to those with preserved endothelial function; (4) There was no association between plasma CNP and blood pressure or arterial elasticity .Besides several negative results, we found a significant association of increased plasma CNP with elevated heart rate and reduced HRV. The positive association of CNP with heart rate is in accordance with the chronotropic effect of CNP found in both clinical and experimental settings. Cheung et al. also noted a significant correlation between CNP and heart rate in hypertensive subjects . MoreoveThe significant and negative association between CNP and HRV in the patients as revealed by our data is very interesting. Since reduced HRV has been proved to be an independent risk factor for cardiovascular events , our datDue to increased stimuli and possible reduced renal clearance, plasma natriuretic peptides, including ANP and BNP are generally elevated in patients with impaired kidney function –24. HoweNppc, exhibited elevated blood pressure, as well as endothelial dysfunction and impaired endothelial-dependent vascular relaxation capacity [The endothelium is the primary secretion site of CNP in peripheral tissues . Mice wicapacity , 8. Howecapacity , 34. Thicapacity , 35.Several limitations of our study should be pointed out for proper interpretation of our results. First, due to the cross-sectional design, we cannot draw any causative conclusion. Second, our findings may be somewhat limited by the small sample size and need to be confirmed in population-based studies. The lack of healthy controls in the current study leaves the question that whether CNP level differs between individuals with and without CKD unsolved. Third, more detailed cardiac evaluations, e.g. echocardiography or cardiac injury biomarker measurements, were lacking in our study, limiting our ability to explore the association of CNP with cardiac function and injury. Nevertheless, our study remains a first step in evaluating the link between circulating CNP and the cardiovascular system in patents with CKD and can offer indications for further exploration.In summary, in a group of patients with CKD, reduced renal function was not associated with elevated plasma CNP. Circulating CNP showed no association with blood pressure, endothelial function or arterial elasticity. There was a significant association between elevated CNP with reduced HRV. Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients.Additional file 1:Table S1. Sensitivity analysis excluding patients with coronary artery disease. (DOCX 17 kb)


Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are considered to have similar renoprotective effects; so far there has been no consensus about their priorities. This study aimed to compare ACEIs and ARBs for major renal outcomes and survival in a 15-year cohort of adults with diabetes.This study utilized Taiwan’s medical and pharmacy claims data in the Longitudinal Cohort of Diabetes Patients. The primary outcome was long-term dialysis, and secondary outcomes were hospitalization for acute kidney injury, hospitalization for hyperkalemia, all-cause death, cardiovascular death, and non-cardiovascular death. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes comparing ACEIs with ARBs. We conducted subgroup analyses and interaction tests among patients with different age and comorbid diseases.P = 0.003) or chronic kidney disease .A total of 34,043 patients received ACEIs and 23,772 patients received ARBs. No differences were found for primary or secondary outcomes in the main analyses. ACEIs showed significantly lower hazard than ARBs for long-term dialysis among patients with cardiovascular disease (HR 0.80, 95% CI 0.66–0.97, interaction Our analyses show similar effects of ACEIs and ARBs in patients with diabetes. However, ACEIs might provide additional renoprotective effects among patients who have cardiovascular disease or chronic kidney disease. The development and progression of chronic kidney disease are closely interrelated to hypertension , 2, and Unlike the mechanisms of ARBs, ACEIs do not completely block the RAS; but ACEIs reduce the degradation of bradykinin and are considered to provide additional renoprotective effects . The ONghttp://nhird.nhri.org.tw/en/Data_Subsets.html#S4). The LHDB defined a patient to have diabetes by matching any one of the following criteria: 1) at least one inpatient record with the diagnosis code of diabetes or the prescription of glucose-lowering drugs; 2) at least two outpatient visits with the diagnosis code of diabetes within one year; or 3) one outpatient visit with the diagnosis code of diabetes, and at least one more outpatient visit with prescription of glucose-lowering drugs within one year. The diagnosis code for diabetes should include the ICD-9-CM  code 250 or 648.0, or A-code A181 (corresponds to ICD-9-CM 250.x). For the present study we analyzed 831,692 patients during the period of 1997 to 2011. We obtained their claims data including inpatient records, outpatient records, registries for beneficiaries , and registries for patients with catastrophic illness . The Institutional Review Board of the National Taiwan University Hospital has approved this study and waived the requirement for informed consent, because the database used in this study had only de-identified information, and linkage to other databases was not allowed. The supporting information  from the National Health Insurance (NHI) Research Database of Taiwan, which is constructed and maintained by the National Health Research Institutes of Taiwan. The NHI system covers more than 99% of Taiwan’s population and has been in operation since 1995 , 21. Theormation  providesTaiwan’s guidelines have recommended ACEIs or ARBs as the first-line therapy for patients with diabetes or chronic kidney disease, and Taiwan’s NHI has allowed physicians to freely prescribe either an ACEI or an ARB if the patient was indicated to receive a RAS inhibitor , 23. ThiWe categorized the participants into either (1) ACEI therapy or (2) ARB therapy based on the prescription at the index date. Data including age, sex, income, occupation, and geographic location at the index date were recorded. We defined the participants’ comorbidities by diagnosis codes from inpatient and outpatient records within one year before the index date , 28. TheThe primary outcome of this study was long-term dialysis. Secondary outcomes were hospitalization for acute kidney injury, hospitalization for hyperkalemia, all-cause death, cardiovascular death, and non-cardiovascular death. The observation period started from the index date to the date of the outcome or on December 31, 2011, whichever occurred earlier. Because results of laboratory exams were not recorded in the original claims data, we defined the outcomes by specific diagnostic codes in the registries for patients with catastrophic illness and the inpatient records. Patients with end-stage renal disease requiring long-term hemodialysis or peritoneal dialysis would be registered as catastrophic illness patients with the ICD-9-CM code of 585, and the date on which long-term dialysis began was defined by the application date for this registry . The datAs the LHDB does not provide the data on mortality, and the linkage to other administrative databases (including the death registrations) is not allowed, we defined the status and the date of death as the following conditions: 1) the discharge date of hospitalization if the patient’s record indicated that the patient had died in the hospital, or 2) the date of withdrawal from NHI, if the record indicated that the patient had chosen to die at home and therefore left the hospital against medical advice. Because Taiwan’s NHI is a compulsory single-payer program, the only reason for withdrawal under such a condition would be death . Patientt test, Wilcoxon signed-rank test, Pearson’s chi-squared test, or Spearman's rank correlation coefficient, as appropriate. Kaplan-Meier cumulative incidence plots were constructed to show time to event for each outcome, and the log-rank test was used to compare ACEI users with ARB users. We used univariable and multivariable Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for study outcomes comparing ACEI therapy with ARB therapy. The analysis was based on an intention-to-treat analysis according to the participants’ blood pressure-lowering drug exposure at index date. We adjusted the multivariable models for age, sex, comorbidities, income, occupation, geographic location, CCI score, and the year of index date. The proportional hazards assumption was assessed using the test of weighted Schoenfeld residuals [The distributional properties of continuous data are expressed as mean ± standard deviation and the categorical data are presented as frequency with percentage. For the descriptive statistics, univariable analyses were performed using the independent two-sample esiduals .P values ≤ 0.05 were considered statistically significant. Statistical analyses were performed with SAS  and Stata software .To examine whether treatment effects of RAS inhibitors varied among participants with different characteristics, we conducted priori subgroup analyses and interaction tests for participants with different age , CCI scores , and the presence of specific comorbid diseases . To evaluate the possibility of a cohort effect among different calendar years, we categorized the participants by years of index date  and assessed the influence by subgroup analyses and interaction tests. For assessing the treatment effects among different follow-up time periods, considering the switch and discontinuation of treatments in later follow-up periods, as well as evaluating the failure of some Cox models to meet the proportional hazards assumption, we performed analysis by partitioning the follow-up time into three intervals . This study had 80% power to detect a relative risk reduction of 15% in the primary outcome. Two-sided The patient selection process is shown in Among the participants, 34,043 (58.9%) received ACEI therapy and 23,772 (41.1%) received ARB therapy. The participants had a mean age of 60.1 years and a female prevalence of 43.8%; and they contributed to a total of 457,742 to 461,611 patient-years of follow-up, depending on the outcome analyzed. Participants who received ACEI therapy were older and had a higher prevalence of male sex and cardiovascular disease . In addiP = 0.003 for cardiovascular disease; P = 0.001 for chronic kidney disease). In addition, ARB therapy demonstrated a lower hazard for long-term dialysis among participants without chronic kidney disease. ACEI therapy showed a lower hazard for long-term dialysis among the participants of the highest category of CCI scores, but the interaction test was not significant . Analyses in the subgroups of different age, year of index date, as well as those with liver disease or cancer, showed similar results as the main analysis for long-term dialysis. Most of the subgroup analyses for secondary outcomes showed non-significant results, except the lower hazards in ACEI therapy for cardiovascular death among participants with index dates during the period of 1997 to 2003 (interaction P = 0.007), and the lower hazards in ARB therapy for acute kidney injury among participants with index dates during the period of 2004 to 2007 (interaction P = 0.04) or all-cause death among participants with CCI scores of 4–5 (interaction P = 0.04). ARB therapy revealed a borderline lower hazard for non-cardiovascular death among participants with CCI scores ≥ 6 but the interaction test was not significant (interaction P = 0.19).In this cohort study of patients with diabetes, the main analyses showed no difference in the outcomes of long-term dialysis, hospitalization for acute kidney injury, hospitalization for hyperkalemia, all-cause death, cardiovascular death, and non-cardiovascular death between ACEI therapy and ARB therapy. However, subgroup analyses and interaction tests suggested that ACEI therapy might provide additional protective effect against long-term dialysis in patients with cardiovascular disease and chronic kidney disease.The strength of this study is its large sample size in a 15-year nationally representative population with diabetes, which is possible to provide sufficient statistical power in major renal outcomes. We applied rigorous methods for survival analyses, including multivariate adjustment of potential confounding factors, subgroup analyses, and interaction tests for important covariates. We also evaluated the assumption of proportional hazard, and partitioned the follow-up time to assess the treatment effects among different time periods. The analyses during the second and the third interval were similar to the main analyses, which showed the consistency and robustness for treatment effects during long-term follow-up periods. In addition, the primary outcome was highly accurate because the registration as a catastrophic-illness patient needing long-term dialysis must meet strict criteria and be submitted by a nephrologist, and that need must be verified by at least two other senior nephrologists .2 reduction compared with 17.9 ml/min/1.73 m2 reduction), and also showed non-significant difference in the change of serum creatinine and urinary albumin excretion [Only a few randomized clinical trials comparing ACEI therapy with ARB therapy were powered to evaluate renal outcomes in patients with diabetes. The Diabetics Exposed to Telmisartan and Enalapril study, which evaluated 250 patients with type 2 diabetes, reported that enalapril was not significantly superior to telmisartan for the five-year reduction of glomerular filtration rate , but they did not evaluate long-term renal outcomes . In anotOur study has several limitations. First, this cohort was based on claims data, and did not contain covariates of laboratory exams, blood pressure, body mass index, lifestyle behavior, and prescription compliance. Therefore, it was not possible to classify participants or adjust models according to the stages of chronic kidney disease, levels of blood pressure, or adequacy of metabolic control. As these covariates would influence outcomes and were commonly associated with comorbid diseases , 5, 40, Our analyses show similar effects of ACEIs and ARBs in patients with diabetes. However, ACEIs might provide additional renoprotective effects among patients with diabetes who have cardiovascular disease or chronic kidney disease.S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.