Volume replacement therapy with colloid is still worth studying in major pediatric surgery with potential risk of bleeding. This study assessed the effects of 6% hydroxyethyl starch (HES) 130/0.4 and 5% Human Albumin (HA) on coagulation tested by thromboelastography (TEG) during elective intracranial tumor surgery in pediatric patients.n = 30), and administered preloads of 20 mL · kg−1 HES 130/0.4 and 5% HA, respectively, prior to dura opening. Primary outcomes were perioperative thromboelastography findings, and hemodynamic and hematological parameters. Blood transfusion, perioperative fluid balance, intracranial pressure, mortality, intensive care unit stay, and hospital stay were also assessed.In this randomized controlled trial, 60 patients undergoing intracranial tumor resection under general anesthesia were assigned to HES and HA groups (p < 0.01), which was restored to preoperative levels 1 h after fluid infusion. Total perioperative fluid balance, blood loss or transfusion, intracranial pressure, and hematological and hemodynamic variables were similar between both groups (p > 0.05). Mortality, length of hospital stay, and clinical complications were similar between both groups.TEG parameters did not differ after preloading compared to baseline values in either group, except for a decrease in maximum amplitude immediately after infusion (HES group, 57.6 ± 6.0 mm vs. 50.9 ± 9.2 mm; HA group, 60.1 ± 7.9 mm vs. 56.6 ± 7.1 mm; These findings suggest that HES and HA might have no significant differences regarding coagulation as assessed by TEG during pediatric intracranial tumor surgery with 20 ml/kg volume pre-loading, which can maintain stable hemodynamics and may represent a new avenue for volume therapy during brain tumor resection in pediatrics.16009333, retrospectively registered October 8, 2016ChiCTR-IPR- Hypovolemia is the most common cause of circulatory failure in children during intracranial tumor surgery. Appropriate fluid replacement is essential for ensuring safety, and reducing morbidity and mortality in the perioperative period. Treatment options for replacing blood volume deficiencies in pediatric surgical patients include crystalloids and colloids. In case of acute and massive blood loss, colloids may be used to rapidly treat or prevent hypovolemia, due to prolonged intravascular half-life and improved intravascular volume effects , 2. HoweHuman albumin (HA) is frequently used for volume therapy in many centers during pediatric anesthesia. For many years, 5% HA was considered the gold standard for plasma volume replacement in infants and children due to physiological hypoproteinemia , 3, but Hydroxyethyl starch (HES) is a plasma substitute widely used to correct perioperative hypovolemia. HES is a superior option over HA for its lower cost, so it has become the most commonly used artificial colloid in the world. The clinical efficacy of 6% HES 130/0.4 appears to be similar to that of other HES choices, with a significantly lower effect on patient coagulation parameters , 6, probThe aim of this prospective, randomized, controlled study was to compare 6% HES 130/0.4 with 5% HA for volume replacement therapy during elective intracranial tumor resection in children aged 1–12 years. We tested the hypothesis that 6% HES 130/0.4 more effectively affects blood coagulation than 5% HA, as assessed by thromboelastography (TEG), during brain tumor resection in pediatric patients.−1) or aspartate aminotransferase (>50 U · L−1); administration of coumarin anticoagulants, non-steroidal anti-inflammatory agents, acetylsalicylic acid, or colloid management within the past 2 weeks. Patients with craniopharyngioma and hypothalamic tumors were also excluded.In this prospective, randomized, double blind trial, 60 pediatric patients (aged 1–12 years) with American Society of Anesthesiologists physical status III, scheduled to undergo elective intracranial tumor resection at Xinhua Hospital affiliated to Shanghai Jiao Tong between October 2011 and January 2013, were sequentially enrolled. The study protocol was approved by the Institutional Ethical Committee of Xinhua Hospital. Parents or legal representatives were informed orally, and provided written consent before enrollment of the pediatric patients. Tumor locations included the saddle area, fourth and third ventricles, and other subcortical regions. Exclusion criteria were: known preoperative coagulation disorders, renal disease or plasma creatinine levels >1.5 mg/dL; known liver disease or increased plasma levels of alanine aminotransferase (>50 U · L−1), midazolam (0.1 mg · kg−1), propofol (2–3 mg · kg−1), remifentanil (1–2 μg · kg−1), and cisatracurium (2 μg · kg−1). Anesthesia was maintained with continuous infusion of propofol (4–6 mg · kg−1h−1), remifentanil (0.05–0.1 μg · kg−1min−1), cisatracurium (1–2 μg · kg−1min−1), and sevoflurane (1.5–2%) in 2 L/min oxygen. Radial artery, great saphenous vein, and jugular vein catheters were inserted after endotracheal intubation. Intraoperative monitoring parameters consisted of end-tidal CO2, electrocardiographic measurements, central venous pressure, arterial blood pressure, pulse oximetry, and esophageal temperature. Mechanical ventilation was performed in all patients (50% air in oxygen) to maintain an O2 saturation of >95% and an end-expiratory CO2 of 25–30 mmHg. A warming air system and fluid warmer were used to avoid hypothermia during surgery. After surgery, mechanical ventilation was discontinued, and the patient was ready for tracheal extubation . All patients were transferred to the intensive care unit (ICU) for postoperative treatment and patient-controlled analgesia.All patients received standardized anesthetic management. General anesthesia was induced with intravenous atropine   and a third-generation low-molecular HES solution  , respectively. Randomization was based on a computer generated code, and sealed in sequentially numbered, opaque envelopes. Both solutions were supplied in identical-looking, sequentially numbered plastic bags containing either 6% HES 130/0.4 or 5% HA according to the random code. Patients remained blinded throughout the study. Allocation to treatment groups was not known to any of the investigators, surgeons, or anesthetists. To compensate for fluid loss by sweating as well as through the gastric tube and urine, 10 mL · kg · h−1 lactated Ringer’s solution was administered to meet the basic requirements of the children. Throughout the study period, packed red blood cells (PRBC) were given when hemoglobin (Hb) was <8 g/dL; fresh frozen plasma (FFP) was administered with bleeding exceeding 50% of blood volume. When mean arterial blood pressure (MAP) was <50 mmHg despite sufficient central venous pressure (CVP >10 cmH2O), phenylephrine (1 μg/kg) was given. Epinephrine (0.03–0.1 μg/kg.min) was added when volume therapy and phenylephrine could not maintain the MAP above 50 mmHg, as a result of massive hemorrhage. Volume administration was completed in 1 h prior to dura opening. Hemodynamic measurements were recorded by invasive blood pressure monitoring. All patients were managed perioperatively by anesthetists not involved in the study and blinded to its aim.Immediately after jugular vein catheter insertion, the patients were randomly divided to receive 20 mL · kgHemodynamic data  were recorded after anesthesia induction (baseline), after volume infusion, 1 h after infusion, and at the end of surgery. Cranial window pressure was also recorded after fluid infusion, according to the surgeon’s level of experience . Then, pH, Hb levels, hematocrit (Hct), base excess, and lactate in whole blood at different time points  were determined on a GEM Premier 3000 BLOOD Gas/Electrolyte Analyzer . Estimated blood loss according to the suction apparatus, urine output, mannitol dosage , and the amounts of blood products and lactated Ringer’s solution transfused were recorded at the end of surgery.Four blood samples for TEG analysis were obtained from the jugular vein catheter at different time points: after anesthesia induction and before HES or HA infusion (baseline), immediately after infusion, 1 h after infusion and at the end of surgery. In order to avoid venous transfusion contamination, the blood sample collection method was standardized. All samples were obtained using the two-syringe method through the jugular vein catheter after first aspirating and discarding 5 mL of blood, a second 3-mL sample used for TEG measurements was collected and transferred into blue-capped non-wettable surface tubes containing 0.2 mL of 3.2% sodium citrate. The tubes were capped, with the blood mixed with citrate three times by gentle inversion. All blood samples were analyzed at 37 °C using disposable plastic cups and pins on a computerized Thrombelastograph Coagulation Analyzer . A 360-μL aliquot was pipetted and analyzed 4 min after sample collection. The TEG analyzer was allowed to run until LY60  value could be completed. Four parameters of clot formation were measured on the TEG analyzer, including r-time (reaction time to clot formation), k-time (time to achieve clot strength), MA and the α-angle (angle of divergence). The coagulation index (CI)of TEG derived from a linear equation that combines the four variables of TEG  was also calculated.The sample size was estimated with two-sided α and β errors of 0.05 and 0.2, respectively. A 20% decrease in the MA of the TEG tracing  with HES treatment was assumed ; the powt-test, chi-square test, or Fisher’s exact test, as appropriate. For intragroup comparisons of variables to baseline values, repeated measures analysis of variance, followed by a post hoc Dunnett’s test were used. P < 0.05 was considered statistically significant.All measured and calculated data were analyzed using SPSS 16.0 , and expressed as mean ± SD or number of patients. Normality was verified using the Kolmogorov-Smirnov test. Data were assessed by unpaired Student’s The 60 enrolled patients all completed the study. Patient demographic and biometric data, and anesthesia and surgery durations did not differ between groups Table .Table 1DP < 0.01 for both groups); however MA was restored to the preoperative level at 1 h after fluid infusion , clot formation time (k-time), speed of solid clot formation (α-angle), and CI were similar to baseline values after preloading fluid infusion Fig. . In both2O; HA group, 5.4 ± 1.6 vs. 7.9 ± 1.9 cm H2O; P < 0.01 for both groups). Perioperative changes were observed in Hb levels  and Hct  after preloading fluid infusion, but not in PH, lactate, or base excess  differed significantly between the two groups within the study period except for CVP, which was elevated after preloading fluid infusion compared with baseline values , but no significant difference was found in mannitol dosage between the two groups  and hospital stay . The cranial window pressure increased moderately in both groups after preloading infusion , Jamnicki  assessedc review  in Europc review , 26.A major limitation of this study is that only changes of short-term coagulation function during the perioperative period were evaluated. Although the MA value can partly reflect fibrinogen activity and platelet function, we did not assess the effects of shear forces on the interactions between coagulation factors and platelet function . In thisIn conclusion, the current study demonstrated that HES 130/0.4 and HA 20 ml/kg volume preloading appear to show no significant differences in coagulation parameters as assessed by TEG during pediatric intracranial tumor surgery. Blood loss or blood products used, hemodynamic changes, and clinical outcomes were also similar, suggesting that HES 130/0.4 can be safely used during intracranial tumor resection in pediatric patients. These findings indicate that HES 130/0.4 preloading may represent a new avenue for volume therapy during brain tumor resection in pediatrics.


Background: Vasovagal syncope is the most common cause of syncope in children and adults, accounting for 50-66% of unexplained syncope. There are no studies establishing the relationship between syncope, baseline heart rate, and blood pressure.Objective: To identify a possible association between baseline blood pressure and heart rate with syncope.Design/Methods: We conducted a questionnaire-based chart review study. A questionnaire was distributed to the guardian of children between eight and 18 years of age who attended the Pediatric Ambulatory Care Clinic at Flushing Hospital Medical Center. Based on the responses in the questionnaire, subjects were classified either as cases (positive for syncope) or controls (negative for syncope). Children and adolescents with neurological, cardiac, or any medical condition that can cause syncopal episodes were excluded from the study. Data collected from the questionnaire included age, gender, ethnicity, medical history, family history of syncope, and the amount of salt used in food. Anthropometric and vital signs for the current visit  and vital signs from two previous visits were collected from electronic medical records. The data was analyzed using t-test and chi-square test with Microsoft Excel software ; p<0.05 was considered significant.Results: A total of 197 subjects were included in this study. There were 18 cases and 179 controls. Of the cases, (4/18) 22.2% were more likely to have a systolic blood pressure lower than the 10th percentile for their gender, age, and height as compared with controls (7/179) 3.9%, p = 0.003. The subjects with a history of syncope were more likely to add salt to their food (p = 0.004). There were no significant differences between cases and controls for age, gender, ethnicity between cases and controls for systolic blood pressure. No significant difference was observed between the heart rates of cases and controls.Conclusions: Children and adolescents with syncope were more likely to have a systolic blood pressure lower than the 10th percentile, and there was no difference in the baseline heart rate. In addition, children with syncope were more likely to add salt to their food. Syncope is defined as a sudden, brief loss of consciousness associated with loss of postural tone from which recovery is spontaneous . It has Vasovagal syncope  accounts for 50 percent or more of cases presenting to the emergency department. It is the most common cause of syncope, found in approximately 20 to 35 percent of cases, particularly in patients without any apparent neurologic or cardiac disease -9. TypicWe conducted this cross-sectional chart review study by a questionnaire in either English or Spanish, from August 2014 to August 2015. Parents or guardians completed a questionnaire on behalf of their children aged between eight to 18 years. Of 197 completed questionnaires, 177 children were of Latin American descent, and remaining 20 children were either Caucasian or Asian. Children and adolescents with neurological, cardiac, or any medical condition that could cause syncope were excluded from the study. Data collected from the questionnaire includes age, gender, ethnicity, medical history, family history of syncope, triggering factor for syncope with prodromal symptoms of nausea, pallor, diaphoresis, lightheadedness and also the amount of salt used in the food. Based on the responses in the questionnaire, subjects were classified either as positive for syncope (cases) or negative for syncope (controls). Anthropometric measurements and vital signs from the current visit  were collected from electronic medical records of the subjects. Vital signs from two previous clinic visits were also collected from the electronic medical records to document the consistency in the baseline blood pressure and heart rate readings. Systolic and diastolic percentiles for the blood pressures were then calculated from age and gender-specific nomograms. The data was analyzed using Microsoft Excel software , t-test, and chi-square; p<0.05 was considered significant.A total of 197 subjects were included in this study. There were 18 cases (9.1% of the subjects) and 179 controls. There were no significant differences between cases and controls for systolic blood pressure, Four out of 18 cases, or 22.2%, were more likely to have a systolic blood pressure lower than the 10th percentile for their gender, age, and height as compared with controls (7/179) 3.9%, p = 0.003, as represented in Figure Subjects with a history of syncope were more likely to add salt to their food (p = 0.004) as shown in Figure There were no significant differences between cases and control for age, gender, ethnicity, and observed heart rate.Association between vasovagal syncope and lower baseline systolic blood pressures (less than 10th percentile for age and gender) provided insight into the nature, risks, and prognosis of the condition. The tendency to add more salt was found in those with a history of syncope, resulting in higher sodium levels in the blood which would cause more water retention and thus higher blood pressure. This could be described as an adaptive mechanism to involuntarily control the blood pressures and keep them in higher range so as to prevent any further episodes of the syncope. Various other preventive mechanisms have been well described and studied, such as assuming the supine position with leg raising at the onset of symptoms, avoiding trigger events, and medications that may induce hypotension. Counter-pressure maneuvers, such as arm tensing with clenching of fists, leg crossing, and leg pumping may help in aborting a syncopal event or at least delay it long enough for patients to assume the supine position. These maneuvers work by reducing lower-extremity venous pooling and improve cardiac output, thus preventing vasovagal syncope. The European Society of Cardiology guidelines (2009) noted that tilt training may be useful for the education of patients; its long-term benefits depend on compliance . AdditioAppropriate management of vasovagal syncope can only come with a clear understanding of the complex pathophysiology of these episodes. Our study showed that children and adolescents with vasovagal syncope were more likely to have a systolic blood pressure lower than the 10th percentile when compared with controls, with no difference in the baseline heart rate. In addition, children and adolescents with syncope were more likely to add salt to their diet. These patients adapt over time to keep their blood pressures higher so as to prevent these syncopal episodes. Further studies and a larger sample size are needed.


Background: The temporal relationship between arterial stiffness and blood pressure (BP) may vary depending on age and other clinical and demographic factors. Since both BP and arterial stiffness are also affected by inflammatory processes, we examined the temporal arterial stiffness-BP relationship in patients with rheumatoid arthritis (RA) treated with either methotrexate (MTX), an anti-rheumatic agent shown to reduce cardiovascular risk in meta-analyses, or other disease-modifying anti-rheumatic drugs (DMARDs).Methods: Measurements of clinic and 24-h peripheral and central systolic and diastolic BP (SBP and DBP), and pulse wave velocity (PWV) were assessed in RA patients on stable treatment with either MTX ± other DMARDs  or other DMARDs . Measurements were performed at baseline and after 8 months. The temporal relationships were examined using cross-lagged path analysis with models that included age, sex, body mass index, prednisolone, and folic acid use and 28-joint disease activity score.Results: There were significant differences in the temporal arterial stiffness-BP relationships between those in the MTX and DMARD groups. A higher PWV at baseline caused a significant increase in 6 out of 8 different measures of SBP at 8 months amongst those treated with DMARDs  and 3 out of 8 different measures of DBP  but was not associated with either SBP or DBP at 8 months amongst those treated with MTX. The difference in the effect of baseline PWV on 8-month BP between the 2 groups was also significant (p < 0.003) for 4 measures including clinic peripheral SBP .Conclusions: Higher arterial stiffness preceded increases in BP in subjects with RA treated with DMARDs, but these effects did not occur amongst those treated with MTX. The different effects were seen mostly in measures of SBP but were also present in some measures of DBP. Our findings suggest MTX may confer a protective effect against stiffness mediated increases in BP in patients with RA. Arterial stiffness and blood pressure (BP) are two well established independent risk factors for cardiovascular disease (CVD), yet both are also closely associated with each other  and in those not using methotrexate and treated only with DMARDs (n = 18).In this medium term follow-up study of 8 months, we performed repeat assessments of arterial stiffness using pulse wave velocity (PWV) and both clinic and 24-h ambulatory blood pressure  in a cohort of 59 subjects with a confirmed diagnosis of RA. We then determined the temporal associations between stiffness and BP in those subjects treated with methotrexate + DMARDs (1) and the association between baseline BP and follow-up PWV (β2).We conducted a repeat cross-sectional study with measurements of BP and PWV at baseline and at 8 months follow-up. A cross-lagged panel approach  was approved by the Southern Adelaide Clinical Human Research Ethics Committee . Each participant gave written consent before entering the study in accordance with the Declaration of Helsinki.Clinic peripheral systolic (SBP) and diastolic (DBP) BP were measured in the morning, in a quite environment at room temperature, using the clinically validated automatic BP monitor  according to current guidelines , and night-time   was measured in serum by latex-enhanced immunoturbidimetry on an automated Modular PPE Analyzer  and the effect of baseline BP on follow-up PWV (β2). Stratifying by MTX treatment status allowed separate coefficient estimates for each group of subjects and also calculation of the difference  for each coefficient between the 2 groups. We also performed a formal Wald test of group invariance in each coefficient to formally test whether the 2 estimates for each coefficient were the same for both groups. Model fit was determined using standard SEM measures: the chi-square (χ2) test of model fit vs. saturated fit for which non-significant values (p > 0.05) indicate acceptable fit, the comparative fit index (CFI) for which values >0.90 reflect acceptable model fit, and values >0.95 reflect excellent model fit, and the standardized root-mean-square residual (SRMSR) for which values of 0.05 or less reflect excellent model fit, while a value of <0.08 reflects a good fit. Given the 16 different measures of BP that were assessed, a Bonferroni correction was applied to the results and coefficients were only considered significant for p < 0.003. Similarly, we also calculated 99.7% confidence intervals (CI's).Each analysis was performed in Stata version 14.2  using commands for structural equation modeling (SEM) with maximum-likelihood estimation. For each of the 16 different BP outcome variables we fitted a separate SEM model with MTX treatment status as a separate strata (grouping) variable. The endogenous (dependent) variables in each model were baseline and follow-up BP, and baseline and follow-up PWV. Exogenous (independent) variables in each model were age, gender, BMI, DAS28, serum CRP, and use of folic acid and prednisolone which were used as predictors of the baseline measures of BP and PWV. Measurement errors between BP and PWV were also allowed to co-vary at each time-point , the use of folic acid , the DAS28 , and the Global Health score .Table n = 59). Across the 2 time points, there was a slight increase in both clinic and ambulatory BP but there was no significant change in PWV. Amongst the 16 different measures of BP, pairwise Pearson correlations between measures of baseline SBP and follow-up PWV were moderate (r = 0.31–0.54), correlations between baseline DBP and follow-up PWV were weak (r = 0.06–0.20), correlations between baseline PWV and follow-up SBP were moderate (r = 0.40–0.55), correlations between baseline PWV and follow-up DBP were weak to moderate (r = −0.02 to 0.44), whilst correlations between baseline and follow-up measures of PWV were high (r = 0.91).Table 1 by DMARD treatment regime. For subjects in the non-MTX group, out of the 8 measures of SBP, all except 24 h peripheral SBP and night-time peripheral SBP showed a significant effect of baseline PWV on follow-up BP . Out of the 8 measures of DBP, 3 showed a significant effect of baseline PWV on follow-up BP  including night-time peripheral, 24-h central and night-time central DBP. There were no significant effects of baseline PWV on measures of either SBP or DBP amongst subjects using MTX.Figure 2 by type of DMARD. For both those subjects in the non-MTX group and those in the MTX group, there were no significant effects of baseline SBP or baseline DBP, on follow-up PWV.Figure 1) for the different treatments (DMARDs vs. MTX). There was a significant difference between groups in the estimated effects for clinic peripheral SBP, clinic central SBP, 24 h central SBP and night central SBP (p < 0.003 for each). The largest difference in the effect occurred for clinic peripheral SBP . There were no significant differences between groups in the effects of baseline PWV on any of the measures of follow-up DBP. There were also no significant differences between groups in β2 (effect of baseline BP on follow-up PWV) for any of the 16 measures of BP. The Wald test for group invariance in the estimated coefficients between the 2 groups showed a significant difference in the β1 coefficient for clinic peripheral SBP (p = 0.0004), clinic central SBP (p = 0.006), day-time peripheral SBP (p = 0.014), 24 h central SBP (p = 0.005), day-time central SBP (p = 0.045), and night-time central SBP (p = 0.013). There was also a significant difference in the β2 coefficient for clinic peripheral DBP (p = 0.043) and clinic central DBP  (p = 0.028) indicating acceptable fit.Table Table In this repeat cross-sectional study of patients with stable RA, we examined the strength of the temporal relationships between arterial stiffness (PWV) and follow-up BP and between baseline BP and follow-up PWV. We observed evidence for a causal effect of arterial stiffness on increased SBP in subjects not treated with MTX. The effects were seen for both central and peripheral and for clinic and ambulatory SBP. The effects were similar during the day and night and we also observed the same effect of PWV on night-time and 24 h central DBP amongst subjects not taking MTX. By contrast, none of the causal effects of increased stiffness on BP were observed amongst subjects treated with MTX medication. Since the differences in causal effects were predominantly related to systolic blood pressure, rather than diastolic pressure, this suggests the possible involvement of effects on stroke volume. Since we did not measure stroke volume directly, further studies are required to determine whether this parameter might explain, at least in part, the observed between-group differences.Since inflammation is believed to have a primary influence in the pathophysiology of increased arterial stiffness (Jain et al., Our results may not be generalizable to all individuals with RA, particularly younger patients. Our cohort was typical of the RA population and consisted of mostly middle-aged to older patients. Recently, the Bogalusa study, a 7 year longitudinal cohort study in a younger population of adults, used similar methods to ours to examine the dominant temporal relationship between arterial stiffness and BP. In this younger cohort they reported that elevated BP precedes increased arterial stiffness rather than vice-versa (Chen et al., Our study had a number of strengths. Firstly we used cross-lagged path analysis, a specific form of path analysis that simultaneously examines reciprocal, longitudinal relationships among a set of inter-correlated variables and allows better determination of causal relationships (Selig and Little, There are several limitations to our study. The duration of follow-up in our study was relatively short with a mean of 8 months. Most of the evidence from other studies have been derived from cohorts with between 4 and 8 years average follow-up in which larger effects are likely to occur (Chen et al., In summary we have demonstrated that although elevated arterial stiffening preceded increases in BP in subjects with RA, these effects did not occur amongst those patients using MTX medication. The beneficial effects were seen mostly in SBP but were also apparent to some degree with DBP, particularly with regards to the more accurate assessment of 24-h blood pressures. These findings suggest MTX may confer a protective effect against stiffness mediated increases in BP in patients with RA.RW performed the analysis, helped conceive the study design, provided Ph.D. supervision, performed the first draft of the manuscript and reviewed later versions. LB collected and formatted the data for the study as part of her Ph.D., performed ethics applications, obtained consent from patients and reviewed several versions of the manuscript. MS was involved in all aspects of the study design, provided clinical patients for the study, and reviewed the manuscript before submission. AM was involved in all aspects of the study design, Ph.D. supervision, helped draft the first version of the manuscript and provided several revisions of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hypertension is an important risk factor for cardiovascular outcomes. Primaryhealth care (PHC) physicians should be prepared to act appropriately in theprevention of cardiovascular risk factors. However, the rates of patientswith control of blood pressure (BP) remain low. The impact of thereclassification of high BP by 24-hour ambulatory BP monitoring (ABPM) canlead to different medical decisions in PHC.To evaluate the agreement between the BP measured by a conventional method byPHC physicians and by 24-hour ABPM, considering different BP normalthresholds for the 24-hour ABPM according to the V Brazilian ABPM Guidelinesand the European Society of Hypertension Guidelines.A cross-sectional study including 569 hypertensive patients. The BP wasinitially measured by the PHC physicians and, later, by 24-hour ABPM. The BPmeasurements were obtained independently between the two methods. Thetherapeutic targets for the conventional BP followed the guidelines by theEighth Joint National Committee (JNC 8), the V ABPM Brazilian Guidelines,and the 2013 European Hypertension Guidelines.There was an accuracy of 54.8% for the BP measured with the conventional method when compared with the24-hour ABPM, with a sensitivity of 85% (95%CI 80.8 - 88.6%), specificity of31.9% (95%CI 28.7 - 34.7%), and kappa value of 0.155, when considering theEuropean Hypertension Guidelines. When using more stringent thresholds tocharacterize the BP as "normal" by ABPM, the accuracy was 45% (95%CI 0.41 -0.47%) for conventional measurement when compared with 24-hour ABPM, with asensitivity of 86.7% (95%CI 0.81 - 0.91%), specificity of 29% (95%CI 0.26 -0.30%), and kappa value of 0.103.The BP measurements obtained by PHC physicians showed low accuracy whencompared with those obtained by 24-hour ABPM, regardless of the thresholdset by the different guidelines. Regarding the IDACO study, 6 the guidelines from the EuropeanSociety of Cardiology (ESC) have maintained BP thresholds for the definition ofhypertension by 24-hour ABPM as values greater than or equal to 130 mmHg forsystolic BP and 80 mmHg for diastolic BP.7A national study compared the BP classification according to new thresholdsestablished by the VI Brazilian Guideline for Hypertension / V Brazilian Guidelinefor ABPM, in relation to those previously established by the IV Brazilian Guidelinefor ABPM.8 Theseinquiries arise from a need for prospective studies and elaboration of databases,preferably national ones, to allow a more adequate assessment of the ABPM normalitythresholds for the hypertensive population, especially those attended by the primaryhealth care (PHC) system.Two questions of application in clinical practice regarding the care of thehypertensive patient remain little explored: the applicability and the importance ofmore rigorous thresholds as criteria of normality for BP, and the prospectiveevaluation of the diagnostic accuracy between the different methods of BPmeasurement.This study proposed to evaluate the diagnostic accuracy of BP measurement by theconventional method, performed by PHC physicians, and the agreement of thesemeasures with those obtained by the 24-hour ABPM, set as normality thresholds by theguidelines.9 All patients were hypertensive, were enrolled in thePrograma de Saúde da Família , took part in regular clinical follow-up at thehypertension outpatient clinic of the city's two UnidadesBásicas de Saúde ,and were on antihypertensive treatment for at least 6 months.The participants of this cross-sectional study conducted at two health postsincluded hypertensive patients from Antônio Prado (RS), a city in thesouth of Brazil with 12,883 inhabitants.8 which included an assessmentwith 24-hour ABPM, were contacted by phone and/or letter to participate in thisnew study. Those who were not able to answer the questionnaire, pregnant women,individuals with a non-sinus rhythm electrocardiogram, residents from outsidethe coverage area of the UBSs, patients who switched cities or who were notfound, and those who did not tolerate the use of ABPM or who presented sometechnical difficulty in the application of the method were excluded. Thus, outof the total of 639 patients, 28 were excluded from the study due tocomplications related to technical problems in the reading and failures in theadjustment of the ABPM cuff (18 patients), sleep disorders that preventedadequate BP measurements (8 patients), and intolerance of the equipment due toanxiety (2 patients).The samples were randomly selected from the total set of hypertensive patientsenrolled in the UBSs, through random numbers generated by the program MicrosoftExcel 2010. Patients were assessed by their own PHC physicians during routinevisits to the hypertension outpatient clinic from January 2013 to October 2014.Patients who had participated in a previous cross-sectional study,All subjects agreed to participate in the study and signed an informed consentform. The results of the biochemical tests and ABPM performed during the studywere delivered to the patients. The project was approved by the Research EthicsCommittee (REC) of the IC/FUC - 4278.08.10The BP was verified by the PHC physicians through three measurements with amercury sphygmomanometer  with orientation for individualized adjustment of the cuff, with thepatients in a seated position and their feet resting on the floor and after aminimum rest period of 5 minutes. The physicians at the health centers wereinstructed to measure the BP in both arms, taking, as a reference, the highestvalue obtained after an approximate interval of 3 minutes between measurements.The first measurement was discarded, and the mean of the two subsequentmeasurements was calculated and recorded on the patient's chart. Then, duringthe same visit, the patient was referred to a nurse trained for this study whoplaced the device for the 24-hour ABPM, applied a standardized questionnaire,and obtained the anthropometric measurements. Subsequently, the patient'smedical records were reviewed, biochemical exams were requested, and the ABPMreport was prepared blindly by the investigating physician. The ABPM device wasapplied during a normal day of the patient's work activity, excluding days onthe weekends and holidays. Based on prognostic evidence, the ABPM was selectedas the standard reference for BP measurements and for assessing the diagnosticaccuracy of the conventional BP measurement.11 The ABPM recorder used was the DMS Brasil model TM 2430 andthe model of the mercury sphygmomanometer was the MDF 800. The ABPM wasscheduled to record a BP measurement every 15 minutes during the waking periodand every 30 minutes during sleep. The schedules were adjusted according to theindividualization of the sleep and awakening habits of each patient. Theobtaining of data from at least 60 records in the 24-hour period was consideredadequate, with at least two records every hour during the sleep period. Theparameters assessed by the ABPM were the mean systolic and diastolic BP from the24-hour, waking, and nocturnal periods. For the conventional measurements,uncontrolled hypertension was defined as the achievement of values ≥140/90 mmHg, according to the main hypertension guidelines. For the group ofpatients aged ≥ 60 years, guidelines from the Eighth Joint NationalCommittee (JNC 8) were also adopted.1The ABPM monitors used in the study were duly validated and calibrated accordingto international recommendations.13Thus, patients with a mean BP of ≥ 130/80 mmHg in 24 hours,≥ 135/85 mmHg in the waking period and ≥ 120/70 mmHg forthe nocturnal mean BP for the first criterion were considered as havinguncontrolled hypertension.12Whereas, when the guidelines of the Brazilian Guidelines for Hypertension wereobserved,13 the valuesfor BP used in the study were the borderline ones considered normal as cutoffpoint for the 24-hour averages: >125/75 mmHg, > 130/85 mmHg for the wakingperiod, and > 110/70 mmHg for the mean BP during sleep.14In order to classify hypertension as uncontrolled, the ABPM criteria of theEuropean Hypertension Guidelines and the Brazilian Hypertension Guidelines fromthe Brazilian Society of Cardiology were adopted.3 The white coat syndrome (WCS)was considered to be present when a patient on antihypertensive treatment hadhigh BP, as measured in the clinic environment and/or under surveillance, butcontrolled BP in other situations.15 Masked hypertension (MH) was characterized by the presenceof a BP that was controlled when obtained with a conventional measurement, buthigh when obtained with ABPM or in-home measurements.16 "Masking effect" was the term used when MH wasobserved in hypertensive patients using antihypertensive treatment. The samevalues for the normality criteria for 24-hour BP were considered for diabeticand nondiabetic patients.A ≤ 10% reduction in the mean nocturnal BP in relation to the daytimemean in the ABPM was defined as an absence of nocturnal descent.8In addition to BP measurements by the conventional method and the 24-hour ABPM,the biochemical profile of the patients in this study was evaluated. Laboratorytests included total cholesterol, LDL-cholesterol, HDL-cholesterol,triglycerides, creatinine, blood count, glycosylated hemoglobin (fraction A1c),microalbuminuria, and fasting blood glucose. Anthropometric data, such as bodymass, height, waist-hip ratio, and body mass index were also evaluated. Thescreening questionnaire also included validated instruments for the evaluationof smoking and nicotine dependence (Fagerström test), abusive alcoholconsumption , and adherence totreatment using the Morisky Medication Adherence Scale.Data entry and analysis were performed using the SPSS statistical software,version 21.0. Descriptive statistics were performed with continuous variables(mean and standard deviation) and categorical variables (frequencydistribution). The estimated sample size was 398 patients and was based on theprevious cross-sectional study conducted at the same site of the current studyand on BP control rates of 55% for ABPM and 41% for conventional measurementsperformed by the PHC physicians for a confidence interval of 95% (95%CI) and 80%power. The sample was considered representative of the PHC service in the cityof Antônio Prado (RS) because it was randomly selected at the twohealth posts with hypertension outpatient clinics, out of a total of 1,216patients enrolled in this system. The hypertension care units, where the studywas conducted, are referential units of the PHC in the city.t test (for variables with homogeneousvariances). To analyze the agreement between the techniques of BP evaluation,kappa statistics was used. A multivariate analysis was also performed forcardiovascular risk factors and agreement of BP control, according to the24-hour ABPM compared with conventional BP. P values < 0.05 were consideredsignificant.The comparison between the subgroups was performed using the chi-square test,Mann-Whitney U test (for continuous variables with non-homogeneous variances),and Student's Between January 2013 and October 2014, a consecutive sample of 639 hypertensivepatients enrolled in the hypertension outpatient clinic of two health posts in thecity of Antônio Prado (RS) was selected from a total of 1,216 patients.ABPM was applied in 611 patients who remained in the study after application of theexclusion criteria, shortly after conventional BP measurements by PHC physicians.The final sample comprised 569 patients after exclusion of patients who abandonedthe research protocol or who presented inadequate ABPM measurements. No patientrequired medical care due to the compressive action of the ABPM cuff, whose reportedevents included: local discomfort (22 patients), mild local erythema (6 patients),and short-term paresthesia in the limb used for placing the cuff (2 patients). versus 24-hourABPM, we observed an accuracy of 54.8% (95%CI 0.51 - 0.58%) and, when consideringthe European Society of Hypertension Guidelines, a sensitivity of 85% (95%CI 80.8 -88.6%), a specificity of 31.9% (95%CI 28.7 - 34.7%), and a kappa value of 0.155.When more stringent thresholds were used to characterize BP as "normal" by ABPM, weidentified an accuracy of 45% (95%CI 0.41 - 0.47%) by the conventional measurementwhen compared with 24-hour ABPM, in addition to a sensitivity of 86.7% (95%CI 0.81 -0.91%), a specificity of 29% (95%CI 0.26 - 0.30%), and a kappa value of 0.103  compared with a more flexible control (< 140 mmHg). Therefore,evidence of reduced outcomes with more stringent cutoff points for BP control maylead to substantial changes in future revisions of hypertensionguidelines.20 Thus, thisneed is in agreement with the evaluation of the impact on the diagnostic accuracy ofusual methods of BP in comparison with the different thresholds of normality for thegold-standard BP evaluation.The Systolic Blood Pressure Intervention Trial (SPRINT) study21The adoption of the 24-hour ABPM through a single measurement in our sample may beconsidered a limitation of the present study. This may imply a limitation in thereproducibility of the measurements, especially when considering the evaluation ofthe nocturnal decreasing BP pattern. However, to mitigate this potential limitation,precautions were taken, such as the individualization of the sleep and wakingperiod, as well as a rigidity regarding the minimum number of measurements and thequality of the measurements during the 24 hours as criteria for inclusion in thestudy. These measurements followed the guidelines and recommendations of the ItalianSociety of Hypertension.The use of ABPM in PHC, as well as the impact of the reclassification of hypertensionaccording to the different normality thresholds for 24-hour BP, may haveimplications for decision-making by PHC physicians. Thus, a more significant numberof national studies may serve as a reference for the elaboration of futureguidelines and indicate BP thresholds for therapeutic definition.This study evaluated the use of 24-hour ABPM within the scope of the PHC. BPmeasurements assessed by PHC physicians presented low accuracy when compared withthose obtained by 24-hour ABPM, regardless of the threshold used as a normalitycriterion.


Purpose: Onopordon acanthium L. is known for its medicinal properties. Our recent study showed that its seed extract is a novel natura angiotensin-converting-enzyme inhibitor (ACEI). This study was carried out to investigate its possible antihypertensive effects in patients receiving losartan.Methods: This uncontrolled clinical trial was carried out among 20 patients (30-60y) with uncontrolled hypertension despite receiving 50 mg losartan (stage I & II) in two hospitals in Iran. After completing informed consent, patients were treated by 2 capsules [each 1g of Onopordon acanthium seed extract (OSE)] as add-on therapy, two times per day.Results: 18 patients completed the study (50.94 ±8.37y). Mean systolic blood pressure (SBP) at the baseline was 151.9 ± 13.74mmHg and at the end of the study, it was 134.6 ± 18.25 mmHg and mean diastolic blood pressure (DBP) was 97.41 ± 10.36 at the baseline and was 85.71 ± 7.481 after 8 weeks. OSE significantly reduced SBP and DBP at the end of 8 weeks . No evidence of hepatic or renal toxicity was detected.Conclusion: Based on the results of this study OSE has antihypertensive property with no significant adverse effects. However, because of the low number of samples, this medication may be not safely administered. The results of this study could be the basis for further studies with larger sample size. IRCT registration number: IRCT2013020712391N. Losartan is an oral medication that belongs to a class of drugs called angiotensin receptor blocker (ARBs) which was approved by the U.S. Food and Drug Administration (FDA) in April 1995. Losartan blocks the angiotensin receptor, relaxes muscle cells and dilates blood vessels and reduces blood pressure.7Hypertension (HTN) is a global concern and affects approximately 75 million adults in the United States and if left untreated increases risk of stroke, myocardial infarction, vascular disease, and chronic kidney disease.50 value of 2.6 ± 0.04 mg/ml).8 This plant has been well known under the name "Khaje Bashi"9 and has long been used in folk medicine as a hypotensive, cardiotonic and diuretic agent.10 Also it has been noted in Persian Medicine (PM) literatures as diuretic, diaphoretic, antipyretic, analgesic. Cotton thistle or Scotch thistle are its common names. It is a flowering plant belonging to the Compositae (Asteraceae) family and is widely naturalized almost globally, particularly in Europe and Western Asia and is a vigorous biennial plant with coarse, spiny leaves and conspicuous spiny-winged stems.11 In modern medicine, O. acanthium has been reported to be a bactericide, cardiotonic, hypotensive and hemostatic agent and is used against hypotonicity.14 This species has several bioactive components among which sesquiterpene lactones have been found to have numerous biological properties including antibacterial, anti-inflammatory, anti-malarial, and hypotensive effects.15 Since the antihypertensive effect of O. acanthium seed extract has not been studied on patients in follow up of our previous in vitro study, we conducted this trial to investigate the possible antihypertensive effects of OSE on patients with stage I-II hypertension who were under treatment with losartan, a chemical ACE inhibitor, as add-on therapy.Our recent study showed that the OSE is a novel natural inhibitor agent and inhibit angiotensin-converting-enzyme by 80.2 ± 2 % at concentration of 330 μg/ml, and exerted antioxidant activity , Iran. The seeds were identified by Prof. Gholamreza Amin and were kept under the voucher number PMP–714 at the herbarium of Faculty of Pharmacy, Tehran University of Medical Sciences.The extract was prepared in the laboratory of traditional pharmacy at faculty of Traditional Medicine, Tehran university of medical sciences via maceration method using ethanol as the solvent (1:8) at three time points . The three extracts were mixed, filtered and evaporated. The total evaporated extract was freeze-dried and grinderies to obtain a powder for preparing the capsule. Each capsule contained 1g of the freeze-dried powder equal to 11 gram of dried seeds, and all the physiochemical quality control (QC) tests were performed on the capsules.Khaje Bashi plant), rats were used and kept at the Animal house of the Faculty of Pharmacy, Tehran University of Medical Sciences. Animals were kept in standard light (12 hours of light and 12 hours of darkness), room temperature (25-35 °C) with adequate water and food. 12 male albino NMRI mice were divided into three groups . The whole extract of the plant was taken in dried form and stored in a dark bottle in the refrigerator until it was tested. Due to its low solubility, the extract was dissolved in dimethyl sulfoxide (DMSO) at a desired concentration and diluted with normal saline at a rate of 1:3 and made as a monotonous suspension.To measure the toxic dose of total extract of OSE (50) was calculated based on the curve.The solution was injected intraperitoneally (i.p.). Animals received the same amount of DMSO in different dose groups. Animals’ condition (lethargy and movement) and animal death were investigated for 24-48 hours. In each group, mortality rate was reported and plotted against the dose used. The dose that causes 50 percent of deaths in animals or “Lethal Dose, 50%”  was determined. According to these results, the extract of this plant was classified in "practically non-poisonous ".Considering that no studies have been done on the toxicity of this plant, in the first step, 0.5, 1, 2, 3.5 and 5 g/kg of body weight were used to find the dose range, but no mortality or change was observed in animals. In the next step, doses of 6-20 g/kg were used, and in dose 20, all animals died. In the next stage, the range of 6-13.5 g/kg was tested in 6 groups of animals. The results were calculated as a percentage of death for each group. LD16 Sample size was calculated as follow: based on predicted 14 mmHg reduction of systolic blood pressure (d=14) at the end point (after 8 weeks), standard deviation 20  of 95% (Z1-α/2=1.96) and taking into account a correlation of 0.5 between frequent measurements and considering 20 % loss to follow, 20 patients were enrolled to determine the effective dose of therapy. Each individual took 2 capsules, two times a day (2 g/BD) and blood pressure was checked every other week. If blood pressure has increased more than 15 mmHg, the patients would have dropped out the study.This open-labeled, non-randomized, uncontrolled clinical trial, a pilot study, was performed on 20 patients, who were under losartan treatment (50mg/d) for at least 6 weeks before starting the study and their blood pressure constantly remained higher than 140/90 (stage I&II) hypertension according to the seventh report of the joint national committee (JNC VII) report.The primary outcome measure was systolic and diastolic blood pressure that was measured using aneroid sphygmomanometer . Metabolic parameters  were measured two times during the study (at the beginning and at the end of study) at Noor laboratory to evaluate the general health status of the patients.The patients (30-60 y) were selected from Imam Khomeini & Amir-alam hospitals of Tehran University of medical sciences. Patients with history of malignant hypertension, blood pressure higher than 200/140 mmHg and whom needed multi-drug treatment or emergency IV drug infusion, history of secondary hypertension, end organ damages (EOD), sudden increase of blood pressure to greater than 15 mmHg at any time during the study, cardiac arrhythmias, symptomatic valvular heart diseases  were excluded from the study. Other exclusion criteria were: diabetes type 1& 2, liver disorders, pregnancy breast feeding, cured or uncured malignancies during the last 5 years, serum potassium >5.2 or <3.5 mEq/L in the first visit, drug or alcohol abuse. The procedure was explained to all patients and written informed consents were obtained. Patients were examined at the beginning of the study and then every two weeks, and their arterial blood pressure was measured. The researcher's contact number was also provided to patients in order to report any problems between every two visits. In addition, patients were asked at each session about possible complications such as coughing, severe headache, visual impairment, any types of arrhythmias, and orthostatic hypotension, and were recorded. Demographic and baseline data, medical history and any concomitant medications of enrolled patients were recorded. The study protocol was approved by the ethics committee of Research Institute for Islamic and Complementary Medicine of Iran University of Medical Sciences at 09/10/2012 with reference number 732/P26/M/T.50 was calculated using nonlinear sigmoid regression and Probit technique. Moreover, the correlation between effect and administered dose was analyzed using Pearson correlation test.The changes in blood pressure were analyzed using repeated measures ANOVA analysis. P value <0.05 was considered significant. The LD50 was 8.44 ± 0.04 g/kg. Sampling began on May 21, 2013 and continued for five months, till October 23, 2013. 54 patients were assessed. Only 24 patients met the inclusion criteria whom four were not willing to participate in the study. At the end, 18 patients (of 20) completed the study and two patients were left the study due to increased blood pressure more than 160/100 mmHg in one patient after 2 days and another, after 3 days from starting point. Based on the ethical issues and respect to the patients’ right, they were excluded and researcher referred both of them to the cardiologist to be treated with two or more drugs (Cytotoxicity of the extract was performed in mice by injecting different doses of OSE (0.5-13.5 g/kg) to measure the minimum toxic dose of OSE and LDre drugs .Patients took 2 capsules two times a day (2 g/BD) and were visited every other week and systolic and diastolic blood pressure and any possible side effects were recorded .After treatment for at least 8 weeks, systolic and diastolic blood pressure decreased significantly  . MoreoveO. acanthium extract consumption in patients during the study.We did not observe hepatic or renal toxicity as the result of The results of these tests showed no significant changes . As shown in the following diagrams, although these changes were not significant, in some cases, such as glucose, cholesterol, triglyceride, LDL, VLDL, and BUN, there was a tendency to reduction. Based on these results, HDL levels show a modest increase. The levels of sodium and creatinine were almost constant. The amount of potassium and liver enzymes were in the normal range  & 4. In Regarding the side effects, we detected mild dyspnea in two patients after 2 weeks. Also two patients showed dizziness and feeling of heaviness in the head in the first month of treatment that resolved later.O. acanthium seed extract for 8 weeks significantly decreases systolic and diastolic blood pressure in patients with stage I and II primary essential hypertension under losartan treatment. In line with our recent findings in which a novel compound was extracted and identified from O. acanthium named Onopordia, OSE showed antioxidant and angiotensin converting enzyme inhibitor (ACEI) activity (80.2 ± 2 %). Its potential of blood pressure decreasing can be due to its different components such as sesquiterpenes and flavonoid.8 There is no study on evaluating the effects of O. acanthium on blood pressure; however, some studies around the world have evaluated the hypotensive effect of some popular and well-known hypotensive herbal medicines.These data indicated that 4 g/day of Achillea wilhelmsii to 120 patients for 8 weeks and showed significant decline of systolic and diastolic blood pressure .17 Walker et al., administered 500 mg/day of dried, full-spectrum aqueous-alcoholic extract of hawthorn (Crataegus laevigata) leaves and flowers to 36 patients with essential HTN for 10 weeks and found that diastolic blood pressure decreased in 19 patients. However the difference was not significant (P=0.08).18 In a follow up study Walker et al., evaluated the hypotensive effect of Crataegus laevigata, 1200mg/day for 16 weeks on 76 patients and indicated significant decrease in diastolic (P=0.03) but no significant decrease in systolic blood pressure (P=0.32).19 Consistent with these findings Ried, et al. indicated that treatment with aged garlic extract for 12 weeks lowered systolic blood pressure 10.2 mmHg.20 Furthermore Susalit, et al., investigated the hypotensive effect of olive (Olea europaea) leaf extract, 500 mg/daily for 8 weeks on 232 patients and indicated the extract lowered 10 mmHg systolic blood pressure.21 Moreover, several other herbal agents were studied independently and showed hypotensive effect. Examples are Sour Cherry (Prunus cerasus L.), Nigella sativa seed extract, pomegranate juice, Hibiscus sabdariffa and canola oil with sunflower oil.29 In this study, OSE lowered systolic blood pressure by 17.3 mmHg that is more potent than all studied hypotensive agents. Similar effects have been reported about aged garlic extract and olive leaf extract that showed a reduction of about 10 mmHg of systolic blood pressure. The reasons for such discripency is not clear but it may be due to the presence of both ACEI and diuretic activity in OSE. This finding was in line with previous report by Sharifi, et al., that revealed OSE has more hypotensive effect than other 50 herbal agents which has been assessed.8Asgary et al., in a study in Iran, administered Several limitations are inherent to the present study. Recruiting hypertensive patients categorized in the first and second stage of hypertension who were also treated with losartan was very difficult. The majority of hypertensive patients had to use two or more drugs to control their blood pressure, due to lack of good response to one-drug therapy. The limitation of recruiting hypertensive patients in this study was consistent with the one in the other studies. The withdrawal of the patients was also an obstacle to obtain the desired results with higher power of analysis.OSE synergistically with diuretic and plasma ACE inhibitor activity reduced blood pressure (both systolic and diastolic) in the patients under treatment with losartan, and did not show remarkable side effects in patients with primary hypertension. Because of the low number of samples, this medication may be not safely recommended. Further clinical trials is needed for increasing certainty with larger sample size and placebo.This study was part of a postgraduate thesis entitled: ''Investigating the Effect of Onopordon Acanthium Seed on Primary Hypertension Reduction in Patients under Treatment by Losartan''; and was supported by a grant from Tehran University of Medical Sciences. The funding source had no involvement in any part of the study. We would like to thank the participants for their contribution to the maintenance of our patient record without which this project would have been impossible. Special thanks to Mr. Hadi Salehi, for his kindly efforts for extraction and drug preparation. We would like to thank Dr. Mohsen Amin assistant Prof. at Faculty of Pharmacy, Tehran University of Medical Sciences for his help in data analysis and manuscript editing.The study protocol was approved by the ethics committee of Research Institute for Islamic and Complementary Medicine of Iran University of Medical Sciences at 09/10/2012 with reference number 732/P26/M/T.The authors have declared no conflicts of interest.


Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome.We enrolled 46 ischemic strokes . Dynamic cerebral autoregulation was assessed by transfer function  of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months.p < 0.05). Both lower eGFR and higher gain correlated with WML grade (p < 0.05). Lower eGFR and increased gain, alone and in combination, progressively reduced the odds of a good functional outcome  and increased risk of HT .High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side  contains supplementary material, which is available to authorized users. Chronic kidney disease (CKD) increases the risk of ischemic stroke , 2, its Because microvascular dysfunction impairs myogenic autoregulation, this could be the missing link between renal dysfunction and stroke morbidity and worthwhile of being explored. Dynamic cerebral autoregulation (CA) is rapidly and noninvasively assessed at the patient bedside by transfer function analysis (TFA) using spontaneous oscillations in ABP and cerebral blood flow velocity (CBFV) , 19–22 wIn this study, we examined the relationship between renal function and CA, assessed from TFA measured within 6 h of symptom-onset and its impact on long-term outcome.The study was conducted in Hospital Center São João, Porto, and its local ethical committee approved the study and all participants or proxy signed written informed consent. We included consecutive patients with acute ischemic stroke admitted to our stroke unit and with time from symptom onset, or from last seen well, within 6 h. Most patients admitted after 8:00 p.m. or weekends were not enrolled because transcranial Doppler (TCD) monitoring was not available. Exclusion criteria included hemodynamic instability requiring vasoactive agents, other central neurological co-morbidities, acute renal injury  or insufAll patients underwent a neurological examination at presentation and National Institute of Health Stroke Scale (NIHSS) scores were calculated at baseline. The outcome, assessed by clinical interview, corresponded to mortality and functional independence [modified Rankin Scale (mRS) 0–2] at 90 days.Evaluations were carried out in the stroke unit with the head of the bed at 0°. ABP was continuously monitored with a finger cuff in the unaffected side using Finometer MIDI . Additionally, ABP was assessed with oscillometric cuff . Heart rate was assessed from lead II of a standard 3-lead electrocardiogram. CBFV was recorded bilaterally from M1 segment of MCA (depth of 50–55 mm) with 2-MHz monitoring probes secured with a headband . End-tidal carbon dioxide was evaluated by nasal cannula attached to Respsense capnograph . All data was synchronized at 400 Hz with Powerlab  and stored for offline analysis. Data collection occurred for 10 min within 6 h from symptoms-onset.All signals were inspected using a custom based Matlab® program and artifacts removed by linear interpolation . SystoliComputed Tomography brain scan , with 3 to 6 mm slices, was performed at presentation and repeated at 24 h. Hemorrhagic transformation was defined as any hemorrhage ranging from petechial hyperdensities to parenchymal hematoma . WML, a 2, respectively) subgroups. Any subgroups were compared with Kruskal-Wallis and Mann-Whitney tests. The impact of eGFR on the outcome (mRS 0–6) and association with WML grades (0–4) were characterized by ordinal regression analysis. The risk of hemorrhagic transformation was assessed by logistic regression analysis. To avoid spurious associations, we considered statistically significant at P < 0.01 level for univariate regression analysis. Otherwise, P < 0.05 cut-off was used. All statistics were performed using IBM Statistical Package for Social Sciences (SPSS) Statistics v21™.Normality was determined by Shapiro-Wilk test. Baseline data are presented for all subjects. The relationship between baseline characteristics, including eGFR, and CA parameters were determined by multivariate and univariate linear regression analysis adjusting for age, gender and other significantly related variables at previous univariate analysis. To better depict the relationship between CA and eGFR, we divided the first by median and the latter into subgroups of low and high .Baseline characteristics and hemodynamic data are reported in Tables p < 0.05, Table n = 10) compared to patients who were not on CCB  and also lower eGFR  but this was not statistically significant if we only compared chronically hypertensive patients . ABP at presentation was not different between those on CCB compared to those not on CCB .Previous use of Calcium Channel Blockers (CCB) was associated with higher gain values bilaterally  and proportionally to higher levels of LF gain . This can be depicted clearly in figs. p = 0.045 and non-infarct side p = 0.009).WML severity was correlated in an inverse manner with lower levels of eGFR , p = 0.002]. Multinomial logistic regression also found an interaction between lower eGFR and higher LF gain with an increased risk of hemorrhagic transformation that was only statistically significant on the contralateral side .An ordinal regression model with interaction between decreasing eGFR and increasing LF gain Fig.  and d foOur data shows significant association between impaired cerebral autoregulation  assessed during acute ischemic stroke (< 6 h) and impaired renal function (lower glomerular filtration rate) independent of age, vascular risk factors and relevant laboratory metabolic control parameters. Moreover, both impaired renal function and impaired cerebral autoregulation  were associated with greater white matter abnormalities and with reduced likelihood of a good functional outcome  as assessed by mRS at 3 months.To understand why impaired renal function might be linked to impaired cerebral autoregulation, we need to consider the physiology of autoregulation. Renal autoregulation adjusts vascular resistance to stabilize renal blood flow and filtration rate during changes in renal perfusion pressure . BasicalThe same characteristics are found in the cerebrovasculature with increased gain in the low-frequency range associated with impaired cerebral autoregulation , 20. In Considering the similarities in the characteristics of autoregulation in the kidney and brain, one could propose that microvascular damage  that causes impairment of kidney function , 16 coulTaken together, this would suggest that if patients demonstrate less effective autoregulation in the cerebral vasculature (high gain) they would likely also have impaired renal myogenic autoregulation, which would cause glomerular dysfunction.One interesting finding was that previous CCB use was correlated to increased LF gain values in both cerebral hemispheres as well as reduced eGFR. A possible explanation for this finding lies in the effect of CCB on autoregulation. In fact, previous work has demonstrated that CCB impairs the myogenic response in the kidney in animal models , 40 and Our finding that both low eGFR and high gain were significantly associated with severe WML grade does suggest that impaired autoregulation in the brain and kidney may be associated. A suggested mechanism for this is that microvascular damage is the basis of this autoregulatory dysfunction. Our work is the first to demonstrate that low eGFR is significantly associated with high gain and severe WML. From our data, we cannot rule out if WML cause cerebral autoregulation impairment or the opposite. Previous work has demonstrated that WML are correlated with cerebral autoregulation efficiency . HoweverAnother finding in our study was the relationship between high gain, low eGFR and hemorrhagic transformation. Higher gain values reflect less effectiveness in the dampening capability of cerebral resistance vessels in the insonated vascular territory to ABP oscillations . These dIn the infarcted hemisphere, gain had more non-significant relationships with outcome measurements. This can be observed by inspecting figs. One possible confounder on ABP variability and transfer function estimates of CA is the effect of atrial fibrillation. To address this we compared values between patients with and without atrial fibrillation and found no statistical difference between groups, suggesting atrial fibrillation did not have a significant effect on our estimates of ABP variability or CA.The small sample is a limitation of this study. Also, we cannot rule out that this brain-kidney interaction is specific of a stroke population, rather than present in all individuals including healthy subjects since we don’t have a control group. Other angiographic imaging modalities (CT or MRI) are more accurate in excluding significant stenosis and since we relied mainly on ultrasound exams this may be a possible limitation. ABP was assessed using non-invasive oscillometric as well as finger photoplethysmography which are known to have limitations but generally provide a relatively accurate estimate of ABP .Our results show that CA assessment may be an important factor to consider in advancing treatment of acute cerebrovascular disease. Given our finding that impaired CA is associated with worse functional outcome, further work is needed to verify and explore the clinical implications of our findings. Future studies could examine CA in ischemic stroke to determine its time course. In addition, longitudinal studies examining CA in a high-risk population could shed light on a new indicator of stroke risk. Studies assessing the effect of treatments targeting those with impaired CA could determine if the poor functional outcome could be mitigated by a treatment that targets cerebral perfusion for example. Finally, longitudinal studies would also be helpful in understanding if this CA impairment is acute or a chronic condition in these stroke patients.In conclusion, our findings provide support that early autoregulatory impairment of cerebral small vessels, as well as renal vessels, may be a possible mechanism linking low renal function with poor outcome of ischemic stroke. Rapid assessment of serum markers of renal dysfunction could be used as surrogates of cerebral microvascular function integrity which may help identify high-risk individuals for complications like hemorrhagic transformation and possibly provide a therapeutic target in the future.Additional file 1:Table S4. Relationship between Cerebral Autoregulation Transfer Function parameters  and demographic, clinical and laboratorial variables at acute stroke (within 6 h) explorer with linear regression analysis  and demographic, clinical and laboratorial variables at chronic stroke (3 months) explorer with linear regression analysis


It also associated positively with troponins (p ≤ 0.02 for both). In conclusion, performance of the PAT test was acceptable in dialysis patients and traditional clinical variables had very limited influence on RHI in these subjects. Among a panel of conventional endothelial injury markers, RHI showed very modest associations with only vWF and tissue factor. RHI associated positively with troponins in the patients.Previous studies suggested that the reactive hyperemia index (RHI) is a promising cardiovascular risk predictor. We aimed to evaluate clinical determinants of RHI and its association with circulating endothelial injury and cardiac markers in hemodialysis patients. Among 368 patients recruited, RHI was evaluated by peripheral arterial tonometry (PAT) on a midweek nondialysis day. Clinical determinants of RHI were explored by multiple stepwise regression analysis and associations between RHI and circulating markers were evaluated by general linear models. The major cause of a failed PAT test was poor signal (82.1%). Intraclass correlation coefficient for reproducibility evaluation was 0.74. Multiple regression analysis showed traditional clinical factors only explained 7% of the variance of natural logarithm RHI (LnRHI) in the patients. In association analyses, LnRHI showed significant positive associations with Von Willebrand factor (vWF) ( Patients with kidney disease suffer from an increased risk of cardiovascular events as renal function declinesIn clinical practice and research studies, the most common technique to evaluate endothelial function is flow-mediated vasodilatation (FMD) of the brachial artery. Previous studies have demonstrated that endothelial function evaluated by this method correlate closely with results measured directly in the coronary artery589A previous study has adopted the index as marker of endothelial function in a group of peritoneal dialysis patientsWe performed this cross-sectional analysis using baseline data from an ongoing prospective cohort study, which aims to study vascular dysfunction in dialysis patients. The study included patients on maintenance hemodialysis (four hours per treatment and thrice weekly over 3 months) and aged 18–80 years. All patients reached their dry weight based on clinical judgement. Exclusion criteria included: 1. Malignant hypertension with systolic blood pressure (SBP) ≥180 mmHg or diastolic blood pressure (DBP) ≥110 mmHg; 2. Acute infection, acute heart failure or the acute phase of stroke; 3. Decompensated liver cirrhosis or malignant tumor; 4. Amyloidosis or dilated cardiomyopathy; 5. Internal jugular venous catheterization, previous fistula creation on the non-access arm or any other conditions that will affect the accuracy of peripheral arterial tonometry. Coordinating centers of the study included dialysis departments of six tertiary hospitals: The Second Affiliated Hospital of Nanjing Medical University , The Third Affiliated Hospital of Soochow University , Luan People’s Hospital , Affiliated Yixing People’s Hospital of Jiangsu University , Affiliated Wuxi People’s Hospital of Nanjing Medical University , Yijishan Hospital of Wannan Medical College . Sixty age and sex-matched healthy controls (without any known history of chronic kidney disease or cardiovascular disease) were also recruited to assess the difference of RHI between patients and healthy subjects. The study was approved by the Institutional Ethical Committee of The Second Affiliated Hospital of Nanjing Medical University. The study was conducted in accordance with approved guidelines and all participants provided written informed consents.PAT measurement was performed on a midweek nondialysis day. Patients were instructed to abstain from meals, caffeine, and nitrates within 2 hours (long-acting nitrates for 12 hours) before the measurement. Test room temperature was set at 21–25 °C. Peripheral blood pressure was measured at least 20 minutes before the test was started. The EndoPAT 2000  device was used for the measurement. Specially designed finger probes were placed on the index finger of each hand. Baseline measurement lasted for 6 minutes and followed by occlusion of pulsatile arterial flow for 5 minutes. Occlusion was done through inflation of a blood pressure cuff on the non-access arm, started 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 minutes. Results were analyzed automatically using an algorithm by the computerBlood pressure (BP) level was determined by ambulatory blood pressure (ABP) monitoring, which started on the midweek nondialysis day and ended before next dialysis treatment. The SpaceLabs 90217  monitor was used and programmed to measure BP every 20 minutes during the day-time (6:00 am.–10:00 pm.) and every 30 minutes during the night-time (10:00 pm.–6:00 am.). Patients were instructed to follow their daily activity and keep their arm immobile during measurements. Recordings were downloaded using manufacturer’s software (SpaceLabs Report Manager System) and were further extracted and analyzed by SPSS 19.0 . For patients who had <6 ABP readings, their predialysis blood pressures from dialysis records were collected and averaged over 2-weeks (6 times) before the ABP measurements and were used instead of ABP results.Blood samples were drawn through vascular access before dialysis treatment. Routine laboratory tests were performed in each coordinating center. Plasma samples were stored at −80 °C until needed for testing.Plasma biomarkers, including brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT proBNP), Troponin I, Troponin T and C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), Von Willebrand factor (vWF), sE-Selectin, tissue factor, thrombomodulin were measured using the Milliplex Map assays . Concentrations were calculated using the 5-parameter logistic curve fit. Results outside the range of the standards or the fit were further analyzed via cubic spline.p < 0.10 were selected and entered into the following multiple stepwise regression model. Associations between RHI and plasma markers were determined by general linear models. Three models for the association analysis were constructed with different adjustments. The Model-1 was a basic model in which only age and sex were adjusted. In Model-2, major cardiovascular risk factors were included: age, sex, body mass index, smoking status, diabetes mellitus, history of cardiovascular disease, use of antihypertensives, use of statins, total and HDL cholesterol, triglycerides and mean arterial pressure. In Model-3, dialysis-specific risk factors  and log-transformed CRP were added as covariates. All statistical analyses were performed using SPSS 19.0 . A p value < 0.05 was considered statistically significant.Data were expressed as mean ± standard deviations or median (interquartile range) for numerical variables and counts (%) for categorical variables. Numerical variables with skewed distribution were logarithm transformed. RHI was expressed in the form of its natural logarithm: LnRHI. Comparisons between two groups were done using the Student’s t test or chi-square test as appropriate. Pearson’s correlation coefficient was used for univariate association analysis and variables with A total of 368 patients were recruited between July 2015 and July 2016. Eighteen of them did not undergo PAT test due to device availability. Among those who underwent the test, PAT results were available for 311 patients. Causes of a failed test included: poor PAT signal , signal with too much noise , incomplete occlusion , computer breakdown , intolerance of occlusion  and hand abnormality . Representative data from successful and unsuccessful tests are presented in Twenty patients were invited to assess reproducibility of testing. Two failed the first test and another two failed the second test. Sixteen had successful first and second tests and the intraclass correlation coefficient was 0.74.General clinical information of the 311 patients who had successful PAT test is presented in p = 0.14)  .p < 0.001) and calcium  remained as independent determinants of LnRHI. The model explained 7% of the variance of LnRHI . After adjusting for traditional cardiovascular risk factors in Model-2, the association between LnRHI and tissue factor became non-significant, with a marginal p value of 0.06. In the extensively adjusted Model-3 with dialysis vintage, interdialytic weight gain and log-CRP included as covariates, LnRHI was positively associated with vWF  and tissue factor .Identifying novel cardiovascular risk markers is of critical importance for dialysis patients. Considering previous evidence from a variety of study populations89The existence of arteriovenous fistula access poses a special challenge for the performance of PAT test among dialysis patients. Obviously, the arm with the fistula should only be used as a control arm to avoid occlusion by the blood pressure cuff. Since a previous history of fistula-associated operation, even a failed one, could affect distal blood perfusion, we excluded those with previous operations for fistula creation on the non-access arm. However, even the fistula on the control arm could also have had unneglectable influences on the test result. First, fistula creation decreases digital perfusion pressure, thus may result in insufficient PAT signalUnlike the general population, BP measurement before PAT test had to be done in the test arm. To avoid the affection of transient induction of NO release on the subsequent reactive hyperemia test, we stipulated that the test could only be performed no earlier than 20 minutes after BP measurement. Under these special restrictions, the test was successful in 88.9% subjects (311 out of 350). The main cause of a failed test was poor PAT signal, accounting for over 80% of the technically inadequate studies. This ratio was significantly higher than that reported in the Framingham cohort (30.9%) and the ELSA-Brasil cohort (54.0%)14et al., the authors found a significantly lower LnRHI in CKD-patients (n = 383) compared with non-CKD patients (n = 474) Unexpectedly, we found no statistically significant difference of LnRHI between dialysis patients and the control population, even though we noted that it tended to be lower in the dialysis patients. In a previous study by Hirata 2 of the model was only 0.07 and the regression coefficient for DBP is particularly low, suggesting that the associations were essentially clinically non-significant, and that this index is largely determined by unknown non-traditional clinical variables. In fact, studies on the determinants of RHI yielded widely varied and sometimes conflicting results and the abilities of their regression models for variance predicting were usually unsatisfied1415171819Previous studies suggested that compared with FMD, RHI correlates more closely with metabolic factors14The associations of RHI with several conventional endothelial injury markers were also evaluated in our study. We found that LnRHI had a modest association with vWF and tissue factor after extensive adjustment. These markers were widely used in different studies as surrogate measures of endothelial dysfunction. However, our results, together with previous studies, suggest that these markers and non-invasive endothelial function measures (both FMD and RHI) should not be regarded as interchangeable21Our analysis also revealed a paradoxically positive association between RHI and troponins. Elevated troponin levels are powerful prognostic predictors in dialysis patientsThere are certain limitations in our study that should be noted. First, due to the cross-sectional design, we cannot establish any causality conclusions. Second, the exact effect of different dialysis access (type and location) on the PAT signal and RHI was not determined in our study, though we observed that poor signal was the major cause of a test failure. Third, although patients underwent repeated PAT testing on the same midweek nondialysis day during consecutive weeks, we did not obtain any measurement about their fluid status. Therefore the exact effect of volume status on RHI cannot be extrapolated from our study.In conclusion, poor signal was the major cause of failed PAT test in dialysis patients. Traditional clinical variables had very limited influence on RHI in these subjects. Among a panel of conventional endothelial injury markers, RHI showed very modest associations with only vWF and tissue factor. RHI was positively associated with troponins in the patients. Our results showed that PAT testing is feasible in patients on hemodialysis. Future studies are warranted to explore the risk discrimination ability of RHI in these patients.How to cite this article: Wenjin, L. et al. Reactive Hyperemia Index in Patients on Maintenance Hemodialysis: Cross-sectional Data from a Cohort Study. Sci. Rep.7, 45757; doi: 10.1038/srep45757 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with high morbidity and mortality. This paper provides a critical review of the etiologies of AKI and a systematic approach toward its diagnosis and management with emphasis on fluid volume assessment and the use of urine biochemical profile and microscopy in identifying the nature and the site of kidney injury.The search of PubMed and selection of papers had employed observational designs or randomized control trials relevant to AKI.AKI is defined by the rate of rise of serum creatinine and a decline in urine output. The pathophysiology is diverse and requires a careful and systematic assessment of predisposing factors and localization of site of injury. The majority of AKIs are due to prerenal causes such as fluid volume deficit, sepsis, or renal as in acute tubular injury. The use of central venous and arterial blood pressure monitoring and inferior vena cava echocardiography complemented by urine analysis and microscopy allows assessment of fluid volume status and AKI etiology.Timely intervention by avoidance of fluid volume deficit and nephrotoxic agents and blood pressure support can reduce the incidence of AKI in critically ill patients. Acute kidney injury (AKI) is a common complication among patients with critical illness in the intensive care unit (ICU). The incidence of AKI is now believed to be significantly higher than previously believed with over 50% of patients in the ICU developing AKI at some point during the course of their critical illness. Mortality among ICU patients with AKI and multi-organ failure has been reported to be more than 50% –3. ThoseThe time-honored classification of AKI to prerenal azotemia, intrinsic renal diseases, and post-renal urinary obstruction provides a conceptual framework by which pathophysiological mechanisms can be investigated . The curThe pathogenesis of AKI is complex due to multiple etiologies and risk factors Table . Risk famacula densa, when blood pressure decreases, the vasodilators (vasodilator prostaglandins and nitric oxide) are released with afferent arteriolar vasodilation and subsequent stimulation of renin-angiotensin-aldosterone system (RAAS) [Prerenal AKI including sepsis accounts for 60–70% of all AKI cases in critically ill patients . Renal bm (RAAS) , 21. Them (RAAS) . Arteriam (RAAS) , 24.Sepsis and septic shock remain the most important causes of AKI in critically ill patients and account for more than 50% of cases of AKI in the ICU . The comRenal AKI develops when the primary cause of AKI is parenchymal injury, caused by drugs, toxins, and ischemia. The mechanisms underlying the renal injury process in AKI have predominantly been studied in animal models of ischemic AKI, characterized by “activation” of epithelial and possibly endothelial cells during the early initiation phase results in the upregulation of a variety of chemokines and cytokines leading up to inflammatory cell infiltration including macrophages with loss of the brush border in the proximal tubular epithelium . NephrotAKI is diagnosed when serum creatinine increases by ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 h or increase in serum creatinine to ≥ 1.5 times baseline within the previous 7 days or urine volume < 0.5 mL/kg/h for 6 h .The real challenge is to determine the cause of AKI. The first order is to assess the fluid volume status of the patient. This can be accomplished by estimating the fluid volume balance in the preceding days, blood pressure trend, and assessment of intravascular volume. Intravascular volume is not measured directly but can be inferred by the presence or absence of fluid responsiveness. Echocardiography examining the inferior vena cava diameter and its respiratory variation is becoming readily available in ICUs. More than 12% variation in the IVC diameter in mechanically ventilated patient with septic shock had greater than 90% positive predictive value (PPV) for fluid responsiveness implying intravascular volume deficit . CentralUrinary diagnostic indices can have confirmatory value Table . ConcentThe current definition and classification of AKI tell nothing about whether the dysfunction is purely functional or completely structural—these two extremes likely do not exist. Serum creatinine is the defining indicator of AKI in KDIGO guideline. But it has been shown, serum creatinine, to be a lagging indicator of AKI development and it is easily influenced by many factors, including sex, muscle mass, and some medications.The search for early identification of AKI has led to the development of multiple biomarkers of AKI capable of detecting kidney injury at its early stage. A series of molecules have been evaluated over the years, and significant advances have been made in the field. Several biomarkers have been shown to have predictive ability in recognizing kidney damage earlier than creatinine but have not entered mainstream use as yet. It has been proposed to measure these biomarkers as functional  and damage  markers in combination to improve the diagnostic categorization of AKI and permit more guided interventions .Cystatin C is a small protein produced by nucleated cells and eliminated by GFR. It behaves therefore similar to serum creatinine but is less dependent on muscle mass. In ICU patients, cystatin C will detect AKI 1–2 days earlier before the rise of serum creatinine. Its costly measurement limits its routine use.Molecules such as NGAL and KIM-1 have demonstrated some capacity to detect an injury to the kidney well before the rise of serum creatinine can be observed. Measurement of serum or urine NGAL has been shown to be a good diagnostic test for AKI and prognostic indicator of RRT need and mortality in patients with shock in many studies –46 but n2/1000, launched as a final commercial product, known as NephroCheck. The cutoffs of > 0.3 and > 2 (ng/mL)2/1000 were associated with a progressively increased risk of AKI and major adverse kidney events  [2/1000 had a negative predictive value of 96% following adjustment for the prevalence of AKI [In 2013, the SAPPHIRE study was the first investigation to find and validate the two top urinary biomarkers for the prediction of AKI risk among 340 proteins in a discovery cohort. These biomarkers, urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), were then validated in > 700 critically ill adult patients . A simplunction) . NephroCe of AKI –52. ThesExamination of urine sediments by microscopy can provide insight into the etiology of renal AKI . Urine sIf clinical assessment points toward intravascular volume deficit, optimization of the hemodynamic status and correction of any volume deficit should have a salutary effect on kidney function and help to minimize further extension of the kidney injury . Fluid rColloid solutions such albumin can be used in patients with hypoalbuminemia in the setting of fluid volume deficit, hypotension, and AKI. Albumin infusion is also indicated in patients with liver cirrhosis with AKI in the form of hepatorenal syndrome in conjunction with vasopressors.In septic shock with AKI norepinephrine is the vasopressor of choice with target mean arterial pressure of 65–70 mmHg. However, in patient with chronic hypertension, a higher target mean arterial pressure of 80–85 mmHg is recommended . The tarEarlier studies have demonstrated improved outcome with aggressive use of loop diuretics in AKI despite an increase in serum creatinine –69. A stCurrently, the decision to start RRT is based most often on clinical features of volume overload and serum biochemical abnormalities . This overall approach should be based on patient’s clinical context and be individualized. Metabolic acidosis associated with AKI can usually be corrected with bicarbonate and should rarely require urgent dialysis if not accompanied by volume overload or uremic syndrome .There have been no systematic studies showing a definitive advantage for any RRT modality—continuous vs. intermittent RRT—on short-term patient or kidney survival . HoweverP = .03). In the early RRT group, renal function recovery was faster with shorter ICU stay compared with the delayed RRT group [The timing of RRT, early vs. late, after AKI has been studied in observational and prospective studies , 76. OveRT group . HoweverRT group , 81. MorRT group , 83. A sEvidence from large clinical trials on RRT suggests that the mean duration of treatment is 12–13 days. In clinical practice, daily assessment of both the intrinsic kidney function and the ongoing appropriateness of RRT are required. The recovery of native kidney function can be assessed during RRT by the serial measurement of serum creatinine as well as attention to urine output. Solute clearance of 25–35 mL/min during RRT will result in a stable serum creatinine after 48 h, and further reduction may imply some return of native function. As the renal tubular cells regenerate and re-establish a normal tubular membrane, glomerular filtration will resume and urine output will increase. Increased spontaneous urinary output > 400 mL/day has been described as a good predictor of successful discontinuation of RRT. Conversely, CKD was a strong negative predictor of successful discontinuation of RRT .AKI is prevalent in critically ill patients in ICU. The most common etiologies of AKI in these patients are due to fluid volume deficit or kidney hypoperfusion and ATN due to shock, inflammatory state, or nephrotoxic drugs. Early recognition of pathophysiology of AKI by careful review of patient’s history and hospital course and intravascular volume assessment complemented by urine biochemical analysis and urine microscopy should guide management strategy in order to reduce further progression of AKI and mortality.