Metabolic syndrome is a cluster of disorders that significantly influence the development and deterioration of numerous diseases. FibroScan is an ultrasound device that was recently shown to predict metabolic syndrome with moderate accuracy. However, previous research regarding prediction of metabolic syndrome in subjects examined with FibroScan has been mainly based on conventional statistical models. Alternatively, machine learning, whereby a computer algorithm learns from prior experience, has better predictive performance over conventional statistical modeling.We aimed to evaluate the accuracy of different decision tree machine learning algorithms to predict the state of metabolic syndrome in self-paid health examination subjects who were examined with FibroScan.Multivariate logistic regression was conducted for every known risk factor of metabolic syndrome. Principal components analysis was used to visualize the distribution of metabolic syndrome patients. We further applied various statistical machine learning techniques to visualize and investigate the pattern and relationship between metabolic syndrome and several risk variables.Obesity, serum glutamic-oxalocetic transaminase, serum glutamic pyruvic transaminase, controlled attenuation parameter score, and glycated hemoglobin emerged as significant risk factors in multivariate logistic regression. The area under the receiver operating characteristic curve values for classification and regression trees and for the random forest were 0.831 and 0.904, respectively.Machine learning technology facilitates the identification of metabolic syndrome in self-paid health examination subjects with high accuracy. Metabolic syndrome is a cluster of disorders, including insulin resistance or hyperglycemia, visceral adiposity (identified by a large waistline or overweight), atherogenic dyslipidemia , and endothelial dysfunction (characterized by elevated blood pressure) . MetabolA recent study showed that nonalcoholic fatty liver disease (NAFLD) is closely correlated to metabolic syndrome. Patients with metabolic syndrome frequently show an increase in fat accumulation in the liver (steatosis) and hepatic insulin resistance . NeverthMachine learning, whereby a computer algorithm learns from prior experience, was recently shown to have better performance over traditional statistical modeling approaches -22. VariThis was a single-center retrospective cohort study. The cohort comprised self-paid health examination subjects at the Health Management Center of Taipei Medical University Hospital who were examined with FibroScan from September 2015 to December 2018.The electronic healthcare records of subjects examined with FibroScan were reviewed at Taipei Medical University Hospital, which is a private, tertiary-care, 800-bed teaching hospital in Taiwan. The Institutional Review Board of Taipei Medical University Hospital approved the study design for data collection (TMU-JIRB No.: N201903080) in accordance with the original and amended Declaration of Helsinki. The requirement for informed consent was waived owing to the retrospective nature of the study.1c), serum glutamic oxaloacetic transaminase (GOT), serum glutamic pyruvic transaminase (GPT), uric acid, creatinine, blood urine nitrogen, red blood cell count, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, percentage of neutrophils, lymphocytes, monocytes, eosinophils and basophils, total protein, albumin, globulin, albumin/globulin ratio, total bilirubin, direct bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (γ-GT), total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, LDL/HDL ratio, triglycerides, fasting blood sugar, and thyroid-stimulating hormone. The estimated glomerular filtration rate (eGFR) was calculated using equations for the Modification of Diet in Renal Disease for Chinese patients [–1.234 × (Age)–0.179 × 0.79 . CKD was defined as an eGFR of <60 mL/min per 1.73 m2 of body surface (mL/min/1.73 m2), according to the definition from the Kidney Disease Outcomes Quality Initiative for CKD ≥ stage 3 [2; overweight, 24-26.9 kg/m2; and normal weight, <23.9 kg/m2, according to the ranges established for Asian populations by the Ministry of Health and Welfare of Taiwan [The study included all Taiwanese adult patients aged >18 years who had undergone a self-paid health examination comprising an abdominal transient elastography inspection using FibroScan 502 Touch . Individuals who underwent FibroScan examination on physician’s orders were excluded. The routine protocols of the Health Management Center were applied to all participants. The subjects were first interviewed by thoroughly trained personnel who verified the correctness of self-completed questionnaires on demographics, existing medical conditions, and medication use. In addition, the personnel confirmed adherence to health examination prerequisites  for the package chosen by the study participant. Those found to have not fulfilled the necessary prerequisites were advised to reschedule their appointment. Anthropometrics, including weight, height, waist circumference, and arterial pressure, were measured. Instruments were regularly calibrated per the manufacturer’s specifications. According to the chosen package, the required samples of blood, urine, and specimens were collected for laboratory tests. Regular laboratory test items included alpha-fetoprotein, glycated hemoglobin , high triglycerides (150 mg/dL) or use of medication to control triglycerides, reduced HDL levels (<50 mg/dL for women and <40 mg/dL for men) or use of medication to control HDL, elevated blood pressure (systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg) or use of relevant medication to control blood pressure, and increased fasting blood sugar (100 mg/dL) or use of relevant medication to control blood sugar. The classification of cutoff points was adopted from the National Cholesterol Education Program Adult Treatment Panel III definition consensus with ethnicity-specific cutoff points for waist circumference ,47 and aFibroScan is a noninvasive device that assesses the hardness of the liver using ultrasound-based elastography. Liver hardness is evaluated by measuring the velocity of a vibration wave, which is determined by measuring the time that the vibration wave takes to travel to a particular depth inside the liver from the skin . For eacA decision tree is a widely used effective nonparametric machine learning modeling technique for regression or classification purposes. To obtain solutions, a decision tree makes a sequential, hierarchical decision regarding outcome variables based on the predictor .Classification and regression trees (CART), the typical tree-based models, explore the structure of data, while evolving to visualize decision rules for predicting a categorical (classification tree) or continuous (regression tree) outcome . The decC5.0 is derived from C4.5 and ID3 with improvements according to the disadvantages of the predecessor trees. The “C50” package was applied to implement the C5.0 tree ,52.Chi-square automatic interaction detection (CHAID) is a specific decision tree using adjusted significance testing (Bonferroni testing) for prediction. An algorithm for recursive partitioning is implemented by maximizing the significance of a chi-square statistic for crosstabulations between the categorical dependent variable and the categorical predictors at each partition. Moreover, CHAID can create nonbinary trees since nominal, ordinal, and continuous data are used. CHAID tree is available from the “CHAID” package in R .Conditional inference trees (ctrees) embed tree-structured regression models into a well-defined theory of conditional inference procedures. They use a significance test procedure to select variables instead of selecting the variable that maximizes any information measure. In addition, ctree is applicable to all types of regression issues, including nominal, ordinal, numeric, censored, and multivariate response variables, as well as arbitrary measurement scales of covariates. A flexible and extensible computational tool in the “partykit” package of R is suitable for fitting and visualizing ctrees ,55.Evolutionary learning of globally optimal trees (evtree) describes recursive partitioning methods that create models using a forward stepwise search. An evtree is learned using an evolutionary algorithm. Notably, a set of trees is initialized with random split rules in the root nodes. Mutation and crossover operators are then applied to modify the tree’s structure and tests that are applied in the internal nodes. After each modification step, a survivor selection mechanism identifies the best candidate models for the next iteration, terminating when the quality of the best trees ceases to improve. The “evtree” package in R applies an evolutionary algorithm for learning globally optimal classification and regression trees .Generalized linear model trees (glmtree) involve model-based recursive partitioning based on generalized linear models. They are convenient for fitting model-based recursive partitions using “mob” functions in R. A glmtree internally sets up a model-fit function for mob using the negative log likelihood as the objective function. It is also implemented by the “partykit” package in R ,57.Random decision forests are an ensemble learning method for classification, regression or other applications based on decision tree structures at the time of training. The idea of random forest is to create multiple decision trees (CART) and then combine the output generated by each of the decision trees. In the decision tree algorithm, the Gini index is a measure of the frequency of a randomly chosen element from the set that would be incorrectly labeled. The Gini index is calculated by subtracting the sum of the squared probabilities of each class from 1. This approach removes the bias that a decision tree model might introduce to a system while considerably improving the predictive power. In addition, random forests can be used to rank the importance of variables in a regression or classification problem in a natural manner, which can be conducted in the R package “randomForest” .Statistical analysis was conducted using R  or SPSS  software.P<.05 was considered statistically significant [Categorical variables were tested using the chi-square test or Fisher exact test. The nonparametric Mann-Whitney U-test was applied to determine differences in the median of continuous variables between the two groups. Multivariate logistic regression was employed to assess the significance of clinical data, and the variance inflation factor was also used to check for multicollinearity. nificant ,60.High-dimension data were processed by principal components analysis (PCA), using an orthogonal transformation to convert a set of observations of correlated variables to provide a two-dimensional or three-dimensional visualization with its leading principal components.ROC curves were used to illustrate the diagnostic ability of classification trees in the machine learning methodology. The area under the ROC curve (AUC), true positive rate , and false positive rate (specificity) are represented in a graphical plot . The F1 Data with missing values were statistically regulated by the expectation-maximization algorithm, which is an iterative procedure that preserves the relationship with other variables. Only 9 factors had missing values, and most of them accounted for less than 5% of the sample size. Direct bilirubin, which had the largest proportion of missing values , was at high risk of multicollinearity; thus, it was not a crucial element in the model .To compare the performance of the aforementioned decision trees, the same setting for the training set and testing set was considered. In addition, the boundary for each tree’s height was limited between 4 and 5 instead of pruning each decision tree according to its own criteria. Finally, outcomes from each decision tree were summarized to investigate common and reliable results supporting the conclusions.P value problems had to be considered owing to the numerous and complex data in this analysis [After data cleaning, a total of 1333 individuals undergoing self-paid annual health examination were enrolled in this study. The baseline characteristics of the 193 patients diagnosed with metabolic syndrome and 1140 participants without metabolic syndrome are compared in analysis . The forThe visualization of the two groups was achieved by PCA with the advantage of dimensionality reduction . All fac1c. Among these, HbA1c was obtained from blood tests, whereas information on obesity and the CAP score was obtained through noninvasive means. Notably, obesity and HbA1c exhibited high odds ratios, exceeding 2. In addition, the variance inflation factor was taken into account for multicollinearity.Next, we applied multivariate logistic regression to assess factors influencing metabolic syndrome. As shown in 1c were found to be important predictive variables in the decision trees. Moreover, important variables appearing in each node of the decision trees were recorded 100 times  that may further improve the prediction of metabolic syndrome .1c emerged as important predictive variables. More research is required to validate the CAP score as a standalone test method to screen for metabolic syndrome, and to determine whether a minimum set of nonblood tests variables can be combined with the CAP score to improve the accuracy of predicting metabolic syndrome.To the best of our knowledge, this is the first study to apply machine learning algorithms to identify metabolic syndrome in subjects examined with FibroScan. We found that decision tree learning algorithms identified metabolic syndrome in self-paid health examination subjects with high accuracy, and obesity, serum GOT, serum GPT, CAP score, and HbA


Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease.2), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD.1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index , estimated glomerular filtration rate . Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP.Among 1178 patients , 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73mAmbulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.The online version contains supplementary material available at 10.1186/s12882-020-02200-1. Chronic kidney disease (CKD) is a worldwide public health problem . In thesAmbulatory blood pressure monitoring (ABPM) could provide detailed information on BP over a 24 h period, and it is unanimously recommended by guidelines for BP management –7. PreviHowever, CKD patients with different etiologies, like primary glomerular disease and diabetic kidney disease, were enrolled in prior studies at the same time. Primary glomerular disease and diabetic kidney disease were two main causes of CKD in many countries. In previous studies, the percentage of patients with diabetic kidney disease or diabetes mellitus at enrollment was 11–65% –15. CompThe study protocol was approved by the ethics committee of our hospital and adhered to the Declaration of Helsinki. Informed consent was obtained from each participant. Patients (14–75 years) with primary glomerular disease proved by renal biopsy or clinic findings after exclusion of secondary renal damage factors, were included. Patients were excluded from the study in case of: 1) diabetes mellitus; 2) acute changes in the eGFR > 30% in the previous 3 months; 3) maintenance dialysis or history of kidney transplantation; 4) cardiovascular disorders ; 5) pregnancy; 6) night work or shift-work employment; 6) intolerance to ABPM or invalid ABPM data; 7) inability to communicate and comply with all of the study requirements; Finally, a total of 1178 patients from our hospitals were enrolled in this study , end-diastolic left ventricular internal dimension (LVIDd), and posterior wall thickness (PWTd) were obtained from M-mode tracings, using 2-dimensional echocardiography. LVM was calculated using the Duvereux method . The lefConcentrations of serum creatinine (Scr) were measured by an enzymatic method traceable to isotope dilution mass spectrometry. The estimated Glomerular Filtration Rate (eGFR) was calculated using 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation . AwakingCarotid intima-media thickness (cIMT) was determined by averaging 3 measurements taken on each carotid artery , measuring the distance between the leading edge of the lumen–intima interface, and the leading edge of the collagenous upper layer of the adventitia using high-resolution B mode ultrasonography. Measurements were taken in areas free of obvious atherosclerotic plaques around the level of the carotid bifurcation.Information including age, sex, height, weight, smoking and alcohol consumption status, antihypertensive medication were obtained at the time of the BP measurement. Laboratory data  were obtained at the initial study visit. Blood samples were taken in the morning and analyzed using a 7180 Biochemistry Autoanalyzer  with reagents from Roche Diagnostics .2; 3) Urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g; 4) cIMT ≥0.9 mm or existence of carotid plaque in ultrasonography.CKD was divided into 5 stages and defined as the presence of kidney damage or decreased renal function (eGFR < 60 mL/min per 1.73 m2) for ≥3 months according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guideline. Clinic hypertension was defined as clinic blood pressure (BP) ≥140/ 90 mmHg and ambulatory blood pressure (ABP) was defined as 24-h BP ≥130/80 mmHg. Masked hypertension was defined as a normal clinic BP (≤140/90 mmHg) and an elevated ABP (> 130/80 mmHg). White coat hypertension was regarded as increased clinic BP (> 140/90 mmHg) and normal ABP (≤130/80 mmHg). Normotension was defined as both clinic BP < 140/ 90 mmHg and ABP < 130/80 mmHg; Sustained hypertension was regarded as clinic BP ≥140/90 mmHg and ABP ≥130/80 mmHg. Nighttime hypertension was defined as nighttime systolic BP (SBP) ≥120 mmHg or/and diastolic BP (DBP) ≥70 mmHg. Isolated nighttime hypertension was defined as daytime BP < 135/85 mmHg and nighttime BP ≥120/70 mmHg. Participants with a reduction in SBP of ≥10% at night-time compared with daytime were considered to have a “dipper” pattern, and an “extreme dipper pattern” referred to a > 20% reduction at nighttime. A “non-dipper” pattern referred to a < 10% reduction at nighttime and a “reversed dipper pattern” referred to higher SBP at nighttime compared with daytime. Target organ damage (TOD) was defined if it met any of four conditions : 1) left2, ACR ≥ 30 mg/g, cIMT≥0.9 mm or carotid plaque), we generated and compared receiver operating characteristic (ROC) curves, including area under the curve (AUC) and their 95% CIs. Considering each TOD may be affected by other important factors, and clinic and ambulatory SBP may have different prognostic value, we established 12 multivariate adjusted logistic regression models in all. All these models in sequence could be divided to four parts according to the TOD categories. Model 1–3, 4–6, 7–9 and 10–12 corresponded with LVH, eGFR< 60 ml/min per 1.73 m2, ACR ≥ 30 mg/g, cIMT≥0.9 mm or carotid plaque, respectively. Model 1 included adjustment for age, sex, BMI, smoking, alcohol consumption status, hemoglobin. Albumin, eGFR, number of BP medications and type of glomerular disease. Model 4 included adjustment for age, sex, BMI, smoking, alcohol consumption status. Hemoglobin. albumin, ACR, iPTH, uric acid, calcium* phosphate product, number of BP medications and type of glomerular disease. Model 7 included adjustment for age, sex, BMI, smoking, alcohol consumption status, hemoglobin, albumin, uric acid, number of BP medications and type of glomerular disease. Model 10 included adjustment for age, sex, BMI, smoking, alcohol consumption status, eGFR, LDL-C, statin use, number of BP medications and type of glomerular disease. Model 2,5,8,11 included adjustment for the variables in Model 1,4,7,10 respectively and additional adjustment for clinic SBP when examining 24 h/daytime/nighttime SBP as the independent variable. Model 3,6,9,12 included adjustment for the variables in Model 1,4,7,10 respectively and additional adjustment for nighttime SBP when examining clinic SBP as the independent variable. Odds ratios of clinic SBP, 24-h SBP, daytime SBP and nighttime SBP, were shown per 1 SD increase separately, so as to make them comparable. Probability values were 2-tailed and P < 0.05 was considered statistically significant for all comparisons.Statistical analysis was performed with SPSS 25.0  and Medcalc 18.9. Descriptive statistics were mean ± SD for continuous variables or median (25-75th interquartile range) for non-normality variables. Frequency and percentage were used for categorical variables. To analyze the sensitivity and specificity of different BP indexes in relationship to TOD  had renal biopsy reports. The number of patients with IgA nephropathy, mesangial proliferative glomerulonephritis (MsPGN), minimal change disease (MCD), membranous nephropathy (MN); focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) was 354, 17, 38, 162, 36 and 9, respectively; 18.5% of patients were current smokers, and101 patients (8.6%) consumed alcohol. The prevalence of LVH, eGFR< 60 ml/min/1.73mThe prevalence of nighttime hypertension in these patients was 62.2%, while 272 patients 23.1%) had isolated nighttime hypertension. A total of 609 (51.7%) patients had non dipper pattern and 197 (16.7%) patients had reversed dipper pattern, while only 341 (28.9%) patients had a dipper pattern. 129(10.9%) of patients had white-coat hypertension and 175 (14.9%) had masked hypertension.  were 0.779, 0.770, 0.760, 0.721 for nighttime SBP, 24 h SBP, daytime SBP and clinic SBP respectively. What’s more, nighttime and 24 h SBP ROC curves had greater AUC compared with clinic SBP in detecting the association with LVH (P < 0.05).2, AUC were 0.756, 0.762, 0.756, 0.725 for nighttime SBP, 24 h SBP, daytime SBP and clinic SBP respectively, and statistical analysis showed daytime, nighttime and 24 h SBP had great AUC compared with clinic SBP in detecting the association with eGFR< 60 ml/min/1.73m2 (P < 0.05).When detecting the association with eGFR< 60 ml/min/1.73mWhen considering ACR ≥ 30 mg/g, AUC were 0.671, 0.654, 0.647, 0.629 for nighttime SBP, 24 h SBP, daytime SBP and clinic SBP respectively, and only nighttime SBP had great AUC compared with clinic SBP in detecting the association with ACR ≥ 30 mg/g by statistical analysis(P < 0.05)..Finally, when detecting the association with cIMT≥0.9 mm or plaque, AUC were 0.680, 0.681, 0.676, 0.694 for nighttime SBP, 24 h SBP, daytime SBP and clinic SBP respectively, and statistical analysis did not show any difference between ambulatory SBP and clinic SBP in detecting the association with cIMT≥0.9 mm or plaque. Fig. .Fig. 2s2, and ACR ≥ 30 mg/g (P < 0.05). 24 h SBP, daytime SBP and nighttime SBP were still significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g (P < 0.05) after adjustment by clinic SBP. However, the association of clinic SBP with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g (P < 0.05) was attenuated after further adjustment for nighttime SBP . With respect to cIMT≥0.9 mm or plaque, ambulatory SBP or clinic SBP was not significant in multivariate adjusted models with clinic and 24 h/daytime/nighttime SBP included. (Table .Multivariate logistic regression analyses were carried out to clarify factors associated with target-organ damage. Higher clinic and ambulatory BPs were significantly associated with higher prevalence of LVH, eGFR< 60 ml/min/1.73mIn this cross section study, we explore and compare associations of different BP indexes with TOD in CKD patients with primary glomerular disease. We found that ambulatory SBP, especially nighttime SBP, was better associated with TOD than clinic SBP. What’s more, higher 24 h, daytime and nighttime SBP were significantly associated with TOD in these patients even adjusted clinic SBP in multivariate logistic regression analyses. All these data suggested that ABPM is superior to clinic blood pressure in estimating TOD in patients with primary glomerular disease, and we should pay special attention to the use of ABPM in these patients in clinical practice.,. However, all these data were from CKD patients with different causes. CKD patients mixed with different etiologies like primary glomerular disease and diabetic kidney disease, were all included in these studies. Many factors such as glucose, inflammatory, salt intake would affect blood pressure status, so studies enrolled more diabetic patients would draw different conclusion compared with studies enrolled fewer diabetic patients. In previous studies, percentage of patients with diabetic kidney disease or diabetes mellitus at enrollment is up to 65% [Over the past years, ABPM developed into the recommended technique for BP measurement, risk stratification and classification of hypertension , 25. Comp to 65% –16. As tPrimary glomerular disease is still predominant in hospitalized rural patients in China . Data ofThe current study strengthened the notion that ABPM, especially nighttime BP carries valuable prognostic information in patients with primary kidney disease. These data confirmed the importance and superiority of ABPM in these patients. Future studies are required to ascertain whether individuals could benefit from BP-lowering interventions targeting the ambulatory monitory results and ultimately reduce cardiovascular events.Some limitations of our study deserve mention. Firstly, the size of the study population was not very large. Secondly, all enrolled CKD patients underwent only one ABPM and we could not rule out subsequent changes in ABPM. Thirdly, some patients with non-severe proteinuria or renal damage might have been excluded, leading to bias. Finally, we cannot infer a cause–effect relationship based on our cross-sectional data.In conclusion, we have provided the first evidence that in CKD patients with primary glomerular disease, 24 h, daytime, and nighttime SBP were better than clinic SBP and significantly associated with TOD, after adjustment for demographics and clinical characteristics. Thus, ABPM should be considered optimal and preferred measurement for estimating cardiovascular risk in these patients.Additional file 1: Supplementary Table 1. Mean blood pressure in each category of study population.


Congenital heart disease in children with pulmonary hypertension is a common and serious complication, which has a direct impact on the surgical effect and prognosis of children. Bosentan and vardenafil are commonly used drugs for the treatment of postoperative pulmonary hypertension in children with congenital heart disease, and there are few clinical studies on their combined use. Therefore, the purpose of this randomized controlled trial is to evaluate the effectiveness and safety of the combined use of 2 drugs in the treatment of postoperative pulmonary hypertension in children with congenital heart disease.This is a prospective randomized controlled trial to study the effectiveness and safety of bosentan combined with vardenafil in the treatment of postoperative pulmonary hypertension in children with congenital heart disease. Approved by the clinical research ethics committee of our hospital. The patients were randomly divided into 1 of 2 treatment regimens:1.bosentan combined with vardenafil oral group and2.vardenafil oral group.Patients, doctors, nurses, and data collection assistants were blinded to group allocation. Observation indicators include: oxyhemoglobin saturation (SpO2), 6-min Walking Test Distance (6 MWTD), systolic pulmonary artery pressure, mean pulmonary artery pressure, Borg score, NYHAFC score, etc. Data were analyzed using the statistical software package SPSS version 25.0 .This study will evaluate the effectiveness and safety of bosentan combined with vardenafil in the treatment of pulmonary hypertension after congenital heart disease in children. The results of this experiment will provide a clinical basis for the use of bosentan combined with vardenafil to treat pulmonary hypertension after congenital heart disease in children.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.DOI 10.17605/OSF.IO/962BT. The blood volume of the pulmonary circulation increases significantly, and the high flow puts the pulmonary blood vessels in a state of high pressure and high resistance, causing pulmonary arterial hypertension. Pulmonary hypertension is one of the common and serious complications of congenital heart disease in children. About 10% of children with congenital heart disease develop into PAH, which can occur at various stages in the evolution of congenital heart disease in children. The surgical effect and prognosis of patients have a direct impact, and the perioperative mortality rate of children with CHD and severe PAH is higher. Therefore, effectively reducing pulmonary hypertension is a key step to improve the surgical efficacy and quality of life of CHD patients.Congenital heart disease (CHD) refers to vascular or heart malformations caused by abnormal growth of cardiac blood vessels during the embryonic period. It is a common cardiovascular disease in pediatrics, Bosentan is a representative drug of endothelin receptor antagonists, which has the effects of reducing pulmonary vascular resistance, improving hemodynamic indicators, improving exercise tolerance, and improving the patient's survival rates.,6 Vardenafil is a highly selective inhibitor of phosphodiesterase-5 (PDE-5), which can selectively inhibit PDE-5 activity and reduce the degradation of cyclic guanosine monophosphate (cGMP). The latter can further activate protein kinase G, increase potassium ion channels, reduce calcium ion concentration, thereby reducing pulmonary artery pressure. At present, clinical studies have pointed out that the two-drug combination therapy can significantly improve the patient's exercise capacity, improve the patient's heart function and relieve the symptoms of dyspnea, but there are too few similar studies, and the sample size is not large, and it is difficult to draw reliable conclusions. Therefore, the purpose of this randomized controlled trial is to evaluate the effectiveness and safety of bosentan combined with vardenafil in the treatment of postoperative pulmonary hypertension in children with congenital heart disease.There are currently 3 types of targeted therapy drugs recommended, including endothelin receptor antagonists, prostaglandin i2, and phosphodiesterase 5 inhibitors (PDE-5 inhibitors).22.1This is a prospective randomized controlled trial to study the effectiveness and safety of bosentan combined with vardenafil in the treatment of postoperative pulmonary hypertension in children with congenital heart disease. We followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting randomized trials and provided a CONSORT flow diagram Fig.  and the 2.2This research program is in accordance with the Helsinki Declaration and approved by the Clinical Research Ethics Committee of our hospital. This protocol has been registered in open Science Framework (OSF) (Registration number: DOI 10.17605/OSF.IO/962BT). All patients need to sign a written informed consent before they are randomly assigned to continue the trial.2.3The calculation of the sample size is based on the results of the 6 MWTD. According to the results of the pre-test, the average score of the experimental group is estimated to be 495.47 and the standard deviation is 54.72. The control group averaged 456.33 and the standard deviation was 54.68. The sample size calculation formula is as followsAt the 5% significance level, a total of 34 patients are required for each group to achieve 90% power. The estimated withdrawal rate is 20%, and 42 patients will be included in each group.2.4Inclusion criteria:1. aged> 6 months and <16 years old;All patients meet the diagnostic criteria of congenital heart disease-pulmonary hypertension (CHD-PAH),2.There is a risk of reactive pulmonary hypertension or pulmonary hypertension at the end of the operation Phenomenon;3.postoperative pulmonary artery systolic pressure/systemic arterial systolic pressure (Pp/Ps) ≥0.3, no decrease within 1 week;4.patients with moderate or higher pulmonary hypertension found in postoperative follow-up;5.preoperative pulmonary vascular resistance index (PVRI) ≥4 persons.Exclusion criteria:1.Children with other types of pulmonary hypertension related to non-congenital heart disease;2.Patients with liver and kidney dysfunction;3.Patients with prolonged QT syndrome;4.Patients concurrently using antiarrhythmic drugs;5.Allergic to test drugs;6.Severe digestive system or blood system abnormalities;7.Unable to understand after explanation.The research protocol may be unwilling to participate.2.5Eligible participants were randomly assigned to the treatment group or control group at a ratio of 1:1 using a random tool based on the central network. Randomization was performed without any stratification using SAS 9.3 software  by independent statisticians who were not involved in the implementation of the experiment or statistical analysis. Randomization was performed without any stratification. The clinical research coordinator enters participant information on the tablet and is given a random number. The research assistant gets the participant's assignment from the computer. Throughout the research process, the research assistant is responsible for screening, recruiting participants, and assigning random numbers to the included participants. The result assessor is responsible for the assessment of the scale. All bed doctors, researchers, research assistants, participants, intervention supervisors, and statisticians who perform statistical analysis are unknowable in the grouping of personnel.The dispensation of medicines will be assigned to patients with corresponding numbers by unknowing nurses according to the medicine numbers.2.6Control group: Oral vardenafil hydrochloride tablets, 20 mg/time, 1 time/d;Treatment group: Oral bosentan tablets on the basis of the control group, according to the weight of the patient, weight <10 kg: 15.625 mg/time; weight: 10 to 20 kg: 31.25 mg/time; weight: 21 to 40 kg: 62.5 mg/time, 1 time/d.The treatment lasts for 6 months. During the treatment period, the patients will be followed up by outpatient or telephone in the first and third months of treatment to understand the symptoms and adverse reactions of the patients, and review the observation indicators at the sixth month.2.71.Oxyhemoglobin saturation SpO2, using GEM3000 blood gas analyzer to measure SpO2 before and after treatment in the 2 groups;2.(2) 6-min walking test distance (6 MWTD): For children who can cooperate with walking to walk back and forth in a quiet and airy 30-m corridor, measure the 6-min walking distance;3.The patient uses a SwanGanz floating catheter for right heart catheterization in a resting state to determine systolic pulmonary artery pressure, pulmonary artery pressure, and aortic pressure. Fick method is used to calculate mean pulmonary artery pressure, pulmonary circulation blood flow quantity/systemic circulation Blood flow quantity, pulmonary artery systolic pressure/systemic artery systolic pressure;4.The patient got 5 ml of fasting venous blood in the morning before and after treatment, and the brain natriuretic peptide was measured by enzyme-linked immunosorbent assay;5. , cardiac function classification (NYHAFC);Borg score6.Adverse reactions: including dizziness, headache, facial flushing, abnormal liver, and kidney function, etc.2.8One or 2 assistants will collect and record the entire data. Personal information about potential participants and registered participants will be collected, shared and stored in an independent storage room to protect confidentiality before, during and after the test. The access to the database will be restricted to the researchers in this study team.2.9P value of <.05 was considered statistically significant.Data were analyzed using the statistical software package SPSS version 25.0 . Continuous variables were described as the mean ± standard deviation, and differences between groups were analyzed using a series of one-way analysis of variance (ANOVA) with Bonferroni posthoc test, while differences between groups over time were analyzed using multiway ANOVA with Bonferroni posthoc test. Categorical variables were described as the number (%), and were analyzed by Fisher exact test. A 3 With continuous research on the pathogenesis of pulmonary hypertension, it has been found that vasoconstriction, cell proliferation, inflammation, fibrosis, and thrombosis are all related to pulmonary vascular remodeling, while thromboxane, exhaled nitric oxide (eNO), and endothelin-1 (ET-1) and prostaglandin and other vasoactive mediators play an important role in it.,13 Therefore, how to effectively reduce the patient's pulmonary vascular resistance and contain or reverse pulmonary vascular disease is of great significance for improving the survival rate of patients and improving the quality of life.Pulmonary hypertension is one of the common complications after congenital heart disease, and it is also an important risk factor for death from right heart failure. and can reduce lung and systemic vascular resistance, increase cardiac output without increasing heart rate. Vardenafil is another new PDE-5 inhibitor after sildenafil, which can significantly reduce arterial pressure (PA) and venous pressure at the same time. In addition to inhibiting PDE-5 and passing In addition to the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) dependent mechanism that causes pulmonary artery relaxation, it can also activate some mechanisms that do not depend on NO-cGMP: nitric oxide-cyclic guanosine monophosphate, that is, induce pulmonary vasodilation by inhibiting the entry of extracellular Ca2+.,18Endothelin (ET) is an active substance with the strongest vasoconstrictor effect. The main place for its production and removal is lung tissue, which is one of the important factors that cause pulmonary hypertension. Bosentan tablets are competitive antagonists of endothelin ETA and ETB receptors. They can compete to antagonize human vascular wall ET-1 receptors, inhibit vasoconstriction and promote cell proliferation,,19 in 2015 the European Society of Cardiology (ESC) pulmonary artery. The guidelines for the diagnosis and treatment of hypertension recommend starting oral drug combination therapy for patients with cardiac function class II to III. The combination therapy is becoming more and more important for the treatment of pulmonary hypertension after children with congenital heart disease. This study will be evaluated the effect of bosentan combined with vardena on the treatment of pulmonary hypertension after nonchildren's congenital heart disease.Some studies have pointed out that bosentan combined with vardenafil or sildenafil is better than monotherapy in the treatment of pulmonary hypertension after congenital heart disease in children,This study also has the following limitations: Since this is a singlecenter randomized controlled study, the included population may be regionalized, and the results may be biased; factors such as the age of the patients included in the study may have an impact on the results.Data curation: Chao Gao and Junting Liu.Investigation: Junting Liu and Runhan Zhang.Resources: Manting Zhao.Funding acquisition: Yongli Wu.Software: Runhan Zhang.Supervision: Yongli Wu.Writing – original draft: Chao Gao and Junting Liu.Writing – review & editing: Chao Gao and Yongli Wu.


To compare the inferior vena cava (IVC) indices, identify their variation rates at positive pressure values and accurate predictive values for the volume status in patients with spontaneous respiration receiving different positive pressure support.The study included 100 patients who were divided into 4 pressure support groups, according to the different pressure supports received, and 3 volume groups according to their CVP values. Ultrasonography was applied to all of the patients to define their IVC diameters at different pressure supports. Dynamic parameters were derived from the ultrasonographic assessment of the IVC diameter .There were significant differences between the 3 indices  according to the pressure groups . The median value for the dIVC percentages was ≤18% for all of the positive pressure support hypervolemic groups, apart from the hypervolemic t tube group (19%). For the hypervolemic groups, the best estimation according to the cut-off value appeared to be for the dIVC. Values with the highest sensitivity for differentiation of the hypovolemic individuals were calculated with the dIVC.The dIVC had a more accurate predictive role in predicting the volume status when compared with the CI-IVC and ΔIVC, and may be used reliably with positive pressure supports. For critical patients, determining the intravascular volume status and appropriate fluid management are the most important elements of early targeted treatment [1].There are many methods used to assess the intravascular volume and for successful fluid resuscitation. Among these monitoring methods, hemodynamic monitoring using ultrasonography (US) remains current due to properties like being noninvasive, ready-to-use, applicable at the bedside, being economic, and being available in most intensive care units [2].Central venous pressure (CVP) is used to identify the present fluid status and possible fluid requirements, but reliability is reduced due to the invasive nature of the procedure, linked complication risks, and low sensitivity and specificity. As an alternative to this method for assessment of the intravascular volume status among critical patients, the inferior vena cava collapsibility (CI-IVC), distensibility (dIVC), and delta (ΔIVC) indices on dynamic measurements of the IVC diameter have been encountered as more current and increasingly common measurements [3–5]. Measuring the volume status during triggered positive pressure support is necessary to reveal which IVC index is valid. Additionally, the number of studies comparing different positive pressure supports and positive end expiratory pressures (PS/PEEP), IVC indices, prediction of the volume status, and superiority of the indices are limited. This study, based on these debates about applications in the relevant literature, aimed to compare the IVC indexes, identify their variation rates at positive pressure values, and correlate with the CVP and accurate predictive values for the volume status of patients with spontaneous respiration receiving different positive pressure support.This study was approved by the institutional review board and ethics committee of the İzmir Tepecik Training and Research Hospital, Faculty of Medicine Sciences (No: 29/4 18/08/2016), and written informed consent was obtained from each patient’s next of kin. The clinical trial  registration number is NCT03452046.This prospective observational study was completed in the tertiary intensive care unit at the Tepecik Training and Research Hospital from September 2016 to February 2018. The study included 100 patients. Inclusion criteria for the study were as follows; patients who were >18 years, on a mechanical ventilator with a tidal volume of 6–8 mL/kg, and spontaneous respiration. The main exclusion criteria were as follows: patients who were <18 years, had high intraabdominal pressure findings, had severe right heart failure (tricuspid insufficiency), could not lie in a supine position, had severe tachypnea, whose present peripheral oxygen saturation (SpO2) was <88% without spontaneous respiration, had PS requirements of >16 mmHg and PEEP requirements of >10 mmHg, used high-dose vasopressors, were morbidly obese, and had no clear images obtained via US.US was applied to all of the patients in a supine position. IVC ultrasonographic measurements were completed with a Sonosite M-Turbo  2–6 mHz phased array probe, longitudinally from the subxiphoidal area, by determining the best localization for imaging, 3–4 cm distal of the IVC-right atrium junction or 2 cm caudal of the IVC-hepatic vein junction . First, the measurement location was identified with 2-D (B mode), and then the M-mode was used for time-motion recording of the IVC. All of the measurements were completed in M-mode, which was also used to capture a 10-s cine loop of the IVC over 2 or 3 respiratory cycles. During the respiratory cycle, the maximum IVC diameter (IVCmax) was measured as the maximum anterior-posterior dimension at the end-expiration and the minimum IVC diameter (IVCmin) was measured at the end-inspiration. The following were calculated: CI-IVC: [(IVCmax – IVCmin) / IVCmax] × 100), dIVC: [(IVCmax – IVCmin) / IVCmin] × 100, and ΔIVC: [(IVCmax – IVCmin) / IVCmedian] × 100). To ensure the interrater reliability, all of the IVC measurements were performed by a clinician with sufficient US education and experience . All of the recorded videos were investigated by an independent expert.After obtaining the location for clear images of the IVC measurement on the US and ensuring probe stabilization, the IVC diameters at different pressure supports were measured by the same clinician. The process of changing the pressure supports was completed by an intensive care doctor blind to the study. In the 5th min after the pressure change, the clinician performing the ultrasonography was allowed to measure, with pressure supports, and the ultrasonographic measurements were recorded by another independent researcher. The pressure support received by the patients was not reported to the clinician measuring the IVC on US to prevent bias during measurements. After the US measurements were complete, the data was combined. Patients were divided into 4 pressure support (PS) groups according to the different pressure supports received:1. PS 10 mmHg-PEEP 5 mmHg, 2. PS 0 mmHg-PEEP 5 mmHg 3. PS 10 mmHg-PEEP 0 mmHg.4. T tube (PS 0 mmHg-PEEP 0 mmHg)After each pressure setting, a wait time of 5 min was ensured to obtain optimal sonographic images and for hemodynamics to reach a stable state. Sonographic measurements were performed in the 5th min, after the stable state was reached,Immediately after obtaining the US images at each different pressure setting of the ventilator, an intensive care nurse blind to the study recorded the numerical values of the CVP wave forms in the distal lumen of the central venous catheter. For each CVP wave form measurement, the pressure transducer was set to zero in the midthoracic position. Simultaneous to each CVP measurement, the mean arterial pressure (MAP), heart rate (HR), and SpO2 values were recorded.The IVC index cut-off values were taken as a CI-IVC of >50%, dIVC of >18%, and ΔIVC of >12% for the hypovolemia. According to the CVP values, 3 volume groups were distinguished:1. <8 mmHg hypovolemic 2. 8–12 mmHg euvolemic 3. >13 mmHg hypervolemic Additionally, for a more detailed assessment of the variations in the CVP with the IVC index percentages, measurements at all positive pressure supports were combined, and from the obtained data , the patients were reclassified as:1. CVP; 0–4 mmHg 2. 5–9 mmHg 3. 10–14 mmHg 4. >15 mmHg Descriptive information for the participants in the study are presented as n (%), mean, standard deviation, median, minimum, and maximum values.To check the distribution of the data in the groups, parametric methods were used for the data with normal distribution, while nonparametric methods were used to analyze data with nonnormal distribution. For the dependent multiple group comparisons, the repeated measure ANOVA/Friedman test was used for repeated measurements, while the Dunn test was used for the 2-way comparisons. The receiver operating characteristic (ROC) curve analysis was used for the diagnostic cut-off values of indices, with the sensitivity and specificity values calculated. The CVP was taken as the gold standard, with the sensitivity and specificity values of the IVC indices assessed according to the CVP.When conducting the a priori power analysis, it was calculated such that for the 2-way analysis of variance on repetitive measurements, it was necessary to have a total of 176 measurements (44 measurement in each group), so as to have 80% power for detecting a size effect (f = 0.25) for the partial η2 = 0.06* at P = 0.5 , 1977).The study included 100 patients, and of those, 54% were male and 46% were female. The mean body mass index (BMI) for male patients was 26.06 ± 2.22, while for female patients it was 25.19 ± 25.79. Classification of the patients according to the BMI found that the majority were in the overweight (preobesity) group [6] (Table 1).When the CI-IVC, dIVC, and ΔIVC indices were investigated at different positive pressure supports (PS/PEEP), there were significant differences between the 3 indices according to the pressure groups  (P < 0.001) (Table 2) .Two-way comparisons of each CI-IVC, dIVC, and ΔIVC index, according to the positive pressure groups, identified significant differences (PS/PEEP) .There were significant differences between different pressure groups in terms of the CVP, SpO2, and HR (P < 0.001); however, there was no statistically significant difference between the groups in terms of the MAP (P = 0.07) (Table 2).When classification was made according to the CVP values , the group numbers were reorganized at each different positive pressure support (Table 3).When the differences between the volume groups were assessed for each IVC index within each positive pressure support (pressure support groups), significant differences were obtained between the medians within the 95% CIs (P < 0.001). Two-way comparisons between the volume groups and PS groups found statistically significant differences for each of the indices between the hypervolemic and hypovolemic groups (Table 3).The CI-IVC percentage was <50% in all of the volume and PS groups. In the hypervolemic groups, the median CI-IVC value was significantly low.The ΔIVC was >12% in all of the volume and PS groups. The median for the hypervolemic groups was significantly low compared to the medians for the hypovolemic and euvolemic groups.The median value for the dIVC percentages was ≤18% for all of the positive pressure support hypervolemic groups, apart from the hypervolemic t tube group (19%). For the hypervolemic groups, the best estimation according to the cut-off value appeared to be for the dIVC. The median for the hypervolemic groups was significantly low compared to the medians for the hypovolemic and euvolemic groups (Table 3).After the groups were reclassified according to the CVP values, as <4, 5–9, 10—14, and >15, the medians of the indices in the groups were compared. For each of the 3 indices, as the CVP values increased, the indices reduced. Although this numerical decrease was statistically significant in all 3 indices, while the indexes were examined when determining the volume status according to the cut-off values, according to the CVP of >15 group, the most accurate estimation was made from the dIVC index (<18%) (Table 4). For each index value at the same pressure, the correlation with the CVP values was assessed with high correlation analysis. For all of the pressure groups, the IVC indices had a strong inverse relationship with the CVP values (P < 0.001) (Table 5).Assessment of the index values evaluated the sensitivity and specificity values of the other indices using the CVP as the gold standard.According to the ROC analysis results, values with the highest sensitivity for the differentiation of the hypovolemic individuals were calculated with the dIVC (Table 6). In this study, the percentages of the 3 IVC indices varied significantly at each different positive pressure support and it appeared that the dIVC was more effective in the prediction of the volume status when compared to the CI-IVC and ΔIVC.Olsen et al. determined that positive pressure support in Trendelenburg and reverse Trendelenburg positions changed the CI-IVC, while in the supine position, there was no significant change, although there was a reducing trend observed with PS, PEEP, or a combination of both. This situation was reported to be due to the insufficient sample size  [4]. In the current study, all of the patients were assessed in the supine position, with variations observed in the max IVC, min IVC, and each IVC index at each different positive pressure support. The IVCmax and IVCmin diameters were determined with the highest at (PS/PEEP) 10/5 mmHg pressure support and the lowest was at t tube (0/0 mmHg). Specifically, in the 0/5 mmHg pressure support group, the IVCmax and IVCmin diameters were higher when compared to the 10/0 mmHg group, leading to the consideration that PEEP support had more effect on the IVC. The largest diameter was observed in the group with PS and PEEP support together. At each different pressure support, although there were significant variations in the IVC indices, the increase that occurred in the t tube group was more obvious. Campodonico et al. reported that increasing the PEEP from 0 to 10 or from 5 to 10 in patients with spontaneous respiration caused a significant reduction in CI-IVC values; however, increasing it from 0 to 5 mmHg did not cause a significant reduction [7]. We thought that the smaller effect on the CI-IVC values at low PEEP levels may have been due to the protocol used in the study. Measurement of the PEEP at 10 mmHg that was completed a short time after the measurements at PEEP 5 mmHg may have caused this. In this study, the measurements were performed after waiting for 5 min between each pressure change, after which hemodynamic stabilization was achieved. Herein, we identified a significant reduction for all of the IVC indices with PEEP and PS support. Stawicki et al., in a study on patients with and without mechanical ventilation support, could not find a statistically significant reduction in the CI-IVC with an increase in the PEEP and reported a significant increase in CVP levels [8].The results of studies investigating the correlation of the CVP with the sonographic measurements of the IVC diameter are contradictory. Many studies have stated a positive (IVC diameter) or negative (IVC index) correlation between the dynamic measurements of the IVC indices with US and CVP, and stated that it may be reliably used [9–12]. Many previous studies have included patients on mechanical ventilators with spontaneous respiration or deeply sedated. There are very few studies on the correlation between different positive pressure supports and IVC indices. Specifically, studies investigating the relationship between positive pressure ventilation and the dIVC and ΔIVC are very limited.Baumann et al., in studies researching the correlation between the CI-IVC and internal jugular vein, found a good correlation in patients with spontaneous respiration; however, they determined that there was no statistically significant correlation when positive pressure ventilation was applied [13]. In the current study, for all of the pressure support variables, there was a high negative correlation between the CI-IVC, dIVC, and ΔIVC with the CVP.Herein, researching the predictive role for the intravascular volume of the IVC indices compared with the CVP, although the CI-IVC values had a statistically significant reduction from hypovolemic group to hypervolemic group, the CI-IVC values were <50% at all of the pressure variables. The 50% cut-off value for the CI-IVC was observed to be insufficient to distinguish the hyper- and hypovolemic status of the patients. There have been many cut-off values defined for the CI-IVC as a marker of fluid responsiveness. Low CVP values (<7 mmHg) are considered to be a good marker of fluid responsiveness [14]. Nagdev et al. stated that a CI-IVC of ≥50% was strongly correlated with low CVP (<8 mmHg) [12]. Contrarily, our study found that the CI-IVC was <50% when the CVP was <8 mmHg. With regards to fluid responsiveness, Müller et al. reported an association with a CI-IVC of >40% , while Corl et al. reported an association with a CI-IVC of ≥25% . According to the hypothesis herein, although no cut-off value was determined according to the fluid response, for all of the pressure groups, no patient with a CI-IVC of < 25% was in the hypovolemia group. All of the patients who were euvolemic and/or hypervolemic had a CI-IVC of < 25%, which was in parallel with the study of Corl et al. According to the statistical analysis, when all of the pressure measurements were combined (100 patients and 4 different pressures for 400 measurements), among patients with a CVP ≥10, a CI-IVC of <25% was assessed as fluid unresponsive.Although there was a statistically significant reduction in the ΔIVC values from the hypovolemic group to the hypervolemic group, all of the pressure values of all of the patients, including the hypervolemic patients, had ΔIVC values of >12%. The ΔIVC cut-off value of 12% was insufficient to distinguish the hyper and hypovolemic status of the patients. According to the statistical analysis, when all of the pressure measurements were combined, in patients with a CVP of ≥10, a ΔIVC of >12% was unsuccessful in predicting fluid responsiveness.In this study, the dIVC values statistically significantly reduced from the hypovolemic group toward the hypervolemic group and as the CVP increased, the dIVC decreased. The 18% cut-off value for the dIVC was successful in distinguishing the hypervolemic patients. Although the t tube hypervolemic group had a value of 19%, for all of the other positive pressure supports, <18% successfully distinguished the hypervolemic patients. According to the statistical analysis, combining all of the pressure measurements, in patients with a CVP of 10–14, a dIVC of >18% was found (19.74), while for those with a CVP of ≥15, a dIVC of <18% was identified. As the dIVC value for patients with a CVP of 10–14 was close to the 18% cut-off value, it was accepted as successful in distinguishing hyper- and hypovolemia. There was no proximity to the cut-off values identified for the CI-IVC and ΔIVC values. In all of the CVP groups, a CI-IVC of >50% and ΔIVC of >12% were found, and was insufficient to distinguish the volume status according to the cut-off values. The large difference between the dIVC value for patients with a CVP of 5–9 (70.27) and for patients with a CVP of 10–14 (19.74) was noteworthy. This difference and the study results led us to the consideration that the cut-off value for the dIVC may be determined as higher than 18%. Achar et al., in a study of a pediatric population, determined that the dIVC cut-off value for responsive and non-responsive patients was 23.5%, and with the ΔIVC they determined it as 12.2% [5]. Duwat et al. stated that there was a gray zone for dIVC cut-off values (15%–30%) with sensitivity and specificity that was better for values below 15% and above 30% [17]. This topic may be clarified in the future by wider specific studies.The ideal index will accurately predict volume status, will be sensitive to fluid response, repeatable, easy, and non-invasive. Herein, sensitivity and specificity were calculated to find the index with the most accurate prediction of the intravascular volume status.For all of the positive pressure variables, the highest value for sensitivity to distinguish the hypovolemic individuals was for the dIVC.This study had several limitations. First, determination of the volume groups was made only according to the CVP values. Together with the CVP, there was no comparison of the IVC diameter measurements with dynamic preload indices like extravascular lung water, systolic pressure variation, and stroke volume variations. Second, due to the exclusion criteria, the whole intensive care unit population did not participate in the evaluation, with specific results obtained for a restricted population of patients. Third, the correlation of the IVC indices with fluid loading or passive leg raising was not investigated as, they were not part of the study hypothesis.In critical patients, we think that the dIVC has a more accurate predictive role in predicting volume status when compared with the CI-IVC and ΔIVC, and may be used reliably with positive pressure supports. Additionally, numerical values of the IVC indices are not sufficient to determine the intravascular volume status of critical patients, but should definitely be used with other monitoring methods, and clinical and hemodynamic assessments.


Platelet activation is an important side effect of dialysis, resulted in a subsequent release of arachidonic acid (AA) from activated platelets. AA is involved in many pathologic conditions, such as inflammation, asthma, cancer, diabetes, hypertension, and the pathogenesis of kidney disease. The aim of this study was to define whether the dialysis type affects the concentration of AA derivatives in patients with chronic kidney disease.117 patients were qualified to the study group. Based on the type of renal replacement therapy, patients were divided into the following groups: hemodialysis , peritoneal dialysis (PD), kidney transplant patients (TE - before/TE A – after transplantation) and conservative treatment (CT) . The control group consisted of 30 healthy volunteers (NK). The ELISA methods were used to measure the concentrations of TXB2, 5-HETE, 12-HETE, and 15-HETE in the blood serum.2 , 5-HETE  and 15-HETE . There was a significant relationship between the type of renal replacement therapy and the duration of dialysis, and the concentration of TXB2, 12-HETE acid, and 15-HETE.Renal replacement therapy significantly influences the concentration of TXBThe type of renal replacement therapy significantly affects the concentration of AA derivatives. Peritoneal dialysis is the best method of dialysis, taking into account the concentration of arachidonic acid derivatives. Chronic kidney disease (CKD) is one of the most frequently occurring diseases that affects 6–15% of the world’s population . ProgresConservative treatment is used in the initial stages of CKD, and dialysis or renal transplantation is necessary at the end-stage. One of the side effects of dialysis is the synthesis of pro-inflammatory factors and increased oxidative stress as a result of the blood contact with artificial materials of dialyzers and the creation of vascular access, which is necessary for dialysis. Consequences of this include transient leukopenia, activation of platelets and cells of the immune and complement systems, and an increase in interleukin-1 concentration .2) and nitric oxide to prevent adhesion and activation of platelets. During ischemia and reperfusion of organs undergoing transplantation, there is excessive adhesion of platelets and leukocytes, leading to inflammation and tissue damage. As a result, it can strongly stimulate the immune response, as well as cause an increase in organ alloreactivity [Platelets also play a crucial role during organ transplantation. Many cell-derived blood-borne factors regulate their activation, and to a large extent, depend on the pro-oxidative-antioxidant balance. Healthy endothelium synthesizes prostacyclin (PGIactivity .Arachidonic acid (AA) derivatives released from activated platelets are involved in many physical processes. Notably, they take part in the development of inflammation, asthma, cancer, diabetes, hypertension, and the pathogenesis of kidney diseases.2 rapidly degraded to an inactive but more stable form TXB2 [2 appears to be of minor importance in maintaining renal function under physiological conditions, increased TXA2 biosynthesis in the kidney was observed in various animal models of kidney disease. Unfortunately, one of the inherent and most important aspects of organ transplantation that occur in the transplanted organ is ischemia-reperfusion injury (I/R) [2 (TXB2) concentration. Inhibition of TXA2 synthesis during reperfusion significantly improves graft function in animal models of kidney transplantation [Activated platelets mainly synthesize thromboxane A2 (TXA2) in response to platelet aggregation and vasoconstriction. In solutions, unstable TXAorm TXB2 –9. Althory (I/R) . Severalantation , 12.The 5-, 12-, and 15- hydroxyeicosatetraenoic (HETE) acids are formed from arachidonic acid by the lipoxygenase pathway . 12-HETEKnowledge of the relationship between the type of renal replacement therapy used and the level of circulating arachidonic acid derivatives can be extremely important. It has been shown that during peritoneal dialysis, increased eicosanoids are synthesized by macrophages and peritoneal mesenchymal cells due to the properties of dialysis fluids, which are generally not biocompatible . Underst2EDTA)  and serum  were drawn from all study participants. Blood was drawn from hemodialysis patients via their arteriovenous fistula, and peripheral venipuncture was used for all other participants .The concentrations of TXBThe Schapiro Wilk test was used to evaluate data distributions, which in the case of some variables (5-HETE concentrations), showed a non-parametric distribution. The Exact Fisher and Chi-square tests were used to analyze quantitative data. A T-test and ANOVA were used for univariate systems, the differences between associated (paired) and unrelated (unpaired) (parametric distribution). The Kruskal-Wallis ANOVA was used to evaluate differences, as well as the U - Test for unpaired data or the Wilcoxon test for paired data (non-parametric distributions). A linear multiple regression model was used to determine the multifactor evaluation of relationships between the parameters studied. Statistical analysis of the results was carried out using Statistica PL 12 Trial (StatSoft) .The study involved 147 participants, including 117 patients qualified. Based on the type of renal replacement therapy used, patients were divided into the following groups: before (HD A) and after (HD B) hemodialysis , patients before (TE) and after (TE A) kidney transplantation (5–7 days after the surgery), and conservative treatment (CT) (CKD stages 2–5) . Patients recruited into the TE group did not simultaneously belong to the group of hemodialysis or peritoneal dialysis patients. The control group consisted of 30 healthy volunteers [2 and the studied groups     Table , and bet5) Table .p < 0.001) . There were also statistically significant differences between the concentration of the examined parameters, the type of renal replacement therapy, and the age of the patient (p < 0.001) (Table p = 0.003) , which, unfortunately is an inherent aspect of transplantation. The mechanism of I/R damage includes activation of the inflammatory response, formation of reactive oxygen species, and microcirculation disorders. In addition, several mediators such as TNF-α, endothelin, and arachidonic acid eicosanoid metabolites contribute to such mechanisms, including hydroxyeicosatetraenoic (HETE) acids and thromboxane [2 concentration. Inhibition of TXA2 synthesis during reperfusion significantly improves graft function in animal models of kidney transplantation [Activated platelets mainly synthesize thromboxane A2 in response to platelet aggregation and vasoconstriction. Thromboxane A2 is characterized by very short half-life (about 30 s). In aqueous solutions, TXAomboxane . Severalantation , 12.2 is synthesized by mesangial cells and podocytes. Decrease of renal blood flow to afferent and efferent arterioles caused by glomerulonephritis, cyclosporin overdose, or renal transplant rejection. As a consequence, there is a decrease in the number of mesangial cells, increase in the activity of the plasminogen activator inhibitor-1 (PAI-1), decrease in the activity of the tissue plasminogen activator (t -PA) and increase in the level of TGF-β. This leads to the deposition of fibrin and matrix proteins in the glomeruli and the mesangial matrix, which leads to worsening of renal failure [TXA failure , 19.2 and the groups studied. The lowest concentration of TXB2 was found in the control group and the highest in patients before renal transplantation. Statistically significant differences were also observed between the concentration of TXB2 in the TE and NK groups and TE A and NK. In patients after kidney transplantation, a not statistically significant decrease in thromboxane concentration was observed. There was no statistically significant difference between TXB2 concentration in patients before or after hemodialysis. On the other hand, there were significant differences between the concentration of thromboxane in hemodialysis patients and peritoneal dialysis, with a lower concentration of TBX2 in the PD group.In our study, a statistically significant relationship was found between the concentration of thromboxane B2 concentration and that thromboxane alone may be a marker of organ function. In addition, after kidney transplant patients were divided into three groups: early graft function (EGF), slow graft function (SGF), and delayed graft function (DGF), the authors showed that the concentration of thromboxane increased within the first 5 min after transplantation in each of these groups [2 concentration within a few days after kidney transplantation. Averna et al. (2001) showed that the administration of drugs that reduce or eliminate thromboxane-dependent activation of platelets in vivo might reduce the risk of cardiovascular events but may also prevent the long-term survival of patients with kidney transplantation [2 and TGF-β after kidney transplantation may be a sign of good prognosis for this group of patients. The relationship between the concentration of thromboxane and TGF-β is also confirmed by correlations obtained in our own studies. A positive correlation was found between the concentrations of thromboxane and TGF-β and platelet-derived growth factor-B (PDGF-B) in patients treated conservatively, as well as the positive correlation between PDGF-B and TXB2 concentrations after renal transplantation, and a strong positive correlation between the concentration of thromboxane and TGF-β in the control group. Orlińska et al. (1995) showed that both exogenous and endogenous transforming growth factor (TGF) regulates the production of thromboxane, And elevated levels of TGF-β lead to the increased production of TXB2 [In the literature, there are many reports on the concentration of thromboxane in patients with different types of renal replacement therapy. Dołęgowska et al. 2009) showed that kidney transplantation is associated with changes in TXBe groups . However09 showedantation , 19, tog of TXB2 .2 and TGF-β after transplantation is a good prognosis for these patients because no significant correlation was found between TXB2 and TGF-β after kidney transplantation. Stępniewska et al. (2019) observed a significantly lower concentration of thromboxane in hemodialysis patients than in peritoneal dialyzes patients and in those treated conservatively (stage 3–5). They also showed that the type of renal replacement therapy affects the concentration of arachidonic acid metabolites, and the concentrations of thromboxane Moreover, they showed that the levels of 20-HETE and 15-HETE acids can be indicators of kidney damage and possible cardiovascular diseases [The data also supports the hypothesis that a lower concentration of TXBdiseases . Zhao etdiseases .2, and so the excessive activation of platelets may lead to an increased release of TXB2.In other studies, however, the platelets of patients undergoing regular hemodialysis have been shown to be exposed to increased oxidative stress due to endothelial damage and carbohydrate and lipid metabolism disorders. They are activated excessively because their function is weakened due to ineffective antioxidant activity , 23. PlaIn our own studies, thromboxane concentrations were low in the PD group and significantly higher in the groups before and after hemodialysis, as well as in patients treated conservatively. This may support the thesis that platelets are excessively activated during hemodialysis and that these patients are more exposed to oxidative stress than PD patients.The 5-, 12-, and 15-HETE acids are formed from arachidonic acid on the lipoxygenase pathway . The relAccording to the latest research, HETE acids can have a strong influence on the intensity of the inflammatory process. For example, the levels of 12-HETE, 15-HETE stimulate the overexpression of pro-inflammatory genes in macrophages, while the levels of 5-HETE promote the production of T cells. Moreover, 12-HETE together with 15-HETE induces the synthesis of TGF-β1 in mesangial cells, where it stimulates the synthesis of proteins of the extracellular matrix, thus leading to renal fibrosis. Due to the very short half-life of HETE acids and its unstable nature, the activities of HETE acids only occur in an autocrine or paracrine manner –28.AA lipoxygenase derivatives are also involved in the regulation of blood pressure. Increased urinary excretion of 12-HETE was found in patients with essential arterial hypertension . HETE acWang et al.  have shoStępniewska et al. (2017) did not demonstrate a relationship between the concentration of 5- and 15-HETE acids and the type of renal replacement therapy used . In the Dołęgowska et al. (2010) showed significant perioperative changes in the metabolism of AA derivatives arising in the LOX pathway, expressed as changes in 5-, 12- and 15-HETE concentrations, accompany kidney transplants in humans. These changes relate to early renal function after transplantation (EGF). Moreover, concentrations of 5-, 12- and 15-HETE decreased in the first 5 min after transplantation in the EGF and DGF groups with the exception of the SGF group . HETE acIn our study, there was a significant relationship between 5-HETE concentration before and after kidney transplantation and the control group. The concentration of 5-HETE was highest in the control group and lowest after kidney transplantation. There was also a significant difference between 15-HETE concentration before and after kidney transplantation, with an increase in the concentration of 15-HETE acid after kidney transplantation. There was no relationship between serum 12-HETE concentrations between the groups. However, a significantly lower concentration of 12-HETE acid after renal transplantation was demonstrated compared to the control group and patients treated conservatively. Considering the results obtained by other scientists, and taking into account the high importance of these acids in the body’s inflammatory response, an increase in the concentration of HETE acids after transplantation may indicate poor functioning of a transplanted kidney.Based on our results, it is difficult to state clearly whether the concentration of HETE acids can indicate the possibility of graft rejection or not, due to the increase in 15-HETE acid concentration and decrease in 5-HETE acid concentration after kidney transplantation, and the lower concentration of 12-HETE compared, for example, compared with patients treated conservatively or the control group. Long-term observation of patients after kidney transplantation would be necessary to fully understand the importance of HETE acids in predicting graft rejection.It should also be pointed out that eicosanoids are mediators of inflammation, and can also influence the metabolism of fibroblasts in wound healing processes and the reorganization of connective tissue . The cre2 and 15-HETE acid. In the case of 12-HETE acid, its highest concentration occurred in patients before kidney transplantation, who, on average, had the most prolonged duration of dialysis. Also, based on a multivariate regression analysis, it was found that parameters such as the type of renal replacement therapy, age of patients, duration of dialysis, cause, and stage of CKD affected thromboxane concentration in 37%. The type of renal replacement therapy (p = 0.042) and dialysis duration (p = 0.004) both had a significant effect on the concentration of thromboxane.The present study describes the relationship between the thromboxane, 12-HETE, and 15-HETE concentration and the duration of dialysis and the type of therapy used. It has been shown that the longer the dialysis takes, the lower concentration of TXBThe results obtained in this study do not confirm those obtained by other scientists, except the concentration of 12-HETE, which indicates increased activation of platelets in patients undergoing long-term dialysis. Because increased production of thromboxane leads to the deposition of fibrin and matrix proteins in the glomeruli and mesangium, and subsequently leads to the worsening of renal failure , 19, a lThere are no reports on the dependence of 5-HETE on the subject of chronic disease and the stage of chronic kidney disease. It has been shown, however, that supplementation with polyunsaturated fatty acids (PUFA) over 8 weeks results in a decrease in the pro-inflammatory leukotriene-B4 (LTB4) and 5-HETE, and increases the synthesis of less inflammatory leukotriene, LTB5 and 5-hydroperoxyeicosatetraenoic (5-HPETE) in patients with CKD stages 2–5 . In our The type of renal replacement therapy used significantly affects the level of arachidonic acid derivatives . Apart from the type of therapy used in CKD patients, the factors significantly affecting the release of arachidonic acid derivatives were the age of patients, the duration of dialysis, the cause of CKD, and the stage of its advancement. Considering the concentration of arachidonic acid derivatives, peritoneal dialysis is the best method of dialysis. Concentrations of arachidonic acid derivatives in patients with CKD may be helpful in the selection of appropriate renal replacement therapy, prognosis of patients after kidney transplantation or long-term dialysis.


The same risk is 3.8 times greater for men than women (p = .01). Among subjects with SBP < 120 mmHg, men have an SBP 5.22 mmHg higher than women (p < .001). The increase in the age of 1 year is significantly correlated with a rise of 36% of having a DBP ≥ 85 mmHg (p = .0001). Also, in men population, the age increase of 1 year is associated with a rise of 41% of having a DBP ≥ 85 mmHg (p = .0001). Among young black African students aged between 18 and 30 years in Côte d’Ivoire, SBP is positively associated with male gender, age, and BMI. For DBP, it is only an increase with age.In Africa, abnormal high blood pressure is common and affects young subjects. The risk of organ damage and mortality increases with blood pressure level. Therefore, the purpose of this study was to assess the blood pressure profile of a black African population aged between 18 and 30 years in Côte d’Ivoire. Five hundred fifty‐one healthy black African students, men and women, with sedentary lifestyle, aged between 18 and 30 years were selected. Systolic (SBP) and diastolic (DBP) blood pressures and heart rate were recorded after 5 min of rest. Regression models were used to estimate the effects of age, gender, and body mass index (BMI) on SBP and DBP. Each increase of 1 year in age and 1 kg/m Among young black African students, the increase in age is significantly associated with higher systolic and diastolic blood pressures. The risk of having higher systolic blood pressure is greater for men than women. In 2015, it affected 1.13 billion people worldwide NCD, . AccordiIn Africa, this abnormal high blood pressure has specific features. It is the leading cause of cardiovascular diseases, ahead of smoking, diabetes, and dyslipidemia Steyn, . It is mThe prevalence of abnormal high blood pressure increases with age  and complied with the guidelines set by the Declaration of Helsinki. All patients were informed about the purpose and procedures of the study and gave their written consent.2.2The study population consisted of student volunteers from the Félix Houphouët‐Boigny University in Abidjan, Côte d'Ivoire. They were selected from October 2004 to August 2019. Among 728 volunteers, 551 (391 men and 160 women) were selected using inclusion and exclusion criteria through a questionnaire. They were all black Africans, aged between 18 and 30 years old and had a sedentary lifestyle. They did not take any medication, alcohol, coffee nor tea. We excluded subjects with known cardiovascular risk factors  and with signs, symptoms or history of cardiovascular, respiratory, and hematological diseases, which define them as healthy subjects in this study. Files with missing information were not retained. Women did not have any episodes of amenorrhea for at least 3 months. They were included regardless of their menstrual cycle phases. A previous study conducted in this black African women population found no significant difference in systolic blood pressure between phases of the menstrual cycle. Moreover, regardless of their menstrual cycle phases, all women had diastolic blood pressure below 80 mmHg . On the test day, major stress, medical signs, and possible medication intake were searched. Body weight was assessed to the nearest 0.5 kg using an electronic scale. The patients were lightly dressed, with no belt on, no shoes, and empty pockets when body weight was measured. Height was recorded to the nearest 0.5 cm for each patient, using a vertical scale. Measurements of systolic (SBP) and diastolic (DBP) blood pressures and heart rate were taken using an electronic blood pressure monitor  with a cuff fixed on the non‐dominant arm. These parameters were recorded after 5 min of rest, in a seated position with back and arms supported, in a quiet and semi‐illuminated air‐conditioned room at 22°C.2.4The overall women and men populations were divided into four (4) groups according to the level of systolic and diastolic blood pressures based on the European Society of Cardiology (ESC) classification of blood pressure . After adjusting for gender and age, the increase in the BMI of 1 kg/m2 is significantly correlated with the risk of having an SBP ≥ 130 mmHg, . Compare to women, men have 3.8 times higher risk of having an SBP ≥ 130 mmHg, after stratifying by age and BMI .After controlling gender and BMI, the increase in the age of 1 year significantly increases by 20% the risk of having an SBP ≥ 130 mmHg  and SBP (p < .0001) compare to women. When controlling variables’ effects in linear regression, we noticed that only gender and BMI have a significant effect on SBP variation in this group. Indeed, with similar age and BMI, men have a 5.22 mmHg higher SBP than women . After adjusting for age and gender, each 1 kg/m2 increase in BMI leads to 0.42 mmHg increase in SBP .Among subjects with SBP <120 mmHg . Gender and BMI have no significant influence on DBP variation.Because of the fewer sample size observed in some DBP groups Table , DBP is p = .0001). BMI has no significant influence on DBP variations.In men population, age distribution is found significantly different between DBP groups Table . After cIn women population, no difference is observed between DBP groups Table .3.4Results show that in the overall population, subjects with a family history of abnormal high blood pressure have a significantly higher DBP than those with no abnormal high blood pressure in family history. This significant difference is also found in men population but not in women population Table .4Therefore, the purpose of this study was to determine the blood pressure profile according to age and anthropometric parameters in healthy young black African students aged between 18 and 30 years, living in Côte d’Ivoire, West Africa.4.1Taking into account the genetic and environmental aspects of populations, our results can not be extrapolated to black Africans in general. Further studies are needed to compare black Africans of several countries.The classification of SBP and DBP, each into four groups, significantly reduces the number of subjects in a certain group without possible statistical testing.4.2In the overall population, higher SBP (≥130 mmHg) was positively associated with age, BMI, and male gender. In SBP range <120 mmHg, SBP was significantly correlated with BMI and male gender.Systolic blood pressure (SBP) is determined by cardiac output, vascular resistance of large arterial trunks, and peripheral reflection waves Asmar, . Over th2 increase in BMI was associated with an 11% increase in the prevalence of abnormal high blood pressure (p = .013). Also, Yano et al. (p < .001). For Hosseini et al. . Similarly, Choukem and al  and was significantly higher in men than in women . DBP is dependent on peripheral arterial resistances, duration of diastole, and little on the wall condition of large arterial trunks  and was similar between men and women. DBP was positively correlated with age. This DBP/age relationship has been observed in men population. Moreover, men had a significant increase of DBP when having an abnormal high blood pressure family history. However, in women, this DBP/age relationship was not observed. In line with our results, Choukem and al . The relevance of adiposity to blood pressure varies between populations (Gnatiuc et al., In our study, DBP was not associated with BMI. For Whitlock and al, (Whitlock et al., 5In this population of young black African students of Côte d’Ivoire aged between 18 and 30 years, systolic blood pressure is positively associated with male gender, age, and body mass index. Whereas diastolic blood pressure is correlated only with age. These results strengthen the need to develop preventive measures against high blood pressure in Côte d’Ivoire from the age of 18.The authors have no conflicts of interest.Edwige Siransy‐Balayssac: Conception of the work, Analysis, and interpretation of data for the work, Drafting of the work, Approved the final version of the manuscript Agree to be accountable for all aspects of the work; Soualiho Ouattara: Analysis, and interpretation of data for the work, Drafting of the work, Approved the final version of the manuscript, Agree to be accountable for all aspects of the work; Téniloh Augustin Yéo: Conception of the work, Acquisition, and analysis of data for the work, Drafting of the work, Approved the final version of the manuscript, Agree to be accountable for all aspects of the work; Aya Liliane Kondo: Acquisition of data for the work, Drafting of the work, Approved the final version of the manuscript, Agree to be accountable for all aspects of the work; Massiré Touré: Acquisition, analysis, and interpretation of data for the work, Drafting of the work, Approved the final version of the manuscript, Agree to be accountable for all aspects of the work; Cyrille Serges Dah: Conception of the work, Revising it critically for important intellectual content, Drafting of the work, Approved the final version of the manuscript, Agree to be accountable for all aspects of the work.