Background: Ventricular septal defect is a common congenital heart disease. As the disease progresses, the likelihood of lung infection and heart failure increases, leading to prolonged hospital stays and an increased likelihood of complications such as nosocomial infections. We aimed to develop a nomogram for predicting hospital stays over 14 days in pediatric patients with ventricular septal defect and to evaluate the predictive power of the nomogram. We hope that nomogram can provide clinicians with more information to identify high-risk groups as soon as possible and give early treatment to reduce hospital stay and complications.Methods: The population of this study was pediatric patients with ventricular septal defect, and data were obtained from the Pediatric Intensive Care Database. The resulting event was a hospital stay longer than 14 days. Variables with a variance inflation factor (VIF) greater than 5 were excluded. Variables were selected using the least absolute shrinkage and selection operator (Lasso), and the selected variables were incorporated into logistic regression to construct a nomogram. The performance of the nomogram was assessed by using the area under the receiver operating characteristic curve (AUC), Decision Curve Analysis (DCA) and calibration curve. Finally, the importance of variables in the model is calculated based on the XGboost method.Results: A total of 705 patients with ventricular septal defect were included in the study. After screening with VIF and Lasso, the variables finally included in the statistical analysis include: Brain Natriuretic Peptide, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate. The AUC values of nomogram in the training cohort and validation cohort were 0.812 and 0.736, respectively. The results of the calibration curve and DCA also indicated that the nomogram had good performance and good clinical application value.Conclusion: The nomogram established by BNP, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate has good predictive performance and clinical applicability. The nomogram can effectively identify specific populations at risk for adverse outcomes. Ventricular septal defect (VSD) is the most common form of congenital heart disease, accounting for approximately 40% of congenital heart disease cases . VSD leaOccurrence of infection may be a risk factor for prolonged hospital stay in patients with VSD. Extended hospital stays may further increase the likelihood of nosocomial infections. Pulmonary infection may cause pulmonary interstitial edema, resulting in decreased pulmonary ventilation and hypoxemia, which ultimately leads to rapid breathing. The infection diagnoses of some cases are not clear, making it difficult to determine whether a hospital stay was prolonged. However, the respiratory rate (Rr) is an easy metric to monitor and its measurement accuracy is high, and hence it may have predictive value for the length of hospital stay. A study found that a higher respiratory rate on admission was associated with an increased risk of in-hospital mortality in patients admitted from nursing homes . We therThis is a single center retrospective study. Data for the study were extracted from the Paediatric Intensive Care (PIC) database. This is a large, single-center, pediatric-specific database that includes the clinical data of all patients admitted to different ICUs at the Children’s Hospital Zhejiang University School of Medicine during 2010–2018, and includes the admission information of 13,499 cases from among 12,881 different pediatric patients . The datAll of the included patients had been diagnosed with a ventricular septal defect.We used Structured Query Language to extract metrics within 24 h of admission from the PIC database. These included the basic information, vital signs, and laboratory test indicators of the patients. Basic information included sex, marital status, language. Since the subjects of this study were infants and young children, we did not include the language and marital statuses. Vital-sign information included body temperature (T), heart rate (Hr), respiratory rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), and blood oxygen saturation (SpO2). We also collected laboratory variables including adenosine deaminase (ADA), serum albumin, alanine aminotransferase (ALT), serum creatinine, total bilirubin (Tbil), globulin, hemoglobin, lymphocyte count, red blood cell count (RBC), white blood cell count (WBC), platelet count (PLT), eosinophils, D-dimer, fibrinogen, international normalized ratio (INR), serum sodium (Na), brain natriuretic peptide (BNP) and bicarbonate .We used variance inflation factor (VIF) to assess whether there was collinearity between variables, and excluded variables with VIF values > 5. The existence of a variable with multicollinearity means that the corresponding information provided by this variable is redundant in the presence of other variables. The variables were incorporated into the least absolute shrinkage and selection operator model (Lasso). The LASSO regression method was used to reduce the dimensionality of variables with certain correlations, and variables with non-zero coefficient characteristics were selected. Calculate the cut-off point of continuous variables, and divide the continuous variables into two groups according to the cut-off point, one is above the cut-off point, and the other is below the cut-off value. The Odds ratio of the variables was calculated using a logistic regression model and represented by a forest plot. Eligible variables were incorporated into logistic regression to build the nomogram. The performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC), with AUC >0.7 indicating good model performance. Calibration curves and Decision Curve Analysis (DCA) were used to evaluate the predictive and clinical performance of the nomogram. The feature importance of variables in the model is calculated based on the XGboost method. Restricted cubic splines (RCS) were used to explore the relationship between respiratory rate and hospital stay longer than 14 days.Continuous variables were represented by medians and quartiles, and differences between groups were determined using analysis of variance. Categorical variables were expressed as frequency and percentage values, and differences between groups were determined using chi-square tests. We used R software (4.2.0) for statistical analysis. The R packages used in this study include gtsummary , dplyr, p-value >0.05). The baseline data of the two groups of patients are shown in We extracted data from the PIC database on 705 patients with a diagnosis of ventricular septal defect, 362 of whom were male. We randomly assigned 60% of patients to the training cohort and 40% to the validation cohort. Except for lymphocyte counts, baseline data for both cohorts were balanced (Ventricular septal defect is the most common congenital heart disease caused by hypoplasia of the ventricular septum during the embryonic stage. In the early stage of ventricular septal defect, blood is shunted from the left to the right ventricle, which leads to an increase in the pulmonary blood circulation volume that causes pulmonary interstitial edema, which is prone to pulmonary infection.Previous studies have shown that risk factors for unplanned readmission to pediatric intensive care units include age, disease type, disease severity, source of admission, unplanned initial admission, time of initial discharge, and respiratory support at discharge . Most of2. The compensatory mechanism of the body deepens and accelerates the breathing rate, which often worsens the illness, so the risk of a hospital stay longer than 14 days increases. Respiratory frequency also plays an important role in monitoring infectious and respiratory diseases. Studies have found that respiratory rate is also an important prognostic factor in pulmonary infection and heart failure (When pulmonary infection or heart failure occurs in patients with ventricular septum, pulmonary interstitial edema and pulmonary diffusion dysfunction may occur, resulting in hypoxemia and decreased SpO failure . The res failure . A study failure . Studies failure . TherefoFibrinogen is a plasma protein coagulation factor synthesized and secreted by hepatocytes, which can participate in hemostasis and thrombosis, regulate coagulation and fibrosis, and prevent the spread of infection and inflammation . StudiesWe hope that clinicians can use the nomogram from this study to accurately identify high-risk groups in pediatric patients with VSD, and provide early interventions to reduce hospital stays, which can help reduce the risk of in-hospital complications and improve outcomes.The limitations of this study were as follows: First, it had a single-center retrospective design, and its conclusions are not representative of all juvenile patients with ventricular septal defect. Second, we excluded some variables due to high rates of missing data. Due to database limitations, we did not include age, trisomy 21 syndrome, and Eisenmenger syndrome in the analysis. In future studies we hope to include troponin and other variables that can reflect myocardial injury, which may increase the accuracy of the findings.The nomogram we developed includes heart rate, respiratory rate, SBP, Spo2, ALT, Urea, fibrinogen, bicarbonate, BNP. The model has good predictive performance and clinical utility, and is convenient for clinicians to use. Therefore, the new model can help clinicians assess the risk of hospitalization for longer than 14 days in pediatric patients with VSD.


Physical exercise (PE) is a recommended lifestyle intervention for different mental disorders and has shown specific positive therapeutic effects in unipolar depressive disorder. Considering the similar symptomatology of the depressive phase in patients with bipolar disorder (BD) and unipolar depressive disorder, it is reasonable to suggest that PE may also be beneficial for bipolar depression. However, there is an absence of studies evaluating the antidepressant effect of a structured PE intervention in BD.This is an open-label, single-arm study trial. Fifteen patients with a diagnosis of BD Type I or Type II, presenting a depressive episode were included in the study. After physical and functional evaluation, patients participated in supervised training sessions with aerobics followed by strength exercises, three times per week, for 12 weeks (36 training sessions). Depressive and manic symptoms were assessed at baseline and 2, 4, 8, and 12 weeks. Additionally, quality of Life and functioning were assessed at baseline and 4, 8, and 12 weeks). Finally, we tested cardiorespiratory fitness, muscle strength and body composition at baseline and week-12.Montgomery Asberg Depression Rating Scale (MADRS) score at baseline was 23.6 ± 8.3 points and after 12 weeks of PE the mean score was 10.2 ± 4.8 points. Nine patients (82%) presented an antidepressant response defined as a reduction of more than 50% of depressive symptoms at week 12 with five of those patients (45%) presenting criteria for full remission. A large and significant Cohen’s D Effect Size (pre-post) was verified for MADRS reduction [1.98 ]. We did not detect a significant change in manic symptoms, functioning, and quality of life during the 12-week follow-up. At week-12, all patients increased their muscular strength  and reduced the percentage of body fat .The mean (± SD) This study, using rigorous criteria and a structured intervention, provides valid pilot data, showing the feasibility of a structured PE intervention for the treatment of depressive symptoms in BD, and suggesting a potential adjunctive antidepressant effect. Moreover, PE showed a positive impact on muscle strength and body composition. This should be further verified by randomized controlled studies. Bipolar disorder (BD) affects more than 100 million people worldwide and is associated with high disability and premature mortality , several studies have shown an antidepressant effect of PE  as well as assessing adherence and tolerability of the intervention for 12 weeks. Furthermore, we also aimed to evaluate the potential impact of our exercise protocol on cardiorespiratory fitness, muscular strength and body composition.Hospital das Clínicas of the University of Sao Paulo Medical School. All patients were interviewed for the study after providing informed consent. Eligibility criteria included the following: (a) Diagnosis of BD Type I or Type II by Structured Clinical Interview for DSM (SCID-P); (b) Aged between 18 and 55 years; (c) Mild or moderate depressive episode at recruitment - Score on Montgomery–Åsberg Depression Rating Scale (MADRS) ≥ 14 points; (d) No regular PE in the previous six months; (e) Using lithium, quetiapine, valproate, lamotrigine, or a combination of these stabilizers for at least four weeks, without remission of the depressive episode; (f) Patients who were on antidepressants were required to have been taking a stable dose for at least four weeks; (g) No medication change in the four weeks prior to study entry; (h) Patients using a maximum of 2 mg of Lorazepam and/or 10 mg of Zolpidem for insomnia; (i) Body mass index (BMI) ≤ 40. The exclusion criteria were as follows: (a) Being in a manic or hypomanic episode at recruitment - Score on the Young Mania Rating Scale (YMRS) > 12 points; (b) having an organic mental disorder; (c) Abuse of alcohol or illicit drugs in the previous two weeks; (d) Using of beta-blocker.This open trial followed the guidelines of the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement: extension to pilot and feasibility trials . This study was conducted by the Declaration of Helsinki  and Quality of Life  were assessed at baseline and after 4, 8, and 12 weeks. The MADRS and YRMS scales are scales typically used in interventions in patients with BD (assessing symptoms of depression and mania)   was assessed at baseline and after 12 weeks.2peak) used a treadmill , and was conduced modified Heck protocol . In resume, a unilateral leg press 45° 1RM testing were performed considering the American Society of Exercise Physiologists’ recommendations (Brown and Weir The following exercises were completed under supervision: Aerobic training (treadmill); strength training (specific equipment).max), 20 min at 70–85% of HRmax, and 5 min at 65–70% of HRmax.Aerobic training on a treadmill  consisted in 5 min at 65–70% of heart rate maximum  with Polar Beat.The intensity was based on a percentage of the HRThe protocol consisted of five exercises , with specific equipment , been realized by three sets of 15 repetitions with one to two minutes intervals.The strength training during the first two weeks, self-selected loads were used due to the need to learn the movement. After this period, loads of 15 repetitions were used, and in each training session, if the subject was able to perform more than 15 repetitions, the load was adjusted.The data were analyzed using IBM SPSS Statistics, version 22 . Data are described as individual values. The mean scores (+- SD – standard deviation) of eleven patients and groups are presented. The Cohen’s D Effect Size Cohen  – . We did not detect a significant change in manic symptoms, functioning, and quality of life during the 12-week follow-up  showing very good adherence to the protocol.Considering the adverse events observed during the intervention, we highlight the request to reduce exercise load in the early training sessions due to complaints of musculoskeletal pain (6 patients). Moreover, no manic switch was observed during the 12-week follow-up period with none of the patients presenting a score in the YMRS higher than 10 at any point during the study . Prior to the exercise intervention, subjects received four medications on average to treat BD. In relation to MADRS scores, we followed the categories of depression severity in patients with BD defined by Thase et al. : (I) Apparent sadness = 2.5 to 1.2 points; (II) Reported sadness = 4.0 to 0.8 points; (III) Inner tension = 2.9 to 1.3 points; (IV) Reduced sleep = 1.2 to 0.9 points; (V) Reduced appetite = 1.2 to 0.2 points; (VI) Concentration difficulties = 3.3 to 2.1 points; (VII) Lassitude = 3.1 to 1.5 points; (VIII) Inability to feel = 3.0 to 1.1 points; (IX) Pessimistic thoughts = 1.8 to 0.9 points; (X) Suicidal thoughts = 0.8 to 0.0 points. Finally, all five patients with a MADRS score higher than 24 (markedly ill or extremely ill), presented at least a 50% reduction in MADRS score at week-12.2peak (Panel A), muscular strength (Panel B), percentual body fat (Panel C), and body muscle mass (Panel D) considering baseline and 12 weeks. The Graphs show the individual values and mean of the weeks for tests .Finally, Figure 2peak, and eight patients increased their body muscle mass at week-12.This pilot, open-label, single-arm study in patients diagnosed with BD demonstrated a robust improvement in depressive symptoms (MADRS) at 12 weeks of exercise (aerobic and resistance training) and 2, 4, 8, and 12 weeks compared to baseline, with a large and significant Cohen’s D effect. Five patients presented total remission (MADRS < 9 points) and four patients presented a reduction of more than 50% in depressive symptoms with a response rate of 82% (9/11). No significant changes were observed in manic symptoms, functioning, and quality of life. Additionally, all patients increased their muscular strength, and reduced the percentual body fat. Finally, six patients presented increased VODepression Anxiety Stress Scales (DASS). Actually, this was the first study to investigate the effect of a walking group in BD. However, the study presented a retrospective design and only reported the benefits of a walking group, which is not considered a structured PE. Another study, by Sylvia et al., showed that 20 weeks of an intervention combining nutrition, exercise, and wellness in BD, promoted a change in depressive symptoms (MADRS) of four points (means of 17.2 to 13.2 points) and ES of 0.26 (non-significant)  is similar to the effect size  reported by Heisell et al., in a meta-analysis in MDD patients , patients with scores greater than 12 were excluded from this study. In this sense, the group started the study with mild manic symptoms (mean at baseline = 3 points - outside the manic phase) and remained in this classification throughout the intervention period. As a result, there was no significant change in manic symptoms. However, compared to the Ng study which does not assess manic symptoms, our finding of no difference is positive evidence. Finally, our findings on manic symptoms contradict two cross-sectional studies linking exercise with manic episodes , the high score presented here (baseline: mean = 39 points and week 12: mean = 37 points) showed our patients had moderate, and severe functional impairment, as categorized by the Bonnín et al. study , conflicting results may be highlighted in the subjects with psychiatric disorders. Schuch et al. showed that add-on PE for two weeks is an efficacious treatment for MDD patients, improving their quality of life . The adherence to exercise programs has a big variance in studies that evolved physical exercise - adherence lower to 75% (Malmo et al. Our pilot study aimed to investigate the feasibility of an exercise protocol in subjects with bipolar depression. One important limitation was the small sample size and a lack of comparison group. We also did not include a longer follow-up period after the intervention, which limited our ability to measure the likelihood of eventual relapse and worsening of depressive symptoms after the intervention or our ability to detect long-term improvements in functioning and quality of life. The strengths of this study include the use of a structured and individual PE intervention, a validated method to confirm the diagnosis, and frequent measurements of depressive and manic symptoms during 12 weeks, which allowed us to detect no manic/mixed switches during the intervention.Despite limitations, our study provides valid pilot data suggesting an adjuvant antidepressant effect of exercise in patients with BD, without triggering manic symptoms, and points to the importance of conducting randomized, controlled clinical trials to better confirm the promising effects of PE in BD.


Type 2 diabetic kidney disease (DKD), a chronic microvascular complication of diabetes, may exhibit a complex interrelation with coagulation function. This study is aimed at elucidating the association between coagulation function and DKD.  This was a real-world observational study conducted in Beijing, involving 2,703 participants. All patients with diabetes were classified into two groups, viz., DKD and non-DKD groups. Effect magnitudes are denoted as odds ratios (OR) with a 95% confidence interval (CI). To mitigate potential bias in group comparisons, we employed propensity score matching (PSM). P: 1.565, 1.289-1.901, <0.001) and fibrinogen degradation products (FDP)  were significantly correlated with an increased risk of DKD. To facilitate clinical applications, a nomogram prediction model was established, demonstrating commendable accuracy for DKD prediction.  After adjusting for variables such as age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), triglyceride (TG), c-reactive protein (CRP), platelet (PLT), and serum albumin (sALB), it was discerned that fibrinogen (FIB) (OR, 95% CI,  Our findings suggest that elevated levels of FIB and FDP serve as potential risk indicators for DKD, and coagulation function may play an important role in the occurrence and development of DKD. Diabetic kidney disease (DKD) occurs frequently, accounting for 40-50% of patients with type 2 diabetes mellitus , 2. As dClinically, DKD is recognized as a chronic microvascular complication of diabetes mellitus, and a growing body of evidence underscores its intimate association with coagulation anomalies. Some studies have shown a significant association of coagulation parameters with the onset and progression of DKD, whereas others failed to replicate this association –10. For From January 2011 to January 2021, a total of 4,903 patients diagnosed with type 2 diabetes mellitus were initially recruited for this study, and they were hospitalized at the Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University. The study secured approval from the Ethics Committee of Beijing Hospital of Traditional Chinese Medicine (no. 2020BL02-062) and adhered to the principles outlined in the Helsinki Declaration. Given the retrospective cross-sectional nature of this study, the requirement for patient consent was exempted, as the data utilized were anonymized and deidentified.For inclusion in this study, patients needed to be between the ages of 18 and 80 and had to align with the established standards for the classification and diagnosis of diabetes . The stuFollowing these criteria, 2,703 eligible patients diagnosed with type 2 diabetes mellitus were enrolled in the study. Of these, 2,157 patients with DKD constituted the case group, while the remaining 546 non-DKD patients were categorized into the control group.2 sustained over a 3-month period, provided there are no indications or manifestations of other primary causes of kidney damage [DKD is characterized by a consistent presence of UACR ≥ 30 mg/g and/or an eGFR < 60 mL/min/1.73 my damage . The eGFy damage , 13.Data for this study were sourced from the Scientific Research Sharing Platform (Yidu Cloud (Beijing) Technology Ltd.) at the Beijing Hospital of Traditional Chinese Medicine, Capital Medical University. This data encompassed demographic details, medical histories, laboratory test results, and diagnostic information during the patients' hospital stays.Blood pressure (BP) for each participant was gauged twice while seated using an automated sphygmomanometer, with the mean of the two readings being utilized.Postblood sampling, serum was promptly isolated following centrifugation within a 2-hour window. Concentrations of D-D and FDP were assessed through immunoturbidimetry, while PT, APTT, TT, and FIB concentrations were measured using the von Clauss technique. The established reference intervals for PT, APTT, TT, D-D, FIB, and FDP are 9.9-12.2 (s), 25.1-36.5 (s), 10.3-16.6 (s), 0-0.24 (mg/L), 2.00-4.00 (g/L), and 0.00-5.00 (mg/L), respectively. Creatinine concentrations were gauged using enzymatic methods, while urine microalbumin levels were determined through immunoturbidimetric methods. Concentrations of serum albumin (sALB), C-reactive protein (CRP), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were ascertained using an automated biochemical analyzer. HbA1c levels were evaluated using high-performance liquid chromatography.All laboratory tests, including coagulation parameters, biochemical indexes , HbA1c, and PLT levels, were conducted twice before reporting by proficient laboratory personnel at the Beijing Hospital of Traditional Chinese Medicine, Capital Medical University.χ2 test was employed for between-group comparisons of categorical variables, and the Wilcoxon rank sum test was used for continuous variables. The interrelation among the six coagulation parameters  was ascertained using the Spearman correlation analyses. The relationship between coagulation parameters and DKD, both pre- and postadjustment for potential confounders, was probed using logistic regression analyses. The effect sizes are articulated as odds ratios (OR) with a 95% confidence interval (95% CI). To mitigate potential bias in group comparisons, propensity score matching (PSM) was utilized after balancing confounding factors. Advanced age, male gender, hyperglycemia, hyperlipidemia, and hypertension are well-established risk factors for DKD [P < 0.05. The study's power was determined using the PS Power and Sample Size Calculation software (version 3.0).Analyses were executed using Stata version 16  and R version 4.0.5 . Continuous variables with a normal distribution are presented as mean values ± standard deviation, while those with a skewed distribution are denoted as median (interquartile range). Categorical variables are described as counts (percentages). The  for DKD –17. Cons for DKD –20. ModeP ≤ 0.001).P ≤ 0.001). There was no significant difference in HDL-C, CRP, and PLT between the two groups (P > 0.05).Regarding coagulation metrics, the DKD group exhibited reduced PT, augmented D-D, FIB, and FDP levels, and an extended TT compared to the control group , succeeded by FIB and FDP . Other correlations were relatively weak .P values < 0.05/6 denoting statistical significance. Postadjustments for various factors such as age, sex, FIB , and FDP  emerged as significant risk factors for DKD, while the associations of TT, D-D, PT, and APTT with DKD were not statistically significant. The power for these significant comparisons exceeded 80%.As depicted in P < 0.001), signifying a notable enhancement in model performance.To bolster clinical utility, we devised a DKD prediction nomogram model, as depicted in To illustrate the practical application, consider a 57-year-old man with the following scores: gender (7.5 points), SBP of 180 mmHg (30 points), TG at 4.2 mmol/L (5 points), FIB at 5 g/L (50 points), and FDP at 6.5 mg/L (20 points). With a cumulative score of 122.5, this estimated DKD probability is approximately 77.5%.To the best of our understanding, this study represents the inaugural effort to probe the association of six clinically relevant coagulation parameters with DKD in the adult Chinese demographic. Our analysis revealed that DKD patients exhibited a shorter PT, an extended TT, and elevated levels of D-D, FIB, and FDP compared to their non-DKD counterparts. Even after accounting for common risk factors and several pivotal parameters influencing blood coagulation, heightened levels of FIB and FDP maintained a significant correlation with DKD susceptibility. These observations underscore the potential of FIB and FDP as noteworthy markers in the coagulation profile of DKD patients. Such insights could pave the way for enhanced preventive and therapeutic strategies targeting DKD.In our investigation, DKD patients exhibited heightened levels of FIB and FDP, indicative of a hypercoagulable state. This observation aligns with numerous findings in the literature, albeit with certain distinctions in specific coagulation parameters. Yu et al.  discerneThe pathogenesis of DKD is believed to be multifaceted. Numerous studies have underscored the pivotal role of abnormal coagulation, highlighting the hypercoagulable state observed in a significant proportion of DKD patients , 21, 22.These findings suggest a pronounced hypercoagulable state in DKD patients. Crucially, there exist clinical interventions tailored to address coagulation anomalies. Benck et al.  demonstrA notable contribution of our research is the development of a nomogram prediction model, designed to elucidate the association between coagulation and DKD more effectively and to enhance its utility for clinicians. Crucially, this model boasts commendable predictive accuracy, serving as a valuable tool for informed clinical decision-making and individualized DKD management.However, several limitations of our study warrant mention. Firstly, due to its cross-sectional design, we cannot establish a causative link between underlying factors and DKD. Secondly, our participant pool was sourced from a single center and exclusively comprised of individuals of Chinese descent. Consequently, caution is advised when generalizing these findings to other racial or ethnic demographics. Furthermore, while our results underwent rigorous internal validation, external validation in diverse, independent cohorts remains imperative.In our analysis of data from 2,703 patients with T2DM in China, we discerned that FIB and FDP could serve as potential risk indicators for DKD. This suggests that coagulation anomalies might have a pivotal role in the progression of this disease. Additionally, we formulated a nomogram prediction model that exhibited commendable accuracy. From a clinical perspective, we anticipate that our findings will catalyze more extensive cohort and mechanistic investigations. Such studies could further illuminate the intricate role of the coagulation system in DKD's multifaceted mechanisms, thereby enhancing therapeutic approaches.


Diabetes is one of the main risk factors for vascular damage, including endothelial dysfunction and arterial stiffness. The aim of this study was to compare selected parameters of vascular damage in patients with type 2 diabetes (T2D) in different age categories and to determine their relationship to indicators of glycometabolic control. A total of 160 patients with T2D were included in this cross-sectional study. They were divided into four age quartiles . All subjects were evaluated for indicators of glycometabolic control and for arterial stiffness parameters along with markers of endothelial damage—tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF). The oldest compared to the youngest participants showed significantly increased parameters of arterial stiffness  vs. 8.2 (7.7–9.8) m/s) despite having similar glycometabolic control. Arterial stiffness parameters were mainly associated with age and blood pressure. Age and systolic blood pressure were major determinants of arterial stiffness regardless of glycometabolic control. The oldest patients also had the highest levels of vWF (153.7 ± 51.9 vs. 121.7 ± 42.5 %) but the lowest levels of PAI-1 (81.8 ± 47.5 vs. 90.0 ± 44.9 ng/mL). Markers of endothelial dysfunction correlated with metabolic parameters, but did not correlate with arterial stiffness. Age and systolic blood pressure are major determinants of arterial stiffness in patients with T2D regardless of glycometabolic control, whereas an unfavorable metabolic profile is mainly related to endothelial dysfunction. These results suggest a differential contribution of cardiometabolic risk factors to vascular damage in T2D patients over their lifetime. In recent decades, the incidence of diabetes has been increasing worldwide, especially among the elderly. An aging population is considered one of the most significant contributors to the increasing prevalence of diabetes. In the US, more than one-third of the adult population with diabetes is currently 65 years of age and older . In highVascular stiffness represents a subclinical marker of CVD risk. Both age and diabetes are important determinants of vascular damage ,5,6. SevBoth arterial stiffness and endothelial dysfunction represent surrogate markers for CVD; however, they reflect different aspects of vascular damage . ArteriaThe aim of this study was to compare markers of glycometabolic control and vascular damage in patients with type 2 diabetes (T2D) according to age and to determine whether the parameters of arterial stiffness and/or endothelial dysfunction are influenced by the glycometabolic control.2 (kg/m2). Waist circumference was measured while standing, in the middle between the anterior iliac crest and the lower border of the ribs.This cross-sectional study comprised T2D patients consecutively examined during their visits in an outpatient diabetic clinic. The principles of the Declaration of Helsinki for human experiments were respected. The study design and informed consent were reviewed and approved by the Ethics Committee of the Faculty of Medicine and University Hospital Olomouc. All participants were asked about their previous medical history, especially their cardiovascular status, medication, diabetic complications and diabetes duration. We used the following criteria to diagnose diabetes: fasting plasma glucose level ≥7 mmol/L and/or oral antidiabetic drugs (OADs) or insulin administration. Subjects with type 1 diabetes, secondary or genetic diabetes, infection, active cancer, and trauma were not included in this study. Body mass index (BMI), waist circumference, systolic and diastolic blood pressure (SBP and DBP) were also measured. BMI was calculated as body weight/body heightThese markers of arterial stiffness were used: augmentation index (AIx), augmentation index normalized for a heart rate of 75 beats per minute (AIx-75), augmentation pressure (AP), aortic systolic pressure (Aortic SP), aortic pulse pressure (Aortic PP), and pulse wave velocity (PWV) ,15. The Distance measurements were made using a tape measure from the sternum (carotid site) to the femoral arteries at the sensor site. Subsequently, PWV was calculated using the distance and average time difference between the two recorded sites according to the formula: PWV (m/s) = carotid–femoral distance (m)/carotid–femoral transit time (s).Venous blood samples were drawn in the morning after a 12 h fast. Routine serum biochemical parameters were analyzed on the day of blood collection. The modular system SWA  was used for biochemical examinations. Total cholesterol (TC), TG, and high-density lipoprotein cholesterol (HDL-C) were determined enzymatically. Low-density lipoprotein cholesterol (LDL-C) was calculated according to the Friedewald formula (LDL-C = TC—TG*0.4537—HDL-C for TG < 4.5 mmol/L). Non-HDL cholesterol (non-HDL-C) was calculated as follows: non-HDL-C = TC—HDL-C. Glucose was determined by the GOD-PAP method  and apoB by immunoturbidimetric method . Glycated hemoglobin (HbA1C) levels were measured by ion-exchange chromatography using the ADAMS A1c HA-8180V analyzer . High-sensitive C-reactive protein (hs-CRP) was assessed by the ultra-sensitive latex immunoturbidimetric method . Specific antibodies and an immunoradiometric assay in commercially available kits  were used for insulin and C-peptide concentrations. Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) were chosen as humoral markers of endothelial damage. VWF antigen was measured by immunoturbidimetric assay . Concentrations of t-PA and PAI-1 were determined from human plasma by using ELISA .t-test and ANOVA for normally distributed variables, the Mann–Whitney U-test and the Kruskal–Wallis test for non-normally distributed variables and the chi-squared (χ2) test for categorical variables. Spearman’s coefficient (ρ) was used to express the value of correlation. Multiple regression analysis was used to estimate the relationship between independent and dependent variables. p < 0.05 was considered as significant. Statistical analyses were performed using Statistica 12.0 . Probability values of p < 0.05 were considered as statistically significant.All values are expressed as means ± standard deviation (SD) or medians and interquartile ranges . Non-normal distribution was tested by the Shapiro–Wilk test. Differences in variables between the groups were analyzed with the A total of 160 patients with T2D participated in this study . All T2D patients were treated with diet. Of the total number of participants, 72% were on insulin and 91% were on oral antidiabetic drugs (OADs), as follows: metformin 86%, dipeptidyl peptidase-4 inhibitors 36%, gliflozin 14%, sulfonylureas 9% and GLP-1 receptor agonists 7%. Eighty-three percent of subjects were treated with antihypertensive therapy . Hypolipidemic drugs were administered to 60% of patients . Among all participants, 35% were smokers.The results are shown in All markers of arterial stiffness correlated with age . Some parameters correlated with SBP . Aortic SP, in addition, correlated with DBP (ρ = 0.54) and waist circumference (ρ = 0.18); moreover, aortic PP and PWV correlated with insulin levels . There were no associations between arterial stiffness and parameters of glycometabolic control. PAI-1 correlated positively with BMI (ρ = 0.39), waist circumference (ρ = 0.38), hs-CRP (ρ = 0.23), TG (ρ = 0.40), non-HDL-C (ρ = 0.39), apoB (ρ = 0.35), fasting glucose (ρ = 0.20), C-peptide (ρ = 0.37), and negatively with HDL-C (ρ = −0.27). VWF correlated positively with TG (ρ = 0.26), and negatively with HDL-C (ρ = −0.36). Levels of t-PA correlated only with C-peptide (ρ = 0.20) and PAI-1 (ρ = 0.24). There were no significant correlations between endothelial markers and parameters of arterial stiffness. Multiple regression analyses were performed to identify independent predictors for markers of vascular damage—see Patients with T2D in the highest age quartile have shown the most striking signs of vascular damage. Parameters of arterial stiffness  were significantly increased in this group compared to younger individuals regardless of glycometabolic control. Arterial stiffness was mainly associated with age and systolic blood pressure. The oldest patients also had the highest levels of vWF, but the lowest levels of PAI-1. Markers of endothelial dysfunction correlated with metabolic parameters, but did not correlate with parameters of arterial stiffness.Age and blood pressure are among the strongest predictors of arterial stiffness ,4,7. BotReduced bioavailability of NO leading to endothelial dysfunction results in impaired vasodilation, increased vascular fibrosis and arterial stiffness . Age-relVon Willebrand factor is known to be a more specific marker of endothelial dysfunction than PAI-1 because plasma levels of vWF are exclusively produced by endothelial cells ,18,19,20The lowest PAI-1 levels found in the oldest patients with T2D probably reflect the relatively smaller proportion of adipose tissue in these individuals. Surprisingly, the existence of the lowest PAI-1 levels in the oldest T2D patients of this study contradicts some previous observations . This maA limitation of this study is its cross-sectional and non-randomized design, especially in relation to drugs that potentially affect both parameters of arterial stiffness and indicators of endothelial dysfunction. Only 14% of study participants were treated with gliflozins and 7% with GLP-1 receptor agonists, which did not allow statistical evaluation with significant power. Conversely, a relatively high number of participants were treated with drugs , potentially affecting arterial stiffness and/or endothelial function. Moreover, the effect of drugs on vascular damage is likely to be time- and dose-dependent. Thus, larger prospective studies are needed to determine whether better glycometabolic control can improve arterial elasticity in elderly patients with T2D and to find the possible role of different classes of other antidiabetic drugs.Age, together with systolic blood pressure, seems to be the main determinant of arterial stiffness in patients with T2D, regardless of glycometabolic control. This is consistent with the results of previous studies where diabetes per se was only a weak predictor of arterial stiffness. An unfavorable metabolic profile is mainly related to endothelial dysfunction. The lack of correlation between markers of endothelial dysfunction and arterial stiffness suggests a differential contribution of cardiometabolic risk factors to various markers of vascular damage in T2D patients throughout their lifetime. This may require a different, age-specific therapeutic approach.


Supplemental oxygen leads to an increase in peripheral vascular resistance which finally increases systemic blood pressure in healthy subjects and patients with coronary artery disease, heart failure, undergoing heart surgery, and with sepsis. However, it is unknown whether this effect can also be observed in anesthetized patients having surgery. Thus, we evaluated in this exploratory analysis of a randomized controlled trial the effect of 80% versus 30% oxygen on intraoperative blood pressure and heart rate.2 of 0.8 (128 patients) versus 0.3 (130 patients) for major abdominal surgery. Continuous arterial blood pressure values were recorded every three seconds and were exported from the electronic anesthesia record system. We calculated time-weighted average (TWA) and Average Real Variability (ARV) of mean arterial blood pressure and of heart rate.We present data from a previous study including 258 patients, who were randomized to a perioperative inspiratory FiOp = 0.85). There was also no significant difference in TWA of heart rate between the 80 and 30% oxygen group . Also for ARV values, no significant differences between groups could be detected.There was no significant difference in TWA of mean arterial pressure between the 80%  and 30%  oxygen group (effect estimate −0.16 mmHg, CI –1.83 to 1.51; In contrast to previous results, we did not observe a significant increase in blood pressure or a significant decrease in heart rate in patients, who received 80% oxygen as compared to patients, who received 30% oxygen during surgery and for the first two postoperative hours. Thus, hemodynamic effects of supplemental oxygen might play a negligible role in anesthetized patients.https://clinicaltrials.gov/ct2/show/NCT03366857?term=vienna&cond=oxygen&draw=2&rank=1 These include patients on the intensive care unit, perioperative patients, emergency patients and patients on the ward . Former Although supplemental oxygen has no impact on mortality, myocardial ischemia, pulmonary atelectasis, oxidative stress, several studies described a significant hemodynamic effect when 80% oxygen was administered . Some smIn the perioperative setting, the concentration of administered oxygen varies significantly and is mainly based on individual preferences of the attending anesthesiologists. While the effects of perioperative oxygen administration on postoperative outcomes such as wound infections, long-term mortality or myocardial injury have been investigated intensively, the detailed effects on intraoperative hemodynamic parameters have not been evaluated before , 15, 16.Based on previous studies, we hypothesized that the administration of 80% oxygen leads to an increase in TWA of intraoperative blood pressure and a reduction in TWA of intraoperative heart rate in patients at-risk for cardiovascular complications undergoing moderate- to high-risk major noncardiac surgery. We further analyzed the effect of 80% versus 30% oxygen on intraoperative average real variability (ARV).ClinicalTrials.gov  and was further registered at the and the European Trial Database (EudraCT 2017–003714-68).This study was approved by the University’s Institutional Review Board (EK: 1477/2017) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at We conducted exploratory analyses of the observed data on intraoperative mean arterial blood pressure and heart rate of our randomized trial in which we investigated the effect of 80% versus 30% oxygen on postoperative maximum NT-proBNP concentration as primary hypothesis in 260 patients at-risk for cardiovascular complications undergoing moderate- to high-risk abdominal surgery . The stuPatients, who were at least 45 years of age and had at least one cardiovascular risk factor have been included in our original trial. Detailed inclusion and exclusion criteria and a detailed description of patient characteristics have been published previously . Patient−1via facemask with reservoir, and patients, who were assigned to the 30% oxygen group received 3 L.min−1 for the first two postoperative hours.We randomly assigned patients to receive 80% versus 30% oxygen concentration throughout surgery and for the first two postoperative hours. We included 260 patients between December 2017 and December 2019. Patients received the assigned oxygen concentration after endotracheal intubation. Patients, who were assigned to the 80% oxygen group received 8 L.minWe performed esophagus guided fluid management in all patients according to a previously published algorithm. We aimed to held blood pressure within 20% of preoperative baseline values. All patients received an arterial line for continuous blood pressure measurement. From the underlying trial we extracted arterial blood pressure values with a 1-min resolution. Other than oxygen concentration, anesthetic management was at the discretion of the anesthesia team.We summarized continuous variables using mean, standard deviation, median, quartiles as well as minimum and maximum. Descriptive statistics are given for both randomization groups separately.To investigate the influence of the group assignment on the time weighted average (TWA), average real variability (ARV), generalized ARV as well as squared ARV  of mean, diastolic and systolic arterial blood pressure as well as heart frequency, we first calculated univariable linear regression models. Hansen et al.  proposed2, as well as pH, were analyzed using univariable linear regression models. Additionally, if more than one influence parameter showed a significant result in the univariable models (p < 0.05), we performed a multivariable linear regression model accounting for all factors being significant in the univariable analyses.Additionally, potential confounding factors as age, BMI, sex , type of surgery (laparoscopic vs. open), history of coronary artery disease, peripheral artery disease, stroke, heart failure, diabetes as well as hypertension, vasopressor use, Albumin administration (yes vs. no), crystalloids, the time weighted average of pCOp-values smaller or equal to 0.05 were considered as statistically significant. Detailed discussion on the calculation of ARV has been published previously  from 258 patients, who were randomly assigned to 80% versus 30% perioperative inspired oxygen concentration. 127 patients received 80% oxygen and 130 patients received 30% oxygen. Baseline characteristics between the groups were well balanced and published previously . A significantly larger TWA of mean arterial blood pressure was found for laparoscopic surgery as compared to open surgery . Furthermore, a significant smaller TWA of MAP was found for patients, who received vasopressors (p < 0.01), and patients, who received Albumin (p = 0.03). Larger TWA of MAP values were found for decreasing amount of crystalloids (p = <0.01) and increasing pH values (p < 0.01). In the multivariable analysis accounting for type of surgery, vasopressor use, Albumin administration, amount of crystalloids, and pH, the factors vasopressor use and pH remained significant (Online Median TWA of mean blood pressure was 80 mmHg  in the 80% oxygen group and 81 mmHg  in the 30% oxygen group , generalized ARV (p = 0.50) or squared ARV (p = 0.18) of mean arterial blood pressure. Detailed descriptive analysis of mean, diastolic and systolic blood pressure are presented in We did not observe a significant difference between 80 and 30% oxygen in ARV (p = 0.93).Median ARV of mean arterial blood pressure was 2.8 mmHg  in the 80% oxygen group and 2.9 mmHg  in the 30% oxygen group . A significant larger ARV of the MAP was found for older patients (p < 0.01). Larger ARV values were found for decreased amount of crystalloids , smaller BMI (p < 0.01), females (p = 0.01) and patients without diabetes (p = 0.04). Larger generalized ARV values were found for decreasing amount of crystalloids . Larger squared ARV values were found for decreasing amount of crystalloids .No significant difference in TWA of heart rate between patients receiving 80% versus 30% oxygen was observed (median TWA of heart rate in the 80% oxygen group: 65 beats.minp = 0.04), patients, who had an open surgery (p < 0.01) as well as in patient without coronary artery diseases (p = 0.03). Furthermore, TWA of heart rate was significantly higher in patients, who received vasopressors (p < 0.01) and in patients, who received albumin , TWA: pH: estimate: –39.49, CI: −65.91 to −12.88; , patients with lower BMI (p = 0.027), females (p < 0.01) as well as in patients with history of heart failure (p = 0.02).Furthermore, no significant difference in ARV of heart rate between the 80 and 30% oxygen was found .In the multivariable analyses only the variables Age, Sex and Heart failure remained significant  as well as the squared ARV (p = 0.44) of heart rate did not differ significantly between the two groups. A significantly larger generalized ARV of heart rate was found for older patients (p < 0.01), females (p < 0.01) as well as in patients with heart failure (p = 0.04). Only age and sex remained significant in the multivariable analysis .The generalized ARV (p < 0.01) as well as female patients (p < 0.01). In the multivariable analyses both factors remained significant . Detailed results of analyses of heart rate are presented in A significant larger squared ARV of the heart frequency was found for older patients   . TherefoA further explanation for the different results might be that our patients received supplemental oxygen during the whole surgical procedure, which was approximately 4 h in both groups. Instead, the exposure time of supplemental oxygen in the above studies ranged only between 5 and 30 min . The aut24) was a predictor for mortality, cardiovascular- and cerebrovascular-events. Furthermore, Mascha et al. evaluated the ARV of MAP in over 106,000 patients, who had noncardiac surgery, and showed that generalized ARV of MAP and TWA of MAP were independently associated with 30-day mortality. In detail, they have shown that 30-day mortality increased steeply within an increase of generalized ARV to 3 mmHg.min−1  is more reliable than standard deviation to estimate variability for time series data . Hansen Hg.min−1 . HoweverHg.min−1 .Since previous studies suggested that supplemental oxygen increases systemic vascular resistance, we assumed that oxygen may thus reduce hypotensive periods leading to a lower ARV. Thus, we analyzed ARV of MAP between the groups. However, we did not observe any significant difference in ARV of blood pressure between the groups. This is reasonable since we also did not observe any significant effect on TWA of MAP as well. We further found in our multivariable analysis that age, sex, BMI, and diabetes had significantly higher generalized ARV of MAP. This is consistent with Mascha et al. , who fouper se  as compared to normal physiological partial pressure of oxygen which lies at 75–100 mmHg (2 during surgery is very uncommon, thus our study represents the current clinical practice, in which higher concentrations are often administered due to avoid hypoxemia. Beyond that, a pronounced beneficial effect of postoperative supplemental oxygen on hemodynamics in mildly hypoxic patients, who often remain unnoticed on the surgical ward has not be studied and thus cannot be excluded.Another limitation of our study is that we compared an intraoperative FiOIn summary, we observed in our several analyses that intraoperative supplemental oxygen has no significant hemodynamic effects neither on TWA and ARV of MAP nor on TWA and ARV of heart rate. This is consistent with our previous studies in which we showed that postoperative NT-proBNP, Troponin T, catecholamines and copeptin concentrations were also not significantly influenced by intraoperative supplemental oxygen administration. Based on our results and recent trials it is very likely that the intraoperative used oxygen concentration is a negligible factor regarding influencing clinical meaningful events.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics committee of the Medical University of Vienna. The patients/participants provided their written informed consent to participate in this study.CR: conceptualization, material preparation, data collection, data analysis, writing the first draft and final manuscript. EF and BK: conceptualization, material preparation, writing the first draft and final manuscript. AT, NA, and MS: material preparation, data collection, revision of the manuscript AK: material preparation, data interpretation, writing the first draft and final manuscript. MF: conceptualizaiton, data management, data analysis, revision of the manuscript AG: conceptualizaiton, data analysis plan and data analysis, revision of the manuscript. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Ideal timing of Renal Replacement Therapy (RRT) discontinuation in Acute Kidney Injury (AKI) is still unknown. We aimed to study the role of creatinine-related variables in predicting RRT successful discontinuation and to propose a clinical predictive score.In this single-centre retrospective study, we evaluated all AKI patients in whom RRT was interrupted for at least 48 hours. Patients who were still RRT-independent 7 days after initial RRT cessation were included in the “Success” group and opposed to the “Failure” group. We evaluated baseline characteristics and variables collected at the time of RRT interruption, as well as the Kinetic estimated Glomerular Filtration Rate (KeGFR), the simple variation in serum Creatinine (ΔsCr), and the incremental creatinine ratio on the first three days after RRT interruption. Multivariable analysis was performed to evaluate prediction of success. Internal validation using a simple binomial generalized regression model with Lasso estimation and 5-fold cross validation method was performed.We included 124 patients, 49 in the “Failure” group and 75 in the “Success” group. All creatinine-related variables predicted success in simple and multiple logistic regression models. The best model generated a clinical score based on the odds ratio obtained for each variable and included urine output, non-renal SOFA score, fluid balance, serum urea, serum potassium, blood pH, and the variation in sCr values after RRT discontinuation. The score presented an area under the ROC of 0.86 (95% CI 0.76‒1.00).Creatinine variation between the first 2 consecutive days after RRT discontinuation might predict success in RRT discontinuation. The developed clinical score based on these variables might be a useful clinical decision tool to guide hemodialysis catheter safe removal. Renal Replacement Therapy (RRT) is a major supportive treatment offered to patients with severe Acute Kidney Injury (AKI) in Intensive Care Units (ICU). The ideal time to start RRT in patients with AKI has been widely discussed and most clinicians agree that RRT should be commenced when life-threatening changes in electrolyte, acid-base or fluid balance exist.,,Despite the fact that RRT provides beneficial support to patient recovery, unnecessary RRT may be harmful. Inappropriate removal of antibiotics and amino acids may occurOnce RRT has been initiated, the appropriate timing to interrupt RRT and remove the vascular access is still unknown. Previous studies have shown utility in assessing urine output at the time of RRT discontinuation as an important predictor of successful cessation, especially in patients not receiving diuretics.Equations using only plasma functional markers, such as creatinine or cystatin C, do not accurately reflect real GFR in non-steady states, such as AKI. To counter these circumstances and determine kidney function in the acute setting, a formula considering acute changes in GFR was developed: the Kinetic Estimated Glomerular Filtration Rate (KeGFR).The purpose of this study is to find the value of KeGFR and to compare it with the simple variation in serum creatinine between two consecutive days at the time of RRT interruption and with the incremental creatinine ratio (creatinine day 2/day 1 and creatinine day 3/day 1) to predict successful RRT weaning. We aim to assess how all variables interact with other clinical important measures  in prediction of successful RRT discontinuation.This was a single-centre, retrospective, observational study, assessing critically ill patients from Hospital das Clínicas, a large tertiary care hospital in São Paulo, Brazil. All patients receiving RRT due to AKI from October 2020 to February 2022 were considered for inclusion in the study. Modalities of RRT included intermittent haemodialysis, prolonged intermittent RRT and continuous renal replacement therapy.The criteria for initiation and interruption of RRT were at the discretion of the attending physician. Patients who managed to remain at least 48 consecutive hours without receiving RRT prescription were included. Those who had RRT interrupted exclusively due to hemodynamic instability, death or decision for palliative care were excluded.,Successful RRT discontinuation criteria were met when included patients were alive and free from RRT 7 days after interrupting RRT.12At ICU admission, clinical and demographic data were retrieved. Baseline serum Creatinine (sCr) was defined as the lowest value from 3 months before admission to one month after discharge and baseline estimated glomerular filtration rate was calculated using CKD-EPI 2021 formula.Clinical variables that are usually considered as important by clinicians when deciding RRT discontinuation were collected by the time of RRT interruption: levels of serum urea and potassium, levels of blood bicarbonate and pH, Urine Output (UO), daily fluid balance, need of diuretic and overall clinical status determined by the “non-renal” Sequential Organ Failure Assessment (SOFA) score. The “non-renal” SOFA (nrSOFA) was determined by the sum of all components of SOFA score apart from sCr . In addition, we calculated nrSOFA variation between the day of RRT initiation and the day of RRT discontinuation (ΔnrSOFA), as a surrogate of improving (if positive) or deteriorating (if negative) overall clinical status of each patient during RRT interruption.Serum creatinine measurements on the first three consecutive days after RRT discontinuation were used to calculate KeGFR and to calculate the simple variation in serum creatinine (ΔsCr), calculated as the difference in sCr levels between 2 consecutive days after RRT discontinuation adjusted for 24h . We have also calculated the creatinine ratios (day 2/day 1 and day 3/day 1), as suggested by other authors.The primary outcome is the success status within 7 days after RRT discontinuation, as described above.This study was approved by CAPPesq, the local institutional human research ethics committee (Reference n° 51678521.0.0000.0068) and was registered in ClinicalTrials.gov under the number NCT06005896. This study was performed following the Strengthening the Reporting of Observational Studies in Epidemiology statement.p < 0.05.Normally distributed continuous variables are reported as mean ± Standard Deviation (SD), skewed-distributed continuous variables as median and Interquartile Range (IQR), and categorical variables are summarised as absolute numbers and proportions. “Success” and “Failure” patients were compared by the appropriate test according to the distribution of continuous variables , and categorical variables were compared by Fisher's exact test. Differences in means/median are reported and were considered statistically significant if p-value significance. Univariable models allowed the generation of Receiver Operating Characteristic (ROC) curves and the assessment of the optimal cut-off values considering the maximum [sensitivity + specificity − 1] of each variable.We used simple and multiple logistic regression models to predict success in RRT discontinuation. In simple logistic regression models, we tested each of all collected variables as predictors and identified those associated with the outcome according to Clinically important variables which were also considered as predictors in the univariable models were included in the multivariable models. Multiple binomial logistic regression models were initially performed using continuous predictors. We compared models using KeGFR, ΔsCr and incremental creatinine ratio both from RRT discontinuation up to the following day  and from one day after RRT discontinuation up to the following day  using ROC curves. The decision between the best model was made based on the area under the ROC curve.If no difference existed in model performance according to the ROC curve, we preferred to choose models comprising variables collected at D1 instead of D2, because this would permit more timely clinical decisions and possible earlier catheter removal.We subsequently created multiple logistic regression models using the same variables included in the model chosen, but categorizing them according to the optimal cutoff values generated at each individual univariable model. We have chosen this approach to simplify interpretation and allow a score generation to guide clinical decisions. The Odds Ratio (OR) obtained for each variable was rounded to the nearest integer to determine the value of each variable at the final discontinuation score.We applied the final discontinuation score to each patient in this cohort, and generated training and internal validation ROC curves to predict success in RRT discontinuation based on a simple binomial generalized regression model with Lasso estimation and 5-fold cross validation method (using only the created score as a predictor). The likelihood of success depending on the final discontinuation score was assessed. We constructed 5000-times bootstrap 95% Confidence Intervals for the areas under the ROC curve regarding training and internal validation. Analyses were performed with the R statistical software, version 4.0.5; Rstudio, version 1.4.1106  and JMP Pro version 16 .We screened 476 patients. Of those, 346 patients were excluded because RRT was interrupted due to haemodynamic instability, death, or a decision for exclusive palliative care. Extra 6 patients were excluded because of insufficient data to calculate KeGFR. We included 124 patients, 49 in the “Failure” group and 75 in the “Success” group (60.5%) . PatientThe occurrence of missing data was low (only 2 variables with missing data above 15%) and we considered all the variables in the database. On the interruption day, half of the patients were using diuretics with no difference between groups. Non-renal SOFA at the time of RRT discontinuation was higher in the “Failure” group when compared with patients in the “Success” group. The ΔnrSOFA was positive in both groups, showing that non-renal SOFA on the day of RRT initiation was higher than on the day of discontinuation, compatible with overall clinical improvement . At the On the first three days after RRT interruption, values of sCr progressively increased in both groups. However, patients in the “Success” group presented a lower increase than patients in the “Failure” group, as demonstrated by ΔsCr1 and ΔsCr2. The KeGFR of both groups were different at the second and third days after RRT discontinuation and both the incremental creatinine ratios (D2/D1 and D3/D1) were different between groups . The traBaseline characteristics and variables collected at the time of RRT discontinuation were tested as potential predictors of RRT weaning success using simple logistic regression models. Results are shown at To generate multivariate models, we selected one of the clinical score variables , urine output, daily fluid balance, serum urea, serum potassium, blood pH, and one variable related to sCr ]). We chose nrSOFA among clinical score variables because it was the easiest to calculate and correlated very well with the outcome. The variable need of diuretics was not included because it is clinically related to urine output, which is a more relevant parameter to be analysed. We decided not to include hypertension in the model because this information is usually difficult to timely obtain in a reliable manner in critically ill patients. As we wanted to compare the KeGFR with the simple variation in serum creatinine between two consecutive days and the incremental sCr ratio at the time of RRT interruption to predict successful weaning, we generated six multivariable logistic regression models, each one including one of the creatinine-related predictors . We decided not to include single values of sCr because this variable was already included in the results of ΔsCr, KeGFR, and sCr ratio. Multivariable models to predict success in discontinuation were compared using ROC curves and the result is depicted in As there was no difference among models, we chose a final model that comprised variables collected earlier, known after only two days after RRT discontinuation . Model 2 was chosen because of an AUC under ROC curve slightly better than Models 1 and 3. Variables used to generate Model 2 were transformed into binomial variables according to the optimal cutoff originated by the ROC curves at each univariable model. Based on this, we generated a new multivariable model using those binomial variables as predictors of “Success” . The OddIn this study, we found that the success in RRT independence at 7 days after AKI-associated RRT discontinuation can be predicted by the KeGFR calculated using sCr levels on the first and second days (KeGFR1) as well as on the second and third days after RRT discontinuation (KeGFR2). The incremental sCr ratio day 2/day 1 and day 3/day 1 had similar performance and the simple variation in serum creatinine between 2 consecutive days after RRT discontinuation could also similarly predict the outcome, either when the difference between sCr levels on the first and second days (ΔsCr1) or the difference between sCr levels on the second and third days was considered (ΔsCr2).We demonstrated that there is no need for a decrease in sCr to predict recovery and successful discontinuation. In fact, even for successful patients the raw value of sCr continued to increase between the first and second days after RRT interruption . On day 3, sCr values started to reach a steady pattern and were similar to values at day 2 in patients who succeeded, but not in patients who failed.,Both KeGFR and incremental creatinine values have already been shown to predict RRT discontinuation in prior studies,No previous study showed an acceptable success RRT discontinuation rate with urine output lower than 400 mL daily. Thus, it will be very unlikely that any patient would be discontinued from RRT due to the expectation of renal recovery with a urine output lower than that. The Standardized Clinical Assessment and Management Plans (SCAMP) Study discontinuation algorithm recommends a urine output cut-off of at least 500 mL per day.Previous studies assessing recovery from AKI and RRT discontinuation have not studied non-renal SOFA score on the day of discontinuation. In this study, we showed that this variable was importantly associated with success . The nrSOFA can translate the bedside clinical impression into an objective measurable data and contribute to guide RRT discontinuation.,In multivariable models including non-renal SOFA score, daily fluid balance, urea and potassium levels, blood pH and daily urine output, all the six mentioned sCr-related variables had similar performance in prediction of RRT discontinuation success. Models constructed using later sCr values, such as KeGFR2, ΔsCr2 and sCr ratio (day 3/day 1), seemed to be slightly better than models using earlier sCr levels. However, the difference among them was meaningless and we gave preference to models that would provide earlier clinical information to guide medical decisions and prevent unnecessary maintenance of RRT. The second step to guide model choice was model performance and we showed that the one including ΔsCr1 (Model 2) presented a slightly higher area under ROC than the models including KeGFR1 (Model 1) or sCr ratio (day 2/day 1) (Model 3). The difference was minimal and we could select any of those, although ΔsCr1 and sCr ratio (day 2/day 1) are easier to apply without an online calculation tool, compared to KeGFR1, thus the choice for a model including a simple variation in daily sCr would facilitate clinical use. While ΔsCr provides the direction of change in GFR but not the degree of GFR, the KeGFR provides the magnitude of GFR and not the direction of change. To see the direction of change using KeGFR, three values of sCr would be needed, to calculate two subsequent KeGFR levels. Christiadi et al demonstrated that the ratio of KeGFR at any time to baseline KeGFR could timely predict AKI.The ΔsCr may not replace the KeGFR in all clinical settings. The knowledge about the amount of kidney function may be important to adjust medication dosing in patients with AKI,In this study, we suggested a clinical score to predict success in RRT discontinuation. The model generated using the clinical score as a predictor had a good internal validation provided by the 5-fold validation statistical tool. However, external validation could not be provided here.The KDIGO guidelines recommend RRT interruption when intrinsic kidney function has recovered to the point that it is adequate to meet patient needs.Our model included widely available predictors that are clinically relevant to discontinuation success, such as urine output, serum potassium, serum urea and creatinine rise ratio, and combines them into a simple clinical score to facilitate decision making. To the best of our knowledge, this study provides the first clinical score to predict success on haemodialysis discontinuation in critically ill patients with AKI. It presents a promising clinical tool that may help doctors to make better decisions regarding AKI management.In the studied population, 90% of patients with ≥18 points (out of 29 points) in the clinical score proposed were successfully withdrawn from RRT 7 days after RRT interruption. This finding might be a striking contribution if further confirmed in future studies. Many patients who interrupt AKI-related RRT have to resume therapy in the following 2‒3 days. A clinical score that sorts out who these patients are would be very informative. Patients with high score levels, e.g., ≥ 18 points, maybe would be able to have their vascular access removed. In settings with low RRT machine availability, RRT machines that would be required for those patients would possibly be reallocated, allowing better usage of limited resources.,Although there are many studies regarding RRT initiation on AKI,Our study has several limitations. Firstly, it is a retrospective observational single-centre study, so results might not be generalised to some populations. Secondly, despite our sample size being larger than most RRT discontinuation studies, it is still not a large cohort. This can lead to biases caused by, for example, the high prevalence of COVID-19 patients in our cohort, which does not correspond to the current reality of most ICUs after widespread vaccination. Finally, our score was validated internally with the 5-fold validation method but still lacks a prospective external validation cohort before it can be implemented in clinical practice and proposed as a clinical utility tool.New biomarkers such as urine NGAL are not readily available in our centre and were not included in our analysis. It is important to point out that new biomarkers in the setting of RRT discontinuation are being studied. In 2021, Daniels et al.Both KeGFR and simple variation in serum creatinine between 2 consecutive days after RRT discontinuation might predict success in RRT discontinuation. The suggested clinical score developed based on these variables might be a useful clinical decision tool to guide medical decisions, but still requires validation in larger studies before it can be implemented in clinical practice.The authors declare no conflicts of interest.


This study aimed to investigate changes in dynamic cerebral autoregulation (dCA), 20 stroke‐related blood biomarkers, and autonomic regulation after patent foramen ovale (PFO) closure in severe migraine patients.Patent foramen ovale severe migraine patients, matched non‐PFO severe migraine patients, and healthy controls were included. dCA and autonomic regulation were evaluated in each participant at baseline, and within 48‐h and 30 days after closure in PFO migraineurs. A panel of stroke‐related blood biomarkers was detected pre‐surgically in arterial‐and venous blood, and post‐surgically in the arterial blood in PFO migraineurs.Forty‐five PFO severe migraine patients, 50 non‐PFO severe migraine patients, and 50 controls were enrolled. The baseline dCA function of PFO migraineurs was significantly lower than that of non‐PFO migraineurs and controls but was rapidly improved with PFO closure, remaining stable at 1‐month follow‐up. Arterial blood platelet‐derived growth factor‐BB (PDGF‐BB) levels were higher in PFO migraineurs than in controls, which was immediately and significantly reduced after closure. No differences in autonomic regulation were observed among the three groups.Patent foramen ovale closure can improve dCA and alter elevated arterial PDGF‐BB levels in migraine patients with PFO, both of which may be related to the preventive effect of PFO closure on stroke occurrence/recurrence. Patent foramen ovale (PFO) closure can improve dynamic cerebral autoregulation (dCA) and alter elevated arterial blood platelet‐derived growth factor‐BB (PDGF‐BB) levels in migraine patients with PFO, both of which may be related to the preventive effect of PFO closure on stroke occurrence and recurrence in these patients. Dynamic cerebral autoregulation (dCA) is critical in regulating cerebral hemodynamics and its dysfunction plays a role in the occurrence and progression of stroke,In patients with a PFO, venous blood can enter the arterial blood circulation through the oval foramen, which may produce alterations in several stroke‐related blood biomarkers in the arterial blood, such as in homocysteine,Traditional risk factors for ischemic stroke include body stressors that may lead to autonomic dysfunction, which can be reflected by beat‐to‐beat heart rate variability (HRV).2The raw data of this study are available from the corresponding author upon reasonable request. This prospective study was approved by the ethics committee of the First Hospital of Jilin University (2012–111). Written informed consent was obtained from all participants. The participants had the right to withdraw at any time point during the course of the study.2.1Severe migraine was defined as Headache Impact Test‐6 score > 55.The exclusion criteria include: (1) insufficient bilateral temporal bone window for insonation of the middle cerebral artery (MCA); (2) extracranial/intracranial artery stenosis  or occlusionAge‐ and sex‐matched severe migraineurs without a PFO  and healthy migraine‐free volunteers were also enrolled as non‐PFO migraineurs and healthy controls. Informed consent was obtained. The exclusion criteria applied were (1)–(4) and (6), like patients in the PFO migraineurs. Simultaneously, volunteers with a right‐to‐left shunt  were included in PFO non‐migraineurs group.Basic demographic and clinical characteristics were collected from all participants, and dCA assessment, biomarker measurement, and autonomic function evaluation were performed on all participants.2.2We performed contrast‐enhanced transcranial Doppler before PFO closure, as previously described.2.3Patients in the PFO migraineurs group underwent PFO closure surgery. Procedures were performed by a chief surgeon and involved a femoral approach with the patient under local anesthesia. A long sheath was advanced into the left atrium and an Amplatzer PFO Occluder , which was a self‐expanding double‐disk device, was used to occlude the PFO under fluoroscopic guidance, and closure was confirmed via intra‐cardiac echocardiography. Patients were administered heparin (80–100 U/kg) during the procedure and they subsequently underwent routine electrocardiography, contrast transthoracic echocardiography, and chest radiography 24 h after the PFO closure procedure. Aspirin (100 mg/day) alone or in combination with clopidogrel (75 mg/day) was administered as antiplatelet therapy for 6 months following the procedure.2.4dCA data were collected from all participants, and PFO migraineurs received two additional dCA measurements, one within 48 h post‐surgery and the other at 1‐month post‐surgery.2 was also measured using a capnograph  with a face mask attached to the nasal cannula to confirm the stability of respiration during the experiment, in accordance with the recommendations of the dCA monitoring white paper.dCA was evaluated in a dedicated soundproof room, as previously reported.The dynamic relationship between the continuous CBFV and ABP was assessed via transfer function analysis (TFA) using MATLAB (Math Works). Evaluation parameters included phase difference , gain (difference in the amplitude between CBFV and ABP), and the coherence function . Each parameter was averaged in 0.06–0.12 Hz,2.5https://sourceforge.net/projects/hrvas/). The time‐domain analysis of HRV comprised normal‐to‐normal (NN) intervals, standard deviation of all NN intervals (SDNN), and square root of the mean of the sum of squares of differences between adjacent NN intervals (RMSSD). The spectral power of NN intervals was calculated using the Welch method, based on a fast‐Fourier transform. HRV variables were analyzed in the frequency domain, and total power (TP), power of very‐low‐frequency , low‐frequency , high‐frequency , and LF to HF ratios (LF/HF) were assessed.2 and normalized units (nu), calculated using the following formula: nLF or nHF = LF or HF/(TP–VLF) × 100. The SDNN, RMSSD, TP, VLF, LF (ms2), and HF (ms2) components were log‐transformed to ensure normal distribution of parameters. Individuals with data involving ectopic beats occurring at a rate > 20% during HRV measurements were excluded.The autonomic function was assessed through beat‐to‐beat HRV analysis. The baseline beat‐to‐beat HRV of each participant was determined while dCA values were measured. Then, PFO migraineurs underwent two additional HRV measurements: one within the 48‐h period following surgery and the other 1 month after surgery. Continuous recordings of beat‐to‐beat information obtained from the servo‐controlled plethysmograph were processed using MATLAB scripts developed by our research team, as previously reported.2.6Human specimens were obtained from the Department of Biobank, Division of Clinical Research, the first hospital of Jilin University. Arterial blood  and venous blood  were collected in all participants, and arterial blood was collected again immediately post‐surgery from the PFO migraineurs. Twenty stroke‐related blood biomarkers were analyzed with the Quantibody Human custom array from RayBiotech using a quantitative cytokine chip as previously reported.2.7t‐test. Non‐normally distributed data are expressed as median (interquartile range) and analyzed with Wilcoxon signed‐rank test (for paired continuous data) or Mann–Whitney test (for independent data). A general linear model was used to detect differences among PFO migraineurs of repeated measurements , as deemed appropriate based on data distributions. Comparisons were corrected post hoc via Bonferroni adjustment. Enumeration variables are expressed as absolute values and percentages and compared using the chi‐square test or Fisher's exact test. Calculated two‐tailed p‐values < 0.05 were considered significant.Data were analyzed using Statistical Program for Social Sciences version 19.0 . The distribution of data was assessed using a one‐sample Kolmogorov–Smirnov test and numerical variables were analyzed based on normality. Normally distributed data are expressed as mean ± standard deviation (SD) and analyzed with one‐way ANOVA or Student's 33.1Of the 61 PFO migraineurs, five had an insufficient bilateral temporal bone window and 11 had a large residual shunting at the 1‐month follow‐up; these patients were excluded. Thus, a total of 45 PFO migraineurs were included. Of the 58 non‐PFO migraineurs, six had an insufficient bilateral temporal bone window, and two had intracranial artery stenosis. Finally, a total of 50 non‐PFO migraineurs were included. In addition, after screening 67 age‐ and sex‐matched migraine‐free volunteers, 14 had a right‐to‐left shunt and three had an insufficient bilateral temporal bone window. Of these, 14 PFO volunteers, nine had a large right‐to‐left shunt. Thus, 50 healthy controls and 9 PFO non‐migraineurs were included. The flowchart was shown in Figure 2 between the groups.The demographic and clinical information of PFO migraineurs, non‐PFO migraineurs, and healthy controls are presented in Table Two PFO migraineurs, one non‐PFO migraineur, and one healthy control presented with ectopic beats occurring at a frequency > 20% during HRV measurement, and were therefore excluded from the HRV analysis. Forty‐five paired arterial blood samples (before and after PFO closure), 42 venous blood samples from PFO migraineurs, and both arterial and venous blood samples from 16 healthy controls (the rest of the volunteers were reluctant to undergo venipuncture) were assessed for 20 stroke‐related arterial blood biomarkers.3.2As shown in Table 3.33.3.1p = 0.002).The arterial PDGF‐BB levels were higher in PFO migraineurs than in healthy controls, which were immediately corrected by PFO closure Table . And venInterestingly, we observed that in the control group, the venous PDGF‐BB level was about 8‐fold higher than the arterial level .Owing to dCA, constant cerebral blood flow could be maintained despite changes in cerebral perfusion pressure and ABP. dCA is an important indicator of a normal cerebrovascular functioning.In the analysis of blood biomarkers, we found dramatically high arterial PDGF‐BB levels, and an altered arteriovenous PDGF‐BB ratio in PFO migraineurs. Several in vivo and in vitro studies have shown that PDGF‐BB is one of the most potent stimulants for vascular smooth muscle cell proliferation. PDGF‐BB is also potent in transforming vascular smooth muscle cells from a contractile phenotype to a synthetic phenotype, a critical step in the development of atherosclerosis.Furthermore, as known, the lung is located between the venous blood and the arterial blood, and a dramatic drop in PDGF‐BB is observed in the arterial blood in healthy controls. It is reasonable to suspect that the lung could somewhat eliminate the PDGF‐BB through unknown mechanisms. PFO patients with large right‐to‐left shunt typically have pulmonary congestion, pulmonary hypertension, and/or dysfunctional pulmonary microcirculation,By analyzing cardiac autonomic function, we found that there were no significant changes in HRV values of migraine patients with PFO, indicating that autonomic dysfunction may not be involved in the corresponding stroke susceptibility. Notably, we observed that time‐domain and absolute frequency‐domain HRV after PFO closure decreased significantly, consistent with the previous findings.This study had some limitations. First, because of patient intolerance, we did not collect venous and arterial blood samples throughout the long‐term follow‐up from patients who underwent PFO closure. Second, the sample size in our study was relatively small. Thus, our findings warrant further investigation using large‐scale studies. Third, changes in beat‐to‐beat variability may not directly and comprehensively reflect cardiac autonomic changes, therefore, the findings of cardiac autonomic regulation in our study should be further verified using other methods such as plasma markers.In conclusion, PFO closure can improve dCA and alter elevated arterial blood PDGF‐BB levels in migraine patients with PFO, both of which may be related to the preventive effect of PFO closure on stroke occurrence and recurrence in these patients.YY and Z‐NG drafted the initial protocol, which was reviewed with critical revisions and approval by all authors. YQ and PZ did the statistical analysis. YY, Z‐NG, JL, and JC wrote the first draft of the manuscript. YG, YX, HM, Y‐ZG, HJ, XS, and QH collected data. KH, H‐HH, and DMS revised the manuscript. All authors contributed to data acquisition. All authors contributed to the critical revision of the manuscript and approved the final manuscript for submission.The authors declare no conﬂict of interest.This work was supported by the National Natural Science Foundation of China (Grant No. 82071291), the Norman Bethune Health Science Center of Jilin University (2022JBGS03), the Science and Technology Department of Jilin Province (YDZJ202302CXJD061), and the Jilin Provincial Key Laboratory (YDZJ202302CXJD017) to YY, and the Norman Bethune Program of Jilin University (2022B02) to Z‐NG.Written informed consent was obtained from all participants.Tables S1‐S3.Click here for additional data file.


Norepinephrine is a commonly used drug for treating vasoplegic acute circulatory failure in ICU. The prediction of norepinephrine macro- and micro-circulatory response is complicated by its uneven receptors’ distribution between the arterial and the venous structures, and by the presence of a physiological vascular waterfall (VW) that disconnects the arterial and the venous circulation in two pressure systems. The objectives of this study were to describe the VW in patients with arterial hypotension due to vasodilatory circulatory shock, and its behavior according to its response to norepinephrine infusion.A prospective, observational, bi-centric study has included adult patients, for whom the physician decided to initiate norepinephrine during the six first hours following admission to the ICU after cardiac surgery, and unresponsive to a fluid challenge. The mean systemic pressure (MSP) and the critical closing pressure (CCP) were measured at inclusion and after norepinephrine infusion.p < 0.001) with norepinephrine infusion, being classified as VW responders. The VW responders improved cardiac index (from 1.8 (0.6) L min−1 m−2 to 2.2 (0.5) L min−1 m−2, p = 0.002), capillary refill time (from to 4.2 (1.1) s to 3.1 (1) s, p = 0.006), and pCO2 gap . No baseline parameters were able to predict the VW response to norepinephrine. In comparison, VW non-responders did not significantly change the VW , cardiac index (from 1.6 (0.3) L min−1 m−2 to 1.8 (0.4) L min−1 m−2, p = 0.09) and capillary refill time (from 4.1 (1) s to 3.7 (1.4), p = 0.44).Thirty patients were included. Norepinephrine increased arterial pressure and total peripheral resistances in all cohort. The cohort was dichotomized as VW responders (patients with a change of VW over the least significant change (≥ 93% increase in VW)), and as VW non-responders. In 19 (63%) of the 30 patients, VW increased from 3.47  mmHg to 43.6  mmHg, In post-cardiac surgery patients with vasoplegic arterial hypotension, the vascular waterfall is low. Norepinephrine did not systematically restore the vascular waterfall. Increase of the vascular waterfall was associated with an improvement of laboratory and clinical parameters of tissue perfusion. Acute vasodilatory circulatory shock is one of the common hemodynamic syndromes in the intensive care unit (ICU), characterized by arterial hypotension caused by the alteration of vascular vasomotor tone, and a consequent alteration of tissue perfusion. The treatment consists in vasopressor infusion to restore blood pressure and tissue perfusion, the most used being norepinephrine (NE) . NE has In the classic flow–pressure relationship description of the cardiovascular system, the tissue perfusion pressure depends on CO, mean arterial pressure (MAP), central venous pressure (CVP), and systemic vascular resistance. However, the arterial and the venous circulation are disconnected in two pressure systems by a vascular waterfall (VW) . AccordiNE has vascular effects both on arterial and on venous side, with an increase of arterial and venous pressure . NeverthThe main objective of this study was to describe the VW in patients with vasodilatory circulatory shock and its response to norepinephrine. The secondary objectives were to describe the hemodynamic differences between patients with significant changes of VW and these effects on indirect parameters of tissue perfusion.A prospective observational study was performed in two University Hospital cardiovascular ICU. The study was approved by the national independent ethics committee (17/2017). All subjects received written information about the study and provided their consent to participate prior to cardiac surgery. The study complied with the tenets of the Declaration of Helsinki.Inclusion criteria were: adult patients (≥ 18 years), monitoring with a central venous access and invasive blood pressure, for whom the physician decided to initiate a norepinephrine infusion during the six first hours following admission to the ICU after cardiac surgery, and unresponsiveness of blood pressure to a fluid challenge . Non-inc−2). Cardiac index (CI) (l.min−1.m−2) was calculated as SVi × heart rate (HR). Mean echocardiographic parameters were calculated from the average over five consecutives cardiac cycles and analyzed retrospectively.The systolic blood pressure (SAP), diastolic blood pressure (DAP) and mean blood pressure (MAP) were measured using an invasive arterial catheter. Transthoracic echocardiography  was performed by a board-certified physician. Left ventricular ejection fraction (LVEF) was calculated using Simpson’s method on a four-chamber view. The diameter of the left ventricular outflow tract was measured on a long-axis parasternal view at the time of patient inclusion. The aortic velocity–time integral (VTIAo) was measured with pulsed Doppler on a five-chamber apical view. Stroke volume  was calculated as VTIAo × aortic area and was expressed as indexed SV (SVi) = SV/body surface area  and CCP were measured using the inspiratory breath-hold maneuver, as previously described , within −1.m−2) was calculated as (MAP—CCP)/CI. The indexed total peripheral resistance (TPRi) was calculated as (MAP-CVP)/CI (mmHg ml−1.m−2).Indexed systemic arterial resistance  and arterial–venous oxygen tension difference (CavO2) were calculated on arterial and venous blood gases as follows: CaO2 = 1.34 × Hb x SaO2 + 0.003 × PaO2; CvO2 = 1.34 × Hb x ScvO2 + 0.003 × PvO2, where Hb is the hemoglobin concentration (g dl−1), PaO2 is the arterial oxygen pressure (mmHg), SaO2 is the arterial oxygen saturation (%), PvO2 is the venous oxygen pressure (mmHg), ScvO2 is the central venous oxygen saturation (%), and 0.003 is the solubility coefficient of oxygen, pCO2 gap = PcvCO2–PaCO2 (mmHg), C(a-v)O2 = CaO2-CvO2 (ml)  mmHg, the MSP was 22  mmHg, the CVP was 7 (4) mmHg. The resulting VW was 4  mmHg. The mean amount of fluid bolus did not differ between the two groups (9.3 (3.7) ml kgp < 0.001, Wilcoxon matched-pair signed rank test), the CVP from 7 (4) to 9 (4) mmHg , the CI from 1.7 (0.6) L min−1 m−2 to 2 (0.5) L min−1 m−2 , the indexed total peripheral resistances from 34 (17) mmHg L−1 min−1 m−2 to 40 (15) mmHg L−1 min−1 m−2 , the CCP from 25  mmHg to 45  mmHg  and the VW from 3.5  mmHg to 23  mmHg . Other parameters like the MSP did not statistically significantly change from 23  mmHg to 22  mmHg .The NE infusion increased the mean arterial pressure from 59 (7) mmHg to 80 (12) mmHg  with NE. These patients were classified as VW-responders , CVP (from 7 (4) mmHg to 9 (4), p = 0.01, Wilcoxon matched-pair signed rank test), CI (from 1.8 (0.6) L min−1 m−2 to 2.2 (0.5) L min−1 m−2, p = 0.002, Wilcoxon matched-pair signed rank test), TPRi (from 34 (21) mmHg min−1 m−2 to 40 (18) mmHg min−1 m−2, p = 0.002, Wilcoxon matched-pair signed rank test), SvO2 (from 64 (10) % to 69 (8) %, p = 0.02, Wilcoxon matched-pair signed rank test), and decreased SRAi , capillary refill time (from to 4.2 (1.1) s to 3.1 (1) s, p = 0.006), pCO2 gap  and pCO2 gap/arterio-venous oxygen tension .In 19 (63%) of the 30 patients, VW increased from 3.47  mmHg to 43.6  mmHg, p < 0.001, Wilcoxon matched-pair signed rank test), TPRi (from 34 (9) mmHg min−1 m−2 to 40 (8) mmHg min−1 m−2, p = 0.013, Wilcoxon matched-pair signed rank test) and SRAi . VW , CCP , CI (from 1.6 (0.3) L min−1 m−2 to 1.8 (0.4) L min−1 m−2, p = 0.09, Wilcoxon matched-pair signed rank test), tissue perfusion parameters  did not significantly change.NE increased blood pressure (MAP from 58 (9) mmHg to 77 (8) mmHg, −1 min−1 vs 0.09  gamma kg−1 min−1, p = 0.93, Wilcoxon signed rank test). At baseline, none of the hemodynamic , and tissue perfusion parameters differed between the two groups (Table p > 0.05). A graphic representation of an exploratory correlation matrix regarding the measured baseline hemodynamic parameters and their changes with NE infusion is provided in Fig. NE dose did not differ between the responders and non-responders' groups . Despite systematically increasing blood pressure, NE only restored the VW in two-thirds of patients. Improvement of CI and tissue perfusion parameters was only observed in patients who have restored the VW. None of the hemodynamic parameters predicted the behavior of VW with NE infusion.Our results add more knowledge on arterial hypotension, vasoplegia, VW and their response to NE. The VW was suggested to have a role in maintaining tissue (and organ) perfusion 17, 18, 19). We confirmed that the VW is altered during arterial hypotension owing to vasoplegia, as it was observed during experimental vasodilation . The VW . We confShrier et al.  demonstr2 gap that reflect persistent abnormal tissue blood flow [One question is why some patients did not increase the VW. The main difference between responder and non-responder patients was the CCP that has only increased in responder patients. In non-responder patients, we observed an increase of arteriolar tone with NE infusion, suggesting that increases of blood flow and blood pressure were unbalanced. Because the increase of blood flow was too low to counterbalance the NE induced changes of vascular properties , the arteriolar tone has more increased than blood flow. In such situation, tissue perfusion could be compromised as we observed sustained abnormal values of pCOood flow . In the Our results bring further explanation regarding the underlying physiological mechanism related to the effects of NE on the VW, pressure tissue perfusion and blood flow tissue. The main effect seemed to be taken by the arterial determinant of VW, as the MSP was not modified by the NE infusion. The effect of NE on the venous side is a dose dependent phenomenon. The MSP did not change because the NE dose was lower than the dose associated with changes of the venous return and preload . The end2 gap) [2/CavO2 decreases in VW responders, suggesting that this group might have a reduction in tissue hypoxia after NE infusion. To simplify the message, the persistence of high arterial lactate, pCO2 gap value or capillary refill time values despite normalization of blood pressure with NE infusion, should lead to evaluate cardiac output and/or to reconsider the dose of NE. Blood flow may be too low with regard to the blood pressure. A further step might be to add an inodilator drug to increase blood flow when tissue perfusion parameters are not completely restored with NE .Our findings strengthen the importance of monitoring the coherence between (and within parameters of) macro-circulation  and micro-circulation when physician use vasoactive treatment in order to improve tissue perfusion. NE may be associated with alteration of tissue blood flow despite an increase in blood pressure because of unbalance between flow and pressure at the level of the tissue . This re2 gap) , 35. TheBecause we have evaluated the VW as a whole and we did not measure other possible explicative parameters  (such asThe present study is limited by the low number of patients. The study could be underpowered to detect some correlations and differences, whereas the sample size is enough to assess VW changes. Firstly, one question concerns the method used to measure the VW and CCP. This method was previously demonstrated to be reasonably accurate, reliable, and reproducible , 11, 12.In post-cardiac surgery patients with vasoplegic hypotension requiring low-dose vasopressor, the VW is low. Norepinephrine restores the VW in only two-thirds of patients. The increase of the VW was associated with an increase of tissue perfusion parameters.