Background: Fibrinogen albumin ratio (FAR) is significantly correlated with the severity and prognosis of cardiovascular disease (CVD). Arterial stiffness is an early lesion of CVD, but no studies have examined the correlation between arterial stiffness and FAR. This study aimed to examine the relationship between FAR and arterial stiffness in patients with type 2 diabetes (T2D), as measured by brachial-ankle pulse wave velocity (baPWV).Methods: In this cross-sectional investigation, patients with T2D were enrolled between January 2021 and April 2022. In each patient, the levels of fibrinogen and albumin in the serum, and baPWV in the serum were measured. A baPWV greater than 1800 cm/s was utilized to diagnose arterial stiffness.Results: The study included 413 T2D patients. The mean age of these participants was 52.56 ± 11.53 years, 60.8% of them were male, and 18.6% of them had arterial stiffness. There were significant differences in baPWV level and proportion of arterial stiffness (p < .001) between the four subgroups categorized by the FAR quartile. The relationships between the FAR and baPWV and arterial stiffness were significantly favorable in the overall population and subgroups of elderly men and non-elderly men (p < .01), while they were insignificant in subgroups of elderly and non-elderly women (p > .05). To investigate the correlation between the FAR and baPWV, the arterial stiffness and the FAR in male T2D patients, respectively, multivariable logistic regression analysis and multiple linear regression analysis were developed. The lnFAR and lnbaPWV had a significant relationship in the multiple linear regression analysis fully adjusted model. After adjusting for potential covariables, multivariable logistic regression analysis revealed that the FAR was independently associated with arterial stiffness . In addition, receiver operating characteristic analysis indicated that the best FAR cutoff value for detecting arterial stiffness in male T2D patients was 76.67 mg/g.Conclusion: The level of FAR had an independent and positive correlation with baPWV and arterial stiffness in male patients with T2D, but not in female patients. The rate of type 2 diabetes (T2D) is rising each year, posing a significant threat to public health, as a result of China’s rapid economic development, lifestyle changes, and ageing population . In 2015Both fibrinogen and albumin are produced in the liver; fibrinogen is implicated in inflammation and clotting cascades , whereasTherefore, this observational study was carried out to investigate the relationship between FAR and baPWV in T2D patients.The current study included T2D patients who were hospitalized in the endocrinology department of the second affiliated hospital of Nantong University from January 2021 to April 2022. T2D was diagnosed using the American Diabetes Association criteria . ExclusiChecking medical records allowed for the collection of information on demographics, drinking and smoking habits, past medication usage, and disease diagnoses. The medication history was particularly focused on the use of drugs for T2D, hypertension, and dyslipidemia.2). The average of the two blood pressure readings was recorded for further analysis after being measured twice with a standard mercury sphygmomanometer.Each subject was measured for anthropometric characteristics, including weight, height, and blood pressure. Body mass index (BMI) was determined by the following formula: weight (kg)/height  was computed utilizing the CKD-EPI creatinine-cystatin C equation (2012) .As previously described, each subject’s baPWV was measured by a trained technician utilizing an automated system  . Each sup value < .05 was considered as statistical significance. Continuous variables with skewed and normal distributions and categorical variables were presented as the mean ± standard deviation (SD), frequencies with percentages, and medians with interquartile range, respectively. For analysis, the data on fibrinogen and albumin levels were ln-transformed due to their skewed distributions. Comparisons of continuous variables with skewed and normal distributions and categorical variables were conducted between groups using the Kruskal–Wallis test and the one-way analysis of variance, and the chi-square test, respectively. Spearman’s analyses of bivariate correlation were applied to measure the strength of associations between FAR level and other clinical variables. In addition, spearman’s bivariate correlation analyses were employed to investigate the associations between the FAR and baPWV and arterial stiffness in the overall population and subgroups of elderly men, non-elderly men, elderly women, and non-elderly women, respectively. To investigate the independent relationships between the FAR level and the baPWV level and the independent relationships between the FAR level and arterial stiffness, multiple linear regression analyses and multivariable logistic regression analyses were constructed. Receiver operating characteristic (ROC) analysis was also carried out to examine the FAR levels’ capacity to detect arterial stiffness.SPSS statistical software version 18.0  was utilized for the analysis of the data. A p < .001) along with the gradual rise in the FAR quartiles. Age, the duration of diabetes, the utilization of acarbose, triglyceride (TG) level, albumin level, fibrinogen level, hemoglobin level, neutrophil percentage, platelet count, and neutrophil/lymphocyte ratio (NLR) level were all significantly different between the four subgroups (p < .05). While there were no significant differences in the proportion of males, smoking and drinking status, systolic and diastolic blood pressure, use of additional antihypertensive and antidiabetic treatments, HbA1c level, eGFR level, urinary albumin-to-creatinine ratio (UACR) level, total cholesterol (TC) level, low-density lipoprotein cholesterol (LDL-C) level high-density lipoprotein cholesterol (HDL-C) level, and white blood cells (WBC) count (p > .05).In total, 413 T2D patients were enrolled in the study. The mean age was 52.56 ± 11.53 years, 60.8% of the participants were male, and 18.6% of the participants had arterial stiffness. The clinical characteristics of the four subgroups are presented in p < .001), as well as significant negative associations with eGFR, TG, and hemoglobin level .As shown in p < .01), but were not significantly associated in subgroups of elderly and non-elderly women (p > .05). The independent association between the FAR and baPWV in male patients with T2D was further investigated using multiple linear regression models, as shown in p < 0.001, R2 = 0.609).The multivariable logistic regression analysis of the correlation between FAR and arterial stiffness in male T2D patients is presented in In addition, a ROC analysis was conducted to determine the FAR cutoff value that would indicate the presence of arterial stiffness instances in male T2D patients. As depicted in In the present investigation, the association between FAR and arterial stiffness as determined by baPWV in T2D patients was investigated. In comparison to female T2D patients, male T2D patients had a positive association between the FAR and baPWV and the prevalence of arterial stiffness.Arterial stiffness can increase cardiac afterload, causing cardiac hypertrophy and left ventricular dysfunction , as wellArterial stiffness is caused by a combination of variables such as an imbalance in elastin collagen ratio, oxidative stress, chronic inflammation, and so on, and diabetes can accelerate this process . NumerouIn a cross-sectional examination of risk factors for diabetic kidney disease (DKD) in T2D patients, FAR was significantly found to be positively associated with neutrophil count and NLR, leading researchers to hypothesize that FAR may be substantially associated with inflammation and consequently DKD . SimilarThe relationship between FAR and platelet count, a critical component of the coagulation system, was found to be statistically significant and positive in this study. Platelet, the primary cause of coronary thrombosis and atherosclerosis, is an essential target for the management of coronary heart disease . AlbuminThe relationships between arterial stiffness and the FAR in T2D patients were shown to differ by gender in this study. Numerous investigations have conclusively shown that the clinical features and sex-specific processes underlying arterial stiffness in males and females were different . In a crThe following are the study’s limitations, which cannot be avoided. First, the limitation of cross-sectional studies prevents the demonstration of a coincidental relationship between FAR and arterial stiffness. Second, due to a lack of data, it was impossible to account for confounding variables, including detailed alcohol and tobacco consumption and daily activity levels. Finally, all of the participants in this study were Chinese, which may restrict the generalizability of the findings.In conclusion, the FAR level was positively and independently associated with baPWV and arterial stiffness in male T2D patients. When considered in combination with other investigations, FAR has the potential to assist in the better management of cardiovascular problems in patients with T2D, particularly male patients.


Laparoscopic adrenalectomy for pheochromocytoma is associated with high risk of intraoperative hemodynamic instability. Our study aimed to identify predictive factors for hemodynamic instability during laparoscopic resection of pheochromocytoma.Between January 2011 and December 2021, 136 patients underwent unilateral laparoscopic adrenalectomy for pheochromocytoma. The patients were divided into 2 groups depending on the presence or absence of hemodynamic instability during surgery. Intraoperative hemodynamic parameters were compared between the 2 groups. Patient demographic characteristics and preoperative evaluations were assessed for their prognostic relevance with respect to intraoperative hemodynamic instability via both univariate analysis and multivariate logistic regression analysis.There was greater blood pressure fluctuations and higher maximum blood pressure and heart rate in the hemodynamic instability group. More patients need intraoperative administration of vasoactive drugs in the hemodynamic instability group. In the univariate analysis, presence of coronary artery disease, tumour size, and previous hypertension history were significantly associated with intraoperative hemodynamic instability. The multivariate logistic regression analysis showed that tumour size and previous hypertension history were independent risk factors for intraoperative hemodynamic instability.Tumour size and previous hypertension history were associated with hemodynamic instability during laparoscopic resection of pheochromocytoma. Adrenal pheochromocytoma derives from catecholamine producing chromaffin cells in the adrenal medulla. Resection of pheochromocytoma carries a high risk of eliciting massive catecholamine release, which can cause severe hypertension , 2. HypoThe present retrospective study was approved by the institutional review board. 144 pheochromocytoma patients underwent unilateral LA via transperitoneal or retroperitoneal approach from January 2011 and December 2021. 2 patients with history of homolateral abdominal surgery and 6 patients undergoing conversion to laparotomy were excluded, leaving 136 patients enrolled in the study. Patients were divided into 2 groups depending on presence or absence of intraoperative HI. As previously described , HI was The preoperative diagnosis of pheochromocytoma was based on clinical manifestations and computed tomography or magnetic resonance image findings. All patients suspected of pheochromocytoma were prepared for surgery by administration of phenoxybenzamine for at least 2 weeks to normalize blood pressure (BP) (＜140/90 mmHg), irrespective of previous hypertension history. Beta-blockers was added to control tachyarrhythmia if necessary. Adequate hydration was administered to all patients preoperatively. The final diagnosis of pheochromocytoma was confirmed by postoperative pathology.Transperitoneal or retroperitoneal LA was performed by surgeons expertizing in adrenal surgery (> 50 cases per surgeon). Four surgeons preferred transperitoneal approach, whereas one surgeon preferred retroperitoneal approach.For transperitoneal LA, patients were placed in semi-lateral decubitus positions with the side of the lesion elevated at 70°. Pneumoperitoneum with a pressure of 12 mmHg was established using a Veress needle through a 10-mm supraumbilical incision. A 10-mm trocar was introduced via the incision to serve as camera port. Two subcostal trocars were placed in the midclavicular and anterior axillary lines, respectively. For right-sided procedures, an additional trocar was placed below the xiphoid for liver traction. An incision on the posterior parietal peritoneum above the descending segment of duodenum was made longitudinally along the right margin of vena cava and subsequently extended outward along the reflection of the peritoneum and liver. Attachments between the adrenal gland and the liver were divided. The vena cava was separated from the adrenal gland to expose the medial adrenal border, through which an aspirator was inserted into the space between the gland and diaphragm to retract the gland laterally. The arterioles along the medial border were divided until the right adrenal vein was identified and divided. Attachments along the upper adrenal border were subsequently divided. Finally, the gland was separated from the upper pole of the kidney and resected. For left-sided procedures, an incision of the spleno-diaphragmatic ligaments was made deep enough to visualize the gastric fundus and the left diaphragmatic crus. The spleno-pancreatic bloc was mobilized medially to expose the adrenal region. The left renal vein was identified and an aspirator was inserted between the adrenal gland and the renal vein to retract the tumour upward. Attachments along the lower adrenal border were divided until the adrenal vein was identified and divided. The attachments along the medial border were divided. Finally, the adrenal gland was separated from the upper pole of the kidney and resected.For retroperitoneal LA, patients were placed in lateral decubitus positions. Operating table was flexed to expand the space between the 12th rib and the iliac crest. A 15-mm incision was made in the midaxillary line, 1 cm above the iliac crest. The retroperitoneal space was initially created using the index finger of the surgeon and then expanded using a self-made dissector inflated with 700 ml of air. A 10-mm trocar was introduced through the incision to serve as camera port. Two operating trocars were placed below the costal margin in the anterior axillary and the posterior axillary lines, respectively. Gerota’s fascia was incised. Dissection was initially performed between the perirenal fat and anterior renal fascia, and subsequently along the psoas muscle to expose the adrenal gland. The gland was separated from the upper pole of the kidney until the adrenal vein was identified and divided. Finally, attachments of the upper and medial adrenal borders were divided and the tumour was resected.Intraoperative hemodynamic parameters were compared between the HI and non-HI groups. Demographic characteristics of the patients and preoperative evaluations were assessed for their prognostic relevance for intraoperative HI. The variables considered were age, sex, body mass index (BMI), presence or absence of preoperative symptoms, comorbidities, smoking and drinking, tumour laterality, tumour size, surgical approach, previous hypertension history, duration of hypertension, family history of hypertension and BP after alpha-blockade. Hypertension was defined as SBP > 140 mmHg or diastolic blood pressure (DBP) > 90 mmHg.Statistical analyses were conducted to determine the prognostic relevance of preoperative factors for HI. Parametric data (presented as mean ± standard) were compared using t-test. Non-parametric data (presented as median and min–max range) were compared using Mann-Whitney U test. Categorical data were compared using χ2 test or Fisher’s exact test. A multivariate logistic regression analysis was conducted to determine the independent risk factors for HI. All p-values were two-sided and p < 0.05 was considered significant. Analyses were conducted using SPSS 25.0 .The HI group and non-HI group included 84 and 52 patients, respectively. Table Patient characteristics of both groups were listed in Table Of the investigated risk factors, presence of coronary artery disease, tumour size and previous hypertension history were included in multivariate logistic regression analysis. Age was also included in the multivariate analysis, considering the difference between the 2 groups was marginally significant. The result revealed that tumour size  and previous hypertension history  were independent risk factors associated with intraoperative HI (Table HI during surgical resection of pheochromocytomais is still a big concern for surgeons and anesthesiologists, since it has been proven to be associated with morbidity , 9. HoweNowadays LA is the gold standard of surgical treatment for adrenal tumours. For pheochromocytoma, there has been debate in the literature whether the formation of pneumoperitoneum could lead to a massive release of catecholamines, resulting in hypertension and tachycardia . HoweverSimilar to the results of the previous studies , 10, we Some underlying diseases can impair the cardiovascular function, which may in turn influence intraoperative hemodynamic parameters. Pisarska-Adamczyk et al.  and Bai Our study showed that previous hypertension history was an independent risk factor for intraoperative HI. As is known, a proportion of patients with pheochromocytoma are normotensive. Normotension is seen mostly in patients with relatively small amounts of catecholamines in circulation. On the other hand, sustained and paroxysmal hypertension strongly correlates with high levels of plasma norepinephrine and epinephrine, respectively . IncreasWith respect to LA for pheochromocytoma, only a few studies have evaluated the effects of surgical approach on the occurrence of HI with conflicting results. Vorselaars et al. showed that retroperitoneal approach carried greater risk of intraoperative hypotension than transperitoneal approach . On the Numerous other risk factors for HI were reported in the literature, including plasma or urinary level of catecholamine, BMI, clinical symptoms and et al. , 23, 24.This study has limitations typical of a single center study. A relatively limited number of patients were included, mainly due to the rare occurrence of pheochromocytoma. Second, this is a retrospective study, and selection bias was not avoidable. Another important limitation of the study seems to be the choice of the definition of HI. The multitude of definitions presented by various authors makes it difficult to compare the results.Overall, in our group, hemodynamic instability occurred in more than half of the patients undergoing LA for pheochromocytoma. The size of the adrenal tumour and previous hypertension history were independent risk factors of HI during laparoscopic resection of pheochromocytoma.


Intraoperative hypotension is common in patients having non-cardiac surgery and is associated with serious complications and death. However, optimal intraoperative blood pressures for individual patients remain unknown. We therefore aim to test the hypothesis that personalized perioperative blood pressure management—based on preoperative automated blood pressure monitoring—reduces the incidence of a composite outcome of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery.IMPROVE-multi is a multicenter randomized trial in 1272 high-risk patients having elective major abdominal surgery that we plan to conduct at 16 German university medical centers. Preoperative automated blood pressure monitoring using upper arm cuff oscillometry will be performed in all patients for one night to obtain the mean of the nighttime mean arterial pressures. Patients will then be randomized either to personalized blood pressure management or to routine blood pressure management. In patients assigned to personalized management, intraoperative mean arterial pressure will be maintained at least at the mean of the nighttime mean arterial pressures. In patients assigned to routine management, intraoperative blood pressure will be managed per routine. The primary outcome will be a composite of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery.Our trial will determine whether personalized perioperative blood pressure management reduces the incidence of major postoperative complications and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery.ClinicalTrials.gov NCT05416944. Registered on June 14, 2022.The online version contains supplementary material available at 10.1186/s13063-022-06854-0. About 2% of patients having inpatient non-cardiac surgery die within the first month after surgery in Europe  and the Intraoperative hypotension is common in patients having non-cardiac surgery and is associated with serious complications—such as postoperative acute kidney and myocardial injury –6—and evOptimal intraoperative blood pressures for individual patients also remain unknown. On a population basis, intraoperative mean arterial pressures less than 60–70 mmHg are associated with organ injury , 5, 9, lUniversally targeting higher intraoperative mean arterial pressures  does not reduce postoperative complications in patients having major non-cardiac surgery . In contWe aim to test the hypothesis that personalized perioperative blood pressure management—based on preoperative automated blood pressure monitoring—reduces the incidence of a composite outcome of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery.The proposed trial will be conducted in accordance with the ethical principles based on the Declaration of Helsinki  and the IMPROVE-multi will be a multicenter randomized controlled blinded  clinical superiority trial in 1272 high-risk patients having elective major abdominal surgery. We plan to enroll patients at approximately 16 German university medical centers. The trial coordinating center will be the University Medical Center Hamburg-Eppendorf, Hamburg, Germany.2 within the last 6 months); coronary artery disease (any stage); chronic heart failure ; valvular heart disease (moderate or severe); history of stroke; peripheral arterial occlusive disease (any stage); chronic obstructive pulmonary disease (any stage) or pulmonary fibrosis (any stage); diabetes mellitus requiring oral hypoglycemic agent or insulin; immunodeficiency due to a disease  or therapy ; liver cirrhosis (any Child–Pugh class); body mass index ≥ 30 kg/m2; current smoking or 15 pack-year history of smoking; age ≥ 65 years; expected anesthesia duration ≥ 180 min; B-type natriuretic peptide > 80 ng/L or N-terminal B-type natriuretic peptide > 200 ng/L within the last 6 months.We will include consenting patients ≥ 45 years scheduled for elective major abdominal surgery with general anesthesia that is expected to last ≥ 90 min. Patients must fulfill at least one of the following high-risk criteria: exercise tolerance < 4 metabolic equivalents as defined by the guidelines of the American College of Cardiology/American Heart Association; renal impairment ; pregnant women; and patients in whom preoperative automated blood pressure monitoring is not possible.The trial flow and measures for each participating patient are provided in Fig. Written informed consent will be obtained by dedicated trial personnel. Baseline demographic and medical characteristics will be recorded and entered in an electronic Case Report Form (eCRF). Preoperative automated blood pressure monitoring will be performed either at home or in the hospital for one night using upper arm cuff oscillometry at 30-min intervals. After excluding artifacts, we will calculate the mean of the nighttime mean arterial pressures. We will define nighttime as 00:00 to 06:00 h , 21.Patients will be randomized in a 1:1 ratio using central block-wise randomization with variable block length stratified by centers with an electronic tool to personalized blood pressure management or to routine blood pressure management. The randomization will be performed directly before the induction of general anesthesia.In patients assigned to personalized management, intraoperative mean arterial pressure will be maintained at least at the mean of the nighttime mean arterial pressures. If the mean of the nighttime mean arterial pressures will be lower than 65 mmHg, the intraoperative mean arterial pressure will be maintained at least at 65 mmHg; if the mean of the nighttime mean arterial pressures will be higher than 110 mmHg, the intraoperative mean arterial pressure will be maintained only at least at 110 mmHg. The intervention period will start at the induction of general anesthesia and will end 2 h after the end of surgery.In patients assigned to routine management, intraoperative blood pressure will be managed per routine which usually includes keeping mean arterial pressure ≥ 65 mmHg . AnestheIn both groups, the interventions used to achieve the mean arterial pressure target will be at the discretion of treating anesthesiologists and will include intravenous fluid administration, vasoactive medications, adjusting anesthetic depth, and modifying patient position.In all patients, perioperative blood pressure will be routinely monitored using intraarterial blood pressure monitoring  or upper arm cuff oscillometry. All other anesthesiologic and surgical procedures will be performed according to routine care and the discretion of the attending anesthesiologists.The primary outcome will be a composite of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery.Incidence of the composite primary outcome within 3 days after surgery and the incidences of each of the individual components of the primary outcome within 3 and 7 days after surgeryIncidence of a composite outcome of need for renal replacement therapy, myocardial infarction, non-fatal cardiac arrest, and death within 30 and 90 days after surgery and the incidences of each of the individual components of this composite outcome within 30 and 90 days after surgeryIncidence of a composite outcome of infectious complications within 7 days after surgery and the incidences of each of the individual components of this composite outcome within 7 days after surgeryTime-to-event outcome with the event “transfer from intensive care unit to normal ward” within 90 days after surgeryTime-to-event outcome with the event “hospital discharge” within 90 days after surgeryIncidence of unplanned hospital re-admission within 30 days after surgerySecondary outcomes will be as follows:Acute kidney injury will be defined as an increase in serum creatinine of ≥ 50% from baseline or need for renal replacement therapy within the first 7 postoperative days .Acute myocardial injury will be defined as an increase in high-sensitivity troponin concentration within the first 7 postoperative days according to the definition of “myocardial injury and infarction associated with non-cardiac procedures” set forth in the Fourth Universal Definition of Myocardial Infarction (2018) .Serum creatinine and high-sensitivity troponin I or T (whichever is used in each center) will be measured before surgery  and on postoperative days 1, 2, 3, and 7. When patients are discharged earlier, serum creatinine and high-sensitivity troponin will be measured on the day of discharge. Additional serum creatinine and high-sensitivity troponin concentrations will be recorded during the initial 30 postoperative days on an as-available basis.Non-fatal cardiac arrest will be defined as successful resuscitation from ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless electrical activity requiring cardiopulmonary resuscitation, pharmacological therapy, or cardiac defibrillation.Clostridium difficile, endometritis, surgical site infection, deep incisional surgical site infection, organ or space surgical site infection, unknown infection with pathogenic organisms in tissue or fluid, and sepsis.Infectious complications will be defined according to the “Standardised Endpoints in Perioperative Medicine (StEP)” initiative  and inclData for the outcome assessment will be collected using medical records and telephone interviews on postoperative days 3, 7, 30, and 90.Serious adverse events will be documented during the trial and will be reported to the primary ethics committee.The sample size was estimated from the anticipated incidence of the composite primary outcome of at least one severe complication or death within 7 days after surgery. We expected an incidence of 25% in the routine management group (adapted from own data and literature ) and 17%We will use a group sequential-design with one unblinded interim analysis using the O’Brien-Fleming spending function . A totalp-value is < 0.0015 one-sided, the null hypothesis will be rejected, and the trial will be stopped for efficacy. Otherwise, recruitment will be continued. At the end of the trial, the statistical test for the primary outcome will be performed at a significance level of 0.049 two-sided.Descriptive analysis will be performed to describe the patient characteristics and clinical data. The primary and secondary outcomes will be analyzed according to the intention-to-treat principle. The primary outcome analyses  will be conducted using a two-sided test of proportions with continuity correction. When a total of 636 patients will have been observed for 7 days, an unblinded interim analysis will be performed. If the resulting In secondary outcome analyses, the incidence of each of the individual components of the primary outcome and of the additional secondary outcomes will be analyzed using a two-sided test of proportions with continuity correction. In additional analyses, the primary outcome and its individual components will be treated as time-to-event outcomes. Due to the competing event death, all time-to-event outcomes will be assessed using Aalen-Johansen estimators and accompanied by effect estimates based on cause-specific Cox regressions. In further analyses, the primary and secondary outcome analyses will be repeated in the per-protocol population. As a sensitivity analysis, the primary outcome will be analyzed using a mixed logistic regression model including a fixed effect for the random group and a random effect for the center to account for the cluster structure in the data. In further sensitivity analyses, regression models (logistic and cause-specific Cox regression) including potential prognostic baseline variables will be used.If more than 5% of values are missing for the primary outcome, we will use multiple imputation in a sensitivity analysis. The number of imputations for multiple imputation will be chosen depending on the proportion of missing data according to White et al. .A full statistical analysis plan will be developed before any data are evaluated.Screening logs will be collected to assess the risk for selection bias in patient recruitment. Randomization codes will be provided by an independent biostatistician to ensure blinding as long as practical. Participating patients, outcome adjudicators, and data analysts will be blinded to group assignment. Furthermore, a blinded outcome committee will be implemented to avoid detection bias. Anesthesiologists treating patients assigned to personalized management cannot be blinded as the results of preoperative automated blood pressure monitoring are necessary for perioperative personalized blood pressure management.Patient data will be documented by dedicated trial personnel and managed in an eCRF using a trial management software. Data will be entered via an encrypted connection (HTTPS) in web browser input masks. Each patient will be given an identification number to ensure pseudonymized data analysis. Each change in the data, e.g., due to resolved queries, will be documented by an automated audit trail. Pseudonymized data will be stored in accordance with local data protection laws.Trial site monitoring will be conducted to ensure that the rights and well-being of patients are protected; that the reported trial data are accurate, complete, and verifiable; and that the conduct of the trial follows the currently approved protocol/amendment(s), with good clinical practice and with applicable regulatory requirements. The monitoring comprises the following tasks: training of the trial personnel prior to trial start (site initiation visit), regular on-site monitoring visits, and a close-out visit at the end of the trial. Central elements of the monitoring are the verification of consent and inclusion criteria, along with trial conduct.Three independent experts—including a biostatistician—will be the members of the Data Safety Monitoring Board (DSMB). DSMB members will meet before trial initiation, 3 months after the inclusion of the first patient, thereafter every 6 months, and after the interim analysis—and more often as they deem necessary or advisable. DSMB members will consider by-group results on a blinded basis. If DSMB members identify safety issues, they will have the prerogative to request unblinded outcomes. DSMB members will advise whether to continue, modify, or stop the trial. DSMB members will act independently from the sponsor and competing interests.http://www.icmje.org/).The results of this trial will be published in an international peer-reviewed medical journal. Both positive and negative results will be reported. The principal investigator is responsible for the preparation of the final report and therefore will have access to all available data. The full protocol, anonymized data, and the statistical code used for the analysis will be available from the corresponding author upon reasonable request. Authorships will be based on the recommendations of the International Committee of Medical Journal Editors .Additional file 1. SPIRIT checklist.


Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies. It is well known that metabolic, cardiovascular (CV), and renal diseases closely interact with each other, forming the so-called cardio-renal-metabolic (CRM) syndrome , 2, wherOne class of glucose-lowering drugs, sodium-glucose co-transporter-2 inhibitors (SGLT2i) , has recThe development of SGLT2i started from the discovery of phlorizin in the bark of apple trees by Petersen in 1835 and the subsequent discovery of its effects on glucosuria and plasma glucose-lowering by von Mering in 1886 . In 1962It is well known that patients with diabetes frequently develop micro- and macrovascular complications, which worsen the prognosis and quality of life (QOL) of patients. More recently, a multinational cohort study demonstrated that HF and CKD are early and frequent complications in patients with T2DM , and then = 17,160; median follow-up, 4.2 years), was conducted  and the CANVAS program   (2 = 0%) and CV death with a significant intertrial difference . Furthermore, there were significant risk reductions for CV death and all-cause mortality in EMPA-REG OUTCOME but not in the other two trials. The difference in baseline CV disease risk may explain these differing outcomes. The results of a meta-analysis showing a numerically higher incidence and a greater efficacy of SGLT2i in patients with a history of ASCVD than in patients with multiple risk factors support this notion  . For thes notion .In DECLARE-TIMI 58, non-inferiority of dapagliflozin to placebo with respect to 3P-MACE was first assessed and superiority was sequentially tested with hierarchical closed testing procedure. The study verified non-inferiority of dapagliflozin, but not superiority, as described above. In addition to 3P-MACE, the effects of SGLT2i were rigidly tested on a composite of HHF and CV death as a co-primary endpoint. DECLARE-TIMI 58 first demonstrated a statistically significant risk reduction in HHF/CV death, and EMPA-REG OUTCOME and CANVAS also reported positive effects on this outcome , 38, 39.2, ESRD, and renal death and it slowed the rate of eGFR decline  and other glucose-lowering drugs   . SGLT2i o −1.06) . Moreoveo −1.06) . Althoug2)  , 55. Col2 (The 2022 American Diabetes Association (ADA) standards of medical care in diabetes recommend a comprehensive approach to reduce the risk of diabetic complications, in which the following four factors are considered to be fundamental: management of glycemia, blood pressure, and lipids and the incorporation of specific therapies with efficacy on CV and renal outcomes . The imp2 Table 2.HF is a diabetic complication that must be managed; simultaneously, it is a serious issue for individuals without diabetes. The global prevalence of HF is estimated to be approximately 64 million, and it is the world’s leading cause of hospitalization with a high risk of re-hospitalization , 64. As n = 4,744; median follow-up, 18.2 months)  or death from any cause , a meta-analysis of DAPA-HF and EMPEROR-Reduced showed significant risk reductions for both outcomes  with or without DM ( months) . Dapagli months) . Signifi months) . In addioutcomes . These fApproximately half of the patients with HF have LVEF of >40%, HF with preserved or mildly reduced ejection fraction (HFpEF or HFmrEF) , 69. Then = 6,263; median follow-up, 2.3 years) , in patients who start treatment during the subacute phase , or in patients with a prior LVEF of ≤40% (HFrEF) that has since improved to >40% . These gaps in evidence were addressed in the DELIVER trial, which evaluated the efficacy and safety of dapagliflozin in patients with HFmrEF and HFpEF (3 years) . In this3 years) . An impr3 years) . Notably3 years) , SGLT2i n = 9,718) and dapagliflozin  further support this notion /angiotensin converting enzyme inhibitors (ACEi), β-blockers (BB), and mineralocorticoid receptor antagonists (MRA) for reducing HHF and death in all patients with HFrEF (Class I) . MoreoveSGLT2i were included in the 2022 AHA/ACC/HFSA HF guidelines for the treatment of HFmrEF and HFpEF to reduce HHF and CV mortality (Class 2a) . This isn = 4,304; median follow-up, 2.4 years) .Although it was not a primary endpoint, protective effects of SGLT2i on renal function were demonstrated in three CVOTs, EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, in which most enrolled patients had preserved renal function –16. The 4 years) . This tr4 years) . Favorab4 years) . In addiDAPA-CKD also assessed the effects of dapagliflozin on HF events and mortality. The HR for the CV composite of death from CV causes or HHF was 0.71 (95% CI 0.55 to 0.92) and the HR for death from any cause was 0.69 (95% CI 0.53 to 0.88) . These bn = 6,609; median follow-up, 2.0 years) were recently published  or CV death, by 28%  regardless of diabetes status. The HRs for each component were 0.71 (95% CI 0.62 to 0.81) for progression of kidney disease and 0.84 (95% CI 0.60 to 1.19) for CV death. Furthermore, the rate of annual decline in eGFR was slower in the empagliflozin group than in the placebo group, with a between-group difference for the change from randomization to the final follow-up visit of 0.75 mL/min/1.73 m2 per year (95% CI 0.54 to 0.96). Overall, EMPA-KIDNEY confirmed the efficacy of SGLT2i in patients with CKD regardless of T2DM.Results of the EMPA-KIDNEY trial  in the SGLT2i group than in the placebo group in a meta-analysis that included EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 . On the In this review, we have summarized the results of RCTs and real-world data for SGLT2i treatment in patients with T2DM, HF, and CKD. Although the primary action of SGLT2i involves inhibition of SGLT2 expressed on proximal tubule cells, these drugs exhibit pleiotropic effects, which include reductions in body weight, blood pressure, intra-glomerular pressure, hyperuricemia, inflammation and oxidative stress, inhibition of the sympathetic nervous system, and improvements in erythropoiesis, cardiac energy metabolism and vascular function –93. The Although the efficacy of SGLT2i in CRM interactions is becoming increasingly clear, some issues remain unclear. Acute HF management with SGLT2i is one such example, and has received growing attention. A relatively small RCT was conducted and reported a significant clinical benefit of SGLT2i on the prognosis and symptoms in patients hospitalized for acute HF . A largeConsidering the emerging concept of CRM interactions, SGLT2i have shown better performance than initially expected. SGLT2i have not only been used as an antidiabetic agent but have also become a new treatment option for patients with HF (irrespective of LVEF or care settings) and/or CKD. Regardless of the presence of diabetes, patient management focusing on cardiorenal protection is important in terms of prognosis and QOL. SGLT2i can contribute to better treatment strategies for a huge number of patients suffering from CRM diseases.All authors contributed to the conception of the review. HA and AN wrote the first draft, and NM and TY revised it critically for important intellectual content. All authors contributed to the article and approved the submitted version.


Subclavian artery stenosis (SAS) is a peripheral arterial disease of asymptomatic appearance and disastrous consequences. The traditional screening method remains unsatisfactory.The study aimed to assess the diagnostic performances of inter-arm systolic pressure difference (IASBPD), derivatives of pulse volume recording (PVR), and their combination in detecting subclavian artery stenosis.The present study was a retrospective analysis of clinical data from inpatients suspected of supra-arch artery stenosis in Fuwai hospital during 1 year, who underwent selective arterial angiographies. We obtained simultaneous blood pressure measurements on four limbs and pulse waves for calculating IASBPD and PVR derivatives prior to the angiographies. We utilized the receiver operating characteristic curve (ROC) to calculate the optimal cut-off value of IASBPD, upstroke time (UT), and upstroke time per cardiac cycle (UTCC) for detecting SAS. Moreover, we compared the sensitivity and specificity of IASBPD, UT, UTCC, and their combinations for diagnosing SAS .P < 0.001). And their corresponding cut-off points were 9 mmHg, 202 milliseconds, and 23.2%. The sensitivity and specificity of IASBPD ≥ 9 mmHg were 57.0 and 94.1%. UT ≥ 202 ms and UTCC ≥ 23.2% yielded similar sensitivity , but UTCC had higher specificity . The sensitivity of the combination of IASBPD and UT (85.2%) or UTCC (78.5%) was significantly higher than IASBPD alone . The specificity of either combination decreased to 67.6 and 76.8% (P < 0.05).We consecutively enrolled 320 eligible patients. Based on SAS’s definition of stenosis above 50%, the area under the curve of IASBPD, UT, and UTCC were 0.84, 0.76, and 0.80 (This present study showed that the combinations of IASBPD and PVR-derived parameters promoted diagnostic sensitivity and preserved adequate specificity than those alone for detecting SAS. Subclavian artery stenosis (SAS) is a peripheral arterial disease mainly caused by atherosclerosis. Its prevalence is around 1.5% in the general population and has significantly increased as the aging society exacerbates worldwide. . SAS canThe inter-arm systolic pressure difference (IASBPD) has been widely used in detecting SAS due to its non-invasive nature and convenience. However, the relatively small epidemiological data on IASBPD has yet to establish an optimal cut-off value , 5, 7, 8The present study aims to assess the diagnostic value of IASBPD, UT, and UTCC, emphasizing their sensitivity and specificity alone or when combined in detecting SAS.ClinicalTrials.gov. We consecutively included the patients suspected of superior arch artery stenosis and later confirmed by angiography in the Fuwai hospital from October 2017 to October 2018. Apart from signing standard informed consent regarding the disease and the interventional procedure, all patients agreed to participate in the study after they were fully informed about the research plan. All participants had records of baseline characteristics, including age, sex, ID number, contacts information, relevant risk factors, smoking habits, left ventricular ejection fraction measured by echocardiography, medications, and lab test results such as hemoglobin levels, cardiac enzymes, and liver and kidney functions both before and after the intervention. We also collected simultaneous blood pressure measurements in the four limbs, the pulse waves, and the supra-arch angiographies results. Those who met the following criteria were excluded: (1) Moderate to severe aortic valve stenosis or left ventricular outflow tract obstruction. (2) Diseases that caused severe arrhythmia and significant blood pressure fluctuations during the measurements, such as atrial fibrillation. (3) There are missing limbs, limb malformation, or limb pain at the blood pressure measurement site. (4) Non-atherosclerotic arterial disease, such as Takayasu arteritis. (5) Missing data of IABPSD, PVR derivatives, or angiographies.The Ethics Committee in our institution has approved the study. Our study is a retrospective analysis of the population from the cohort of “Chinese Registered Study on Synchronizing Extremity Blood Pressure and Pulse Wave Velocity and Cardiovascular Outcomes, ASORPWICE” (Registration Number: NCT03521739). The entire protocol can be accessed online at In a quiet clinical office with a temperature of 22–25°C, we collected the patient’s general information . The subjects then took a relaxed supine position, with upper limbs on both sides of the body, and rested for 5 min. We then attached ECG and heart sound sensors to the patients. As previously described in other literature, We adopted the extremity blood pressure meter  to record the measurements , 13, 14.Nurses with professional training performed these procedures. We defined IASBPD as the absolute difference in systolic pressure of the bilateral brachial arteries. We measured UT and UTCC based on brachial arteries. And we selected the highest value among the limbs to report. According to the common standard, we performed the subclavian arteriography three to five days after the IABPSD and PVR derivative measurements . In brieWe used electronic vernier calipers to measure the diameters of the narrowest lumen of the stenosis and the normal lumen at the distal to the stenosis. We adopted the NACSET standard to calculate the degree of stenosis: the degree of stenosis =  × 100% .t-test. Categorical variables were represented by frequency and percentage and compared by the χ2 test or Fisher’s exact probability method. The area under the curve (AUC) was calculated using the receiver operating characteristic curve (ROC). We used the Youden index as the cut-off point for the diagnosis of SAS ≥ 50% to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and the diagnostic accuracy of IASBPD, UT, UTCC, and the combination of IASBPD and UT or UTCC in detecting SAS. We considered a P-value less than 0.05 to be statistically significant.We performed all statistical analyses using SPSS 25.0 software. Continuous variables were expressed by mean ± standard deviation (SD) and compared by the student’s Patients or the public WERE NOT involved in our research design, conduct, reporting, or dissemination plans.We retrospectively analyzed 320 patients (640 subclavian arteries) with 248 males (77.5%) in the study. The enrolled participants had a mean age of 64.3 ± 8.5 years (ranging from 39 to 84 years old). As depicted in We measured IASBPD, UT, and UTCC in all 320 SAS patients. No adverse events occur during the measurements. The measured values of IASBPD, UT, and UTCC corresponding to different degrees of SAS patients and their comparison are shown in P < 0.001). Its sensitivity was 57.0%, and its specificity was 94.1% , its sensitivity was 72.6%, and specificity was 72.4% (P < 0.05). In addition, compared with IASBPD, both UT and UTCC showed higher sensitivity (P < 0.01) and lower specificity (P < 0.01) (When the UT cut-off point was set at 202 milliseconds (ms) with AUC 0.76  .P > 0.05). In contrast, the specificity of the combination of IASBPD and UT was significantly lower than that of IASBPD and UTCC . The combination of IASBPD and UT or UTCC significantly improved sensitivity in detecting SAS than IASBPD, UT, or UTCC alone. However, the combinations reduced the specificity  and bilateral SAS   .Having enrolled the largest cohort of 320 SAS patients, The present study evaluated the sensitivity and specificity of IASBPD, PVR derivatives, and their combinations in detecting SAS. For IASBPD, Our study achieved a larger AUC and a greater sensitivity when the cut-off point of IASBPD was 9 mmHg instead of 10 mmHg. The better cut-off points for UT and UTCC on upper limbs were 202 ms and 23.2%. In addition, Our results demonstrated that UT and UTCC were valuable tools for detecting upper extremity arterial stenosis. Furthermore, the combination of IASBPD and UT or UTCC significantly improved the diagnostic sensitivity of SAS than IASBPD, UT, or UTCC alone, especially in the case of bilateral SAS.Because asymptomatic SAS cases are often overlooked in clinical practice, convenient and effective screening methods are direly needed. In 2001, English et al.  analyzedAnother concern of IASBPD in diagnosing SAS is the false-negative result, especially when the patient had bilateral SAS of a similar degree , 4. UT aInstead of IABPSD, UT, or UTCC alone, The study results supported combining IABPSD and UT or UTCC in detecting SAS. As listed above, the sensitivity of the combination of IASBPD and UT or UTCC raised significantly more than those alone. At the same time, the specificity of the combinations decreased slightly to 76.8% (IABPSD and UTCC) and 67.6% (IABPSD and UT). We believe the specificity of the combination is adequate and acceptable for clinical practice.Our study possesses several limitations. First, the study is single-centered and may induce selection bias. However, our study aims to evaluate the diagnostic power of IABPSD, UT, and UTCC in SAS patients. Moreover, our study has enrolled patients with confirmed SAS. So selection bias is limited. Still, the issue of external validity resides due to the nature of the single-centered design. In addition, We excluded individuals with atrial fibrillation because the condition would interfere with the PMR for our exclusion criteria. We also reject participants with non-atherosclerotic causes such as Takayasu arteritis. The exclusions will also limit the external validity. Another issue of concern is observational bias. Pitfalls may lie in diagnosing SAS by relying solely on PVR-derived parameters. First, UT measurement might produce false-positive results in patients with severe aortic valve or left ventricular outflow tract obstruction . CarefulIn summary, our retrospective study supported that combining IASBPD and PVR-derived parameters, including UT and UTCC, provided superior sensitivity and acceptable specificity in detecting SAS. Therefore this method could be a convenient, non-invasive, and cost-effective alternative in detecting individuals with SAS in routine cardiovascular practice.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 the Ethics Committee of Fuwai Hospital. The patients/participants provided their written informed consent to participate in this study.XA and HD drafted the manuscript. HD, YD, and YC conducted the study. YZ and WZ supervised the commencement of the study. XJ was the director of the department of vascular disease, was in charge of the investigation, and he helps edited the manuscript. All authors contributed to the article and approved the submitted version.


The mean change in eGFR over time was 1.24 mL/min/1.73 m2 per year in the denosumab group and 0.45 mL/min/1.73 m2 per year in the raloxifene group (p = 0.0004). However, the risks of acute kidney injury (10.53%) and chronic dialysis (0.66%) in this study cohort were not significantly different for the two anti-osteoporosis treatments. Close monitoring of the residual kidney function and treatment effect is needed in those with denosumab.Both osteoporosis and kidney diseases are common and intercorrelate to increase morbidity and mortality in elderly women. This study aimed to compare adverse kidney outcome between women initiated with denosumab and a matched group of raloxifene initiators using propensity score matching methods in a large healthcare delivery system in Taiwan. The risks of adverse kidney outcomes were estimated using Cox proportional hazard regression and the change in kidney function over time was analyzed using the linear mixed model. A total of 9444 (4722 in each group) women were identified who matched the inclusion criteria between January 2003 and December, 2018. Denosumab use was significantly associated with higher risk of eGFR decline ≥ 30% from baseline than raloxifene use (aHR: 1.26; 95% CI: 1.16–1.36,  As the world is experiencing an unprecedented rise in the elderly population, the prevalence of many age-related disorders, including osteoporosis and chronic kidney disease (CKD), is also increasing. Previous studies have demonstrated that patients with kidney dysfunction show reduced bone mineral density (BMD) and an increased risk of fracture ,2,3. In 2 [Different anti-osteoporotic agents targeting various stages of bone remodeling have been developed in recent decades, including bisphosphonates, selective estrogen receptor modulators (SERM), and inhibitors of the receptor activator of nuclear factor-κB ligand (RANKL). Many of these agents are metabolized by the kidneys, and it has been suggested that they require dose adjustment in patients with renal impairment . Althoug2 . New ant2 ,8.2 per year; p < 0.0001). However, the interpretation of this result in the general population may be limited due to the exclusion of patients with a serum creatinine level above 2.5 mg/dL in this study.Raloxifene, a second-generation SERM, is a common treatment option for women with osteoporosis. By regulating transforming factor-β3 gene expression and suppressing interleukin-6 promoter activity, raloxifene maintains bone mass by inhibiting the differentiation and bone-resorptive activities of osteoclasts ,9. The MDenosumab is a human monoclonal antibody that acts as an osteoprotegerin (OPG) mimic against the receptor activator, RANKL. By interrupting the binding of RANKL to RANK, denosumab suppresses osteoclastogenesis, decreases bone reabsorption, and increases bone density ,13. In tAlong with bisphosphonates, both denosumab and raloxifene are recommended treatment agents in guidelines and are reimbursed by the Taiwan National Health Insurance program ; howeverThis retrospective cohort study used electronic health record (EHR) data from the Chang Gung Research Database (CGRD) of the healthcare delivery system of Chang Gung Memorial Hospital (CGMH) in Taiwan. Briefly, the CGRD contains individual patient-level EHR from the CGMH, providing 10–12% of health services reimbursed by Taiwan National Health Insurance (NHI) program in 2018 . The datUsing the CGRD, we first identified new users of denosumab and raloxifene in the outpatient department. To ensure that new users of denosumab and raloxifene were included, patients without medical records for at least one year before the start of treatment and those who had ever been treated with counterpart therapy were excluded. Other inclusion criteria were patients aged between 30 and 90 years at the index date , with at least one serum creatinine (SCr) baseline measurement. For kidney outcome assessment, patients were excluded due to a lack of medical encounters after the index date, and if they had undergone kidney replacement therapy (KRT) or cancer diagnosis before the index date. Because most patients in the raloxifene group were female, male patients were excluded from the analysis . FurtherBoth denosumab and raloxifene are reimbursed by the Taiwan NHI program as monotherapy for confirmed osteoporosis, which is defined as a T score of bone mineral density ≤−2.5 standard deviation (SD) measured using dual-energy X-ray absorptiometry (DXA) scanning with a history of one or more spinal or femoral fracture, or osteopenia  with two or more spinal or femoral fractures. Denosumab (60 mg/mL/syringe) is recommended to be administered at one unit per 6 months, whereas administration of raloxifene (60 mg/tab) is recommended at one unit per day. To quantify the intensity of treatment exposure, the proportion of days covered (PDC) was defined as  for denosumab users. The PDC for raloxifene users was defined as  .The outcomes of interest were acute kidney injury (AKI), time to ≥30% estimated glomerular filtration rate (eGFR) reduction from baseline measurement , and ini−1.154 × age−0.203 × 0.742 ) [eGFR was calculated using the Taiwan version of the abbreviated Modification of Diet in Renal Disease equation ) . The folThe following study covariates were measured at baseline as potential confounders to be adjusted in the analyses: age, gender, eGFR, other medications with ≥28 days use , aspirin, antithrombotic medications, osteoporosis medications), and the Charlson Comorbid Index , which wIt is known that AKI can accelerate kidney function deterioration  and potePropensity score (PS) matching was applied to balance the differences in baseline demographic and clinical characteristics between the denosumab and raloxifene groups. The individual PS of patients receiving denosumab or raloxifene was estimated using logistic regression. New users of denosumab and raloxifene were matched at a 1:1 ratio using the greedy algorithm of the PS matching method . The com2). A two-tailed test  was considered statistically significant. All statistical analyses were performed using SAS 9.4 .Among the matched denosumab or raloxifene new users, we used the Cox proportional model to estimate the adjusted hazard ratios (aHR) of the study outcomes between denosumab and raloxifene users, controlling for time-varying covariates . A linear mixed-effect model was used to estimate the difference in average changes in eGFR over time between denosumab and raloxifene users. To assess the heterogeneous effects of denosumab  by different baseline characteristics, stratified analyses were performed in the matched cohorts by age < 65 years (vs. age ≥65 years) and baseline eGFR groups . The proportion of patients with a baseline eGFR of <30 mL/min/1.73 m2 was lower in denosumab users than in raloxifene users (7.89 versus 8.56%).We identified 12,773 patients  who met the inclusion criteria. The selection process for the study cohort is shown in n = 4722 in each group), the average age was 72 years. The baseline demographic and clinical characteristics were well balanced between the denosumab and raloxifene users (SMD < 0.1) ; but calcium (24.31 versus 35.92%), vitamin D (16.79 versus 25.63%), and calcitonin (0.72 versus 3.15%) use was lower in denosumab users compared with raloxifene users. The differences in the baseline demographic and clinical characteristics are presented in D < 0.1) .n = 497) and 13.68% (n = 646) in the denosumab and raloxifene groups, respectively. The incidence rate of eGFR decline to ≥ 30% of the baseline value was 30.45% (n = 1438) in the denosumab group and 32.78% (n = 1548) in the raloxifene group (n = 61) of the patients required chronic dialysis therapy.During the 6-year follow-up period, the cumulative incidences of AKI were 10.53% , as was the incidence of advanced AKI  . The results of Cox regression analyses showed that denosumab was not significantly associated with any AKI risk compared with raloxifene , and the association was weaker for advanced AKI  after controlling for baseline demographic, clinical characteristics, and prior medication use (p = 0.0137), as well as in patients with a baseline eGFR of <30 mL/min/1.73 m2 .As shown in tion use . In the tion use A, denosup < 0.001). Cox regression analysis showed that denosumab use was significantly associated with a higher risk of eGFR reduction than raloxifene was  (p < 0.0001). Reduction of eGFR >30% was also greater in the denosumab group  compared with baseline eGFR >60  and 30–59.9 mL/min/1.73 m2 , but was less significant in patients with a baseline eGFR of <30 mL/min/1.73 m2 . The risk of an eGFR reduction of ≥30% did not differ between treatment groups in patients who had an episode of any AKI .As shown in  0.0001) B. The in2 and 0.45  ml/min/1.73 m2 in the raloxifene group. Among patients with an eGFR >60 mL/min/1.73 m2 at baseline, the median yearly decline in eGFR in the denosumab group was 2.04  ml/min/1.73 m2, which was greater than that of raloxifene users 0.75  ml/min/1.73 m2. 2, p < 0.0001) after adjusting for age, baseline eGFR, PDC and AKI event  ml/min/1.73 mKI event .In the current study, we observed that denosumab had an additional risk of eGFR reduction of ≥30% from baseline compared with raloxifene. Patients aged < 65 years who were treated with denosumab had an increased risk of eGFR reduction ≥ 30% and AKI development. The magnitude of the relative risk of adverse kidney events between denosumab and raloxifene was somewhat different according to baseline eGFR. To the best of our knowledge, this is the first study to comprehensively evaluate the kidney safety of denosumab compared with raloxifene in a female population.2 in the denosumab group is consistent with current knowledge, as the underlying renal function worsens and patients are more vulnerable to acute kidney injury [AKI is characterized by an abrupt decline in glomerular filtration rate, which is associated with high mortality and morbidity . AKI is y injury . Howevery injury . Despitey injury . In youn2  [A decrease in eGFR of ≥30% from baseline has been proposed as an indicator of CKD progression . As a hi 0.0132) . However 0.0132) . The majAs an SERM, raloxifene may exert renoprotective effects similar to estrogen, as seen in our subgroup analysis, and almost all patients using raloxifene showed a trend of decreasing CKD progression, despite differences in age, baseline eGFR, and AKI occurrence. The trend of mean eGFR also remained steady in the raloxifene group, whereas eGFR in the denosumab group declined progressively during the 6-year follow-up. This may confirm the prior hypothesis of the MORE post hoc study . HoweverMultiple mechanisms have been proposed in prior studies investigating the role of estrogen and estrogen receptors (ERα and ERβ) in kidney diseases , includiCompared with denosumab, raloxifene seems to be a better choice for long-term kidney function. Further studies on the long-term safety of denosumab and raloxifene should include measures of adverse kidney outcomes as the management of osteoporosis related to CKD-MBD warrants further evidence-based studies. The confirmation of different outcomes based on different CKD stages will also benefit the selection of future treatment choices.Although this large cohort of female patients taking osteoporosis medications enables us to detect and compare the relative risk of adverse kidney outcomes of denosumab and raloxifene, this study has some limitations. First, we used the Taiwan NHI program reimbursement criteria to identify denosumab and raloxifene users. Bone mineral density, T-score, and baseline mineral and bone disorders were not assessed, which may lead to an underestimation of the baseline risk of adverse kidney outcomes in both treatment groups, and may not represent the general patient population. Second, unmeasured confounders such as volume status and major surgeries associated with AKI development were not assessed for AKI outcomes. Third, the prescription pattern or frequency of eGFR monitoring could affect the rate of adverse kidney outcomes. Caution should be exercised when comparing kidney safety across different health care systems.In conclusion, the baseline eGFR and patient age were associated with the relative risk of AKI and long-term kidney outcomes between denosumab and raloxifene. Baseline kidney function assessment and close monitoring are essential for planning treatment initiation and shared decision-making regarding treatment choice in women with osteoporosis who are at a high risk of kidney function progression. Raloxifene might be a better alternative to denosumab when long-term kidney outcomes are a priority.


Patients with chronic kidney disease (CKD) occasionally need to restrict their consumption of vegetables and fruits. However, recent evidence suggests that plant-based diets have beneficial effects in patients with CKD. We aimed to determine the sufficiency of β carotene and dietary fiber intake in patients with CKD. We conducted a cross-sectional study among 4476 patients registered in the Fukuoka Kidney Disease Registry (FKR) study, a Japanese prospective cohort study of patients with CKD. Data from 3545 patients were analyzed after excluding cases with insufficient information. We evaluated the relationship between CKD stages and the intake of vegetables and fruits. The intake of β carotene and dietary fiber in CKD stages was evaluated using analysis of covariance. As the CKD stage advanced, the intake of vegetables, green leafy vegetables, and fruits significantly decreased . The intake of vegetables significantly decreased as the CKD stage advanced (P for trend < 0.01). After adjusting for confounding factors, the intake of β carotene and dietary fiber also decreased (both P < 0.01) as the CKD stage advanced. Patients with CKD had insufficient vegetable and fruit intake and a lack of β carotene and dietary fiber from vegetables and fruits. To prevent hyperkalemia, the 2020 update of the clinical practice guideline for nutrition in CKD provided by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative indicates that “it is reasonable to adjust dietary potassium intake to maintain serum potassium within the normal range”3. The dietary therapy for patients with CKD occasionally needs to restrict the consumption of vegetables and fruits. However, a healthy diet that includes consuming fruits and vegetables several times a day is widely recommended for preventing cardiovascular disease (CVD), diabetes, and cancer4. Nevertheless, the percentage of the adult population that meets the fruit and vegetable intake recommendation is low even in healthy adults5. In 2015, 12.2% of adults met the fruit intake recommendation and 9.3% met the vegetable intake recommendation in the United States5. A lower proportion of adults with CKD may meet fruit and vegetable intake recommendations compared with healthy patients; however, information on fruit and vegetable intake in CKD patients is lacking. Recent studies suggest that a diet rich in vegetables and fruits was associated with a lower risk of mortality in patients with CKD and hemodialysis patients7. Whereas animal-based protein ingestion promotes an acidic environment, inflammation, and renal hyperfiltration, a plant-based diet produces an alkaline environment, is anti-inflammatory, and contains reno-protective properties8.Hyperkalemia is associated with arrhythmia and sudden death and increases mortality in patients with chronic kidney disease (CKD)9. β carotene is provitamin A, which can be transformed into retinoic acid in the body10. β carotene can be found in green leafy vegetables and orange and yellow fruits and is reported to have antioxidant effects10. Moreover, dietary fiber has numerous physiological functions and reduces uremic toxins8. Whether the intake of β carotene and dietary fiber is sufficient in patients with CKD is unknown.Retinoic acid is the major metabolite of vitamin A and promotes embryonic development, post-natal growth, vision, epithelial differentiation, and immunityIn the present study, we aimed to investigate the relationship between CKD stages and the intake of vegetables, fruits, β carotene and dietary fiber.The clinical characteristics of participants at each CKD stage are shown in Table We evaluated the relationship between CKD stage and the intake of vegetables, green leafy vegetables, and fruits. As the CKD stage advanced, the intake of vegetables, green leafy vegetables, and fruits significantly decreased . The intake of β carotene and dietary fiber was significantly lower in advanced CKD patients than in less advanced CKD patients (P for trend < 0.01). In this study, we demonstrated an insufficiency in the quantities of vegetables and fruits and the amount of β carotene and dietary fiber ingested by advanced CKD patients.14. Nephrologists and nutritionists provide CKD patients with dietary instructions to achieve this target intake. Consequently, CKD patients sometimes restrict their consumption of fruits and fresh vegetables. The 2019 report from the Japanese Ministry of Health, Labour and Welfare indicates that the mean intake of vegetables in the general population was 280 g per day. In our study, the mean intake of vegetables in CKD patients was 264.3 g per day. Notably, the mean intake of vegetables in patients with CKD G5 was 196.1 g per day—lower than that in the general population. This result suggests that patients with advanced CKD may be deficient in the nutrients provided by vegetables.Nephrologists have traditionally recommended a limited intake of vegetables and fruits to their renal patients to avoid hyperkalemia in these patients. The Japanese Society of Nephrology’s 2014 dietary recommendations for chronic kidney disease propose restricting potassium intake to 2000 mg per day in CKD G3b patients and 1500 mg per day in CKD G4 and G5 patients7. Previous studies of the Mediterranean diet, the Dietary Approaches to Stop Hypertension diet, and healthy plant-based diets have consistently shown the association of these types of diet with lower CKD prevalence or incidence compared with the average diet16. The evidence in CKD patients supports that these diets delay the progression of end-stage kidney disease17.However, emerging evidence suggests that an elevated consumption of vegetables and fruits is associated with lower mortality among adults with mild to moderate CKD and hemodialysis patients13. A high intake of fiber also promotes saccharolytic fermentation and increases short-chain fatty acid production8. Plant-based diets tend to lower cholesterol levels and body weight13. A low intake of vegetables and fruits increases dietary acid load18. In contrast to a plant-based diet, a diet that is rich in animal proteins leads to the proliferation of proteolytic bacteria and increases uremic toxins13. The uremic milieu in CKD patients leads to disturbances in the intestinal barrier and promotes inflammation, oxidative stress, and CKD progression13. A recent study further showed that plant-sourced protein promotes a slower decline in kidney function than animal protein19. In our study, patients with advanced CKD were more likely to consume insufficient quantities of vegetables and fruits. These results suggest that CKD patients may require a richer plant-based diet to prevent CKD progression and improve mortality.Recent evidence suggests that plant-based diets could have additional beneficial effects in patients with CKD. Increased fiber intake improves gut microbiota by reducing the production of uremic toxins10. Retinoic acid, which is derived from β carotene, has multiple functions in development, cell differentiation and proliferation, and inflammation regulation. Retinoic acid is known to have reno-protective effects in kidney diseases such as diabetic nephropathy, renal fibrosis, and podocyte injury20. We calculated the amount of β carotene intake in CKD patients. Moreover, higher fiber intake improves the gut microbiota and contributes to reducing serum urea and creatinine levels in CKD patients8. In this study, the intake of β carotene and dietary fiber was insufficient in advanced CKD patients; the lack of these nutrients may exacerbate CKD. Therefore, a prospective study is needed to elucidate the renal-protective effects of these nutrients.Beta carotene has the beneficial effects of an antioxidant21. Hemodialysis patients with a higher creatinine index have a large amount of skeletal muscle mass22. Patients with large amounts of skeletal muscle mass may eat more fruits and vegetables. Therefore, we speculate that patients in CKD stages G2 or G3a tend to eat more fruits and vegetables compared with patients in CKD stage G1. Further investigation is required to support this hypothesis.In this study, the consumption of vegetables and fruits increased in the CKD stage G2 and G3a groups compared to CKD stage G1 Tables . We used24. However, vegetables and fruits may have been misclassified. Second, dietary information was based on a single assessment; therefore, misclassification was possibly included. Third, given the cross-sectional design of this study, we were unable to describe the causality between the intake of nutrition and kidney function. Fourth, we did not measure the amount of β carotene and dietary fiber from food other than fruits and vegetables. Fifth, fruit consumption in this study was higher than that in healthy adults from the report of the Japanese Ministry of Health, Labour and Welfare, and was therefore likely overestimated. Nevertheless, the information gained in this study contributes to a better understanding of the lack of nutrition in CKD patients.The present study has several limitations. First, we used a food frequency questionnaire of 138 food and beverage items from the Japan Public Health Center-based Prospective Cohort Study. The validation studies about this questionnaire indicate moderate correlations between many foods and nutrients intakes and the consumption of various nutrients and foods including vegetables and fruitsIn conclusion, CKD patients have insufficient vegetable and fruit intake and lack sufficient β carotene and dietary fiber from vegetables and fruits; further investigation is required to determine the association between CKD progression and the lack of this nutrition.25. The inclusion criteria were patients aged ≥ 16 years and patients managed by nephrologists in 12 hospitals in the Fukuoka Prefecture of Japan. CKD was defined in accordance with Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patients were enrolled between January 2013 to March 2017. The study sample consisted of 4476 outpatients and all patients were scheduled to be followed up for 5 years. Of the 4476 patients, 931 were excluded because of a lack of baseline or food survey data; therefore, data from 3545 patients were analyzed in the present study.The Fukuoka Kidney Disease Registry is a prospective, multicenter cohort study of non-dialysis-dependent patients with CKDBaseline demographic and clinical data were recorded at enrollment. We obtained the age, sex, height, body weight, and blood pressure of all participants. Clinical biochemical parameters  were determined in a central laboratory. Information regarding each participant’s health, the presence of diabetes, CVD history, and any treatment was collected by clinical research coordinators in our research network from patient medical records using a structured data format. Body mass index (BMI) was calculated as body weight (kg) divided by height (m) squared. Patients were not required to fast when supplying blood samples.27. The eGFR was calculated in patients aged < 18 years using the Schwartz formula and in patients aged ≥ 18 years using the following formula: eGFR (mL/min/1.73 m2) = 194 × Cr−1.094 × age−0.287 (× 0.739 for women). Chronic kidney disease was categorized as stages G1 to G5 in accordance with KDIGO guidelines.CKD was defined and classified according to the patient’s eGFR using the KDIGO guidelines28. Proteinuria was evaluated using the urinary protein/creatinine ratio, which was calculated by dividing urinary protein values by urinary creatinine concentrations. Proteinuria was categorized as < 0.15, 0.15–0.49, and ≥ 0.50 g/gCr.Proteinuria was classified according to the KDIGO 2012 clinical practice guideline29. Survey questionnaires were completed by participants and family members. The intake frequency of vegetables and fruits was described in nine categories and ranged from rarely (< 1 time per month) to at least 7 times per day. The standard portion size was recorded as 0.5 times, standard, or > 1.5 times. Daily food intake was calculated by multiplying intake frequency by the standard portion and relative size for each food item in the food frequency questionnaire. From a selection of 138 types of food, 36 types of vegetables—including 17 types of green leafy vegetables—and 15 types of fruits were evaluated. Information on the number of nutrients in each fruit and vegetable was obtained from the Standard Tables of Food Composition in Japan (Seventh Revised Edition)30. We multiplied the number of nutrients (β carotene and fiber) in each vegetable and fruit by the number of vegetables and fruits to calculate the intake of β carotene and dietary fiber. The validity of the food survey has been assessed in previous Japan Public Health Center-based Prospective Cohort studies24.To assess their diets, enrolled participants were provided with self-administered survey questionnaires including pictures of fruits and vegetables. A semi-quantitative food frequency questionnaire was used to identify the usual intake of 138 food and beverage items and was used in the survey sheet of the Japan Public Health Center-based Prospective Cohort Studyhttp://www.r-project.org). A two-tailed P value of < 0.05 was deemed to indicate statistical significance.Data are presented as mean ± standard deviation for normally distributed continuous variables, median and interquartile range for non-normally distributed continuous variables, and percentage for categorical variables. To evaluate trends in continuous and categorical values, we used the Jonckheere–Terpstra and Cochran–Armitage tests, respectively. Multivariate-adjusted trend tests were analyzed using multiple linear regression analysis. Logistic regression analysis was used to calculate age- and sex-adjusted odds ratios, and multivariable-adjusted odds ratios and 95% confidence intervals were used to determine the relationship between CKD stage and the prevalence of low vegetable intake. The multivariate value of the intake of β carotene and dietary fiber in CKD stages was evaluated by the analysis of covariance. Trend tests were analyzed using multiple linear regression analysis. Comparisons between the value in CKD G1 and those in other groups were made with the Bonferroni test. The intake values of β carotene and dietary fiber were transformed to natural log values to improve the slewed distributions of these values when statistical analyses were conducted; they were then transformed into normal values in tables. The multivariable-adjusted model was adjusted for age, sex, the presence of diabetes, CVD history, systolic blood pressure, BMI, serum albumin concentration, LDL cholesterol, log-C-reactive protein, and urinary protein/creatinine ratio. Statistical analyses were conducted using IBM SPSS version 22  and R version 3.5.2  and the ethics committees of all participating institutions; the study was registered in the University Hospital Medical Information Network clinical trials registry (UMIN000007988) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments.Informed consent was obtained from all patients and/or their legal guardians included in the study.


Dengue obstructive shock syndrome is a fatal complication commonly observed in the late critical phase of dengue infection and is associated with a high mortality rate. The main pathogenesis involves a dramatic increase in chest pressure, owing to severe plasma leakage and mechanical respiratory support, hampering the heart’s ability to pump effectively and impeding adequate blood venous return to the heart chambers. To date, there is a paucity of clinical data about Dengue obstructive shock syndrome reported.The 2 reported patients presented with prolonged and decompensated dengue shock with critical multi-organ failures and mechanical ventilation. The patients’ hemodynamics were profoundly affected by high pressure in the thoracic and abdominal cavities resulting from Dengue-induced severe plasma leakage and mechanical ventilation.Clinical presentations, laboratory data, mini-fluid challenge test, and point-of-care (POCUS) were used to make diagnoses and guide management.Clinical monitoring, judicious fluid (colloids and blood products) administration guided by repeated POCUS to properly assess the adequacy of the intravascular volume, homeostasis adjustments by plasma exchange, and continuous renal replacement therapies.The patients had favorable outcomes.Our study highlights the clinical manifestations and management of children with dengue obstructive shock syndrome and underscores the importance of monitoring hemodynamics by consecutive POCUS at the bedside in order to make a timely diagnosis and assess intravascular fluid volume inadequacy accurately as well as closely monitor the fluid management responses. Kirawittaya et al reported low intravascular blood volume, decreased blood flow into the heart, and reduced wall motion of the left ventricle in the diastolic period in critical dengue-infected pediatric patients with severe plasma leakage were significantly observed. Dengue obstructive shock syndrome is a fatal complication commonly observed in the very late critical phase of severe dengue patients with prolonged and decompensated shock, and it is associated with a high mortality rate despite intensive treatment. This syndrome is caused by a dramatic increase in thoracic pressure, which hampers the heart’s ability to pump effectively and impedes adequate venous return to the heart in dengue-infected patients with progressively severe plasma leakage  and mechanical respiratory support. Remarkably, point-of-care ultrasound (POCUS) plays a critical role in rapidly assessing cardiac systolic and diastolic dysfunction, intravascular volume status, pericardial-pleural effusions, and ascites; therefore, it is performed in dengue patients with tension-obstructive shock syndrome.,5 Most importantly, judicious fluid therapy and the risk of pulmonary edema must be carefully considered, and colloid solutions are recommended for severe dengue shock syndrome.,7 To date, there is a paucity of clinical data about dengue obstructive shock syndrome reported. Here, we describe 2 children with dengue obstructive shock syndrome at the pediatric intensive care unit, Children’s Hospital No.2 in Ho Chi Minh City, Vietnam, to add to the limited knowledge on the clinical characteristics and management of these patients.Dengue infection, a common mosquito-borne disease in tropical regions, affects an estimated 2.5 billion inhabitants in more than 120 countries, with an estimated annual incidence of 390 million cases, half a million requiring hospital admission, and 22,000 global deaths each year.9/L, hemoglobin 4.1 g/dL, hematocrit 17%; platelets, 86 × 109/L), positive dengue NS1 antigen and IgM ELISA-based tests, elevated transaminase , serum albumin 35 g/L, normal coagulation function tests, serum creatinine 67 µmol/L, cardiac troponin I 191 pg/mL, and creatine kinase-MB 30 U/L. Her bedside POCUS revealed normal cardiac structures, no signs of cardiac effusion, and normal systolic and diastolic functions, with an ejection fraction (EF) of 70%. The patient was diagnosed with dengue hemorrhagic fever. She was initially treated with a nasal oxygen cannula, red blood cell transfusion, and judicious normal saline infusion, in accordance with the World Health Organization guidelines. Fifteen hours after hospitalization, her clinical status progressively worsened with significant breathing difficulty, bilateral decreases in lung sound, marked ascites, mild pericardial effusion, and EF 64% on bedside sonography. The monitored laboratory tests revealed a dramatic reduction in platelet count of 25 × 109/L, hematocrit of 31%, substantially elevated transaminase levels (AST 1081 U/L and ALT 336 U/L), marked dysfunction of coagulation tests , and a significant increase in cardiac troponin I of 1933 pg/mL, indicating myocarditis. Therefore, she was managed with nasal continuous positive airway pressure, commenced with colloid solution (dextran) and vasopressor infusion . At 24 hours after admission, her respiratory status progressively deteriorated and the abdominal pressure increased significantly; therefore, mechanical ventilation was indicated and a positive end-expiratory pressure of 12 cmH20 and inspiratory pressure of 19 cmH20 were achieved. Chest radiography revealed bilateral pulmonary interstitial congestion and a relatively small cardiac silhouette , invasive arterial blood pressure of 83/68 mm Hg, and capillary refill time >3 seconds. At this time, repeat laboratory test revealed the hematocrit 25%, blood lactate 5.1 mmol/L, and the arterial blood gases showed pH 7.36, pCO2 26 mm Hg, HCO3- 15 mmol/L and base excess −9.4  resulted in a significant increase in invasive arterial blood pressure (118/47 mm Hg) and a decrease in pulse rate (130 beats per minute), indicating low intravascular blood volume and decreased blood flow into the cardiac chambers. On this basis, dengue obstructive shock in this patient was managed with high-dose colloid fluid (10 mL/kg/h × 2 hour), then sustained at 05 mL/kg/h. In addition, peritoneal drainage was performed to decompress the intra-abdominal pressure, positive end-expiratory pressure was adjusted to 10 cmH20 according to the decompressed intra-abdominal pressure, and the vasopressor dose was also slightly scaled up to achieve the target for abdominal perfusion pressure. As a result, the patient’s clinical status of shock improved dramatically, with a marked increase in peripheral perfusion, a strong pulse of 130 beats per minute, and a blood pressure of 100/60 mm Hg. Repeated chest radiography after shock management showed considerable mitigation of pulmonary congestion  and underwent continuous renal replacement therapy. The patient experienced gradual clinical improvement over 3 weeks and was discharged without complications.A 13-year-old female from Binh Duong province, northwest of Ho Chi Minh City, presented in February 2022 with a history of 06 days of high fever. She was diagnosed with β-thalassemia major at a tertiary pediatric hospital in Ho Chi Minh City at the age of 07 years. She received periodic blood transfusions, as indicated by a hematologist. Her main symptoms included persistently high fever, malaise, loss of appetite, vomiting, dark-colored loose stool, and petechiae, and she was undergoing cyclic menstruation. On admission to the provincial hospital, she was alert, with critically pale skin and mucosa, hepatosplenomegaly, increased heart rate of 130 beats per minute, blood pressure of 90/65 mm Hg, normal heart and lung sounds, and a soft abdomen. Laboratory results revealed pancytopenia  from Binh Duong province, northwest of Ho Chi Minh City, presented in June 2021 with a 6-day history of high fever and a positive dengue NS1 antigen test. The patient was referred from a provincial pediatric hospital with a diagnosis of severe and prolonged dengue shock syndrome. On admission, he had a comatose status, hepatoencephalopathy grade 3, and was on oxygenation support via an endotracheal tube and mechanical ventilation, with a rapid weak pulse of 160 beats per minute, blood pressure of 120/70 mm Hg, mottled skin, diffuse petechiae, multiple bruises at injection sites, normal heart sounds and bilaterally decreased breathing sounds at 2 lung bases, substantial ascites, insidious nasal and oral bleeding, and equal and reactive pupils. Laboratory tests revealed a hematocrit of 25%, platelet count of 11 × 109/L, critical transaminases (AST 3646 U/L and ALT 1122 U/L), serum albumin 14 g/L, marked dysfunction of coagulation tests (INR 2.8), and blood lactate of 2.9 mmol/L. Chest radiography revealed bilateral diffuse pulmonary interstitial congestion and a small cardiac silhouette. The total infused crystalloid fluid was 170 mL/kg in 48 hours. The patient was then managed with colloid solution (hydroxyethyl starch 6%) at 10 mL/kg/h for 2 hours, then sustained at 0.5 mL/kg/h and noradrenalin (0.1 µg/kg per minute), red blood cells, fresh frozen plasma and albumin transfusions, and infusion of saline solution (3%) for treating cerebral edema. POCUS revealed marked distention of the IVC and the absence of IVC respiration variation in size; nevertheless, the patient’s obesity hampered the performance of ultrasound. After 11 hours of hospitalization, the patient was still comatose and showed no marked improvement in dengue shock status, pulse of 145 beats per minute, blood pressure of 110/65 mm Hg, and oliguria. The further laboratory tests showed significant metabolic acidosis , blood lactate 6.3 mmol/L, serum ammonia (NH3) 201 μmol/L, dramatically elevated transaminases , severe dysfunction of coagulation tests (INR 3.23), cardiac troponin I 0.32 μg/L (Table 2). Therefore, continuous renal replacement therapies (2 weeks) and therapeutic plasma exchange (2 cycles) were administered to manage the severe liver and kidney failure. The patient experienced gradual clinical improvement over 07 days, completely recovered after 3 weeks and was discharged without complications.A 10-year-old male with age-adjusted obesity  despite left ventricular systolic and diastolic dysfunction on bedside sonography. On this basis, our therapeutic approach was to treat patients with Dengue obstructive shock syndrome with colloid solution infused from 10 to 20 mL/kg/h for 2 hours, subsequently tapering the dose of colloid fluid administration based on ventricular filling guided by POCUS, and closely monitoring tissue perfusion. Notably, colloid solutions were recommended for patients with severe and prolonged dengue shock syndrome on the basis of effective restoration of intravascular volume.,7,10 However, excessive colloid fluid administration increases the risk of severe acute kidney injury, which may require continuous renal replacement therapy. We also supplemented patients with blood products to minimize colloid administration. Our therapeutic approach seems to be sensible, as observed in improving the survival outcomes of the 2 patients reported; nonetheless, further cohort studies are needed to elucidate this.First, this condition can be observed in the late critical phase of dengue infection in patients with progressively severe plasma leakage and mechanical ventilation, and is associated with high mortality despite intensive treatment. The high increase in thoracic pressure dramatically impedes adequate venous return to the cardiac chambers and reduces the filling of the left and right ventricles at the end of the diastolic phase.,13 Patient 1 experienced myocarditis with a significant elevation in cardiac troponin I; nevertheless, this abnormality was previously reported to have a transient effect and resolves spontaneously without specific treatment. These comorbidities dramatically decrease left ventricular systolic and diastolic dysfunctions, which critically aggravate shock status, leading to high mortality.Second, comorbidities such as thalassemia, obesity, myocarditis, and severe liver and kidney failure, as observed in patients 1 and 2, will critically complicate the clinical management and outcomes of dengue patients with obstructive shock syndrome. POCUS reveals significantly empty left and right ventricles, a hyperdynamic heart, and a plethoric IVC.,5 This newly developed case definition will substantially aid timely clinical diagnosis and prompt appropriate intervention to enhance patient survival.In addition, we propose a case definition for dengue obstructive shock syndrome. Pediatric patients with dengue obstructive shock syndrome are defined as children with laboratory-confirmed dengue infection in the critical dengue phase with progressively severe plasma leakage presenting as substantial fluid accumulation in the pericardial, pleural, and abdominal cavities and edema. The patients are ongoingly stable with maintenance fluid management in accordance with the dengue treatment algorithm and mechanical respiratory support; however, they abruptly experience dramatic hypoperfusion of organs manifested as rapid weak pulse, significantly decreased blood pressure, mottled skin, cold clammy skin, and prolonged capillary refill time of >3 seconds.,15 POCUS is a powerful bedside tool for rapid diagnosis and severity prediction, guiding accurate fluid responsiveness to reduce mortality in critically ill patients.,17 We performed consecutive POCUS in patients with severe dengue infection in the pediatric intensive care unit to examine fluid accumulation in the pleural and abdominal cavities, pericardial effusion, ventricular filling volume, systolic and diastolic dysfunctions, IVC distention, and the diameter ratio between the IVC and juxtaposed descending aorta (IVC/Ao). Lim et al showed that an IVC/Ao ratio <0.8 was statistically associated with hematocrit elevation and dengue shock syndrome in Dengue-infected children. Therefore, consecutive POCUS can be applied to patients with dengue obstructive shock to make a timely diagnosis and accurately assess fluid administration as well as to monitor fluid treatment responses.Another significant point is that POCUS is increasingly applicable in emergency and resuscitation units.This case study highlights the clinical manifestations and management of patients with dengue obstructive shock syndrome, underscoring the importance of hemodynamic monitoring by consecutive POCUS for appropriate fluid assessment and management. It also calls for clinical studies to determine the incidence, risk factors, and outcomes of this understudied complication in dengue patients with prolonged and decompensated shock.All authors have contributed to and approved the final manuscript.Conceptualization: Luan Vo Thanh, Thanh Tat Nguyen.Funding acquisition: Viet Chau Do.Investigation: Luan Vo Thanh, Thanh Tat Nguyen, Nhung Thi-Hong Le.Methodology: Luan Vo Thanh, Thanh Tat Nguyen.Supervision: Ngoc Minh Nguyen, Viet Chau Do, Tung Huu Trinh.Writing – original draft: Luan Vo Thanh, Thanh Tat Nguyen.Writing – review & editing: Luan Vo Thanh, Thanh Tat Nguyen, Ngoc Minh Nguyen, Viet Chau Do, Tung Huu Trinh.We are grateful to the patients who participated in this study and gave us permission to report their details. We also thank Nguyen Tat Dat for preparing this manuscript for publication.