Supplemental Digital Content is available in the text Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline  in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.2. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria . In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002–12.992] and 5.409 (95% CI 1.444–20.269), respectively, in comparison to patients of the highest quartile (≥11.45 μg/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5 μg/mL and area under the curve of 0.786 .Follow-up was 57.3 ± 18.7 weeks, baseline age was 60  years, and eGFR was 38  mL/min/1.73 muUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment. Therefore, it is crucial to diagnose patients with CKD early and to identify those who have rapid CKD progression to potentially intervene or prepare them for renal replacement therapy.–7 Biomarkers appear to be an attractive diagnostic approach to early identify CKD patients and those who are at risk for rapid CKD progression.,9 Different parameters for the prediction of ESRD or decline of estimated glomerular filtration rate (eGFR) and death in the long term (>3 years of follow-up) have been evaluated.–16 However, markers that predict kidney function decline in the short term are needed in order to take measures such as hemodialysis access. Recently, urinary uromodulin (uUMOD) has been identified as a valuable parameter for the prediction of ESRD and progression of CKD in a large cohort over a period >9 and >3 years, respectively.,18Chronic kidney disease (CKD) represents one of the major medical burdens in Western countries. Health care costs associated with CKD are high and further increase when end-stage renal disease (ESRD) is reached.In this study, we evaluated whether uUMOD is associated with rapid loss of eGFR and ESRD in CKD patients within 1 year of follow-up.2: “CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health.” Therefore, we established the diagnosis of CKD when either eGFR was <60 mL/min and/or apparent signs of kidney damage were present over a period of 3 months. As apparent signs of kidney damage, we considered proteinuria with a cut-off >150 mg/g creatinine on spot urine specimen and/or histologically proven kidney disease and/or abnormalities detected in imaging techniques . Calculation of eGFR was based on both serum creatinine and cystatin C concentrations (CKD-EPIcrea-cystatin). Exclusion criteria were age <18 years, psychiatric comorbidities that would not allow written informed consent, and lack of serum/urine sample at the time of potential enrollment. Furthermore, patients with symptomatic or asymptomatic urinary tract infection (UTI), defined as detection of leucocytes and/or bacteria in the urinary sediment at the time of enrollment, were excluded, as it is unclear how acute UTI affects uUMOD secretion. The following parameters were assessed, as they were shown to be relevant markers for CKD progression–24: eGFR, systolic blood pressure (SBP), diastolic blood pressure (DBP), spot proteinuria , and C-reactive protein (CrP). We compiled the following demographic variables: age, gender, body mass index (BMI), accompanying coronary heart disease (CHD), peripheral artery disease (PAD), and concomitant diabetes mellitus (data were obtained from electronic chart review). Prevalence of CHD and PAD was recorded according to the last medical report, concomitant diabetes in view of the antidiabetic medication and/or HbA1c levels above the cut-off of 5.9%. All laboratory measurements, except uUMOD, had been performed at the day of enrollment. Medications with a renoprotective effect were recorded, including angiotensin-converting enzyme (ACE)-inhibitors/AT1-antagonists, aldosterone antagonists, bicarbonate, erythropoietin, uric acid lowering agents, active vitamin D, and phosphate binding agents.The final cohort consisted of 230 patients at stages I-V of CKD who presented to the outpatient clinic of a tertiary care university hospital. The study was approved by the local ethics committee of Klinikum rechts der Isar, Technische Universität, Munich, Germany, and adheres to the declaration of Helsinki. All patients enrolled in this study gave their informed consent. The only inclusion criteria followed the definitions for CKD according to the last KDIGO guidelines,26 Follow-up was obtained 12 months after inclusion of the last patient into the study.Primary outcome was reaching ESRD or a 25% decline in eGFR as a composite endpoint within 1 year of follow-up (ascertained through chart review). We chose the 25% cut-off relying on recent studies that demonstrated the ability of a lower eGFR decline to predict renal outcome.Patients’ demographics, medication, and predictive parameters are presented in Table 2.1All urine samples were stored at –80°C before measurements were performed. Urinary uromodulin measurements were performed using a commercially available assay . Short performance characteristics of the ELISA for plasma samples given by the manufacturer are as follows: detection limit for plasma samples 2 ng/mL; mean linearity recovery 97% (83–107% at 59–397 ng/mL); intra-assay precision 1.8–3.2% (at 30–214 ng/mL), inter-assay precision 6.6–7.8% (at 35–228 ng/mL), and inter-lot precision 7.2–10.1% (at 37–227 ng/mL). Urine samples were diluted 1 : 101 using dilution buffer. One hundred microliter of calibrators, controls, or diluted samples were pipetted into coated wells of the microtiter plate (MTP); subsequently, 100 μL of biotinylated detection antibody  were added. The MTP was covered with foil and incubated for 2 hours at 450 rotations per minute (rpm) and room temperature on a rotary shaker. After 2 hours, the MTP was washed 3 times using 300 μL washing buffer, and then the wells were tapped gently. One hundred microliter of Steptavidin-Polyperoxidase  were pipetted into each well followed by another incubation for 30 minutes at 450 rpm. Subsequently, the SPO was soaked and the MTP washed 3 times with 300 μL of washing buffer. Consequently, 100 μL of substrate solution (containing the chromogen tetramethylbenzidin and hydrogen peroxide as the substrate for SPO) were pipetted into each well. The MTP was incubated in the dark for 15 minutes at room temperature. The reaction was terminated by adding 100 μL of stop solution. This causes a color change from blue to yellow. Finally, the substrate solution was measured using a photometer at a wavelength of 450 nm and reference wavelength of 620 nm. Data analysis was performed using the program Magellan .2.2P < .05) were included in the multivariable analysis using forward inclusion. uUMOD was further evaluated in receiver-operating curve (ROC)-analysis to assess the cut-off point (OCO) with optimal sensitivity and specificity to predict the composite endpoint. Kaplan–Meier analysis was performed to illustrate the association between uUMOD and the composite endpoint.Due to skewed distribution, data are presented as median with minimum and maximum. Categorical variables are reported in absolute numbers and percentages. We evaluated the correlations of uUMOD, eGFR, and proteinuria using linear regression modeling adjusted for age, gender, and BMI. To better fit the model, we log transformed uUMOD, eGFR serum concentrations, and proteinuria. Subsequently, we divided the cohort into quartiles according to uUMOD concentrations for further analysis. For comparison of demographic data, medication, and laboratory parameters between the quartiles, exact Fisher test for categorical variables and Kruskal–Wallis test for continuous variables were used. Univariable Cox regression analysis was calculated for each variable with the composite endpoint being the dependent variable and the predictor being the independent one. For further work-up, we chose a stepwise approach: parameters significantly associated with the endpoint in univariable analysis  was used.All reported 33.1Three hundred five patients were initially included in the study. At the time of follow-up assessment, 75 24.6%) patients were lost to follow-up. The patients did not differ substantially from the remaining 230 patients included in the final analysis (Suppl. Table 1 vs Table 1). The mean age of the subjects included was 60  years, and 152 (66%) were male. Glomerulonephritis was the most frequent underlying disease (UD) with 87 of 230 patients  patients reached the composite endpoint, of whom 33 patients reached ESRD and 14 experienced at least 25% decrease in eGFR but not ESRD  patients of quartile 1 (uUMOD ≤2.6 μg/mL), 14 (29.8%) of quartile 2 (uUMOD 2.6–4.75 μg/mL), 3 (6.4%) of quartile 3 (4.75–11.45 μg/mL), and 3 (6.4%) of quartile 4  uUMOD and (log) eGFR showed a significant positive association , the latter decreasing to the quartile with the highest uUMOD concentrations (Table P = .005), active vitamin D, and phosphate binding medication , proteinuria , CrP , oral active vitamin D , and phosphate-binding agents use  were associated with the endpoint in univariable analysis  were associated with an HR of 6.362 (95% CI 1.906–21.234) and 4.600 (95% CI 1.320–16.031) to reach the composite endpoint in comparison to the reference quartile with the patients having the highest uUMOD concentrations  0.786, 95% CI 0.712–0.860, 4 To our knowledge, we demonstrated here for the first time that uUMOD is also associated with rapid progression to ESRD and/or rapid decline of kidney function within 1 year.In order to take necessary steps to treat CKD patients , biomarkers that predict rapid deterioration of kidney function are needed, but data on this topic are very rare. uUMOD has been shown to predict development of CKD over a period of >9 years. uUMOD has been only moderately well correlated to eGFR previously.,28 We detected a moderate association between logarithmic uUMOD and eGFR in our cohort. This suggests that uUMOD potentially represents tubular mass independently from glomerular function, as urinary uromodulin excretion has been shown to correlate with tubular mass. Furthermore, luminal secretion of UMOD into the urine appears to be differently regulated from apical release, as circulatory UMOD was shown to nominally correlate stronger to eGFR than uUMOD. Besides this, tubular mass appears to be important for the preservation of overall kidney function, as we detected that loss of kidney function was predicted by uUMOD independently from eGFR. The question if the predictive value of uUMOD is based on pathophysiologic mechanisms or simply by reflection of tubular mass is beyond the scope of this article.uUMOD is discussed to play a pathogenic role in CKD. However, a larger study on >3000 patients did not show a substantial benefit of urinary NGAL concentrations as a predictor when added to known parameters such as proteinuria in CKD patients for adjustment. Urinary cystatin C has not been extensively studied in this context. A Korean study proved its value only in normoalbuminuric diabetic patients. Urinary kidney injury molecule 1 (KIM-1) was also evaluated for predicting CKD progression.–35 Bhavsar et al and Nielsen et al could not demonstrate a benefit using KIM-1 for risk stratification. Similarly, the value of KIM-1 as a predictor was also rather limited in the study of Peralta et al, only showing a significant difference when comparing the highest decile with the lower 90% of patients. Another problem is that urinary KIM-1 is significantly influenced by medication and sodium restriction. As KIM-1 is suggested to be a marker for acute tubular injury , KIM-1 appears to be rather useful in the setting of acute kidney failure.,38Other urinary markers were evaluated with regard to their predictive value for loss of kidney function. Urinary neutrophil gelatinase associated lipocalin (NGAL) concentrations in combination with urinary creatinine concentrations were associated with rapid loss of renal function and ESRD in a cohort of 158 patients at stage 3 and 4 of CKD. Although this appears to be a promising way to identify alterations of renal cell activity, interaction, and loss of renal tissue in a dynamic analysis, we currently consider this method a long way off clinical practice due to very high costs. In addition, further reliable data are needed.Recent research focused on a urinary proteomic analysis approach to predict the risk of CKD progression. suggested a simple approach to estimate the risk for ESRD in CKD patients from urinary creatinine adjusted for fat-free mass. Although a significant predictive value of urinary creatinine was seen, the study did not adjust for parameters that we would assume to be of relevance such as concomitant pharmacologic treatment. Di Micco et al also suggested that lower urinary creatinine concentration predicted ESRD in stage 3 to 5 of CKD. However, a very moderate relationship was seen in multivariable analysis with an increased risk of 2% with every 20 mg/dL reduction of urinary creatinine concentration. Furthermore, no significant differences of urinary creatinine concentrations were seen in patients at CKD stage 5, hampering the use of urinary creatinine as a tool for risk evaluation within this important subcohort. eGFR and albuminuria were evaluated in a large meta-analysis with over 20,000 patients. Both parameters were predictive for ESRD, but the heterogeneity concerning eGFR was quite large between the studies. As our data suggest, eGFR might only be of value for risk stratification over a longer period. Proteinuria/albuminuria is indeed a helpful parameter that can also be influenced by clinical measures, but in the study of Astor et al, an 8-fold elevation of proteinuria was needed to reach a HR of 3.04. As the range in uUMOD was smaller in our study, uUMOD might be more promising, as also more subtle differences might indicate a change in risk.Wilson et al Furthermore, data cannot be generalized, as we predominantly involved Caucasian patients. Also, a disproportional large percentage of patients included had glomerulonephritis as the UD, which does not fully represent the overall CKD population. Furthermore, over 30% of the patients included were at CKD stage IV-V, limiting the generalizability of the results to earlier CKD stages. Data were assessed in a single center, so local particularities could have an impact on the results. Samples were stored at -80°C before measurements were performed.Our study has limitations: we only analyzed the short-term outcomes, so no data on long-term relevance of uUMOD can be provided. However, this was already demonstrated by Garimella et al.In conclusion, uUMOD appears to be a promising independent biomarker for risk stratification of rapid disease progression in CKD patients.We thank Dr Anna-Lena Hasenau, MD, for excellent logistic support.(1)Conception or design, or analysis and interpretation of data, or both: DS, MB, VH, PSG, JS.(2)Collection of data and/or samples: DS, SK, QB, SA, MW.(3)Drafting the article or revising it: DS, MB, VH, PSG, JS.(4)Providing intellectual content of critical importance to the work described: WAN, WS, UH, LR, PSG.Conceptualization: Dominik Steubl, Andreas Wolfgang Nockher, Wolfgang Schlumberger, Jürgen Scherberich.Data curation: Dominik Steubl, Stephan Kemmner, Quirin Bachmann, Ming Wen.Formal analysis: Dominik Steubl, Matthias Block.Investigation: Dominik Steubl.Methodology: Matthias Block, Wolfgang Schlumberger.Project administration: Victor Herbst.Software: Dominik Steubl.Supervision: Uwe Heemann, Lutz Renders, Pranav S. Garimella, Jürgen Scherberich.Validation: Dominik Steubl.Writing – original draft: Dominik Steubl, Susanne Angermann, Jürgen Scherberich.Writing – review & editing: Dominik Steubl, Susanne Angermann, Pranav S. Garimella, Jürgen Scherberich.


In the older population, especially the hospitalized patients who are prone to dehydration and hypovolemia, orthostatic hypotension (OH) presents as a debilitating disease. How different pharmacological and non-pharmacological interventions affect the incapacitating symptoms , morbidity, and mortality related to OH has become a topic of debate. OH can predispose to ischemic heart disease (IHD). A non-pharmacological approach consisting of mobilization, early lifestyle changes, and therapeutic maneuvers is the first choice in the management of these patients. Individuals with persistent symptoms require pharmaceutical therapy to increase blood volume and peripheral vascular resistance. This article summarizes the management of OH that is vital to cope with the needs of the growing geriatric populations. Orthostatic hypotension (OH) is characterized by a sustained decrease in blood pressure (BP) on standing. This drop in BP must be more than 20 mmHg for systolic pressure or more than 10 mmHg for diastolic pressure three minutes after standing upright or during a head-up tilt at 60 degrees . Among hSymptomsOH may be asymptomatic in most cases with an unscathed cerebral autoregulation. However, these patients are also susceptible to falls and syncope . SymptomDiagnosisThere are no recommendations that prefer a specific method while diagnosing OH in the hospital setting, and thus, both head-up tilt-table testing and active standing approaches can be used . OH asseThe correct diagnosis of OH also requires a medical practitioner to take an exhaustive clinical history that includes comorbidities, medication compliance, current symptoms, detailed physical examination with BP measurements, electrocardiogram, general laboratory tests  .PathophysiologyAn upright posture leads to pooling of 500-1000 ml of blood in the lower extremities and splanchnic and pulmonary circulations . This leConsidering the onset, OH is classified into two groups: acute OH and chronic OH. OH can be triggered by acute conditions such as valvular heart disease, hypovolemia, and acute illness . Some drChronic OH is caused by an autonomic dysfunction associated with the aging process. Chronic disorders that increase the risk of chronic OH include diabetes, Parkinson's disease, and multiple system atrophy . Supine ManagementThe patient should register the symptoms and vital signs daily to assess the effectiveness of the applied treatment, the final objective of which is to improve the symptomatology and reestablish their independence in daily activities. In addition, the severity of OH coupled with the presence of comorbidities should be considered for the individualization of the treatment plan. In this sense, the treatment must be managed as a process of hierarchical steps that include both non-pharmacological and pharmacological approaches ,15.Nonpharmacological TreatmentThe non-pharmacological approach is considered the first-line treatment and includes physical counter-maneuvers and lifestyle modifications. Initially, acute OH management starts with outlining the acute medical conditions , ensuring that the patients fully understand the nature of OH and the possible clinical outcomes such as falls, syncope, and presyncope, and discussing the importance of lifestyle modifications .External compression, through compression garments for abdominal and lower extremities, allows reduction of venous stasis and thereby orthostatic arterial hypotension, especially in the elderly patients. At their maximum efficiency, these external compression garments are able to handle pressures ranging between 15 and 40 mmHg . To treaPhysical counter-maneuvers, such as lunges, half-squats, and calf-raises, involve the contraction of large muscles , causing an increase in venous return and, hence, decreasing OH symptoms . In the Increase in the intravascular volume and avoidance of hypovolemia should be the final objectives of any treatment for OH to ensure the effectiveness of the pharmacological approach. Hence, an adequate intake of liquid (2.0-2.5 L/day) and a liberal salt diet (daily intake 10-20 g) is recommended. In addition, patients can consider the rapid ingestion of 500 ml of water (in about five minutes) for the rapid rise in systolic arterial pressure of 30 mmHg . DiuretiThe non-pharmacological treatment of OH is usually sufficient in mild diseases; however, pharmacological approaches should be considered in moderate and severe diseases .Pharmacological InterventionsPharmacological therapy focuses on either increasing blood volume or raising peripheral vascular resistance.1. Increasing blood volumeIncreasing blood volume is considered as a long-term strategy that depends on an increase in the baseline BP throughout the day . Fludroc2. Increasing peripheral vascular resistanceUsing direct and indirect sympathomimetic agents, such as short-acting peripheral-selective alpha-1 adrenergic agonist medications, a higher level of peripheral vascular resistance can be achieved. This approach is applied in the case of patients with chronic OH and persistent symptoms regardless of volume expansion. Midodrine causes direct activation of the a-adrenoreceptors by desglymidodrine (active metabolite of midodrine), which reduces the venous pooling in the splanchnic circulation and the legs, increases the peripheral vascular resistance, and improves orthostatic BP . The indDroxidopa is a synthetic norepinephrine prodrug that is converted into norepinephrine by aromatic L-amino acid (DOPA) decarboxylase  in both Prostaglandin inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), which block the vasodilating effects of prostaglandins can increase BP, but their use should be limited due to their side effects in elderly patients, such as gastrointestinal bleeding, renal failure, and electrolyte abnormalities .The alpha-2 adrenergic agonists, such as clonidine and yohimbine, can be used to treat OH, especially in Parkinson’s disease. For OH patients with autonomic dysfunction, clonidine activates peripheral alpha-2 adrenoreceptors, thereby increasing BP. However, given the existence of studies with controversial evidence about its mechanism of action, it should be used carefully in patients with OH -26. YohiThe ideal treatment is managed on an individual basis by progressively titrating its dose until it reaches the maximum tolerable levels. If symptoms persist, it has been suggested that a change or an addition of another pharmacological agent to the regimen is warranted, again titrating from a lower indicated initial dose to a higher one .As the healthcare settings in the world improve and the average human lifespan gradually rises, geriatric populations and age-related inevitable complications are on the rise. OH is a similar disorder related to aging and despite the existence of standard protocols for the management of OH, there is massive room for research. More in-depth studies to find out effective ways of managing this condition are warranted to improve the quality of life in our increasing elderly populations.


The study aimed to examine hypertension prevalence and management in China. Data were from a national survey of a probability sample of 45+ in China . Self-reported hypertension diagnosis and readings from electronic blood pressure monitors were used to create four variables: diagnosed, measured (>=140/90 as high), undiagnosed, and overall (diagnosed + undiagnosed) hypertension. Respondents with diagnosed hypertension were asked about medication use, blood pressure monitoring, and lifestyle advice from doctors; and were considered inadequate blood pressure control if having measured hypertension. Weighted descriptive statistics and multivariate logistic regression were conducted. The prevalence of diagnosed, measured, undiagnosed and overall hypertension was 27%, 37%, 14%, and 51%, respectively. Across all four, older age adults, women, and urban residents had higher rates. Among hypertensive patients, 82% took anti-hypertensive medications, 91% monitored blood pressure, 60% received lifestyle advice, and 53% had inadequate blood pressure control. Compared to the 45-54 years old, the 75+ was less likely to receive lifestyle advice  and the 65-74 was less likely to have adequate control . Men were less likely to use medications  but more likely to receive lifestyle advice  than women. More education and urban  were associated with better hypertension management and control. In conclusion, hypertension affects half of the middle-aged and older population in China. More than half of hypertensive patients have inadequate blood pressure control. People who are older, women, low-educated, and rural residents are disadvantaged in hypertension management.


Diabetic kidney disease. Diabetic kidney disease (DKD) is a leading cause of end‐stage renal disease (ESRD) worldwide and is induced by hyperglycemia, obesity, and high blood pressureEmpagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) study, CANagliflozin cardioVascular Assessment Study (CANVAS) program and DECLAIR TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) studyet al.et al.2, two‐year treatment with SGLT2 inhibitors significantly preserved the eGFR compared to treatment with non‐SGLT2 inhibitors. Surprisingly, in the CREDENCE  study, the primary outcome was a composite of ESRD, the doubling of the serum creatinine level, and death from renal or cardiovascular disease. The canagliflozin treatment group reduced the primary outcome by 30% compared to the placebo groupIn the past 4 years, sodium glucose cotransporter 2 inhibitors (SGLT2i) have been shown to have a high ability to intervene in the progression of DKD in the EMPA‐REG Outcome  for 8 weeks and divided them into groups receiving the vehicle or ipragloflozin treatment for another 8 weeksIt is important to know the underlying mechanisms by which SGLT2 inhibitors exert DKD protection. SGLT2 inhibitors reduce high levels of glucose, systolic blood pressure (SBP), body weight, uric acid, and ectopic fat, while they increase the levels of hematocrit and high density lipoprotein (HDL) cholesterol. Thus, SGLT2 inhibitors have systematic pleiotropic effects, thereby protecting the kidney from diabetic conditions. One of the other mechanisms is the normalization of altered tubuloglomerular feedback induced by diabetic conditions Figure . This reThe author declares no conflict of interest.


To investigate the relationships between blood pressure (BP) circadian rhythms and acute cerebral infarction (ACI), silent cerebral infarction (SCI) and the severity of leukoaraiosis in hypertensive patients.A retrospective case-control study was performed among hypertensive patients with 24-h ambulatory blood pressure monitoring (ABPM) and cranial magnetic resonance imaging (MRI).P = 0.047) or extreme-dipper pattern (ED)  were found to be independent risk factors for moderate-severe leukoaraiosis. Moreover, the greater the severity of leukoaraiosis was, the higher the ratio of abnormal BP circadian rhythms.A total of 1267 patients were enrolled. Lower nocturnal blood pressure (BP) decreases were observed in ACI patients than in controls . Reverse-dipper pattern (RD) and non-dipper pattern (ND) were found to be independent risk factors for ACI. In ACI patients, both RD and ND BP circadian rhythms were revealed to be independent risk factors for moderate-severe leukoaraiosis. In addition, in SCI patients, RD (OR = 1.7, 95% CI, 0.9–3.0; RD and ND BP circadian rhythms might not only be relevant to the onset of ACI but also correlate with the severity of leukoaraiosis. Thus, when modulating BP with antihypertensive drugs, the BP circadian rhythms, and not merely the BP level, should warrant more attention. Cerebral infarction (CI), one of the leading causes of global adult mortality and disability with a younger age of onset than before, threatens the health of human beings . HyperteIn healthy populations, physiological 24-h BP circadian rhythms play a vital role in protecting the structure and function of vessels. The loss or attenuation of rhythms might lead to impairments in endothelial function, inflammatory reactions  and furtDue to the limitations of sample size and inconsistent conclusions in current articles targeting the relevance of BP circadian rhythms to acute cerebral infarction (ACI), silent cerebral infarction (SCI) and leukoaraiosis, no benefits have resulted from clinical disease treatment. Based on retrospective research, we investigated the exact relevance of BP circadian rhythms to the onset of ACI and SCI and the severity of leukoaraiosis.The study was a retrospective case-control study recruiting 1267 hypertensive patients matching the inclusion criteria in Ruijin Hospital, affiliated with the School of Medicine, Shanghai Jiaotong University, and Minhang Hospital, affiliated with Fudan University, from January 2010 to November 2017. The inclusion criteria were as follows. First, adults were aged over 18 years old and had a hypertensive history. Hypertension were defined as 1) having a past hypertension history and 2) having persisting hypertension (SBP over 140 mmHg or DBP over 90 mmHg) in three separate BP measurements when hospitalized. In addition, evidence of end-stage organ impairments  was required. The second inclusion criterion pertained to acute cerebral infarction, silent cerebral infarction, and the control group. ACI was characterized as follows: a) sudden onset; b) focal neurological deficits such as hemiplegia, aphasia and others; and c) in cranial MRI examination, lesions showed high signal in the DWI sequence and were diagnosed as ACI by neurology physicians. Silent cerebral infarction was characterized by the following: patients without clear CI or transient ischaemic attack (TIA) history but lesions with high signal in the T2 WI or FLAIR sequences, low signal in the T1 WI sequence and low or equal signal in the DWI sequence. For the control group, the cranial MRI was normal. The third inclusion criterion was that ACI patients were examined with noninvasive ambulatory blood pressure monitoring (ABPM) 1 month after onset. The exclusion criteria were as follows: 1) Cardiogenic cerebral infarction ; 2) Past stroke history; 3) Intracranial lesions such as bleeding or occupying lesions detected by cerebral CT or MRI; 4) Having severe respiratory diseases, coronary heart diseases, malignant tumours, metabolic diseases such as severe liver and kidney dysfunction or thyroid dysfunction; and 5) Having contraindications for MRI, pregnancy or refusal to participate in the study.The data of the eligible patients were collected, comprising general demographic data , smoking, alcohol intake), laboratory data , triglycerides (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)), imaging information  and ABPM data , diurnal mean SBP, diurnal mean DBP, diurnal MAP, nocturnal mean SBP, nocturnal mean DBP, nocturnal MAP and nocturnal BP decline rate (NBPDR)).This study was approved by the ethics committee of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University.All the subjects were examined with cranial MRI in the axial T1 WI and T2 WI sequences first and the DWI sequence next. Noninvasive ABPM was applied. The cuff was located on the left arm, and the measuring gap during the daytime 6:00 to 22:00) was 30 min, while it was 60 min at night. The SBP, DBP, mean BP and heart rate were recorded. The examination lasted over 24 h. The SCI and control group subjects were mainly from the hypertension clinic and cardiology clinic. For these subjects, ABPM was performed at home or at work. The daily activities of subjects were not limited; rather, they had a strict wake-up time of 6:00 and sleep time of 22:00. ABPM parameters were calculated and analysed with microcomputers, including diurnal mean BP and nocturnal mean BP, and further led to diurnal MAP, nocturnal MAP and NBPDR with formulas. The formulas were listed as follows: MAP = DBP + 1/3 *(SBP - DBP), NBPDR = / diurnal MAP . Dipper :00 was 32 test and Fisher’s exact test. Patients with dipper patterns were defined as 1 [reference]. With binary stepwise logistic regression analysis, the risk factors for CI, such as gender, age, smoking, diabetes mellitus, cholesterol, and low-density lipoprotein (LDL), were included in the model in the analysis of the relationship between 24-h ambulatory BP rhythms and the onset of ACI and SCI, the independent risk factors of moderate-severe leukoaraiosis and the relationship between 24-h ambulatory BP rhythms and moderate-severe leukoaraiosis. P < 0.05 was regarded as the sign of statistically significant differences.SPSS18.0 and GraphPad Prism 5.0 were utilized for the statistical analysis. Baseline clinical data, laboratory data and BP data were assigned into three groups: the control group, the ACI group and the SCI group, and spontaneously in another way, into three groups: the non-leukoaraiosis group, the mild leukoaraiosis group and the moderate-severe leukoaraiosis group. The Kolmogorov-Smirnova normality test was applied for quantitative data. If the data were normally distributed, the data were expressed in the form of the mean ± SD, and comparisons between two groups were performed with the t-test, while comparisons among several groups were performed with the Dunnett test. The interquartile range (IQR) was used for data not fitting the normal distribution. The Mann-Whitney U test was used for comparisons between two groups, while the Kruskal-Wallis H test was used for comparisons among several groups. Frequencies and percentages were used to represent the count data with the χAccording to the inclusion and exclusion criteria, 1267 hypertensive patients were eligible, with an average age of 65 ± 13 years old, among whom 702 subjects were male (55.4%). A flowchart of patient selection is provided in Fig. P<0.001) in ACI patients and no significant difference in SCI patients.The characteristics and demographics of the ACI, SCI and control groups at baseline are listed in Table The BP circadian rhythms in ACI, SCI and control patients are shown in Fig. P = 0.047) and ED pattern  BP rhythms were independent risk factors for moderate-severe leukoaraiosis in SCI patients.In ACI and SCI patients, comparisons were processed according to different leukoaraiosis severities, BP levels and BP rhythm types separately Table . We diviWe drew the following conclusions from our results. First, the NBPDR of ACI patients was obviously lower than that of controls. RD pattern and ND pattern BP rhythms were found to be independent risk factors for ACI, including atherothrombotic stroke and lacunar stroke, with binary stepwise logistic regression analysis. No distinct difference in NBPDR existed between the SCI and control groups. Second, the more severe the leukoaraiosis is, the higher the ratio of abnormal BP rhythms. Third, RD and ND BP rhythms were independent risk factors for moderate-severe leukoaraiosis in ACI patients. Fourth, RD and ED BP rhythms were independent risk factors for moderate-severe leukoaraiosis in SCI patients.In recent years, an increasing number of studies have shown not only that CI is related to BP levels, but also that elevated BP variances play a role as an independent predictive factor . A studyLeukoaraiosis could increase the risk of stroke, lead to a poor prognosis , and be Similar to many past studies, the lower the NBPDR  was, the worse the leukoaraiosis would be . HyperteAll cases of leukoaraiosis were evaluated by MRI. However, the following deficiencies still existed in our study. First, all of our enrolled patients should be examined with MRI and 24-h ABPM, which could exclude patients with slight or severe symptoms due to the lack of MRI. The strict inclusion criteria caused certain selection bias. Second, most patients took antihypertension drugs when examined with ABPM, which might have influenced our results. Finally, owing to the limited ratio of the population with ED BP rhythm among hypertension patients, the findings regarding ED BP rhythm were not sufficient.Overall, we considered that patients with RD and ND BP rhythms suffered a higher risk of ACI. Abnormal BP rhythms were closely correlated with the severity of leukoaraiosis. Additionally, we can infer that we should perform close follow-up of hypertensive patients with abnormal BP rhythms, given that this is a controllable risk factor, and consider BP rhythm regulation when formulating antihypertension drug intake plans, which have certain clinical significance in preventing CI and cognitive behavioural disorders.


Haemorrhage, hypertension, sepsis and abortion complications (often from haemorrhage or sepsis) contribute to 60% of all maternal deaths. Each is associated with vital signs (blood pressure (BP) and pulse) abnormalities, and the majority of deaths are preventable through simple and timely intervention. This paper presents the development and evaluation of the CRADLE Vital Signs Alert (VSA), an accurate, low-cost and easy-to-use device measuring BP and pulse with an integrated traffic light early warning system. The VSA was designed to be used by all cadres of healthcare providers for pregnant women in low-resource settings with the aim to prevent avoidable maternal mortality and morbidity.The development and the mixed-methods clinical evaluation of the VSA are described.Preliminary fieldwork identified that introduction of BP devices to rural clinics improved antenatal surveillance of BP in pregnant women. The aesthetics of the integrated traffic light system were developed through iterative qualitative evaluation. The traffic lights trigger according to evidence-based vital sign thresholds in hypertension and haemodynamic compromise from haemorrhage and sepsis. The VSA can be reliably used as an auscultatory device, as well as its primary semiautomated function, and is suitable as a self-monitor used by pregnant women.The VSA is an accurate device incorporating an evidence-based traffic light early warning system. It is designed to ensure suitability for healthcare providers with limited training and may improve care for women in pregnancy, childbirth and in the postnatal period. WHO data from 2015 state that the lifetime risk of maternal death in high-income countries is 1 per 6000 pregnancies compared with 1 in 36 in Sub-Saharan Africa.Approximately 800 women die each day from complications of pregnancy and childbirth.Detection of abnormal vital signs, including blood pressure and pulse, allows early recognition of women who require urgent treatment or transfer to higher intensity of care, and is critical in preventing mortality and morbidity. Despite the universally recognised importance of blood pressure and pulse measurement, access to accurate blood pressure devices, healthcare provider training on measurement and adequate escalation pathways are lacking for many women in low-income and middle-income countries (LMICs).Even in high-income countries, it is acknowledged that failures by healthcare providers to immediately recognise and act on signs of life-threatening conditions, particularly haemorrhage, pre-eclampsia and sepsis, contribute to avoidable maternal deaths.In this article, we report the progress of the CRADLE programme: the development and evaluation of the CRADLE Vital Signs Alert (VSA) device, a low-cost, accurate and easy-to-use vital signs measuring device developed over the past 15 years. It is a hand-held, upper-arm, semiautomated device developed in collaboration with Microlife, with the primary goal of ensuring accuracy and applicability in pregnancy.In 2006, we validated the device for use in a non-pregnant adult population, according to a formal validation protocol for assessing accuracy of automated devices.Validation in non-pregnant adults does not imply accuracy in pregnant women. Following the British Hypertension Society (BHS) guidelines,Through Bill & Melinda Gates Foundation funding, we modified the VSA device to ensure suitability for community healthcare providers in LMICs. It now meets the WHO’s requirements, being affordable (US$20), robust, easy-to-use, portable, requiring infrequent calibration and has low power requirements (charging through a micro-USB port) and dual auscultatory/oscillometric function.In 2013, we identified that over 90% of health clinics in a rural district of Tanzania either had no blood pressure devices or broken devices. We introduced 19 of our devices, containing tally counters to monitor use, into these clinics and showed that they were used frequently; focus groups confirmed they were well accepted by healthcare providers. This exploratory work led to a preintervention and postintervention study, conducted over 12 months in three rural hospitals in Tanzania, Zimbabwe and Zambia. During the 3-month preintervention phase, blood pressure was measured on consecutive pregnant women at 20 weeks’ gestation or more presenting to hospital for any reason. Blood pressure was measured twice (with a 5 min rest period between measurements) using the validated CRADLE prototype device  by trained volunteers. Urine dipstick results were recorded if available, together with demographic details and antenatal history, including whether blood pressure had ever been taken in the index pregnancy prior to presentation. These data were entered onto a central study database. During the 3-month intervention phase, 20 rural and semirural peripheral antenatal clinics that referred to each of the three hospitals received one to two of the CRADLE prototype devices (n=100) together with two face-to-face training sessions, translated instructions on its use and a guide on how to refer based on the blood pressure readings. One year later, in a matched time of year to the preintervention period, data collection was repeated as per the preintervention phase.An iterative qualitative evaluation was undertaken to ensure that the VSA’s final traffic light early warning system and display symbols were understandable to users across a range of settings. Participants were shown a video animation of display options for hypertension and shock alerts and device utilities . Multiple choice questionnaires directly relating to the video animation and exploring the understanding of the options for the early warning system and the display symbols were distributed to a range of clinical and non-clinical participants from academic collaborative centres in India, the UK and Canada.Incorrect cuff size leads to blood pressure measurement inaccuracies.The prospective validation study included 52 pregnant women recruited from a large tertiary hospital. Twenty-six women had an arm circumference of 22–32 cm and 26 had an arm circumference of 33–42 cm. Each woman had seven sequential same-arm measurements taken, alternating between mercury sphygmomanometer and the VSA prototype device and appropriate, inappropriate and wide-range cuffs. Data were analysed using adapted validation methods recommended by the BHS, the International Society of Hypertension (ISH) and the International Organization for Standardization (ISO) protocols.The VSA device can be used as an auscultatory device, using a stethoscope, and the falling digital display in a similar fashion to a mercury column while still providing a digital reading derived from oscillometry. This is particularly important in those with heart arrhythmias, as most automated devices fail to give accurate readings in these individuals, or when wanting to verify an unexpected automated reading. We undertook a prospective evaluation of clinician auscultatory VSA device measurement compared with VSA oscillometric measurement.A 15-month prospective validation of the early warning system of the VSA device was undertaken at three tertiary hospitals in South Africa. At the three maternity departments, existing blood pressure devices were replaced with VSA devices. Data, including vital signs and adverse clinical outcomes, were collected on all pregnant/postpartum women admitted with either pre-eclampsia, obstetric haemorrhage or sepsis. The performance of the traffic light early warning system thresholds to predict adverse clinical outcomes was evaluated.Data from 1241 women were analysed . Introduction of the device to rural clinics was associated with improved antenatal surveillance of blood pressure . This informed us that the device was acceptable to healthcare providers and may facilitate early treatment for women with pre-eclampsia.Eighty-eight questionnaires were distributed and fully completed by doctors, nurses, midwives, healthcare assistants, medical students and non-clinical participants from India, the UK and Canada. Options not well understood were abandoned, including a blue traffic light to represent shock and an ‘E’ to represent an error. The options understood by the highest number of participants were selected for the final VSA device. With our team’s awareness that shock, particularly from haemorrhage, often requires more urgent intervention than hypertension, we ensured that the early warning system prioritised shock over hypertension and the shock alert demonstrated a higher level of urgency than hypertension (flashing down arrow as opposed to constant up arrow).The wide-range cuff in combination with the VSA device failed validation in pregnant women with arm circumferences 22–42 cm, significantly overestimating both systolic and diastolic blood pressure in those with large arm circumferences, according to adapted BHS, ISH and ISO protocols. Therefore, the wide-range cuff cannot be recommended for use as a cuff suitable for a range of arm circumferences in a pregnant population. We went on to successfully validate the VSA device in combination with an extra-large cuff, meaning that the device is accurate when used in combination with medium, large and extra-large cuff sizes.Blood pressure readings (n=255) taken by 12 clinicians in the antenatal clinic, taking simultaneous and masked auscultatory and oscillometric readings, were analysed according to formal validation protocols. The mean difference (±SD) between clinician auscultation and oscillometry was 2.2 (±6.1) mm Hg and 2.3 (±5.2) mm Hg for systolic and diastolic blood pressure, respectively, well within the ISO protocol requirements (≤5±8 mm Hg). This confirmed that the VSA device maintains accuracy when used as an auscultatory device by trained healthcare providers.For obstetric haemorrhage and sepsis, the VSA traffic light thresholds strongly predicted risk of complications, including intensive care unit admission and emergency hysterectomy. For hypertension, the risk of renal impairment, preterm delivery, maternal magnesium sulfate use and intensive care unit admission increased with worsening VSA traffic light thresholds.To date (June 2018), over 6700 VSA devices have been used clinically in 12 countries across Africa, Asia and the Caribbean. An earlier version of the VSA device has been used as part of the intervention package in the community-level intervention for pre-eclampsia cluster randomised controlled trial in Mozambique, India and Pakistan, which enrolled a total of 75 532 pregnant women across the intervention and control clusters and completed recruitment in February 2017. In some cases, the VSA device was the first blood pressure device available to a clinic, and in most cases the first accurate blood pressure device for pregnancy in clinics and hospitals. In addition to the benefit to women in LMICs, the device is also suited for use in pregnancy in high-income countries, for non-pregnant adults and for home monitoring. Device accuracy when used as a self-monitor by pregnant women has been confirmed in a recent Danish prospective observational study.We anticipate that women who would have previously gone unnoticed would now be identified early as being at risk. This simple technology may prevent maternal deaths and could contribute to meeting the United Nations Sustainable Development Goal 3: to reduce the global maternal mortality ratio to less than 70 000 per 100 000 live births by 2030. The potential contribution of the VSA device was recognised by the PATH Innovation Countdown 2030 Report, being nominated as one of 30 life-saving innovations with great promise to accelerate progress over the next 15 years to reach the Sustainable Development Goals.It is recommended that all blood pressure devices are validated as accurate in the population for which they are intended.An obstetric early warning system triggered by accurate blood pressure and pulse measurement is important for all settings. Maternity units in high-income countries frequently rely on non-validated blood pressure devices and early warning charts. Considering the high volume of women and frequency of blood pressure and pulse measurement in well-resourced tertiary units, the potential of a fully automated version of the device is being explored. The fully automated VSA device would be more suitable for well-resourced settings (and many LMIC facility-level settings), where power supply and cost are less of an issue. The current VSA device, with its low power requirements and low cost, would remain appropriate for low-resource settings.A stepped-wedge, cluster randomised controlled trial  to determine whether implementation of the CRADLE VSA device and a simple training package  into eve


To identify the causes of central diabetes insipidus (CDI) by evaluating the values of magnetic resonance imaging (MRI) in the diagnosis of pediatric CDI, providing evidence for the clinical diagnosis and treatment of CDI.  Seventy-nine patients with CDI (CDI group) hospitalized from July 2012 to March 2017 and 43 healthy children (control group) were enrolled in this study. All cases underwent MRI examination including T1-weighted three-dimensional magnetization-prepared rapid gradient-echo (T1WI-3D-MP RAGE) imaging sequences. The pituitary volume, the signal intensity of posterior pituitary, and the morphology of pituitary stalk were measured between two groups. The medical history, urine testing, imaging of hypothalamic-pituitary region, and hormone levels were also recorded.  Age and gender were matched between the CDI and control groups. The height and BMI in the CDI group were less and the urine volume in 24 h was higher than those in the control group. The signal intensity of the posterior pituitary was higher in the control group, whereas the pituitary volume was smaller in the CDI group. In the CDI group, 44 cases presented with morphological changes of the pituitary stalk. Clinical symptoms mainly included polydipsia, polyuria, short stature, and vomiting. All patients were confirmed by water deprivation vasopressin test. Forty-four CDI children were associated with hypopituitarism, including 33 cases of PSIS with multiple pituitary hormone deficiencies (MPHD) and 11 cases of growth hormone deficiency (IGHD). The pituitary volume in the cases of pituitary stalk interruption syndrome (PSIS) with MPHD was smaller than that in the IGHD patients.  The signal intensity ratio of the posterior lobe, pituitary volume, and the morphology of pituitary stalk on T1WI-3D-MP RAGE image contribute to the diagnosis of CDI. Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia and caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone which acts on V2 receptors in the kidney to promote reabsorption of free water , 2. PatiWith the development of laboratory examinations and imaging technologies, the diagnosis and etiological identification of CDI have become mature. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region can visually show the lesions, adjacent structures, and the abnormality of hypothalamic-neuronal system, which plays an irreplaceable role in the diagnosis of CDI , 4. HoweIn this study, the saddle area of 79 CDI patients (CDI group) and 43 normal children was collected (control group). The posterior pituitary signal intensity and pituitary stalk diameter were measured and compared between the two groups. The high-resolution T1WI-3D-MP RAGE imaging combined with MRI, analysis of hormonal changes, and long-term follow-up were conducted in children with different causes of CDI, providing an objective basis for timely diagnosis of CDI, assessment of disease condition, and assessment of clinical prognosis.Seventy-nine patients eligible for the criteria of CDI admitted to the Department of Pediatrics and Pediatric Endocrinology, Shandong Provincial Hospital, from July 2012 to March 2017 were selected for the CDI group. Forty-three gender- and age-matched normal children were assigned into the control group.2 within 24 h, or >200 ml/h or >6 ml/kg/h lasting for >24 h; urine specific gravity ≤ 1.005, urine osmotic pressure ≤ 200 mOsm/kg·H2O; plasma osmolality ≥ 300 mOsm/kg·H2O; urine osmolality/blood osmotic pressure < 1; (2) water deprivation test: dehydration symptoms after 4-6 h of water deprivation, constant urine volume, urine specific gravity ≤ 1.015, urine osmotic pressure ≤ plasma osmotic pressure; (3) pituitary vasopressin test: rapid increase in urine specific gravity ≥ 1.018, urinary osmotic pressure rise > 9%, urine osmotic pressure/plasma osmotic pressure > 1; and (4) plasma vasopressin determination: AVP value less than normal .Inclusion criteria are as follows: (1) polydipsia and polyuria, urine output > 3000 ml/mExclusion criteria are as follows: (1) trauma- or surgery-induced transient diabetes insipidus; (2) water pressure test prompted for mental polydipsia, NDI; (3) abnormal heart and kidney function; and (4) MRI images that did not meet diagnostic requirements.A Siemens 3.0 T superconducting MRI scanner was used. All patients underwent pituitary T1WI-3D-MP RAGE scans with sagittal and coronal T2WI plain scans, and gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA) as contrast agent was used at a dose of 0.1 mmol/kg. The enhanced scan was performed immediately after pushing the contrast agent. Scan parameters in each sequence for the enhanced MRI examination of the hypothalamic-pituitary region are shown in The family history, chief complaints, gender, age and duration of onset, water deprivation vasopressin test results, and laboratory test results were recorded for all patients with CDI. The obtained data were analyzed and compared between two groups.+, and blood osmotic pressure were measured.24-hour urine volume was monitored, and urine specific gravity, urine osmolality, blood Na+, and blood osmotic pressure. After water deprivation, the urine output was not significantly reduced, with clear urine, mental irritability, elevated body temperature, weight loss, urine osmotic pressure < osmotic pressure, and elevated blood osmolality (>305 mOsm/kg·H2O could terminate the test), who were DI, and urine osmotic pressure of complete diabetes insipidus was less than blood osmotic pressure, and urine osmotic pressure of partial diabetes insipidus was less than blood osmotic pressure. Some children had obvious polyuria and polydipsia during the day, but enuresis nocturna was normal, there were no signs of water shortage, the basic blood sodium was reduced or the normal lower limit, the urine output was reduced after the water deprivation test, the urine became yellow, the urine osmotic pressure and the urine specific gravity were elevated, SG was above 1.018, weight loss was slight, serum sodium and osmotic pressure remained normal, and preliminary consideration was given to psychogenic polydipsia (PP).The water deprivation test can roughly distinguish between CDI and mental polydipsia. Active water restriction was performed for a period of time before the experiment. Complete water deprivation was performed in the evening of the day after the start of the trial, and some subjects could not tolerate water withdrawal from 4 am. The clinical observation of the water deprivation test was performed at 8 o'clock in the morning. The measurement indicators included body weight, heart rate, blood pressure, urine volume, urine specific gravity, urine osmotic pressure, blood Na2); and the urine volume, urine specific gravity, and urine osmotic pressure were observed. After the injection of vasopressin, urine output in CDI was decreased, urine specific gravity and osmotic pressure were increased, and the response in NDI was not obvious.Water deprivation vasopressin test combined with MRI was used to identify CDI and NDI. After the water deprivation test, when patient's urine volume, urine specific gravity, and urine osmotic pressure were stable, the patient was injected with 5 units of pituitary vasopressin (children 6 units/mμg/l (10 ng/ml) was a normal response, <5 μg/l (5 ng/ml) was complete GH deficiency, and 5-10 ng/ml was partial GH deficiency. (2) Pituitary-thyroid axis function: determination of thyroid-stimulating hormone (TSH), T3, and T4. Patients with free T4 < 12.0 pmol/l and no increase of TSH (TSH < 5 uIU/ml) could be diagnosed as secondary hypothyroidism (TSHD). (3) Pituitary-adrenal axis function: the diagnostic criteria for secondary adrenocortical insufficiency (ACTHD) were that cortisol was less than 138 nmol/l at 8 o'clock in the morning or cortisol was lower than 550 nmol/l in insulin-induced hypoglycemia but adrenocorticotropic hormone (ACTH) was not significantly increased. (4) Pituitary-gonadal axis function: determination of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (TO), and prolactin (PRL). The diagnostic criteria for hypogonadism were that the basal level of gonadotropin  was lower than the normal detection limit (0.1 mIU/ml) or that the LH peak in the GnRH stimulation test was less than 2.8 mIU/ml, with or without FSH peak < 3.7 mIU/ml; LH peaks in peak adolescents undergoing GnRH stimulation were less than 5 mIU/ml; peak of LH/FSH was less than 0.6. (5) Serum prolactin (PRL) levels: diagnostic criterion for hyperprolactinemia was that PRL was higher than 25 ng/ml; the diagnostic criterion for hypoprolactinemia was that PRL was less than 5 ng/ml.Anterior pituitary function: (1) two growth hormone (GH) stimulation experiments were done: insulin hypoglycemic GH stimulation test and levodopa (L-DOPA) or arginine (ARG) GH stimulation test. The arginine test  could be combined with levodopa , and insulin-induced hypoglycemia (0.075-0.1 u/kg) stimulation test was required for the cortisol challenge test. Blood was drawn at 0, 30, 60, 90, and 120 min, and GH was measured. At 0 min, insulin-like growth factor 1 (IGF-1) was added. After stimulation, GH secretion > 10 β-HCG), and carcinoembryonic antigen (CEA) was used to assist in the diagnosis of germ cell tumors.Patients with space-occupying lesions in the sellar area or thickening of the pituitary stalk should also undergo a systemic radionuclide bone scan to assist in the diagnosis of Langerhans cell histiocytosis (LCH) and be diagnosed with Langerhans cell tissue cells detected by a puncture smear from the skin with a hemorrhagic papule or skeletal lesion. Routine determination of alpha-fetoprotein (AFP), human chorionic gonadotropin  Measurement of Pituitary Volume. The pituitary morphology was observed. In the median sagittal position, the height of the central pituitary and the longest diameter before and after the pituitary were measured. The width of the pituitary was measured at the central coronal position. The volume of the pituitary was calculated based on the volume of the pituitary = 1/2 (long diameter × highdiameter × wide diameter).(2) Measurement of Posterior Pituitary Signal. The position and size of the posterior pituitary were carefully observed, and the posterior pituitary signal intensity and the pons signal were measured in the median sagittal position. The region of interest was located posterior to the pituitary or the inner side of the pons. The ratio of posterior pituitary signal intensity = average gray value of the posterior pituitary/average gray value of pons. The ratio of posterior pituitary signal intensity > 1.00 was defined as a high signal, and ≤1.00 was a high signal loss or decrease. Children with CDI showed high signal loss in the posterior pituitary or a significant reduction in high signal volume.(3) Evaluation of Pituitary Stalk Morphology. The morphology of the pituitary stalk, saddle area, and parasellar structures was observed. Pituitary stalks could be classified to be blocked, normal, and thickened depending on the morphology.Pituitary stalk block, including pituitary stalk absent and pituitary stalk sessile, was generally assessed by thin-section MRI and clinically known as pituitary stalk block syndrome. Our MRI classification of blockade  was mainTien et al.  suggesteχ2 test. The measurement data were statistically compared using the independent sample design t-test. A P value of less than 0.05 was considered as statistically significant.All data were analyzed by using SPSS 17.0 statistical software . The results were expressed as the mean ± standard deviation (SD). The count data were statistically compared using the Seventy-nine CDI patients eligible for the criteria were included in the study, 53 male and 26 female. The onset age was ranged from 12 months to 15 years, and the disease duration was ranged from 7 months to 9 years. All patients had no family history of CDI, and 25 patients had a history of central nervous system surgery for more than 3 months. The most common symptoms were polydipsia and polyuria in all patients. Seven patients experienced progressive vision loss, loss of vision, paroxysmal headache, and other nonspecific symptoms with mild polydipsia and polyuria. Other symptoms appeared, such as increased nocturia and bedwetting (75 cases), breast and vulvar development (11 cases), short stature (44 cases), anorexia (63 cases), vomiting (25 cases), headache (3 cases), rash (2 cases), emaciation (10 cases), mental retardation (2 cases), and abnormal walking (1 case). All patients were confirmed as having CDI by the water deprivation vasopressin test and MRI of the pituitary area.β-HCG were increased in 4 patients with polydipsia, polyuria, and dwarfism, and the levels of β-HCG increased in 4 icGCT patients with polydipsia, polyuria, weight loss, and vomiting. The levels of IGF-1 in 5 cases (29.4%) were decreased, 6 cases (35.3%) showed hypopituitary-thyroid dysfunction, 4 cases (23.5%) appeared to have low secondary cortisol, 2 cases (11.8%) experienced an increase in stress cortisol, 2 cases were treated with surgery, 14 (82.4%) icGCT were sensitive to radiotherapy, and tumors disappeared or nearly disappeared. Eleven cases (64.7%) had 1-5 types of hypopituitarism. Two patients have Langerhans cell histiocytosis  had craniopharyngioma surgery (ameloblastoma type) more than 3 months after operation. Three cases (12%) were diagnosed with CDI before craniopharyngioma surgery Figures , 20 case Figures , and 33 P > 0.05), and serum sodium and osmotic pressure were significantly increased (both P < 0.05). After subcutaneous injection of vasopressin aqueous solution in posterior pituitary, urine volume was evidently decreased, urine specific gravity and urine osmotic pressure were considerably increased, and serum sodium and osmotic pressure were dramatically decreased .The 24 h urine volume of 79 patients was 202.7 ± 9.83 ml/kg. Specific data of water deprivation vasopressin test are shown in No significant difference was noted in age and gender between the two groups. However, height and body mass index (BMI) in the CDI group were lower than those in the control group. The 24 h urine volume was higher in the CDI group than in the control group . Of thes3). The pituitary volume in 43 patients was 320.8 ± 64.5 mm3 in the control group; 35 patients in the CDI group have 160.2 ± 30.4 mm3. The pituitary volume of 33/35 cases (94.3%) of patients with CDI had different degrees that became smaller (P < 0.01).The ratio of the posterior pituitary signal intensity was 1.68 ± 0.25 in the control group and 0.88 ± 0.21 in the CDI group. The high signals of the posterior pituitary in CDI patients almost disappeared or were decreased , and mosIn 79 patients, except for 25 cases after craniopharyngioma surgery, pituitary iccCT in the saddle area could not be identified in 11 cases, and pituitary stalk abnormalities were found in 44 cases, among which 33 cases of PSIS patients had complete occlusion of the pituitary stalk, and 3 cases were partially blocked . PituitaP < 0.05). All 44 patients with short stature had growth hormone deficiency, and 2 patients with mental retardation experienced MPHD. As shown in The abnormalities of hormone secretion in the anterior pituitary were found in 44 cases upon the initial diagnosis . The antRecent studies found that DI was due to hypothalamic-neuronal lesions caused by the lack of different levels of antidiuretic hormone (ADH) or due to kidney sensitivity to AVP deficiency caused by a variety of lesions , 14. In Clinical manifestations of CDI include polydipsia induced by lack of AVP. As for a vast majority of patients, polydipsia is the first symptom, and 79 cases presented with polydipsia in this study. Most patients initially had increased initial frequency of urination and increased urine output, followed by polydipsia. In children with onset of illness, the bladder, ureters, and pelvis may dilate due to prolonged polyuria, impairing kidney function and possibly develop osteoporosis. Children may have nocturia and bedwetting in this study. If the patient is unable to drink water, hypovolemia can occur, such as palpitations, decreased blood pressure, cold extremities, shock, and prerenal azotemia, and timely supplementation of blood volume can be promptly corrected. If the hypovolemic state cannot be corrected promptly, headaches, irritability, hopelessness, and coma can occur. Others included 11 cases with breast and exogenous development. Most children with CDI had digestive symptoms, vomiting and poor appetite. In this study, 63 cases presented with anorexia, 25 cases with vomiting, and 10 cases with weight loss, and CDI patients may be complicated with hypopituitary dysfunction, which may affect the growth and development of children. In this study, 44 cases experienced short stature, and 2 cases suffered from mental retardation.GH and GnRH deficiencies often occur before the anterior pituitary hormone deficiency, subsequently followed by TSH and ACTH deficiency , 17. ForWhen the morphological changes  of pituitary stalk occur, it can cause the downward transport channel of the pituitary hormone to be blocked, possibly leading to the occurrence of pituitary hypofunction. Biopsy should be performed when the pituitary stalk thickens >6.5 mm to determine the specific cause . Germ ceStudies have shown that CDI is also an autoimmune disease –23. StudIn conclusion, the high signal intensity of the posterior lobe and the pituitary stalk is clearly displayed on T1WI-3D MP RAGE images. The signal intensity ratio of the posterior lobe, the measurement of pituitary volume, and the morphology assessment of pituitary stalk on T1WI-3D MP RAGE images contribute to the diagnosis of CDI. The thickening of the pituitary stalk in patients with CDI should be subject to long-term follow-up. In addition, the detection of tumor biomarkers, such as beta-HCG, plays a role in identifying the etiology of CDI. The premature outcomes in this study remain to be validated by subsequent investigations, such as antibody detection experiment.


Elevation of intracranial pressure in idiopathic intracranial hypertension induces an edema of the prelaminar section of the optic nerve (papilledema). Beside the commonly observed optic nerve sheath distention, information on a potential pathology of the retrolaminar section of the optic nerve and the short-term effect of normalization of intracranial pressure on these abnormalities remains scarce.In this exploratory study 8 patients diagnosed with idiopathic intracranial hypertension underwent a MRI scan (T2 mapping) as well as a diffusion tensor imaging analysis . In addition, the clinical presentation of headache and its accompanying symptoms were assessed. Intracranial pressure was then normalized by lumbar puncture and the initial parameters  were re-assessed within 26 h.After normalization of CSF pressure, the morphometric MRI scans of the optic nerve and optic nerve sheath remained unchanged. In the diffusion tensor imaging, the fractional anisotropy value was reduced suggesting a tissue decompression of the optic nerve after lumbar puncture. In line with these finding, headache and most of the accompanying symptoms also improved or remitted within that short time frame.The findings support the hypothesis that the elevation of intracranial pressure induces a microstructural compression of the optic nerve impairing axoplasmic flow and thereby causing the prelaminar papilledema. The microstructural compression of the optic nerve as well as the clinical symptoms improve within hours of normalization of intracranial pressure. Idiopathic intracranial hypertension (IIH) is defined as an elevation of intracranial pressure (ICP) without hydrocephalus or mass lesion and with normal CSF composition . CurrentVisual alterations are observed in the vast majority of IIH patients , 33–35 bQuantitative diffusion tensor imaging (DTI) has been used to investigate various white matter diseases in vivo. It was shown that DTI is sensitive enough to detect axonal degeneration in rat glaucoma model  or the wThe aims of the present study were twofold. First, we sought to investigate if microstructural patterns within the ON may be affected by normalization of CSF pressure using state-of-the-art DTI magnetic resonance (MR) techniques. Secondly, we aimed at dissecting the characteristics of IIH-related headache and its accompanying symptoms as well as to analyze a potential improvement after the reduction of CSF opening pressure.The study was approved by the local ethics committee of the Charité - Universitätsmedizin Berlin (EA1/005/15). All patients participating in the study provided written informed consent. MRI measurements were performed between Feb. 11, 2015 and Nov. 25, 2015. Patients received two MRI scans during the study, one prior to the lumbar puncture and the second within 26 h  after the lumbar puncture. In several of the cases the lumbar puncture in the study was not the diagnostic puncture, but all patients had no lumbar puncture within the last six months. Beyond the effect on microstructural alterations of the ON, changes of accompanying symptoms such as nausea, photo-, phono-, osmophobia and trigeminoautonomic symptoms were evaluated within that time frame.2) diagnosed before with IIH according to the revised criteria established by Friedman et al. [Eight patients of Caucasian descent . DTI images were acquired through a single-shot echo planar (EPI) sequence in axial orientation . The diffusion weighting  was set to 0 and 1000 s mm− 2. Images were acquired with diffusion gradients in 126 directions with a number of acquisitions of 6, comprising 41 slices covering the whole brain. For the assessment of sinus vein stenoses (SVS) and the exclusion of sinus vein thrombosis (SVT) as secondary causes of intracranial hypertension, a 2D time-of-flight (2D TOF) venography  was performed.MRI was performed on a 1.5 T scanner . In addition to the circularly polarized head coil, a loop surface coil (7 cm diameter) was placed and fixed over the most affected eye according to visual field defects based on the ophthalmological examination. For the evaluation of the ON and the optic nerve sheath (ONS) a coronal turbo spin echo (TSE) sequence was used . Voxelwise statistical analyses of fractional anisotropy (FA) and mean diffusivity (MD) data were performed using FSL 4.1.8  [DTI data were corrected for eddy current distortion and motion and underwent a bias field correction for tractography purposes –49. DTI ord, UK) , 51, 52.ord, UK) . For theord, UK)  with FNIord, UK) . For ROIord, UK)  . T2 maps were online reconstructed by using a voxelwise, monoexponential nonnegative least-squares fit analysis  with a voxel size of 1.9 × 1.0 × 3 mmp < 0.05. To estimate the strength of the parameters Pearson’s correlation coefficient and correlation matrices were calculated. Crohnbach’s alpha was used to test for interrater variability.Statistical analysis was performed using XLSTAT Version 2016.5 . Normality of the data was calculated using the Shapiro-Wilk test. For the comparison of group means, the Mann-Whitney U-Test was used and data were expressed as median with 5th and 95th percentiles. Statistical significance was assumed at p = 0.130, ONS p = 0.798)    Fig . In cont2) Table . Crohnbap = 0.310)  presented with headache. Of those patients reporting headache, mean pain intensity, as assessed on a verbal analog scale ranging from zero to ten, was 2,94 ± 1,02. As outlined in Table Following the initial assessment and the first MRI scan all patients underwent a fluoroscopically guided lumbar puncture (E.W.) and CSF opening pressures were measured in the lateral decubitus position. The mean CSF pressure at baseline was 31,00 ± 2,20 cm CSF and was reduced to 12,19 ± 1,06 cm CSF. In the average 24 ml ± 4.8 ml of CSF were withdrawn. After lumbar puncture a second MRI scan and a reassessment of the clinical findings (headache and accompanying symptoms) was performed within 26 h. Following normalization of intracranial pressure headache severity improved in over 60% and photophobia in 50% of the patients. If nausea, phonophobia, osmophobia and/or trigeminoautonomic symptoms were present at baseline, these symptoms remitted completely in all of the affected patients within the observation period of 26 h  . Furthermore, no correlations were observed between the difference of CSF pressure before and after lumbar puncture with the change of the FA   of the optic nerve.The change of the headache intensity before and after lumbar puncture did not correlate with the change in the FA values of the optic nerve (97) Fig.  or with In the present study we have shown in IIH patients that a reduction of ICP through a lumbar puncture does not induce a reduction of the ON and ONS diameters within the short time frame of 26 h. Furthermore, the DTI analysis of the ON revealed that the reduction in CSF pressure induced a decrease in the FA value reflecting a reduced restriction of the directionality of molecular diffusion. In contrast MD values remained unaffected after lumbar puncture as were the T2 values, indicating that the dysfunction of the ON is unlikely to involve an edematous process.Neuroimaging techniques and in particular MRI are an essential component of the diagnostic workup of IIH to exclude secondary causes and to identify typical morphometric alterations commonly observed in IIH , 15, 18.The present study investigated the IIH-related alterations of the ON and the ONS as well as their development after normalization of ICP using a loop surface coil on the orbita allowing the acquisition of high-resolution images of these structures.The findings of our study indicate that the normalization of ICP does not have a short-term effect on morphological alterations of the ON. In contrast, the alteration of the FA value seen in the DTI suggests that elevated ICP affects microstructural integrity of the ON as the pressure-induced compression of the ON tissue leads to an increase in the directionality of molecular diffusion, a consequence that is reversed within hours of pressure relief. It may be speculated that the compression of the optic nerve as such and its microstructural consequences could add to the functional visual deficit induced by the papilledema, which is induced by a pressure-induced decrease in axoplasmic flow, but the answering of this question was beyond the scope of our study. The fact that we did not observe an alteration in the MD value of the ON supports the current pathophysiological concept that the pressure-induced edema is limited to the prelaminar part of the ON head , 59, whiPhysiological axoplasmic flow depends on an intraaxonal pressure gradient between the ocular portion (maintained by intraocular pressure) and the extraocular portion (maintained by the pressure of the ON tissue) of the ON. The elevation of intracranial and ONS CSF pressure causes an increase of the retrolaminar tissue pressure that is reflected in the observations we made in the DTI of the ON. The elevated tissue pressure results in an imbalance of the intraaxonal pressure gradient that affects axoplasmic flow leading to an axoplasmic flow stasis in the ON head and a papilledema. Axoplasmic stasis leads to a swelling of the ON head and optic disc swelling that, if untreated, result in retinal hemorrhages and ischemia and finally to optic disc atrophy. This pathomechanism, the slow velocity of the axoplasmic flow and therefore the time needed to create an axoplasmic stasis and edema upon mechanical obstruction as well as the narrow capillary CSF communication in the optic canal explain the delay between the elevation of intracranial pressure and papilledema and why these changes are only observed in chronic but not in acute elevations of intracranial pressure .Until now it remains to be clarified in which time frame the reduction of intracranial pressure reverses these findings. Studies investigating the effect on normalization of intracranial pressure on papilledema and visual disturbances generally investigate the evolution of these abnormalities in longer time frames. For example the NORDIC trial investigating the effect of acetazolamide assessed these parameters after 1 month . To the Beyond the effect of normalization of ICP on microstructural alterations of the ON observed in the DTI, most of the patients presented accompanying symptoms commonly seen in migraine such as nausea, photo-, phono- and osmophobia and some had trigeminoautonomic symptoms. With the exception of photophobia, all the other accompanying symptoms remitted completely within the observed time frame. While the prevalences of these accompanying symptoms at initial presentation are similar to those observed by Yri et al. , 42, ourWhile the described findings are novel to the field, the study has a few but significant limitations that need to be taken into account when interpreting the data. First, the results of this study are based on 8 IIH patients so that they are of an exploratory nature and therefore need to be confirmed by larger studies. In this context the DTI results are only slightly significant given the limited amount of patients in this study. However, considering the exploratory nature of the study, the rather large error margin that affected the significance level and the fact that the decrease in the FA value after lumbar puncture reflects the finding of our previous study showing an increased FA value in IIH patients compared to healthy controls , suggestSecondly, the lack of a control group is another limiting factor. However, as the study required a lumbar puncture and two MRI scans within a short time frame, a healthy control group was not included due to ethical considerations.Thirdly, from a methodological perspective, the FA values provide a measurement that may be the sum of multiple structures and factors within a voxel. Therefore, FA values have to be interpreted in relation to anatomy, pathology and increase in intra- and extracellular water content. Because of the size differences between the axons and the voxels it is only possible and to observe optic nerve microstructure from a macroscopic point of view with DTI. Furthermore, a single voxel may be composed by fiber populations with different spatial orientation resulting in an average increase in FA, that is not due to changes in axonal structure. Therefore, FA is not always a reliable marker of white matter integrity and FA values have to be interpreted with caution, in particular in relation to clinical data , 64.Fourthly, while papilledema was assessed externally by ophthalmoscopic examination at another campus or by the referring ophthalmologist to establish the diagnosis of IIH, we did not re-assess papilledema after lumbar puncture due to logistical reasons. We therefore had only the confirmation that patients had a papilledema but we did not have information on its extent. Therefore, we could not correlate the alteration of the optic nerve measured by changes of fractional anisotropy in relation to the papilledema. Given that this was intended as an exploratory study this question was beyond its scope. However, considering the pathomechanism of the papilledema induced by an elevation of ICP, it is highly unlikely that the papilledema may improve significantly in such a short time frame despite the differences measured in the optic nerve. In addition, assuming that the majority of patients had only a mild papilledema we would expect that our findings would have been more pronounced with more severe papilledemas or with higher CSF pressures.Finally, in respect to the clinical outcome parameters, a more objective assessment of headache and its impact on quality of life would have been desirable. However, given the exploratory nature of the study and the focusing on the short-term effects post-LP we did not have a longer follow-up period that would have allowed us to use structured quality of life or disability questionnaires as these are commonly based on longer observational periods. However, in that context we would assume that the clinical improvement we observed post-LP is most likely of a short-lived nature as other groups have convincingly shown that most IIH patients do not have a long-term improvement of their headache even if opening pressure is normalized .The findings of our exploratory study show in a DTI analysis that the microstructural abnormalities, which elevation of ICP induces within the ON, can be reversed within 26 h of normalization of ICP. In contrast, high-resolution MRI revealed that morphometric alterations of the retrolaminar, myelinated section of the ON remain unaffected by ICP normalization. As alterations in the T2 values of the morphometric analysis as well as in the MD values of the DTI analysis were also not observed, we deduce that the affection of the retrolaminar section of the ON does not involve an edematous process. Therefore, the pressure-induced edema appears to be restricted to the prelaminar optic disc and retina.The study further suggests, that alterations of the ON observed in the MRI as well as some clinical features of the disorder (headache and accompanying symptoms) may improve in the hours following normalization of intracranial pressure. Given the exploratory nature of this study, further studies are needed to confirm these findings.visual alterations are observed in the vast majority of IIH patientsvisual deficits result mainly from a pressure-induced papilledemathe underlying mechanisms are only partially understoodno obvious change in optic nerve T2 values after withdrawal of CSFsmall changes in fractional anisotropy of the optic nerve could be observed after lumbar punctureafter withdrawal of CSF a small distention of the ON fibers occur


Terlipressin, in general, is a vasopressor which acts via V1 receptors. Its infusion elevates mean blood pressure and can reduce bleeding which has a splanchnic origin. The primary outcome was to assess the impact of intraoperative terlipressin infusion on portal venous pressure during hepatobiliary surgery; the 2ry outcomes included effects upon systemic hemodynamics, estimated blood loss, and postoperative renal functions.This prospective randomized study involved 50 patients undergoing hepatobiliary surgery who were randomly and equally allocated into terlipressin group, or a control group. The terlipressin group received an initial bolus dose of (1 mg over 30 min) followed by a continuous infusion of 2 μg/kg/h throughout the procedure and gradually weaned over the first four postoperative hours, whereas the control group received the same volumes of normal saline. The portal venous pressure changes were measured directly through a portal vein angiocatheter.p < .001). Mean arterial blood pressure was significantly higher in the terlipressin group. Estimated blood loss was significantly higher in the control group than the terlipressin group , and the units of packed RBCs transfused were significantly higher in the control group ((0–2) versus (0–4) p = 0.003). There was no significant difference between groups as regards the incidence of acute kidney injury.Portal pressure was significantly reduced over time in the terlipressin group only (from 17.88 ± 7.32 to 15.96 ± 6.55 mmHg, Intraoperative infusion of terlipressin during hepatobiliary surgery was shown to improve intraoperative portal hemodynamics with subsequent reduction in blood loss.NCT02718599. Name of registry: ClinicalTrials.gov. URL of registry: https://clinicaltrials.gov/ct2/show/NCT02718599. Date of registration: March 2016. Date of enrolment of the first participant to the trial: April 2016.Clinical trial number and registry URL: Trial registration number:  Intraoperative blood volume loss as little as 10 to 15% could result in splanchnic hypoperfusion, which usually persists during the period of hypovolemia –4. AvoidTerlipressin is a synthetic analog of arginine vasopressin but with longer duration of action. It has been utilized in the management of circulatory dysfunction after paracentesis, hepatorenal syndrome and esophageal variceal bleeding in end-stage liver disease patients . TerliprThe primary aim of our study was to evaluate the impact of intraoperative terlipressin infusion on the hepatic hemodynamics . Secondary goals included the effects of terlipressin infusion upon intraoperative systemic hemodynamics, estimated blood loss during open hepatobiliary surgery, and the early postoperative renal function.ClinicalTrials.gov (NCT02718599). The study was carried out at Assiut University Hospitals, Al Rajhy Liver Hospital, between April 2016 and July 2017 in accordance with the Consolidating Standards of Reporting Trials (CONSORT) 2010 statement.This prospective, randomized, controlled study was approved by the Medical Ethics Committee at Assiut University (reference number IRB17200284). All participants provided written informed consent. The trial was registered prior to patient enrollment at + < 132 mmol/l), severe valvular heart disease, heart failure, symptomatic coronary heart disease, bradycardic arrhythmia (heart rate < 60/min), peripheral artery occlusive disease , uncontrolled arterial hypertension (Blood pressure > 160/100 mmHg despite intensive treatment), pregnancy and intraoperative need for Pringle maneuver. Fifty patients were randomly and equally allocated into one of two groups, control group  and terlipressin groups  by simple randomization technique  done by a study coordinator, who also encodes the drugs with matching random numbers. Surgeon, his assistants, and outcome assessing physician were kept blind to the grouping. All cases recruited to the study were done by the same surgeon.Eligible participants were adult patients aged > 18 years old with American Society of Anesthesiologists (ASA) Classification (Class I-II) undergoing major elective hepatobiliary surgery. Exclusion criteria included patients with preoperative renal failure, severe liver dysfunction (Child-Turcotte-Pugh grade C), hyponatremia (NaAll patients received standardized premedication with midazolam (0.02 mg/kg) and atropine (0.5 mg I.V). Anesthesia was induced in all patients with propofol (2 mg/kg) and fentanyl (1 μg/kg). Muscle relaxation for intubation was achieved by rocuronium (0.6–0.8 mg/kg) in both groups. Anesthesia was maintained with sevoflurane 1 MAC in medical air oxygen mixture (fraction of inspired oxygen 0.5), fentanyl infusion (1 μg/kg/hr.) and rocuronium infusion (0.01–0.012 mg/kg/min). Mechanical ventilation was controlled through a tidal volume of 6 to 8 mL/kg, and the ventilator rate (8–12/min) was adjusted to maintain an end-tidal CO2 of 35 to 40 mmHg. We used no PEEP with recruitment maneuvers repeated every 30 min after tracheal intubation. Each recruitment maneuver consisted of applying a continuous positive airway pressure of 30 cm of water for 30 s. Intraoperative normothermia was attained using warm intravenous fluids, a warm blanket, and humidifier. A 3-lm central venous catheter was placed through the right internal jugular vein, and central venous pressure (CVP) was monitored to guide fluid management during parenchymal dissection of the liver through maintaining CVP below 10 mmHg. A 22-gauge angiocatheter was inserted into the radial artery (after performing modified Allen’s test) and connected to the FloTrac/Vigileo™ monitor  for monitoring of cardiac output (COP), cardiac index (CI), stroke volume variation (SVV), and systemic vascular resistance (SVR). All blood pressure measurements were referenced to the level of the mid-axillary line. After surgical exposure of the portal vein, a 22-gauge angiocatheter was inserted into the portal vein and connected to a pressure transducer to measure the portal pressure at scheduled times, and for blood gas analysis of portal venous blood.2) after appropriate fluid administration, and the goal was to maintain CI between 2.5 and 4 l/min/m2. Ephedrine boluses (5–15 mg), or norepinephrine infusion was allowed in addition to colloid blouses to correct a fall in systolic arterial pressure < 90 mmHg, or mean arterial pressure < 65 mmHg to maintain it above 70 mmHg and the systemic vascular resistance above 600 dyn. s/cm5. Transfusion of packed RBCs was allowed if the hemoglobin level has diminished below 7 g/dl. All patients were transferred postoperatively to the post-anesthesia care unit.In a separate room, syringes containing Terlipressin for group T, and NaCl as a placebo for group C were prepared by an anesthesia technician who was not involved in the study after opening the sealed envelope and identification to which group the patient was to be enrolled. In group T, terlipressin was started just after exposure of the portal vein and obtaining a basal portal pressure reading, as an initial loading dose of 1 mg over 30 min followed by a continuous infusion of 2 μg/kg/hr. throughout the procedure and gradually weaned over the first 4 h postoperatively. In group C, patients received the same volume of normal saline. Intraoperative basal fluid replacement was attained in both groups through infusion of crystalloids (8 ml/kg/hr.), additional boluses of colloid solution in a dose of 3 ml/kg (Human Albumin 5% solution) were given when SVV was raised above 10% (a sustained rise during the previous 5 minutes) or in case of positive response (cardiac index increases above 10%) to previous fluid challenge. An infusion of dobutamine was initiated to raise the low cardiac output state conditions , mean arterial blood pressure (MAP), CVP, CI, SVV, SVR, and urine output (UOP). Fluid input , and output ) were recorded. The mean postoperative hemodynamic data  were recorded from the averaged 24 h’ measurements of the first day after surgery. Conventional renal function, hemoglobin level (Hb), sodium, and potassium levels were also reported preoperative as a baseline and daily for the first three postoperative days. The incidence of renal impairment was calculated according to AKIN criteria.p = .0001). Based on that literature [Power analysis was performed on the level of portal pressure (the 1ry outcome). A previous study showed that infusion of terlipressin was accompanied by a significant reduction of portal pressure from 25.3 ± 3.2 mmHg to 21.1 ± 3.3 mmHg  for Windows®. A A total of 50 patients were enrolled in this study and randomly allocated to the two groups as shown in the CONSORT flow-chart Fig. . There wP = 0.21). The initiation of terlipressin infusion was accompanied by a significant reduction of portal pressure from 17.88 ± 7.32 mmHg at baseline to 15.96 ± 6.55 mmHg (p < .001) in terlipressin, whereas in the control group, there was an insignificant change of portal pressure from 15.48 ± 5.92 mmHg at baseline to 16.48 ± 5.04 mmHg (p = 0.52). No significant difference was observed between both groups concerning the mean intraoperative values of portal pressure , and there was a significantly higher intraoperative SVR in terlipressin group in comparison to the control group (Table Hemodynamic changes are shown in Table . There wup Table . Three pup Table .Table 2HP = 0.002)  Table .Table 3Rp = 0.004); consequently, colloids and the units of transfused packed RBCs were significantly higher in the control group respectively   decrease of portal pressure. Terlipressin works through (V1) receptors in the vascular smooth muscle in the splanchnic blood vessels, which induces vasoconstriction and reduction in arterial blood flow to the splanchnic area with subsequent reduction in portal blood flow and thus a reduction in portal blood pressure . ElevatePrevious studies have demonstrated that intravenous injection of terlipressin improves renal function in hepatorenal syndrome patients, and at the same time can affect splanchnic and systemic circulations in cirrhotic patients , 15. HowFahrner and his colleagues reported better liver regeneration due to reduced portal venous pressure through terlipressin administration during the postoperative period . A randoWagener’s study had mentioned that vasopressin administration could decrease portal vein pressure as well as the flow in the native liver without reducing cardiac output or intestinal perfusion in liver transplant patients . MukhtarOur results as regards the improvement in SVR and the higher mean blood pressure in the terlipressin group are in agree with Hong and his colleagues’ study where they utilized terlipressin infusion in a dose of 1.0–4.0 μg/kg per hour in living donor liver transplant. They noted that terlipressin infusion was associated with increased SVR, and this offered better postoperative renal function, and shorter duration in ICU in comparison to patients who did not receive terlipressin .Many side effects to the use of terlipressin has been detected in different studies. Intestinal hypoperfusion is one of these side effects that might be noticed in patients with esophageal variceal hemorrhage, and portal hypertension who are treated with terlipressin , 23. SamIn the past, terlipressin was used to be administered by intermittent intravenous bolus injections. Recently, continuous infusion of (1.3–2.6 μg/kg/hr) of terlipressin early in distributive shock was used. This protocol significantly increased SVR with no undesirable side-effects, such as an excessive elevation in peripheral vascular resistance , 25. TheIn our study, one of the benefits of intraoperative terlipressin infusion in such major prolonged surgeries was the significant reduction of estimated blood loss in the terlipressin group which was reflected in the form of a significant reduction in the transfused packed RBCs units. This is in agreement with our previous study on liver resection surgeries  Fayed anIt has been documented that terlipressin administration can decrease plasma concentrations of renin, aldosterone, and norepinephrine. This reduction in such vasoconstrictors increases renal blood flow and improves kidney function , 28–30. It was mentioned in a retrospective study done by Yim and co-workers that the risk factors for the development of hyponatremia with terlipressin administration are young age patients, low body mass index, longer duration of terlipressin administration, and high base values of serum sodium which was not the case in our study .one limitation is that we have included patients with and without portal hypertension. Also, the use of colloid solution (Voluven) was not the ideal especially when we study renal function, but in our country, we don’t have other colloid options. One more limitation is that we did not consider the influence of terlipressin on renal tubular function through the sensitive markers, e.g., cystatin c, and urinary neutrophil gelatinase-associated lipocalin and our results about renal parameters were not correlated with postoperative fluid intake and balance. Another limitation of this study is that we didn’t document other side effects of terlipressin as limb ischemia and postoperative mortality.intraoperative infusion of terlipressin is shown to be an effective technique for reduction of portal venous pressure, and blood loss with better maintenance of systemic mean blood pressure and no significant sign of intestinal ischemia in patients undergoing major hepatobiliary surgery.