This randomized clinical trial examines the use of high-sensitivity cardiac troponin testing for patients with kidney impairment. Before use, results from the hs-cTnI assay were suppressed, and the contemporary assay (single threshold based on the coefficient of variation) guided care. Sites were then randomly assigned to early or late use of hs-cTnI testing, for which results from the contemporary assay were suppressed and care was guided by the hs-cTnI assay with sex-specific 99th percentile diagnostic thresholds.High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome (High-STEACS) was a stepped-wedge, cluster-randomized clinical trial that evaluated the use of a hs-cTnI assay in consecutive patients with suspected acute coronary syndrome across 10 hospitals (1852123) .3 The tr2. In this prespecified secondary analysis, the primary outcome of subsequent type 1 or 4b myocardial infarction following the index presentation or cardiovascular death within 1 year was compared before and after implementation of the hs-cTnI assay in all patients with elevated hs-cTnI concentrations and in the subgroup of patients reclassified by hs-cTnI testing with normal contemporary troponin concentrations, as stratified by eGFR (<60/≥60 mL/min/1.73 m2) using Cox models that were adjusted for age, sex, phase, hospital site (random effect), seasonality, presentation date, diabetes, ischemic heart disease or cerebrovascular disease, hs-cTnI concentrations, and deprivation status. Statistical analysis was performed in R, version 3.6.1 (R Foundation). A 2-sided P value of less than .05 was considered to indicate statistical significance.Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Kidney impairment was defined as an eGFR of less than 60 mL/min/1.73 m2 (P < .001) (P < .001) , of whom 4220 (42%) had kidney impairment. The proportion of patients with elevated hs-cTnI concentrations increased as kidney function declined, from 10% (1911 of 19 763) at an eGFR of 90 or greater to 66% (1171 of 1766) at an eGFR of less than 30 mL/min/1.73 m < .001) , A. In c < .001) , B.P < .001 for both). Despite identifying more patients at risk, the rate of subsequent type 1 or 4b myocardial infarction or cardiovascular death at 1 year in all patients with an elevated hs-cTnI concentration was similar before and after use in those with  and without kidney impairment   to 47% (2503 of 5359) and from 13% (1918 of 14 686) to 16% (3610 of 23 161) in those with and without kidney impairment, respectively (73-1.08) . Similar2, the proportion attributable to type 1 myocardial infarction halved. Although hs-cTnI is effective at enabling the early rule out of myocardial infarction in patients with kidney impairment,5 use did not improve outcomes in patients with elevated levels whether they had kidney impairment or not. The reasons for this are complex. Two-thirds of patients with kidney impairment and elevated hs-cTnI concentrations had a diagnosis other than type 1 myocardial infarction. In the absence of evidence from randomized trials, there is little guidance to inform clinical decisions for this heterogeneous group. Moreover, for those with kidney impairment and type 1 myocardial infarction, the available evidence is largely extrapolated from clinical trials in patients with broadly normal kidney function.6 Further research is therefore needed to convince clinicians of the safety and efficacy of these treatments in patients with kidney impairment. A limitation of this study is that it was not possible to discriminate between acute and chronic kidney injury. While both are associated with cardiovascular risk, these conditions are distinct. Following the use of hs-cTnI testing in clinical practice, 1 in 2 patients with kidney impairment had an elevated troponin concentration, but these were less likely due to myocardial infarction, and outcomes did not improve.While the frequency of elevated hs-cTnI concentrations increased 6-fold as kidney function declined from an eGFR of 90 or greater to less than 30 mL/min/1.73 m


Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunoreactivity-based fibro-inflammatory disease. Immunoglobulin G4-related kidney disease (IgG4-RKD) is a frequently overlooked diagnosis. This study aimed to describe IgG4-RKD and examine the factors relevant to the renal outcomes of IgG4-RD.Methods: We studied a prospective IgG4-RKD cohort between January 2012 and December 2020 with close follow-up. Clinicopathologic data at kidney biopsy were collected and analyzed. We aimed to explore independent risk factors for long-term renal outcome and disease relapse. Patients with an eGFR<45 ml/min per 1.73m2 at 12 months were defined as having poor outcomes.Results: The included 42 patients with IgG4-RKD had a mean age of 58.5 ± 8.7 years . The IgG4-RD responder index (RI) was 12.2 ± 3.3. A total of 66.7% of the patients presented with acute on kidney disease or acute on chronic kidney disease. Eight patients (19.0%) showed nephrotic-range proteinuria, and nine (21.4%) had high-titer IgG4-autoantibodies, including antineutrophil cytoplasmic antibody and anti-phospholipase A2 receptor. A kidney biopsy was conducted in 40 patients. Thirty-seven (90.0%) patients were diagnosed with IgG4-related tubulointerstitial nephritis, and 19 (47.5%) of them had concurrent glomerular diseases . IgG4-RD RI had a close relationship with serum C3 , C4  levels, and peripheral blood eosinophil count , factors that were not included in RI scores. Correlation analysis disclosed that IgG4-RD RI , organs involved , and C3  were correlated with the percentage decrease of serum creatinine at 1 month. However, multivariate regression analysis failed to identify any clinicopathological parameters that could predict short-term renal restoration and IgG4-RKD relapse. Ten out of 29 variables, of most importance, were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis. By multivariate logistic regression a higher serum IgG4 , IgG1 , IgG3 , and erythrocyte sedimentation rate  were found to be independent factors for poor long-term outcome. Conventional immunosuppressive medications and/or rituximab were prescribed, and in 83.3% of the patients, the kidney function improved. Repeat kidney biopsies confirmed the remission of interstitial inflammation in two patients under immunosuppressive therapy. However, the disease relapse rate was as high as 31.0%.Conclusions: We strongly recommend a kidney biopsy in active IgG4-RD, especially when there is proteinuria and renal dysfunction, because concurrent glomerular involvement and active interstitial inflammation should be assessed. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however, elevated IgG4 predicted a good renal prognosis, and appropriate and timely immunosuppressive therapy can help achieve a better prognosis. Immunoglobulin G4-related disease (IgG4-RD) is characterized by immunoreactivity-based fibro-inflammation and multiple-organ involvement (including the kidney). IgG4-related kidney disease (IgG4-RKD) represents any disease with renal involvement by IgG4-RD , 2. The However, the renal outcomes of IgG4-RKD remain unexplained, and the assessment of the systemic inflammatory state in IgG4-RD with the IgG4-RD responder index (RI) inadequately quantifies the degree of renal inflammation . An imprThis study was approved by the Committee on Research Ethics of the Peking University First Hospital 2021Y042). A prospective IgG4-RKD cohort was established in 2012. IgG4-RD was diagnosed following the 2011 comprehensive diagnostic criteria . As show021Y042. The pattern and severity of kidney injury were assessed and graded using serum creatinine (SCr) levels and the estimated glomerular filtration rate (eGFR) by the Kidney Disease Improving Global Outcome (KDIGO) clinical practice guidelines for AKI and acute kidney disease (AKD), and the KDOQI guidelines for CKD –12. Pati9/μL. Organ involvement was determined by physical examination and radiological findings, such as ultrasonography, CT, MRI, and positron emission tomography (PET). We used the IgG4-RD RI to evaluate systemic disease activity.Data relevant to IgG4-RD were collected, comprising a history of concurrent diseases, organ involvement, and the following inflammatory markers: erythrocyte sedimentation rate (ESR); C-reactive protein (CRP) levels; peripheral blood eosinophil count (PBEC); serum levels of IgG subclasses, IgG and IgE; and complement (C)3 and C4 levels. Eosinophilia was diagnosed if the PBEC was >0.50 × 10Kidney biopsy specimens were collected for immunofluorescence test (IF), and light and electron microscopy analyses. Two experienced renal pathologists made the pathological diagnosis and determined the renal tubulointerstitial injury score (TiIS). The modified renal TiIS was determined by the Banff working group classification standards , 14, bas2 at 12 months. Those who had an eGFR <45 ml/min per 1.73 m2 were considered to have a poor outcome. IgG4-RKD relapse was defined as an elevated SCr that exceeded 30% of the lowest value within 4 weeks. The incidence of extrarenal neoplasms during the observation period was also recorded.All patients were followed up regularly at our specialty clinic monthly for the first month and then every 3–6 months after biopsy. We performed complete blood counts, blood tests for biochemistry, ESR, CRP levels, IgG subclasses, complements, and urinalysis. The effect of immunosuppressive therapies and the changes in laboratory parameters were monitored closely. The short-term renal outcome measure was described by the decrease in the SCr level 1 month after the level peaked and classified according to the percentage decrease of the SCr level as follows: unimproved , partly improved (20%−40%), and significantly improved (>40%). The long-term outcomes were evaluated based on the eGFR levels during follow-up. We considered patients having a good outcome if they had an eGFR of ≥ 45 ml/min per 1.73 mt-test. Continuous variables with a non-normal distribution were defined as median or quartiles and were compared using the Mann–Whitney U-test between groups. Classified variables were expressed by the number of cases (percentage) and compared using chi-squared test, whereas ordered variables were compared using Wilcoxon rank-sum test. Correlation analysis was used to determine variables related to short-term and long-term renal outcomes. Twenty-nine risk factors including age, gender, IgG4-RD RI, ESR, CRP, total IgG and IgG subclasses, serum C3 and C4 concentration, eosinophil count or eosinophilia, pathological Ti-AI and Ti-CI scores, peak SCr at onset, and the percent of SCr decrease at 1 month after were all included as variables affecting long-term poor renal outcome and disease relapse. Least absolute shrinkage and selection operator (LASSO) regression  was applied to minimize the potential collinearity and over-fitting of variables. Variables identified by LASSO regression analysis were entered into regression models. The missing values of C3, C4, IgG subclasses, CRP, and ESR were effectively complemented by a median or average data (missing three to four data per variable) for multifactorial prognostic analysis. The multivariate regression was performed to screen predictors of reversible short-term renal recovery. The logistic regression using a backward stepwise elimination was performed to determine independent risk factors for poor renal outcome and relapse. Results of the regression analyses were reported as odds ratios with 95% confidence intervals. Values of P < 0.05 were considered to indicate statistical significance (two-sided).SPSS software version 20.0  was used for all statistical analyses to compare the baseline differences between patients. Continuous variables with a normal distribution, expressed as mean ± SD, were compared between groups using a In the entire IgG4-RKD cohort, 42 patients were included in the study with a male-to-female ratio of 5:1. The mean age of the included cohort was 58.5 ± 8.7 years. The mean number of organs involved was 2.8 ± 1.4. The extra-renal organs involved were the lymph nodes (57.1%), pancreas (28.8%), salivary glands (28.8%), lungs (19.0%), hepatobiliary duct (7.1%), retroperitoneum (7.1%) showing obstructive nephropathy (ON), and large arteries . The mean IgG4-RD RI was 12.2 ± 3.3.n = 3) and IgG-λ (n = 2).Comorbidities included hypertension (23.8%), diabetes (14.4%), hepatitis-B virus infection (4.8%), psoriasis (2.4%), skeletal fluorosis (2.4%), and pneumoconiosis (2.4%). Eight patients (19.0%) were antineutrophil cytoplasmic antibody (ANCA)-positive and met the diagnostic criteria of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) , 16. Fou9/μL (quartiles: 0.1–0.74).Laboratory findings are shown in max values of high-uptake kidney lesions in the PET-CT examination (n = 6) ranged from 3.7 to 11.1.All patients showed intumescent kidneys. Scar formation was found in two patients. Five patients showed multiple low-density lesions of the kidneys in CT scans. The SUVThe median CRP level was 6.45 mg/L , and the mean ESR was 83.7 ± 40.3 mm/h. Elevated serum IgG levels were observed in 88.1% of all the patients; IgM and IgE levels were elevated in 2.4 and 75.0% of the patients, respectively. The prevalence of hypocomplementemia was 69.0% for C3 and 50.0% for C4. Increased IgG1, IgG2, IgG3, and IgG4 levels were found in 86.8, 28.9, 52.6, and 94.7% of the patients, respectively (IgG subclasses were not tested in two patients). We found that the MPO–ANCA was IgG1 plus IgG4 in five patients, IgG3 plus IgG4 in one patient, and IgG4 in one patient. PR3-ANCA was IgG4 in one patient, and PLA2R antibody was IgG3 plus IgG4 in another patient.All IgG4-RKD patients with overlapped AAV were grouped in the AKD subgroup having extremely high ESR and CRP levels compared with the non-AAV patients . HoweverA kidney biopsy was conducted in 40 patients. The renal pathology showed typical IgG4-tubulointerstitial nephritis (IgG4-TIN) in most (90.0%) patients ; 17 patiThe IF staining features of glomeruli are shown in Two patients (#1 and #2) received rebiopsy 4–6 weeks after a strengthened immunosuppressive treatment. The Ti-AI score was extremely lowered. Another two patients (#3 and #4) underwent a repeated biopsy after an ~2-year interval. The initial pathological finding was of MN with TBM deposits. Proteinuria and AKD relapsed several months after steroid withdrawal. The Ti-AI and Ti-CI scores were both elevated, together with interstitial eosinophil infiltration .All patients were initially prescribed prednisone (0.5–1.0 mg/kg/day) for 4–8 weeks, which was regularly tapered by 5 mg every 2 weeks. Six patients (14.3%) with CrGN received methylprednisolone–pulse therapy combined with plasmapheresis. Nine (21.4%) patients had single steroid therapy. Twenty-one patients were given cyclophosphamide (50.0%), mycophenolate mofetil (4.8%), or other conventional immunosuppressive agents  combined with steroids. Eight patients (19.0%) received a rituximab regimen. For all, prednisone administration was maintained at 5–10 mg/day.The patients were followed up for 45.4 ± 33.8 months. In 1 month of immunosuppressive therapy, the reversible recovery part of renal function was as follows: (1) unimproved in 14 patients (35.0%), (2) partly improved in 17 patients (40.5%), and (3) significantly improved in nine patients (22.5%). All patients had CKD at 12 months, with CKD stages 3–5 accounting for 50.0, 10.0, and 7.5%, respectively. All patients had remission of hypocomplementemia. Unfortunately, elevated IgG4 level  remained, involving 47.8% of patients during maintenance immunosuppressive therapy, and the percent of uncontrolled non-IgG4 subclass was found to be 16.7–22.2%. Thirteen patients (31.0%) presented with an IgG4-RKD relapse. Recurrent eosinophilia was present in another four patients (9.5%). Before relapse, six patients (46%) received a single steroid; combination strategies included cyclosporin A, cyclophosphamide, mycophenolate mofetil, azathioprine, and the R-CHOP regimen. Four patients developed new neoplasms . The prevalence of malignancies in the current cohort was 21.4%.R = −0.509, P = 0.001), C4  levels, and PBEC , factors that were not included in RI scores. The systemic inflammatory indicator ESR was found to correlate with IgG1 , and CRP correlated with serum C3 level . Pathological Ti-AI had an inverse relationship with serum IgG4 . Ti-CI correlated with serum C3  and IgG3 . Renal eosinophil infiltration existed when there was eosinophilia  and TBM deposit . Correlation analysis further disclosed that IgG4-RD RI , organs involved , and C3  were correlated with the percentage decrease of SCr at 1 month , higher IgG1 , IgG3 , and ESR  were found to be independent factors of poor long-term outcome , Sjogren's syndrome, and IgG4-associated MN and TMA have been rising , 29–33. Even though some IgG4-recognized target antigens have been found –41, IgG4lowCD20negCD27+CD38hiplasmablasts at diagnosis.Patients show different characteristics of IgG4-RKD and progression, which correspond to the acceleration or remission of the immune response. Takanashi et al.  reportedIn conclusion, this study indicates that IgG4-RKD patients have complex and diverse clinicopathological manifestations. In the absence of sensitive and specific predictors, pathological kidney findings are still the most reliable basis for diagnosing, assessing, and treating IgG4-RKD. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however elevated IgG4 predicted a good renal prognosis. An appropriate and timely immunosuppressive therapy is helpful in improving renal function restoration.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Peking University First Hospital (2021Y042). The patients/participants provided their written informed consent to participate in this study.TS and LY participated in research design and data analysis. TS, LY, HW, and SW participated in the performance of the study. TS drafted the manuscript. All authors contributed to the article and approved the final manuscript for submission.This research was supported by the National Science and Technology Major Projects for major new drugs innovation and development (Grant No. 2017ZX09304028 to TS), National Natural Science Foundation of China (Grant Nos. 91742205 and 81625004 to LY), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Grant No. 2019-I2M-5-046).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Regression analyses revealed significant correlations of the mean deviation of the visual field with age , IOP , and LVH . Atrial fibrillation, LVH and bradycardia may decrease the cerebral blood flow, and may also affect the ocular blood flow. Cardiac abnormalities may be associated with the development and severity of glaucoma.The purpose of this study was to examine the relationship between glaucoma and cardiac abnormalities. We evaluated 581 patients with open-angle glaucoma (285 men and 296 women) and 595 individuals without glaucoma (273 men and 322 women). All of the participants underwent visual field testing using a Humphrey Visual Field Analyzer (30-2 program), an electrocardiogram (ECG), and blood pressure measurement. We examined the ECG abnormalities and other factors  and systemic hypertension) involved in the development and severity of glaucoma. Logistic regression analyses revealed significant correlations of glaucoma with IOP (OR = 1.43; 95% CI: 1.36–1.51;  Primary open-angle glaucoma is a chronic disease associated with intraocular pressure (IOP) that causes retinal nerve fiber layer loss and visual field (VF) defects . It is wThere are various types of ophthalmic solution that can be used for the treatment of glaucoma, and they have different mechanisms of action. Prostaglandin-related drugs—such as latanoprost, bimatoprost and toravoprost—mainly decrease IOP by increasing the outflow facility through an IOP-independent uveoscleral pathway, and they are most commonly used in current glaucoma treatments . BrinzolHigh IOP, aging, family history, and systemic hypotension  are amonThe study protocol was approved by the institutional ethics committee of Japan Community Health Care Organization, Mishima General Hospital. All of the procedures conformed to the tenets of the Declaration of Helsinki. All of the measurements in this study were performed in the Japan Community Health Care Organization at Mishima General Hospital. Informed consent was obtained from all of the subjects before participation in this study. Informed consent was obtained from all of the subjects involved in the study. Written informed consent was obtained from the patients regarding the publication of this paper.p < 5%), or when a cluster of three contiguous points was below the 5% level on the pattern deviation plot [Our study included 581 patients  with open-angle glaucoma . IOP wasion plot . Only thion plot  is basedThe control group consisted of 595 subjects , who volunteered to participate in this study . All of We excluded subjects taking beta-blocking medications and diuretics from the study, as those medicines can affect IOP. We defined a washout period of 8 weeks  for prosIn a preliminary study, the prevalence of all ECG abnormalities was estimated to be 40% in the glaucoma group and 30% in the control group. The sample size required to detect a significant difference at a power of 80% and a significance level of 5% was 376 in both the glaucoma and control groups. Similarly, the prevalence of AF, LVH, and premature contraction was estimated to be 7% in the glaucoma group and 3.5% in the control group. The sample size required to detect a significant difference at a power of 80% and a significance level of 5% was 559 in both the glaucoma and control groups.Standard 10-s 12-lead ECGs were obtained from all of the patients with glaucoma, and the control subjects. ECG abnormalities and heart rate were recorded. In the patients taking beta-bloker ophthalmic solutions, the ECG was recorded after the discontinuation of the ophthalmic solutions. From the results of the ECGs with automatic analysis, we examined the frequencies of ischemic abnormalities , atrial fibrillation (AF), QT prolongation, ST-T abnormality, left ventricular hypertrophy (LVH), an atrioventricular (A-V) block, a left bundle branch block (LBBB), premature contraction, a right bundle branch block (RBBB) and bradycardia in the glaucoma and control group. In the present study, the definition of bradycardia was 50/min or less.We classified the ECG abnormalities into three levels of severity  according to the standard criteria . Severe After resting for 2 min, the blood pressure of each case was measured in the sitting position in our hospital. We defined systemic hypertension as a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher, and we defined systemic hypotension as a systolic blood pressure of 100 mmHg or lower or a diastolic blood pressure of 60 mmHg or lower. In cases with white-coat hypertension, the results of the measurements may not reflect blood pressure in daily life. We tested the difference in the frequency of systemic hypertension and hypotension between the patient and control groups using the chi-square test.p < 0.05.We performed multivariable logistic regression analyses on all of the subjects (patients and control subjects) in order to investigate the risk factors for the development of glaucoma. Multivariable logistic regression analyses were performed to determine the association between the parameters  and a diagnosis of glaucoma. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for each factor. Statistical significance for all of the analyses was defined as t-statistic and 95% CI were estimated for each factor. Statistical significance for all of the analyses was defined as p < 0.05.Moreover, we performed a multiple regression analysis in patients with glaucoma in order to investigate the risk of the severity of the glaucoma. Multiple regression analyses were performed in order to determine the association between the mean deviation of VF and the parameters . The These regression models were constructed following the identification of potential confounding variables. All of the analyses were conducted using EZR  (Saitamap = 0.01) and systemic hypertension (p = 0.005) were higher in the glaucoma group, while systemic hypotension was more frequent in the control group.Some ECG abnormalities were observed in 240 of the 581 patients with glaucoma and 184 of the 595 controls . Severe p < 0.00001), AF , LVH  and bradycardia   . No signt = −6.22; 95% CI: −0.15, −0.08; p < 0.00001), IOP , and LVH   . The freOphthalmic solution treatment was temporarily discontinued in 69 patients; the IOP before discontinuation was 14.4 ± 2.5 on the right and 14.4 ± 2.6 on the left, and the intraocular pressure after discontinuation was 19.5 ± 2.5 on the right and 19.6 ± 2.5 on the left. Three patients did not participate in the study for this reason.p = 0.01) and systemic hypertension (p = 0.005) were higher in the glaucoma group, while systemic hypotension (p = 0.008) was more frequent in the control group. Similarly, ischemic abnormalities (p = 0.003), AF (p = 0.03), LVH (p = 0.003), ST-T abnormality (p = 0.03) and premature contraction (p = 0.04) also were higher in the glaucoma group. IOP, AF, LVH, and bradycardia may be associated with the development of glaucoma, whereas age, IOP, and LVH may be associated with the severity of glaucoma. About 4.8% of the patients with glaucoma had bradycardia, as an adverse effect of beta-blokers.The frequencies of mild ECG abnormalities  of ophthalmic timolol in plasma (1.14 ng/mL) was lower than that of intravenous timolol (4.85 ng/mL). However, the heart rate and blood pressure decreased after the administration of both ophthalmic and intravenous timolol. The heart rate decreased by 1 to 12 beats per minute (bpm) from the base level. Ishii et al. [The A-V block is a conduction disorder from the atrium to the ventricle in the stimulation conduction system of the heart, and is classified into three degrees of severity. Second-degree A-V block includes the Wenckebach type and the Mobitz II type. The first-degree and Wenckebach type A-V block usually do not require treatment. Mobitz II type and third-degree A-V block may require sudden cardiac arrest and cardiac pacemaker implantation . Beta-bli et al.  also obsFrom these observations, we can see that ophthalmic beta-blockers not only reduce intraocular pressure but also affect the heart rate and blood pressure ,53. MoreWe used only ECGs in this study to diagnose cardiac diseases, but there is limitation regarding the diagnosis of LVH. The sensitivity and specificity of ECG to LVH is moderate, and it may not be adequately diagnosed . LVH can be diagnosed more accurately by using echocardiography or cardiac magnetic resonance imaging.Cardiac abnormalities in addition to IOP may be associated with the development and severity of glaucoma. Bradycardia is present in about 5% of glaucoma patients, and thus the ECG or heart rate of the patient should be checked before the prescription of beta-bloker ophthalmic solutions. We would like to investigate the effect of cardiac disease on the progression of glaucoma by observing the long-term course of glaucoma patients with cardiac disease in the future.


They can further moderate massive release of endogenous catecholamine. Therefore, the purpose of this study was to investigate the effect of DXM on outcomes of patients with septic shock, especially their needs for vasopressors and impacts on their hemodynamic status. This single-blind randomized controlled trial was performed on a total number of 66 patients with septic shock admitted to the intensive care unit (ICU) of Imam Khomeini Teaching Hospital in the city of Sari, in northern Iran. To this end, DXM (0.6 µg/kg/h) and normal saline (6 mL/kg/h) were infused for 12 h in the study and control groups, respectively. The results revealed that DXM could increase mean arterial pressure (MAP) (P = 0.021), systolic blood pressure (SBP) (P = 0.002), and reduced heart rate (P < 0.001) but diastolic blood pressure (DBP) (P =0.32) and norepinephrine dose requirement didn’t change statistically in septic shock patients (P = 0.12).Septic shock, known as the most severe complication of sepsis, is a serious medical condition that can lead to death. Clinical symptoms of sepsis include changes in body temperature in the form of hypothermia or hyperthermia, tachypnea or hyperventilation, tachycardia, leukocytosis or leukopenia, and variations in blood pressure, as well as altered state of consciousness. One of the main problems in septic shock is poor response along with reduced vascular reactivity to vasopressors used to increase blood pressure. Therefore, low vascular response associated with reduced sensitivity or lower number of alpha-1 agonist receptors can result in shock and death. In addition to being the state-of-the-art treatment including volume load and vasopressor, use of alpha-2 agonists  Obtaining enough information about sepsis has been considered as one of the medical science concerns . After eSince 2016, sepsis has been termed as a life-threatening organ dysfunction; as Sequential Organ Failure Assessment (SOFA) score > 2, with a mortality of over 10% in hospitals. Clinically, patients with septic shock are described as those requiring a vasopressor to maintain their mean arterial pressure (MAP) of 65 mmHg or more and serum lactate levels greater than 2 mmol/L (> 8 mg/dL) in the absence of a hypovolemia. Individuals with suspected sepsis infection can correspondingly have very poor recovery outcomes if they have at least two of criteria of Quick SOFA (qSOFA) including tachypnea , and altered state of consciousness .In the first phase, systemic inflammatory response can be considered as a result of host responses to bacterial products such as endotoxin. Then, cytokines are activated and cause further physiological disorders. The onset of septic shock is thus characterized by high concentrations of catecholamines in the circulation. Disturbance in sympathetic regulation of the cardiovascular system also indicates that autonomic system impairment produces circulatory failure . The most common causes of severe sepsis are pneumonia  as well as intra-abdominal and urinary tract infections. Even with intensive care, mortality rates in hospitalized septic shock patients have been reported by 80% over the past 30 years. Following the administration of norepinephrine, MAP can increase from 65 mmHg to 85 mm Hg; however, systemic oxygen metabolism, skin microcirculatory blood flow, and exudation and visceral perfusion do not significantly improve. Increasing doses of dopamine and dobutamine alone and in combination can be also effective in arterial hypotension treatment. Norepinephrine alone can further increase MAP and systemic vascular resistance and epinephrine can instigate a slight rise in heart rate .One of the frequently reported problems in septic shock is poor response and reduced vascular reactivity to vasopressors used to increase blood pressure. In this regard, efforts to restore vascular responses with nitric oxide inhibitors or low-dose steroids have been also unsuccessful. Low vascular responses associated with reduced sensitivity and number of alpha-1 agonist receptors can correspondingly result in resistance shock and death. i.e. a central alpha-2 agonist), as the active isomer of medetomidin, was licensed by the Food and Drug Administration (FDA) in 1999 to sedate patients admitted to intensive care units (ICUs). Accordingly, addition of alpha-2 agonist agents such as clonidine or DXM to common septic shock treatments could reduce vasopressor dose requirements. In other words, alpha-2 agonists can activate receptors in medullary vasomotor center. The second effect also plays an important role in sedation and anti-anxiety of this group, since decreasing the output of noradrenergic neurons from the locus cereulus increases the activity of inhibitory neurons such as gamma aminobutyric acid. Furthermore, several studies have shown that DXM can suppress inflammatory reactions and protect organs in both animals and humans. In major surgical procedures, DXM can also improve blood circulation and reduce mortality.Dexmedetomidine (DXM) , Sari, Iran. The study was approved by the Mazandaran University of Ethics Committee (No.IR.MAZUMS.REC.1397.3095), registered in www.IRCT.ir under IRCT No. IRCT20100107003014N22, and financially supported by the Vice-Chancellor’s Office for Research and Technology at MAZUMS with grant No. 3095. Informed consent was also obtained from patients’ legal and personal representatives included in the study.Patient selectionsample sizeConsidering the assumptions, the minimum sample size in each arm was 30 patients, assuming a maximum of 10% fall during the study to 33 patients in each arm.SD = 2.85 POWER = 80%, CI = 95%, CL = 2 Days,2/d2N = )2K × SD(2N = (2 × 7.6 × 2.85) 2/2N = 33 in each armParticipants and setting1C > 7%), heart block grade 2 or 3, sick sinus syndrome, history of chronic obstructive pulmonary disease (COPD) , history of use of beta-blockers, hypovolemia (CVP < 8 cmHg), and sever hepatic failure  were excluded.The patients were recruited from Imam Khomeini Teaching Hospital affiliated to MAZUMS. The informed consent was also obtained from all the participants before their recruitment. It should be noted that participants eligible for the study were those meeting diagnostic criteria of septic shock/sepsis , alteration of consciousness, systolic blood pressure less than or equal to 100 mmHg). Moreover, the inclusion criteria were the patients aged over 18 years with MAP above 65 mmHg. In addition, the patients with uncontrolled diabetes mellitus  was started.In addition, the second group received DXM at a dose of 0.6 μg/kg/h  for 12 h. DXM vials contained 100 μg of drug which needed to be diluted to reach a concentration of 4 μg/mL. Normal saline (6 mL/kg/h) was also infused for 12 h instead of DXM. Infusion was discontinued in both groups, if heart rate decreased or less equal 60 beat/min if MAP dropped and also this condition did not improve via vasopressor therapy. We followed up patients in day 2 and 7, respectively. In this study, the final analyzer was blinded to the study.Primary outcomeThe effect of DXM on hemodynamic status of the patients with septic shock was evaluated for 66 patients. These parameters include SBP, DBP, MAP, HR, and dose of NE requirement.Response assessmentChanges in heart rate, SBP and diastolic blood pressure (DBP), MAP, as well as norepinephrine dose requirement during 12 h of the study were evaluated.Statistical analysist-test or its nonparametric equivalent, i.e. Mann-Whiney U-test. Chi-square test was similarly utilized to compare the frequency of qualitative variables. For the repeated measured value we used “Repeated measure ANOVA”. It should be noted that analysis in this study was of intention-to-treat type and two-tailed P-value less than 0.05 was considered statistically significant in all cases. Descriptive and statistical analyses were performed using IBM SPSS Statistics software (version 21).At first, the distribution of the data was plotted by a histogram and explained by Kolmogorov-Smirnov test. Then, quantitative data were described while calculating mean standard deviation (SD) or median (quartile range) and qualitative data were controlled through percentage frequency. According to the distribution of the data, the means or medians of the quantitative variables were compared using independent Study Participants of 75 patients who were screened for eligibility, showed that 9 patients were excluded and 66 were enrolled. From 66 patients (33 in each study arm) who were randomized in the two groups nobody was lost during allocation and follow up in the case and control groups. Finally, the data analysis was performed on 33 patients, who completed the study . BaselinHemodynamic evaluation of patientsP < 0.01).As shown in P = 0.002). Considering the state of SBP changes over 12 h, illustrated in P = 0.32).With regard to the state of DBP changes during 12-h infusion in P = 0.021).In P = 0.12).As presented in The patients were followed up on days 2 and 7 after septic shock using SOFA criteria and no significant differences were observed between the two groups .i.e. creatinine clearance of less than 30), the half-life of the elimination had decreased. The mean half-life of the drug in healthy people had been by 2.5 h; however, in the patients with hepatic failure, it had been prolonged. As a result, the dose of this drug in the patients with septic shock needed to be reduced in case of liver involvement, depending on the degree of hepatic failure , on Syrian golden hamsters, the groups had been evaluated in terms of microcirculatory parameters, venous leukocyte-endothelial reactions, as well as correlation between intravenous leukocyte-endothelial interactions and capillary perfusion changes, variations in MAP, and heart rate; suggesting that DXM had reduced adhesion and circulation of leukocytes and capillary density. In a research carried out by Marcos On the other hand, DXM had lowered heart rate without any significant drop in MAP . In the et al. (2014) examining the difference between effects of propofol and DXM with 10 mg/mL concentrations on the preload of 16 endotoxemic rabbits receiving norepinephrine, it had been confirmed that propofol had increased heart rate, without affecting contractility of myocardium and vascular resistance; in contrast, DXM had augmented cardiac contractility and vascular resistance at high doses  on a 29-week-old child with septic shock secondary to necrotizing enterocolitis, clonidine had been initiated at a dose of 1 μg/kg/h continued by infusion for 13 h after taking the initial steps and the results had revealed that clonidine could improve blood circulation and subsequently decrease norepinephrine dose requirement  and average maximum concentration had been 81.2 ± 0.27 ng/mL. After intravenous administration of DXM, dual changes in blood pressure had been observed. During the first 5 min of intravenous injection by 2 μg/kg, MAP had increased by 22% and heart rate had decreased by 27% from baseline. Within 4 h after injection, MAP had also decreased by 20% from baseline and heart rate had reached less than 5% of the initial values. The hemodynamic profile had not shown any acute changes after intramuscular administration. Within 4 h after intramuscular injection, MAP and heart rate had subsequently decreased by 20% and 10%, respectively , the effects of simultaneous administration of morphine and DXM for anxiolytic effects had been reported and the results had suggested that morphine at a dose of 1 mg/mL accompanied by 5 µg/mL of DXM had reduced the dose of morphine by 29% within 24 h despite an increase in the analgesic effect from the second hour after surgery.Moreover, in a study by Lin MAP had decreased and pulse rate was higher in the group receiving DXM. Within 4 to 24 h, the incidence of nausea had been lower in DXM group. In general, in this study, performed on 100 women undergoing hysterectomy, the use of this drug had not induced bradycardia or hypotension, respiratory depression, and excessive sedation in the patients . In this study, since individuals with septic shock had failed to have spontaneous oral nutrition, they had been mainly fed through nasogastric tube and nausea had been assessed by the amount of fluid returned through it. Accordingly, the results revealed that the drug had not increased nausea in these patients compared with the control group. Although DXM couldn’t have significant changes in APACHE II, SOFA, hospital and ICU stay, this drug could increase the MAP that is very important in septic shock patients.The present study showed that DXM at a 0.6 µg/kg/h dose during a 12-h infusion had increased SBP, DBP, and MAP, and consequently decreased heart rate and norepinepine dose requirements. Given that there might be numerous mechanisms involved in septic shock, it was suggested to administer DXM to a larger number of septic shock patients with different doses and infusion durations to obtain more definitive conclusions.


In equine anaesthesia, valid and reliable blood pressure monitoring is crucial for adequate blood pressure management. Various non-invasive blood pressure monitors have been studied with varying results. High-definition oscillometry (HDO) promises greater accuracy than conventional oscillometric devices. With the cuff placed at the tail, the monitor gives satisfactory readings in normotensive anaesthetised horses, while for measuring low and high blood pressure, reliability was inadequate. To date, high-definition oscillometry has not been evaluated at the easily accessible equine metatarsal area. Therefore, the objective of this study was to assess agreement between HDO and invasive blood pressure, both obtained at a metatarsal artery at different blood pressure ranges in anaesthetised horses. Additionally, compliance with the American College of Veterinary Internal Medicine consensus guidelines was assessed. Agreement of HDO and invasive blood pressure was acceptable for mean arterial blood pressure during normotension only. During hypotension and hypertension, measurements were not valid. The monitor failed to meet most of the consensus validation criteria. Consequently, invasive blood pressure measurement remains preferable in haemodynamically unstable patients.High-definition oscillometry (HDO) over the metatarsal artery (MA) in anaesthetised horses has not yet been evaluated. This study aimed to assess agreement between HDO and invasive blood pressure (IBP) at the metatarsal artery, and to evaluate compliance with the American College of Veterinary Internal Medicine (ACVIM) consensus guidelines. In this experimental study, 11 horses underwent general anaesthesia for an unrelated, terminal surgical trial. Instrumentation included an IBP catheter in one and an HDO cuff placed over the contralateral MA, as well as thermodilution catheters. Systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and cardiac output were measured simultaneously. Normotension (MAP 61–119 mmHg) was maintained during the surgical study. Subsequently, hypotension (MAP ≤ 60 mmHg) and hypertension (MAP ≥ 120 mmHg) were induced pharmacologically. For MAP, the agreement between HDO and IBP was acceptable during normotension, while during hypotension and hypertension, IBP was overestimated and underestimated by HDO, respectively. The monitor failed to meet most ACVIM validation criteria. Consequently, if haemodynamic compromise or rapid blood pressure changes are anticipated, IBP remains preferable. Determination of cardiac output (CO) as a good indicator for blood flow and perfusion is still laborious. Thus, in clinical settings, invasive blood pressure (IBP) measurements in peripheral arteries are well-accepted surrogates for CO measurements. The mean arterial blood pressure (MAP) is dependent on CO and systemic vascular resistance (SVR) as a measure of vessel tone. Valid IBP measurement requires technical equipment and expertise, and the establishment of arterial access can be time consuming.Various non-invasive blood pressure (NIBP) monitors have been studied in horses at different anatomical locations and with varying results regarding accuracy and precision ,2,3. HigThe performance of the HDO monitor with the cuff placed over the coccygeal artery was assessed in anaesthetised horses ,6. In doIn adult anaesthetised horses, NIBP measurement in the metatarsal region did not seem to be an appropriate alternative to IBP measurement ,2, but aTo the authors’ knowledge, studies evaluating the HDO monitor over the metatarsal artery (MA) in anaesthetised horses are lacking. Changes in wave reflections from more centrally to peripherally located arteries lead to amplification of pulse waves . TherefoThis study was part of an unrelated, terminal surgical trial investigating ischaemic postconditioning at the equine jejunum. All procedures were reviewed and approved by the Ethics Committee for Animal Experiments of Lower Saxony .An a priori power analysis revealed that 20 horses would be necessary to detect a mean difference of 10 mmHg (standard deviation 15 mmHg) between two blood pressure measurement methods , with a In total, 16 horses were designated for the surgical trial. Measurements of 5 horses were excluded due to instrumentational or technical problems. Data of the remaining 11 horses  age of 6 years (4–24 years) and a median (range) body weight of 542 kg (464–596 kg)) were obtained and analysed. The horses had no recent history of cardiovascular disease. Physical examination and routine haematological and biochemical blood examination were without abnormalities. All horses suffered from a chronic, untreatable orthopaedic disease. Therefore, they were euthanised by intravenous (IV) injection of pentobarbitone 80 mg/kg IV  at the end of the study, without regaining consciousness, and subsequently used for educational purposes.2O was initiated. Respiratory rate and PIP were adjusted to maintain an end-tidal carbon dioxide (PE’CO2) between 4.7 and 6 kPa (35–45 mmHg). Standard anaesthetic monitoring included sidestream capnography, a lead II electrocardiogram, and inspiratory and end-expiratory gas concentrations displayed on a multiparameter monitor . The gas analyser was calibrated before each experiment by a 2-point calibration at expected concentrations .Food but not water was withheld for six hours prior to anaesthesia. All horses were premedicated with xylazine 0.7 mg/kg IV . Induction of anaesthesia was performed by ketamine 2.2 mg/kg IV  and diazepam 0.1 mg/kg IV . Following orotracheal intubation, the animals were hoisted to a padded air mattress, positioned in dorsal recumbency, and connected to a large animal anaesthesia machine  via a circle breathing system. Anaesthesia was maintained with isoflurane in 100% oxygen . Pressure cycled mechanical ventilation with positive inspiratory pressure (PIP) of 20–25 cmHFor IBP measurement, horses were equipped with a 20 gauge over-the-needle-catheter  that was inserted into one MA and connected to a pre-calibrated disposable electronic pressure transducer  via a non-compliant fluid-filled  extension line. The pressure transducer was positioned at the level of the shoulder point and zeroed to atmospheric pressure. A fast-flush test with visual evaluation of the arterial pressure waveform was performed to confirm the presence of a square wave and two oscillations at the beginning of the experiment and at a regular interval to avoid excessive overdamping or underdamping and clot formation.For the NIBP measurement, a commercially available HDO equine cuff (width 8 cm)  was placed over the palpable MA around the contralateral cannon bone at the same height as the IBP catheter. The cuff was connected to the HDO monitor Memo Diagnostic Equine . Readings and oscillometric curves were visible in real time on a tablet device using the manufacturer’s software . To account for the effects of hydrostatic pressure, the vertical distance between the middle of the HDO cuff and the level of the xiphoid process was measured by a tape measure, and a correction factor (1 cm~0.74 mmHg) was applied . This vaFor CO measurements, two 8 Fr catheter introducers  were aseptically placed in the right jugular vein. A thermistor-tipped thermodilution catheter  with a length of 110 cm was placed into the pulmonary artery (PA), and a second balloon-tipped catheter was placed into the right atrium (RA). Correct placement was confirmed by visual inspection of the pressure waveforms.After successful instrumentation, blood pressure (IBP and HDO obtained at the MA) and CO measurements were performed simultaneously, representing a measurement time point.The HDO measurement was started manually, and at the end of each HDO cycle, all readings  obtained simultaneously by HDO and IBP were recorded.Cardiac output measurements were performed by the bolus thermodilution method. A bolus of iced 0.9% sodium chloride solution (50 mL) was injected manually into the RA, while the three closest CO values of a maximum of five injections were used for further analysis. For calculation of cardiac index (CI) and systemic vascular resistance index (SVRI) standard equations were used . CalculaAll data were manually recorded in an electronic spreadsheet and used for data analysis. Erroneous NIBP measurements (displayed by the HDO software as ‘error code’) were not considered for statistical analysis. Additionally, retrospective visual evaluation and graduation into ‘good’ and ‘poor’ quality oscillometric curves recorded by HDO software were performed by one author, without excluding any of these measurements from data analysis. Good quality oscillometric curves did not contain any artifacts and were characterised by a linear deflation curve and a bell-shaped oscillation curve.Throughout the surgical study, normotension (MAP 61–119 mmHg) was achieved by infusion of Lactated Ringer’s solution  and dobutamine . The duration of the surgical study was approximately 210 min. After the termination of the surgical trial, the manipulation of blood pressure was initiated, allowing a short stabilisation period of 5 min at each range. To achieve hypotension (MAP ≤ 60 mmHg), inspiratory isoflurane concentration was increased, while infusions  were discontinued. Hypertension (MAP ≥ 120 mmHg) was induced by decreasing inspiratory isoflurane concentration and resuming blood pressure support by crystalloid infusions and dobutamine (2.7–3.0 µg/kg/min). To further increase blood pressure, additional norepinephrine  was administered.A random selection by R statistical software  of threep ≤ 0.05.Repeated-measures correlation or within-participants correlation  was estiCalculations were performed using R statistical software . Bland–AFor comparison of our data with the ACVIM guidelines, the mean difference and standard deviation between paired measurements were calculated, using a standard spreadsheet program .n = 11 horses) for cardiac output and blood pressure obtained simultaneously by IBP and HDO at the MA were analysed. More data were recorded during normotension (96 paired measurements), compared with hypotension (28 paired measurements) and hypertension (28 paired measurements). An overview of data selection for statistical analysis, duration of different measurement periods, and exclusion criteria of data is depicted in In total, 152 paired measurements , bias and upper and lower LOA between IBP and HDO for MAP, DAP, and SAP were 8.1 mmHg (−14.1–30.2), 26.8 mmHg (−4.2–57.8), and −9.5 mmHg (−41.1–22.2), respectively.For the hypotensive blood pressure state (28 paired measurements), bias and upper and lower LOA between IBP and HDO for MAP, DAP, and SAP were −3.5 mmHg (−25.3–18.2), 2.6 mmHg (−15.8–21.0), and −20.1 mmHg (−50.7–10.5), respectively.During hypertension (28 paired measurements), bias and upper and lower LOA between IBP and HDO for MAP, DAP, and SAP were 25.0 mmHg (−14.5–64.5), 39.1 mmHg (−1.9–76.4), and 12.8 mmHg (−60.5–86.2), respectively.The median heart rate (range) of all horses was 35 (29–81) beats/minute. Arrhythmias were not observed in any horse. Agreement between invasively and non-invasively measured heart rate was good .Calculated CI and SVRI in relation to IBP obtained at the MA are shown in When applying the 2007 ACVIM standards to the comparison of IBP and HDO measured MAP, DAP, and SAP obtained at the MA, the criteria were fulfilled neither for SAP nor for DAP in this study. For MAP, only a few criteria met the ACVIM standards .n = 7 horses) erroneous (‘error code’) measurements were observed evenly across all blood pressure states. A retrospective visual assessment revealed a total of 84 ‘good’ quality (n = 7 horses) and 24 ‘poor’ quality (n = 5 horses) oscillometric curves. Poor quality measurements were observed in hypotensive and low normotensive blood pressure ranges.Due to technical problems concerning the HDO software, data of four horses were not available for retrospective evaluation. A total of 25 single  . HoweverIn this study, overall, DAP was underestimated by HDO, while SAP was underestimated at hypertension and overestimated at hypotension. For SAP, these findings are in accordance with the study by . For oscAnother reason for the inaccuracy of HDO measurements might be the characteristics of the anatomic location itself. As proposed by , the geoAppropriate cuff width relative to the circumference of the leg or tail is crucial for the accuracy of NIBP measurement ,6,21. UnHypotension resulted from a reduction in CI and SVRI in most horses. The most probable reason for the reduction in CO is the cessation of inotropic support by dobutamine and fluid support. Additionally, isoflurane enhances myocardial depression and peripheral vasodilation in a dose-dependent fashion, while endotoxaemia caused by surgical intervention may also have played a role. Changes in vasomotor tone may alter the performance of NIBP monitors , which wHypertension mainly resulted from increased CI caused by positive inotropic effects of dobutamine and concomitant reduction in afterload. Due to insufficient raise in MAP by dobutamine alone, additional norepinephrine was administered in all horses. Norepinephrine is considered a potent vasopressor, but it also increases myocardial contractility due to beta-adrenergic stimulation . Since SWhen applying the 2007 ACVIM standards, in this study, the required criteria were not met for SAP and DAP and only partly for MAP. These findings might result from a large variability of the measurements, affecting accuracy and reliability. Similar observations were made in previous studies in anaesthetised horses ,25. OnlyOne limitation of our study is the low number of measurements in the hypotensive and hypertensive blood pressurestates. Considering critical blood pressures, results should, therefore, be interpreted carefully. Large-scaled studies with heterogenous groups of horses and naturally occurring hyper- and hypotension might help to evaluate the source of the inaccuracy.Regardless of the quality of oscillometric curves displayed by HDO, all data were included in the statistical analysis. Since artefacts are claimed to be filtered by HDO and should not influence measurements , it is uThe blood pressure transducers were not calibrated against a mercury manometer, and standard electronic pressure transducers were preferred over microtransducer-tipped catheters to better reflect practical clinical standards, which can be regarded as a limitation of the study.To minimise the influence of individual artery wall properties or blood flow characteristics, ideally, the same artery for IBP and NIBP measurement is used. However, repetitive occlusion of the MA artery by the HDO cuff was very likely to interfere with IBP measurements.Agreement of the HDO monitor with the cuff placed over a metatarsal artery led to an acceptable agreement with IBP measurements for MAP in normotensive anaesthetised horses. However, during hypotension and hypertension, measurements were not valid, which is associated with the risk of clinically relevant hypotension going unnoticed.Consequently, IBP remains preferable for clinical decision making in haemodynamically unstable patients. Overall, determination of MAP by HDO performed better than detection of DAP and SAP. Moreover, poor oscillometric signal quality may indicate the presence of hypotension and warrants further investigation. In this study, the HDO monitor failed to meet most of the American College of Veterinary Internal Medicine validation criteria.


Treatment intensity score correlated positively with plasma MR-proADM concentration , and the correlation was further enhanced after correction by weight . Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r =  − 0.777,  Previous reports suggested that the progression of CKD is a risk factor for complication with cardiovascular disease (CVD)3. Preventing CKD progression decreases the risk of complications of several diseases, contributing to reducing the burden of medical economics and extending healthy life3.Chronic kidney disease (CKD) is defined in the Kidney Disease: Improving Global Outcomes (KDIGO) guideline as abnormalities of kidney structure or function, present for more than 3 months, with implications for health4. On the other hand, many CKD patients are complicated with secondary hypertension due to renal parenchymal disorder5. CKD and hypertension are closely related pathophysiological states and exacerbate each other. Moreover, hypertension is also an independent risk factor for CVD. Appropriate management of blood pressure is important to prevent the development of CVD as well as the progression of CKD.Hypertension is a major risk factor for impaired renal function. In the United States, hypertension is the second leading cause of end-stage kidney disease (ESKD)6. In general, blood pressure is lowered slowly over several months after initiation of antihypertensive therapy. However, patients with high risk for CVD are recommended to achieve target blood pressure within a few weeks if possible, because the difference in blood pressure lowering during 1–3 months after antihypertensive initiation affects the onset of CVD7. Thus, to achieve target blood pressure as soon as possible, a biomarker that can predict the response of each patient to antihypertensive therapy before starting antihypertensive therapy is required.Many patients with hypertension receive antihypertensive therapy in addition to modification of lifestyle to achieve target blood pressure. However, some patients, especially those who have CKD, exhibit poor response to antihypertensive therapy, and determination of the optimal antihypertensive therapy to achieve the target blood pressure takes time8. ADM is produced from cells in various organs, especially vascular endothelial cells, and exerts some important effects to maintain vascular homeostasis. In the kidney, ADM is known to have renoprotective function by increasing renal blood flow9. Furthermore, ADM would regulate proadrenomedullin N-terminal 20 peptide (PAMP) secretion in the juxtaglomerular complex10. Since ADM and PAMP could regulate renin activity, these peptides potentially play a significant role in maintaining systemic blood pressure. Increased blood ADM concentration has been associated with the development of hypertension in normotensive subjects11. However, ADM is difficult to quantify in the clinical setting, because of its nonspecific metabolism in blood, clearance due to binding to receptors and binding to plasma proteins14. Mid-regional proADM (MR-proADM) is produced from an ADM precursor peptide in equal amount as ADM and has been anticipated to be an effective surrogate biomarker for quantification of ADM because of its low physiological activity and high stability in the body compared with ADM15. Focusing on the potential of MR-proADM as a cardiovascular biomarker, we previously reported a relationship between MR-proADM level and resistance to antihypertensive therapy in stable kidney transplant recipients16. Thus, we hypothesized that MR-proADM level serves as a predictive biomarker for the responsiveness to antihypertensive drugs in CKD patients with poor blood pressure control.Adrenomedullin (ADM), a bioactive peptide related to cardiovascular homeostasis, is reported to be a predictor of the development of various diseases such as hypertensionGiven the above background, we conducted a cross-sectional study in CKD patients with poor blood pressure control and determined the relation between MR-proADM and antihypertensive resistance.17, poor blood pressure control was defined as failure to achieve the target systolic and diastolic blood pressure despite antihypertensive therapy with at least two different classes of drugs. Using conventional office blood pressure, the target blood pressure was determined according to the above guideline17. The target blood pressure was < 130/80 mmHg for CKD patients with proteinuria; < 140/90 mmHg for young, middle-aged, and older patients aged below 75 without proteinuria; < 150/90 mmHg for older patients aged 75 or over without proteinuria; < 130/80 mmHg for diabetic patient; and < 140/90 mmHg for patients with cerebrovascular disorder or coronary artery disease. CKD was defined as glomerular filtration rate (GFR) lower than 60 mL/min/1.73 m2, according to the Clinical practice guidebook for diagnosis and treatment of chronic kidney disease 2018 published by the Japanese Society of Nephrology18. Estimated GFR (eGFR) was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation and was substituted for GFR19. Exclusion criteria were as follows: patient under 30 or over 80 years of age; patient with a history of infectious diseases within 1 week before recruitment or acute heart failure within 1 month before recruitment; and patient undergoing dialysis.This cross-sectional study recruited CKD outpatients with poor blood pressure control, who attended the Department of Nephrology in Oita University Hospital. According to the Guidelines for the Management of Hypertension 2014 published by the Japanese Society of Hypertensiong, 25 °C), plasma sample was collected and frozen at − 40 °C until assay. The plasma MR-proADM concentrations were measured using an ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method that we developed previously20. The UPLC–MS/MS assay has high specificity and sensitivity, a lower limit of quantification of 0.4 ng/mL and a calibration range of 0.4–100 ng/mL. Within-batch and batch-to-batch accuracy for three quality control samples ranged from −0.69 to 8.05% and from 1.72 to 5.76%, respectively. Within-batch and batch-to-batch precision ranged from 1.94 to 10.8% and from 7.17 to 8.15%, respectively.Blood sampling from recruited CKD outpatients was conducted at the time of registration. Blood sample was drawn from a vein into a tube containing ethylenediaminetetraacetic acid. After centrifugation  = 10 mg/10 mg = 1; score for telmisartan (maximum daily dose 80 mg) = 40 mg/80 mg = 0.5). Analyses were conducted using both the treatment intensity score and the weight-corrected treatment intensity score.The following clinical data were collected: sex, age, body weight, systolic and diastolic blood pressure, prescribed drugs and primary diseases. The recorded laboratory data included serum creatinine, blood urea nitrogen and urine protein. Estimated quantitative proteinuria was calculated as urine protein to creatinine ratio. To evaluate the degree of treatment resistance in patients taking various doses of different antihypertensive drugs, the treatment intensity score was calculated as the sum of “daily dose/maximum daily dose” of all antihypertensive drugs used16. A p-value less than 0.05 was considered statistically significant. Statistical analyses were performed using the Predictive Analysis Software Statistics version 21.0 .The relations of plasma MR-proADM concentration with clinical data and treatment intensity score with and without correction by weight were evaluated. The relation of plasma MR-proADM concentration with the weight-corrected treatment intensity score for each of the four drug classes  were also evaluated. Since the patients in this analysis received antihypertensive therapy with at least two different classes of drugs, there was overlap of patients among the four groups; i.e., a patient in one drug class was also taking antihypertensive drug(s) of other class(es) . All subjects provided written informed consent for participation in this study before the study started.2 and measured plasma MR-proADM concentration was 2.99 ± 1.85 ng/mL. IgA nephropathy and nephrosclerosis were the main primary diseases of CKD.Thirty-three CKD patients with poor blood pressure control were recruited. The clinical and laboratory data at registration are shown in Table p < 0.001). The relations of treatment intensity score calculated for all the antihypertensive drugs taken by each patient with plasma MR-proADM concentrations and with eGFR are shown in Fig. p = 0.043), but did not correlate with eGFR . On the other hand, the weight-corrected treatment intensity score showed a significant correlation with both eGFR  and plasma MR-pro ADM concentration   and non-overweight patients  . No significant correlation was found for three drug classes , whereas the weight-corrected treatment intensity score for calcium-channel antagonists correlated positively with plasma MR-proADM concentration  as the independent factor associated with weight-corrected treatment intensity score  with re Table .Table 3SPatients with CKD often exhibit resistance to antihypertensive drug, and they require much time to attain the target blood pressure. As sustained hypertension is associated with the progression of CKD or the development of CVD, a biomarker that reliably determines the therapeutic intensity of antihypertensive drugs is useful for early achievement of the target blood pressure. We focused on MR-proADM as the biomarker and evaluated the relationship between plasma MR-proADM concentration and treatment intensity score in CKD patients with poor blood pressure control. This study revealed several findings: (1) eGFR correlated negatively with plasma MR-proADM concentration; (2) treatment intensity score of all drugs taken by each patient correlated positively with plasma MR-proADM concentration, but not with eGFR; (3) the correlation of treatment intensity score with plasma MR-proADM concentration was enhanced after correction by weight; (4) stepwise multiple regression analysis identified MR-proADM concentration as the only independent factor associated with weight-corrected treatment intensity score.22 reported that plasma MR-proADM concentration correlated strongly with GFR measured by iohexol, suggesting that MR-proADM is excreted mainly by filtration in the kidney, especially via the glomeruli. However, at present, the excretion routes of MR-proADM remain unclear, and the possibility of excretion by other routes cannot be ruled out. Renal damage per se may also influence plasma MR-proADM concentration. ADM would regulate PAMP secretion in the juxtaglomerular complex10. Since ADM and PAMP could regulate renin activity, these peptides potentially play a role in systemic blood pressure control and vascular remodeling. Furthermore, ADM is a bioactive peptide identified in sclerotic glomerular cells and fibroblasts in the kidney23 and is known to have renoprotective function by increasing renal blood flow9. Since ADM plays a central role in the compensatory mechanism of CKD, plasma ADM level has been considered to increase with renal dysfunction24. In a previous study22, MR-proADM concentration was identified as an independent factor predicting the progression of CKD even after baseline correction by GFR and proteinuria, suggesting that renal injury per se influences the fluctuation of MR-proADM concentration. Similarly, several studies have reported that plasma MR-proADM levels are high in patients with renal failure and increase as the CKD stage progresses26. These findings support the results in this study.In this study, a negative correlation between eGFR and plasma MR-proADM concentration was found, suggesting that higher renal function correlates with lower plasma MR-proADM concentration. Dieplinger et al.27. For CKD patients with poor blood pressure control, various factors other than renal failure could cause hypertension and resistance to antihypertensive drugs. Therefore, our finding of no significant correlation between eGFR and treatment intensity score in CKD patients with poor blood pressure control in this study was as expected. On the other hand, the treatment intensity score correlated positively with plasma MR-proADM concentration. Moreover, stepwise multiple regression analysis identified plasma MR-proADM concentration as the only independent factor associated with the treatment intensity score. The increase in treatment intensity score, which signifies increased treatment resistance to antihypertensive drugs, is considered to be due to vascular failure caused by vascular injury associated with hypertension and renal injury. ADM is released from the blood vessel wall and possesses blood pressure lowering activity28. Wild et al.29 showed elevated plasma MR-proADM concentration in patients with hypertension. Furthermore, Koyama et al.30 revealed a significant association of plasma MR-proADM concentration with brachial-ankle pulse wave velocity, which is an indicator of arterial stiffness, and suggested that MR-proADM is more suitable for diagnosing arterial stiffness as the criterion for vascular failure. Given these lines of evidence, MR-proADM concentration reflects the vascular condition in hypertensive patients, and its plasma concentration becomes higher under conditions of increased treatment resistance to antihypertensive drugs. Hence, the treatment intensity score correlates with MR-proADM concentration, unlike eGFR.While plasma MR-proADM concentration correlated positively with treatment intensity score, eGFR did not correlate with treatment intensity score. It is commonly known that CKD and hypertension are physiologically related to each other. However, CKD patients with poor blood pressure control are at risk of developing arteriosclerosis, cardiac disease, and other illnesses due to long-term exposure to high blood pressure. Moreover, poor blood pressure control is caused by many factors such as poor adherence; lifestyle factors such as excessive salt intake, obesity and excessive drinking; sleep apnea syndrome; excessive fluid volume; and secondary hypertensionThe correlation between treatment intensity score and plasma MR-proADM concentration was enhanced after treatment intensity score was corrected by weight. In general, heavy patients tend to receive higher doses of antihypertensive drugs since drug clearance and distribution volume are proportional to weight. This probably accounts for the improved correlation between weight-corrected treatment intensity score and plasma MR-proADM concentration. On the other hand, although eGFR also correlated significantly with weight-corrected treatment intensity score, eGFR was not identified as an independent factor in stepwise multiple regression analysis, unlike plasma MR-proADM concentration. A large correlation coefficient was found between eGFR and plasma MR-proADM concentration (r =  − 0.777). Therefore, we speculate that the significant correlation between weight-corrected treatment intensity score and eGFR is due to the indirect influence of the increased correlation of treatment intensity score with plasma MR-proADM concentration. However, since there are no reports of the association between MR-proADM concentration and the treatment intensity score in non-CKD patients with hypertension, the exact reason remains unclear.31. Since these drugs act directly on blood vessels and MR-proADM concentration reflects the vascular condition, these may explain the correlation between treatment intensity score for calcium-channel antagonists and plasma MR-proADM concentration. However, ARB and some αβ blockers (carvedilol and arotinolol) exert antihypertensive effect by antagonizing angiotensin II receptor and α1-receptor, respectively, on vascular endothelial cells. Thus, the reason why plasma MR-proADM concentration correlates with treatment intensity score only for calcium channel blockers is unknown.There was no correlation between plasma MR-proADM concentration and weight-corrected treatment intensity score for three drug classes , but a positive correlation was found only for calcium-channel antagonists. Calcium channel blockers dilate arteries and effectively lower blood pressure by reducing calcium flux into vascular smooth muscle cells14. The present study differs from our previous study in several aspects; namely, study subject  and blood pressure control poor (target blood pressure not achieved despite at least two classes of antihypertensive drugs) versus good . The possible causes of hypertension in stable kidney transplant recipients include not only renal failure but also various factors such as excessive salt intake following rapid recovery of renal function, graft renal parenchymal disorder, adverse effects of immunosuppressive drugs, and angiopathy due to transplanted renal artery stenosis32. Therefore, the cause of hypertension in stable kidney transplant recipients is partially different from that in CKD patients before transplantation. In our previous report14, the correlation between treatment intensity score and MR-proADM was confirmed in patients with good blood pressure control, but it was unclear whether the correlation would be found in patients with poor blood pressure control. The present study demonstrated the relationship between MR-proADM and treatment intensity score in hypertensive CKD patients with poor blood pressure control as well, suggesting the usefulness of MR-proADM for predicting antihypertensive treatment resistance in hypertensive patients.Our previous study in stable kidney transplant recipients also showed a correlation between plasma MR-proADM concentration and anti-hypertensive treatment scoreThe present study has several limitations. First, the number of recruited CKD patients with poor blood pressure control was small (N = 33). Large-scale, prospective research will need to be conducted in the future. Second, some patients included in this study could have falsely high blood pressure reading. Since patient recruitment was based on conventional office blood pressure, patients with white coat hypertension could have been included. Moreover, adherence of these patients is also unknown. Third, we speculate that plasma MR-proADM level is related to antihypertensive drug tolerance because plasma MR-proADM level reflects the status of vascular insufficiency. However, we did not evaluate indicators of arterial stiffness, such as pulse wave velocity and ankle-brachial pressure index. Thus, the detailed mechanism of this relationship remains unknown. Fourth, treatment intensity score is a parameter indicating the therapeutic intensity of an antihypertensive drug. There is a possibility that the score may not adequately reflect resistance to antihypertensive treatment. Fifth, we evaluated the relation of plasma MR-proADM concentration with the weight-corrected treatment intensity score of each of four antihypertensive drug classes. However, since the patients in this analysis received antihypertensive therapy with at least two different classes of drugs, the possible influence of polytherapy on the result of this analysis cannot be ruled out.In conclusion, this study suggests the usefulness of plasma MR-proADM concentration as a biomarker reflecting resistance to antihypertensive therapy in CKD patients with poor blood pressure control. For hypertensive patients at high risk of CVD, while early attainment of the target blood pressure is desirable to prevent onset of CVD, some patients with severe hypertension may need high-intensity antihypertensive therapy from the initiation of treatment, with a concern of adverse events. For these patients, safe and individualized antihypertensive therapy may be planned by selecting drug(s) based on the evaluation of resistance to antihypertensive drug by MR-proADM in advance.Supplementary Information.


Different stimuli can influence posture in daily life and, therefore, impose a risk of a solid balance during standing. To maintain this upright position, the capacity to recognize changes in posture and react appropriately is essential. The increased frequency of falls owing to postural hypotension, along with a lack of postural stability, is a serious problem not just in the elderly, but also different patient groups . Similar changes in blood pressure regulation, as well as cardio-postural control, might occur in patients suffering from lymphedema due to differences in fluid volumes of the lower limbs. Lymphedema therapy could therefore affect hemodynamic responses during orthostatic loading (sit-to-stand test) due to the variable amounts of fluid in the lower limbs throughout therapy. To our knowledge, no previous study has ever longitudinally investigated the inter-relationship between lymphedema and hemodynamic responses and changes in volume regulatory hormones during orthostatic loading over three weeks of lymphedema treatment. We report here that lymphedema patients did not show signs of orthostatic hypotension, demonstrating that those patients do not seem to be at an increased risk for orthostatic intolerance and falls. However, lymphedema treatment showed to have a potential beneficial effect on cardiovascular responses during orthostatic challenge (sit-to-stand test) in lymphedema patients.p = 0.048). No changes in baseline values were shown due to MLD. However, MLD led to a significant decrease in heart rate during orthostatic loading over all epochs on therapy day 14, as well as day 21. Volume regulatory hormones did not show changes over lymphedema therapy. Conclusion: We did not observe any signs of orthostatic hypotension at rest, as well as during to CDT, indicating that lymphedema patients do not display an elevated risk of orthostatic intolerance. Although baseline hemodynamics were not affected, MLD has shown to have potential beneficial effects on hemodynamic responses to a sit-to-stand test in patients undergoing lymphedema therapy.Background: Lymphedema arises due to a malfunction of the lymphatic system, leading to extensive tissue swelling. Complete decongestive therapy (CDT), which is a physical therapy lasting for 3 weeks and includes manual lymphatic drainages (MLD), leads to fluid mobilization and increases in plasma volume. Here, we investigated hemodynamic responses induced by these fluid shifts due to CDT and MLD. Methods: Hemodynamic parameters were assessed continuously during a sit-to-stand test . This intervention was repeated on days 1, 2, 7, 14, and 21 of CDT, before and after MLD. Volume regulatory hormones were assessed in plasma samples. Results: A total number of 13 patients took part in this investigation. Resting diastolic blood pressure significantly decreased over three weeks of CDT ( The effects of gravity on the cardiovascular system while standing up create a dip in blood pressure. This can be explained by the fact that blood is pooled in the lower extremities. Consequences of this can be the loss of consciousness (syncope) if the body cannot compensate this blood pressure drop upon standing up ,2. OrthoThe lymphatic vessels transport several liters of lymphatic fluid throughout the whole body every day ,8,9. As In lymphedema patients, cardio-postural control might be affected due to different fluid volumes in the lower limbs, pre- and post-therapy, as well as due to plasma volume changes during physical therapy ,13,15,16This investigation was performed at the clinical center for lymphatic disorders, KABEG, Wolfsberg, Austria. Data analysis was conducted at the Division of Physiology at the Medical University of Graz, Austria. Prior to commencing the study, a positive ethical vote was received from the responsible Ethics Committee of Carinthia (A 03/17), as well as from the Ethics Committee at the Medical University of Graz (29-090 ex 16/17). The study was conducted following the latest Declaration of Helsinki (2013). Each patient was given extensive information about the procedures, and provided both informed and written consent. The signed consent forms are stored at the Medical University of Graz.Male and female patients diagnosed with stage II primary and secondary lower limb lymphedema were recruited directly at the clinical center for lymphatic disorders. Diagnosis was performed according to the recommendations reported in the most recent consensus document provided by the International Society of Lymphology (ISL) . EnrollmThe treatment protocol was based on the recommendations by Döller ,19 and i®  was utilized to continually assess hemodynamic parameters noninvasively. The following parameters were continuously recorded: heart rate (HR), systolic and diastolic blood pressure (SBP/DBP), as well as mean arterial pressure (MAP). For further details, please see Trozic et al. 2019 [All measurements were performed in the morning (from 8:00 am to noon) in a quiet and slightly dimmed room. Room temperature was set between 21 and 24 °C. Humidity was controlled and remained in the range of 50–60%. Hemodynamic assessment was performed at different timepoints over three weeks of CDT  to investigate a time-course effect of CDT. Patients were asked to refrain from coffee 24 h before the assessment, but were allowed to have breakfast 1 h prior to the measurement. Further, to determine the effect of MLD, the measurements were carried out immediately before and after 30 min of MLD on each of the indicated days, as further depicted in Aldosterone and plasma renin activity (PRA) were assessed via a commercially available ELISA kit . Atrial natriuretic peptide (ANP) was assessed via an RIA kit without prior extraction . Arginine vasopressin (AVP) was assessed via an ELISA kit . A commercially available ELISA kit  was used to measure adrenomedullin (ADM). Pro-brain natriuretic peptide (proBNP) was assessed via a competitive inhibition-enzyme-linked immunosorbent assay . All hormone assessments were performed at the Medical University of Graz, Austria.p-values < 0.05. SPSS Statistics  was utilized for statistical analysis. Figures were generated via GraphPad Prism . All data are displayed as means ± standard deviation (SD). Figures depict means ± standard error of the mean in order to provide better visualization.MATLAB Software  was used to analyze hemodynamic data as previously described in Trozic et al., . Epochs In total, 13 patients  were included. Demographic details are depicted in  = 3.31; p = 0.048) after three weeks of CDT  = 1.17; p = 0.362; F = 2.65; p = 0.085 and F = 2.89; p = 0.069, respectively) as a result of three weeks of CDT (Resting diastolic blood pressure (DBP) (epoch 1) significantly reduced from 90.9 ± 10.6 mmHg before to 82.4 ± 4.0 mmHg  = 1.17; p = 0.699), SBP  = 0.00; p = 0.998), DBP  = 2.28, p = 0.632), and MBP  = 0.07; p = 0.815), as no significant changes could be observed in these parameters  = 6.07; p = 0.036 and F = 5.24; p = 0.048, respectively), due to 30 min of MLD  = 12.53; p = 0.014), seventh  = 6.56; p < 0.001), fourteenth  = 5.14; p < 0.001), and twenty-first = 6.67; p = 0.006) day of CDT. Responses in blood pressure did not show any changes during orthostatic loading pre- compared to post-MLD on each individual measurement day.Heart rate significantly reduced over all indicated epochs on therapy day 14, as well as therapy day 21 .p = 0.048). As we are not aware of any previously published study reporting alterations in blood pressure due to lymphedema therapy, this is a novel finding. It is unclear if the drop of diastolic blood pressure was caused by lymphedema therapy or exercise done as part of full decongestive therapy, as physical activity and exercise is one aspect of lymphedema therapy, along with MLD and compression bandages. A total of 30–60 min of exercise a week has been shown in studies to result in a significant reduction in diastolic blood pressure in critical hypertensives [Over three weeks of CDT, diastolic blood pressure at rest significantly decreased from 90.9 ± 10.6 mmHg to 82.4 ± 4.0 mmHg . An average reduction in heart rate of 4 bpm was seen on the 14th day and a decrease of 5 bpm on the 21st day of CDT over all epochs of the indicated measurements. Therefore, MLD appears to have possible beneficial effects on cardiovascular parameters/hemodynamic responses to an orthostatic challenge in patients with lymphedema.Furthermore, a significant reduction in heart rate was seen due to MLD over all 10 epochs on the 14th and 21st day of CDT . However, we did perform a sample size calculation a priori, which revealed that an estimated total of 13 patients would be a sufficient sample size to show statistical significance. Moreover, the main strength of this investigation is that each individual patient counted as his/her own control. Therefore, each individual patient was followed over the entire time-course of three weeks of complete physical therapy. The same assessments were conducted over several time points in the same patient. Due to the limited number of patients involved in this study, a separate analysis depending on the different therapists who applied MLD to the patients was not possible. Therefore, future studies should also consider the effect of MLD performed by different therapists. Further, larger cohort studies should be performed in future, which will allow the investigation of different stages and disease durations of lymphedema, distinct etiologies (primary or secondary), in various body parts (upper and/or lower limbs), or by differing therapies .One potential weakness of this clinical investigation could be the limited number of patients that could be included  were observed in those patients at baseline, as well as over three weeks of complete decongestive therapy. Baseline hemodynamic parameters were not affected by manual lymphatic drainage. Nevertheless, lymphatic drainage has a possible beneficial effect on hemodynamic parameters during an orthostatic challenge in patients suffering from lymphedema who are undergoing physical therapy.