Duchenne muscular dystrophy is an X-chromosome-linked genetic disorder (locusXp21). Involvement of the cardiovascular system is characterized by fibrousdegeneration/replacement of myocytes with consequent ventricular hypertrophyand arterial hypertension.To assess, by using 24-hour ambulatory blood pressure monitoring, thebehavior of blood pressure variables in children and adolescents with aconfirmed diagnosis of Duchenne muscular dystrophy.Prospective observational cohort study, which selected 46 patients followedup on an outpatient basis, divided according to age groups. Blood pressurewas classified according to the age percentile. The monitoringinterpretation includes systolic and diastolic blood pressure means,systolic and diastolic blood pressure loads, and nocturnal dipping. Theblood pressure means were calculated for the 24-hour, wakefulness and sleepperiods. Nocturnal dipping was defined as a drop in blood pressure meansduring sleep greater than 10%. The significance level adopted was p <0.05.Nocturnal dipping for systolic blood pressure was present in 29.9% of theparticipants. Approximately 53% of them had attenuated nocturnal dipping,and 15%, reverse nocturnal dipping. The age groups of 9-11 years and 6-8years had the greatest percentage of attenuation, 19.1% and 14.9%,respectively. Regarding diastolic blood pressure, nocturnal dipping wasidentified in 53.2% of the children, being extreme in 27.7% of those in theage group of 6-11 years.The early diagnosis of blood pressure changes can allow the appropriate andspecific therapy, aimed at increasing the life expectancy of patients withDuchenne muscular dystrophy. Its global prevalence can reach 63 cases per onemillion individuals. Duchenne muscular dystrophy has a high spontaneous mutationvelocity, and approximately one third of the cases are estimated to be due to newmutations.4 The first clinical signs manifest at an early age as frequentfalls, difficulty climbing stairs, running and getting up from a lying or sittingposition, and mainly calf hypertrophy. The muscle impairment is symmetric, initiatesin the pelvic girdle muscles (hip and legs) and reaches the upper limbs.It is clinically characterized by progressive and irreversible muscle weaknessconsequent to dystrophin deficiency or absence. It is the most frequentneuromuscular disease in human beings, and, although predominating in the male sex,it is occasionally reported in females due to inactivation or abnormalities of the Xchromosome. That anomaly is present in the short arm of the X chromosome published recommendations for the use of ABPM inthe pediatric population, which were reviewed in 2014.15 Many recommendations of ABPM use for adults can be appliedto children. Because of the difficulty of conducting randomized clinical trials inthe pediatric population, the recommendations used are based on expert opinions.However, it is worth considering some aspects, such as equipment selection, whichshould be light (weight between 168 and 457 grams), with appropriate cuffsize.16Ambulatory Blood Pressure Monitoring (ABPM) allows indirect and intermittent bloodpressure (BP) recording for 24 hours, during wakefulness and sleep. In adults, ABPMis a well-established diagnostic and follow-up method, considered "gold standard" inBP assessment.18 A study by Braat et al. has assessed the renal function of 20individuals with DMD and undergoing ABPM, 9 of whom had elevated BP (over the 95thpercentile), 8 of whom were on corticosteroids, and 13 had no nocturnal dipping(ND), 10 of whom were on corticosteroids.19The use of corticosteroid, known to increase BP, has been widely studied. Left and/orright ventricular hypertrophy can cause arterial hypertension (AH) and/or pulmonaryhypertension or mitral and/or tricuspid regurgitation, sometimes culminating inventricular failure.Knowing BP behavior in such patients is fundamental, mainly because it enables earlytreatment, contributing to improve the quality of life, aiming at reducing the highmorbidity rates of those patients. Thus, our study aimed at assessing the behaviorof BP variables, by using 24-hour ABPM, in children and adolescents diagnosed withDMD, followed up at a university-affiliated outpatient clinic specialized inmuscular dystrophies.15 The research project was approved by the local EthicsCommittee, the information was provided by the parents or guardians, and writteninformed consent was provided by all participants. Prior to ABPM, the patients'clinical history was collected, and the height and weight measured in the childrenwho could walk, while, for wheelchair-bound patients, historical height was used.Blood pressure was measured at the medical office with the OMROM digital device (HEM742INT® model) and appropriate cuff size, respecting theproportion width/length 1:2, corresponding to 40% of arm circumference and at least80% of its length. The Spacelabs 90207® ABPM monitor was installedon the "nondominant" arm, with appropriate cuff size, by a trained nurse, andprogrammed to take BP every 15 minutes during wakefulness and every 30 minutesduring sleep. The parents/guardians received a diary to record the most importantevents in 24 hours, mainly the bedtime and wake-up time.This is a descriptive study comprising all 46 boys with a confirmed diagnosis of DMDfollowed up on an outpatient basis. Because DMD is a rare disease, we chose toassess all children and adolescents followed up on a university-affiliatedoutpatient clinic. The boys were divided into five age groups, considering thedistribution of normal BP levels for age, according to the previously reported AHAsuggestion.The following variables were assessed in ABPM interpretation: systolic and diastolicBP  means; systolic and diastolic blood pressure loads; and ND. The SBP and DBP means were calculated for the24-hour, wakefulness and sleep periods. The SBPL and DBPL were calculatedconsidering the proportion of readings over the 95th percentile. Nocturnal dippingwas defined as a drop greater than 10% in BP means during sleep. All parameters werecompared to the normal range values to determine whether BP was normal or elevated,as was the presence or absence of ND. In addition, ND was stratified as follows:"present", BP drop during sleep between 10% and 20% as compared to wakefulness;"absent", no BP drop during sleep; "attenuated", BP drop > 0% and < 10% duringsleep; "reverse", BP during sleep higher than that during wakefulness; and"extreme", BP drop > 20%.The continuous variables with normal distribution were presented as means± standard deviation, while those without normal distribution werepresented as medians and interquartile range. The categorical variables werepresented as absolute numbers and percentages. The significance level adopted inthe statistical analyses was 0.05. Kolmogorov-Smirnov test was used to assessthe normality of the variables, and Pearson chi-square test was used to assessthe association between corticosteroid use and BP classification.p <0.05 were considered significant. All statisticalanalyses were performed with the SPSS software, version 17.0 ®.We used as comparator the BP values of the 95th percentile from the AHArecommendations, as shown in For BP stratification, the BP measurements taken at the office and on ABPM wereconsidered. Although the recommendations of the specialized guidelines suggestclassifying BP in one of the ABPM periods (wakefulness or sleep) or in 24 hours, weclassified BP in all periods .Regardi20However, the advances in treatment, such as non-invasive ventilation and physicaltherapy, have enabled boys with DMD to reach 30 years of age. Considering thisincrease in life expectancy, other aspects, in addition to neuromuscular impairment,need to be assessed.20Duchenne muscular dystrophy is a disease of poor prognosis, whose survival extends tothe second decade of life.22Although office BP classification in pediatrics was standardized by the National HighBlood Pressure Education Program in 2004, the classification of BP obtained fromABPM in children and adolescents has not been standardized. Thus, we used therecommendations based on expert opinions, such as those published by the AHA in2008. Blood pressure classification in children, according to those recommendations,should consider, in addition to measurements taken at the office, those from ABPMduring 24 hours, wakefulness or sleep, and SBPL or DBPL.23 Regarding office BPmeasurement, more than 50% of the boys had stage 1 or 2 AH, and 12.8% had borderlineBP levels. The VII Brazilian Guidelines on Hypertension replaced the term'borderline' with 'prehypertension', and estimates its prevalence between 10% and15% of the pediatric population. However, established AH affects 3% to 5% of thechildren.24 In our study,the highest SBP mean during wakefulness was 126.7 ± 10.0 in the age group of12-14 years, followed by 122 ± 18.6 for office BP in children aged 6-8 years.Considering the percentile for age, the BP mean on ABPM during wakefulness waswithin the expected range. However, the BP mean at the office was above the 95thpercentile. Regarding DBP, the highest mean was observed in the 95thpercentile (78.5 ± 12.4) in the age group of 6-8 years on ABPM duringwakefulness, followed by 77.3 ± 9.1 in the age group of 15-17 years on ABPM,which is above the estimated percentile. Regarding SBPL and DBPL, all age groups hadmedian > 25% in 24 hours, wakefulness or sleep. Considering only wakefulness,38.3% of the children had normal BP, 21.3% had severe AH, and 21.3% had white coathypertension.A study on the BP of boys with DMD has reported the prevalence and correlations oflow BP levels measured at the office with a possible autonomic dysfunction due toDMD.25 Our study showed no association ofcorticosteroid use and AH, blood pressure load elevation and ND. Although asignificant part of the boys was on prednisone, its administration was intermittentand on the first days of the month.The median ND was lower than 10% for SBP and higher than 10% for DBP in all agegroups. It is worth noting that 68% of the boys had no 10% ND for SBP. In adults,the absence of ND is considered a risk factor for target-organ damage, in additionto increasing the cardiovascular risk of hypertensive and normotensive individuals.Although the use of corticosteroid can lead to weight gain and BP elevation, it isthe only drug that can delay the progression of muscle weakness, reduce thedevelopment of scoliosis, and delay respiratory failure. Its mechanism is based onthe hypothesis that its anti-inflammatory property and immunosuppressive actionpromote the proliferation of myoblasts and a reduction in necrosis.locus Xp21) and does not express dystrophin.Although it does not show intense fibrosis and fatty tissue accumulation in muscles,it is considered the most appropriate animal model of DMD. A mechanistic study withthose mice has shown that the absence of dystrophin interferes with nitric oxide(NO)-dependent vascular dilatation. When submitted to pressure variations, thevessel showed no adaptation. Because the endothelium is essential for the arteriesto adapt to chronic changes in blood flow, in the long run that deficiency mightaffect the flow-induced vascular remodeling, with consequence to vascularresistence.26 Otherstudies have shown an abnormal sympathetic neurovascular control indystrophin-deficient muscle, which is evidenced during physical exercise, whensympathetic vasoconstriction is normally absent in active muscles, due to the actionof local vasodilating substances, such as NO.28 The neuronal deficiency of NO sintase, which is reduced in theabsence of dystrophin, seems to be the major cause of vasoregulation deficiencies.However, the vascular tone modulation can also be hindered by dystrophin deficiencyin arterial smooth muscle cells. Dystrophin is usually expressed in the tunica mediaof blood vessels, being absent in the vessels of mdx mice.30However, if corticosteroid did not influence BP behavior, what was the factorresponsible for the elevated number of hypertensives and BP measurements out of thenormal range among those children? The mdx mouse develops X-linked recessivemuscular dystrophy , causing deleterious effects to thecardiovascular system. In addition, excessive sympathetic activity occurs in OSA,which can contribute to the lack of decrease in BP levels during the night.Because DMD is a rare disease, our study can be considered a potential generatorof hypotheses. It is worth noting the lack of standardization for ABPM use forchildren. Thus, we followed the AHA recommendation, which was based on expertopinions. However, such data need to be validated in further studies, with agreater sample power. In addition, it is worth noting the difficulties inmeasuring the height of the children, because many of them werewheelchair-bound. Thus, we used the historical height, reported by the parentsor legal guardians.Another limitation of our study was the patients' stratification based on agegroups, by use of convenience sampling, because of the low incidence of DMD.Because of the difficulty of conducting randomized clinical trials in thepediatric population, the recommendations used were based on expertopinions.The analysis of BP variables, obtained mainly from ABPM, is a useful tool to identifypatients with DMD at higher risk. Considering the cardiovascular changes of thosepatients, the early identification of BP changes would allow the appropriate andspecific therapeutic intervention. In addition, we suggest the regular andmultidisciplinary follow-up of those patients to identify their BP changes, ensuringimprovement in their life expectancy and comfort.


Hypotension is associated with serious complications, including myocardial infarction, acute kidney injury, and mortality. Consequently, predicting and preventing hypotension may improve outcomes. We will therefore determine if use of a novel hypotension prediction tool reduces the duration and severity of hypotension in patients having non-cardiac surgery.N = 213) in noncardiac surgical patients > 45 years old who require intra-arterial blood pressure monitoring. All participating patients will be connected to a Flortrac IQ sensor and EV1000 platform . They will be randomly assigned to blinded or unblinded arms. The Hypotension Prediction Index (HPI) and advanced hemodynamic information will be universally recorded, but will only be available to clinicians when patients are assigned to unblinded monitoring. The primary outcome will be the effect of HPI software guidance on intraoperative time-weighted average mean arterial pressure under a threshold of 65 mmHg, which will be assessed with a Wilcoxon-Mann-Whitney 2-sample, two-tailed test.We will conduct a two-center, pragmatic, randomized controlled trial  contains supplementary material, which is available to authorized users. Intraoperative hypotension is surprisingly common and, depending upon the definition, has an incidence ranging from 5 to 99% . Most paIt seems likely that reducing the frequency, depth, and duration of intraoperative hypotension will reduce organ injury. Currently, anesthesia clinicians respond to blood pressure trends and treat hypotension as necessary when it occurs. But in practice, it is difficult to predict, and therefore prevent, intraoperative hypotension.The Hypotension Prediction Index (HPI) is derived from arterial waveforms and predicts hypotension, and the software also provides advanced hemodynamic data including cardiac output, vascular elastance, and stroke volume—which presumably help clinicians select optimal treatments. HPI uses arterial waveform features, including waveform time, amplitude, area, segment slopes, and complexity features, to predict hypotension, defined by MAP < 65 mmHg for at least one minute . The senWe propose to compare the amount of intraoperative hypotension below a MAP of 65 mmHg in patients requiring invasive arterial pressure monitoring who are randomized to blinded vs unblinded HPI monitoring. Specifically, we will test the primary hypothesis that adding HPI software guidance to the information provided by the invasive arterial pressure monitoring during moderate-to-high-risk noncardiac surgery reduces time-weighted average (TWA) intraoperative hypotension below a threshold of 65 mmHg. Secondarily, we will study the effect of HPI software guidance on TWA MAP below 60 and 55 mmHg.ClinicalTrials.gov on July 13, 2018 (NCT03610165) under the principal investigator Kamal Maheshwari.We will conduct a trial comparing the amount of hypotension in patients requiring invasive arterial pressure monitoring and randomized to blinded vs unblinded HPI monitoring Fig. . We foll2, moderate to severe aortic and/or mitral regurgitation, and moderate to severe mitral stenosis. Patients will also be excluded if they have persistent atrial fibrillation, or congestive heart failure with ejection fraction < 35%. And finally, we will exclude patients scheduled for neurosurgery or cardiovascular procedures.Written informed consent will be obtained from all included patients. Enrolled patients will be at least 45 years old, have an American Society of Anesthesiologists (ASA) physical status III–IV, be scheduled for elective major non-cardiac surgery with general anesthesia, be planned to have intra-arterial pressure monitoring, and have at least overnight hospitalization. Patients will be excluded if they are pregnant or have known clinically important intra-cardiac shunts, aortic stenosis with valve area ≤ 1.5 cmPotentially qualifying patients will be evaluated during their preoperative anesthesia clinic visits. Written informed consent will be obtained from each, and each will be informed that they may decline to participate or withdraw from the study at any time.There will be no restriction on type of general anesthesia, and regional anesthesia/analgesia will be permitted. In addition to the routine anesthetic monitoring, an arterial catheter will be inserted for direct pressure monitoring. The catheter will be connected to a FloTrac IQ sensor, and the sensor connected to an EV1000 platform which includes HPI software . Allocation will thus be concealed, and patients will not be informed of their group assignments. The randomized groups will be:Anesthetic dose, the amount and timing of intravenous fluids and use of vasopressor and inotropic drugs will be determined by the anesthesia team and based on available information in both groups. For patients assigned to blinded monitoring, decisions will be based on patient and surgical characteristics, signals from all routine anesthesia monitors, and the arterial waveform.In patients assigned to unblinded monitoring, clinicians will additionally have access to HPI index, ranging from 0 to 100, corresponding to the likelihood of hypotension in the coming minutes. The system generates an alert to clinicians when HPI reaches or exceeds 85. To standardize interpretation of hemodynamic values, participating clinicians will agree to the conceptual framework presented in Fig. In all cases, good clinical judgment will prevail and the attending anesthesiologist will take all necessary steps to provide optimal and safe care. Blood and blood products will be given per clinical judgment.Patients will be blinded to group allocation. Anesthesiologists, surgeons, and other intraoperative personnel cannot be blinded to monitoring allocation. However, other investigators and the data-analysis team will remain blinded.Trial-related management will end when surgery finishes. Patient disposition to a critical care unit or routine surgical ward will be determined by the clinical team per routine.1c (HbA1c).We will record demographic and morphometric characteristics, including height, weight, age, sex, ASA physical status, and self-declared ethnicity. As available, we will collect social history , medical history , non-steroidal anti-inflammatory drugs (NSAIDs), diabetes (whether insulin-dependent or not), and glucose-tolerance test results, preoperative hemoglobin and hematocrit, blood urea nitrogen and creatinine, electrolytes, preoperative electrocardiogram, and hemoglobin AIntraoperative care data will be accessed from the electronic anesthesia information management system. Anesthetic data will include the volatile anesthetic dose in minimum alveolar concentration-hours (MAC-hours), as well as total doses of propofol, opioids, and sedative hypnotics. Hemodynamic and respiratory values, Bispectral Index, and esophageal temperature will be recorded at regular intervals intraoperatively. Blood loss will be estimated; urine output and fluid administration, including colloids and allergenic blood, will be recorded. Intraoperative use and total dose of vasoactive drugs as well as antibiotic administration will be recorded. If available, arterial blood gas results will be recorded.Hemodynamic data from the HPI software will be secured on Cleveland Clinic computers for subsequent analysis and manually recorded at 5–15-min intervals. In the unblinded group an investigator will evaluate HPI alerts and document the probable cause based on advanced hemodynamic parameters using the conceptual framework presented in Fig. Patients will be followed for the major and minor complications shown in Table Randomized groups will be compared on baseline variables using the standardized difference (difference in means or proportions divided by the pooled standard deviation), and such variables will be considered balanced if the absolute standardized difference is < 1.96 sqrt (2/N), where N is the per group sample size. Imbalanced variables will be adjusted for in all analyses.The treatment effect of HPI guidance (versus no HPI guidance) on the primary outcome of intraoperative time-weighted average (TWA) MAP under a threshold of 65 mmHg will be assessed with a Wilcoxon-Mann-Whitney 2-sample two-tailed test, or analogous test to account for imbalanced baseline variables or non-normal distribution of the outcome, as needed. Secondary and exploratory continuous outcomes will be similarly analyzed. We will assess agreement between clinician and decision support flow chart  area under a MAP < 65 of 80 (127) mmHg.min and median [quartiles] of 24  mmHg.min in a representative sample of patients having non-cardiac surgery (unpublished data). AUC-MAP represents depth and duration of hypotension. AUC-MAP = TWA-MAP × duration of observation. The data were highly skewed, with a non-trivial proportion of zero values. We therefore used a non-parametric test Wilcoxon-Mann-Whitney test to estimate sample size. Based on these data, a sample size of 213 will provide 80% power for detecting an approximately 20% relative reduction in the mean of the primary outcome of AUC-MAP < 65 mmHg.min.Our goal is to determine whether using HPI software reduces the duration and severity of intraoperative hypotension. The goal is important because intraoperative hypotension is associated with adverse outcomes, including myocardial injury , acute kWe will use Flotrac IQ sensors for invasive arterial monitoring because it is necessary for proper functioning of HPI software. In blinded group, we chose not to provide advanced hemodynamic information such as cardiac output because these values are not currently available to our clinicians. Furthermore, HPI is designed to work as a complete hypotension management software and therefore this trial will evaluate both the HPI prediction and the advanced hemodynamic parameters.HPI and Flotrac IQ are designed to work in conjunction with an arterial catheter. Planned use of an arterial catheter is thus an inclusion criterion, and will restrict enrollment to relatively sick patients having major procedures—but these are also the patients who have the greatest cardiovascular risk. HPI requires a good-quality arterial line waveform. To the extent that the waveform is damped or varies consequent to changes in patient position or other mechanical issues, predictions may be compromised. Our research team will continuously monitor the quality of the arterial waveform and adjust the catheter and system as necessary.Once hypotension is predicted by the HPI, clinicians will vary in how proactively they respond, and some may poorly comply with our intervention guidelines, which are recommendations rather than requirements. We will allow considerable flexibility on the theory that clinicians will optimize patient safety even though allowing flexibility will add variability to the results. We will, however, record divergences between the algorithm and actual clinical management and plan sensitivity analyses to evaluate the effects of concordant and discordant responses on the extent and duration of hypotension..HPI software provides reliable prediction of hypotension with good internal and external validation Fig.  9]. As . As 9]. We plan a randomized trial to determine whether guiding intraoperative hemodynamic management with HPI software reduces the duration and severity of hypotension during non-cardiac surgery. Since hypotension is associated with perioperative complications, patients may benefit if the HPI and associated hemodynamic data reduce the amount of intraoperative hypotension.Protocol version 1.0; April 2018. Recruitment began July 12, 2018 and will be completed July, 2020.Additional file 1:SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents. (DOC 130 kb)


Cerebral injury may alter the autoregulation of cerebral blood flow. One index for describing cerebrovascular state is the pressure reactivity (PR). Little is known of whether PR is associated with measures of brain metabolism and indicators of ischemia and cell damage. The aim of this investigation was to explore whether increased interstitial levels of glycerol, a marker of cell membrane damage, are associated with PR, and if prostacyclin, a membrane stabilizer and regulator of the microcirculation, may affect this association in a beneficial way.mean) and maximal glycerol (glycerolmax) during the 96-h sampling period were calculated. The mean PR was calculated as the ICP/mean arterial pressure (MAP) regression coefficient based on hourly mean ICP and MAP during the first 96 h.Patients suffering severe traumatic brain injury (sTBI) were treated according to an intracranial pressure (ICP)-targeted therapy based on the Lund concept and randomized to an add-on treatment with prostacyclin or placebo. Inclusion criteria were verified blunt head trauma, Glasgow Coma Score ≤ 8, age 15–70 years, and a first measured cerebral perfusion pressure of ≥ 10 mmHg. Multimodal monitoring was applied. A brain microdialysis catheter was placed on the worst affected side, close to the penumbra zone. Mean (glycerolp = 0.0164). There was a positive correlation between PR and the glycerolmean  and glycerolmax  levels in the placebo group only.Of the 48 included patients, 45 had valid glycerol and PR measurements available. PR was higher in the placebo group as compared to the prostacyclin group (PR is correlated to the glycerol level in patients suffering from sTBI, a relationship that is not seen in the group treated with prostacyclin. Glycerol has been associated with membrane degradation and may support glycerol as a biomarker for vascular endothelial breakdown. Such a breakdown may impair the regulation of cerebrovascular PR. AR). Thus, it is important in traumatic brain injury (TBI) patients to understand if the CBFAR is intact. This may help in optimizing the treatment in order to secure an adequate cerebral blood flow. As direct measurements of the autoregulatory state of the cerebral blood flow are difficult, surrogate methods have been introduced, including, among others, pressure reactivity indices such as PR [x [Cerebral injury may affect the autoregulation of cerebral blood flow  for a wide range of mean arterial blood pressure (MAP) levels. We implemented the PR-method by Howell et al. . They asfficient , 4. HoweAR is of utmost importance and may help in individualizing the neuro-intensive treatment. Little is known of whether these cerebral autoregulatory measurements correlate to other parameters mirroring the metabolic state of the injured brain [From a clinical point of view, a solid and easy-to-use surrogate measure of CBFed brain . In a siProstacyclin has been shown to possess a variety of biological functions including a vasodilating and membrane stabilizing effect –9 to inhOur hypothesis was that prostacyclin has beneficial effects on cell membrane damage which are mirrored in extracellular glycerol and that this is associated with vascular regulation measured as PR. We have previously reported an effect of prostacyclin on PR  and haveThe patient cohort was investigated in a prospective consecutive double-blinded randomized study on the effect of prostacyclin as an add-on therapy in patients with severe TBI (sTBI) . In shorAn intra-parenchymal ICP measuring device  was implanted as soon as possible. This ICP sensor has been shown to be reliable with very low drift and low complication rate , 16. If Invasive arterial blood pressure was continuously monitored and the reference level set at the heart level. MAP and CPP were calculated using the monitoring equipment . No correction of the CPP was indicated as all patients were treated in a position without head elevation.mean) and the maximal (glycerolmax) level during the sampling period. The glycerolmax value may reflect the severity of the tissue damage better than the mean. The glycerolmean of the first 96 h of sampling was chosen to represent the worst clinical scenario as, after this period, the glycerol often starts to decline. This equals the period of prostacyclin infusion. The lactate/pyruvate ratio during the same period was calculated in order to control for a metabolic difference between the groups.Two microdialysis catheters with gold tip  were placed in the brain parenchyma in a standardized fashion frontally on each side approximately at the Kocher’s point. In this study, we used the results from the side that initially, by the clinician, was designated to be the most injured. The microdialysis catheter tip distance from the lesion, such as hematoma, evacuated hematoma, or contusion, was calculated using the computed tomography (CT) scans. In case of diffuse injury, the catheter tip was in the edematous tissue and these subjects were not included in the calculated distances. CMA 106 or 107 microdialysis pumps  were used. The perfusion flow rate was 0.3 µl/min, and the “Perfusion fluid CNS”  was used. The first dialysate was discarded, and the sampling of the first analyzed sample was started 0.5–2.5 h after the start of the microdialysis. The sampling time for each sample was 2 h. If not directly analyzed, the filled vials were stored in a refrigerator for no more than 24 h and then frozen to − 70 °C. The samples were analyzed as soon as possible with a CMA 600 analyzer . In this report, the glycerol levels are reported and the results categorized as the mean of the first 96 h  system  were stored on a computer using the LABpilot software . The data were simultaneously stored in the patient’s case file in the ICU system . The microdialysis data were transferred from the CMA 600 analyzer to a personal computer and further processed with the LABpilot software. Every case file was scrutinized for outliers due to, for example, calibration periods and mechanical disturbances. Furthermore, the correlation in time of the sampling values was controlled.The brain tissue injury was evaluated by using the first CT scan of the head characterized according to the Rotterdam scoring system . The sco2 > 12 kPa, PaCO2 4.5–5.5 kPa). Normovolemia and normal colloid osmotic pressure were maintained using infusion of packed red blood cells, albumin, Ringer’s acetate, and glucose solutions, with the goal being a neutral fluid balance. When normovolemia and a controlled cardiovascular situation were achieved, clonidine and metoprolol were administered in order to reduce the capillary hydrostatic pressure and the general level of stress in the subjects. If needed in order to control the ICP, a low dose of thiopental infusion was administered. Further interventions included ventriculostomy for drainage of CSF, and uni- or bilateral hemicraniectomy. The subjects were all treated in the supine position without head elevation.An ICP-targeted treatment protocol based on the Lund concept was used , 19. In ®, GlaxoSmithKline, Brentford, UK) or saline (placebo) [The subjects were randomized to receive prostacyclin (Flolanplacebo) . Flolan t test or Wilcoxon rank-sum test were used for comparison of group values. Proportions were evaluated by χ2-test and Spearman’s rho for correlation analysis. A p ≤ 0.05 was considered statistically significant.The statistical analysis was performed using the JMP  software package. Results are reported as mean ± standard error of the mean (SEM) for continuous variables and in cases of discrete variables as median and range. When applicable, two-sided un-paired The study was approved by the regional ethics committee  and by Läkemedelsverket  (151:633/01) and performed in accordance with the ethical standards as stated in the declarations of Helsinki. The study is registered as a clinical trial .Forty-eight patients  were included in the initial study. In 45 of these, valid glycerol and PR measurements were available. Twenty-one subjects received prostacyclin and twenty-four placebo. All results are based on these 45 subjects . Mean age was 35.5 ± 2.2 years, GCS 6 (3–8), and injury severity score (ISS) 29 (9–50), for more details and demographics, see Table p = 0.0164).The microdialysis catheter tip was placed at a distance of 15.0 ± 2.0 mm from the lesion and thus in the penumbra zone. The distance or the number of diffuse cases was not different between the placebo and prostacyclin group, see Table mean , glycerolmax , and PR only in the placebo group, see Table There was a significant positive correlation between glycerolAs shown in Fig. AR.Our main findings were that prostacyclin affects the PR correlation to cerebral interstitial levels of glycerol and that cerebral interstitial glycerol was correlated to PR suggested to be a biomarker for CBFAR [AR have been demonstrated to be affected after a variety of cerebral injury [Complex mechanisms are involved in the regulation of cerebral blood flow –22. The AR  is primaAR , 25 and AR . In thisAR . It is nAR –31. Furtl injury .It has been suggested that trauma disturbs the balance between thromboxane and prostacyclin toward thromboxane. This might have negative effects as the biological effects of prostacyclin, including vasodilating and membrane stabilizing effects –9, inhibAR. It may also affect the interstitial glycerol levels through the breakdown of biological membranes. It is therefore interesting that the correlation between PR and glycerol is attenuated/abolished in the prostacyclin group. One may suggest that, since prostacyclin tends to decrease the interstitial glycerol levels and stops them from being significantly correlated to the PR, it indicates that prostacyclin exerts a biologically beneficial effect on the pathophysiological processes affecting cellular damage and CBFAR. However, one may not exclude the possibility that the disturbed pressure reactivity per se is associated with more structural damages rendering opposite effects as suggested for prostacyclin. The present investigation does not solve this question.The intention with the prostacyclin treatment was to counteract the proposed imbalance between thromboxane and prostacyclin. The above-mentioned effects of prostacyclin may normalize the cerebrovascular reactivity and thus the CBFAR. Our results suggest that glycerol may be an extracellular marker associated with CBFAR. The exact pathophysiological meaning of these findings is obscure and to be further explored.As the brain does not contain triglycerides, cerebral interstitial glycerol has been proposed to be a marker of brain cell membrane degradation and thus cell damage due to the degradation of membranous glycerophospholipids , 35. Thux, but an actual correlation could not be confirmed [x concomitant with an increase in extracellular glucose and decrease in LPR indicated an association of the CBFAR and cerebral metabolism [Our results are in line with results reporting a significantly higher glycerol level in perilesional tissue and deranged PRonfirmed . Other monfirmed . In TBI tabolism . Furthertabolism .x with microdialysis mirroring a very local tissue metabolic milieu. Moreover, the autoregulatory state may vary between vascular territories. Reported results in the literature are difficult to compare as the sampling location of the extracellular metabolites varies between studies and is not always described. In our study, the high levels of glycerol and lactate/pyruvate ratio probably mirror the fact that the microdialysis probes were close to the injury. Another pitfall is the highly dynamic evolution of the tissue damage [Indeed, there is a pitfall in comparing a global measurement of cerebral dynamics such as PR or PRe damage  which maAR. We recognize that PRx is a more dynamic measurement of vascular reactivity than PR and would be the method of choice today. Our prospective consecutive double-blinded randomized study was conducted 10 years ago, and at that time we lacked the suitable equipment for PRx measurements. However, in almost all publications the mean of PRx over several days is reported, thus smoothing the dynamic property of the measurement.As PR is based on hourly mean values, rapid vascular responses in intracranial arterial volume variations are filtered away and thereby also the fluctuations in ICP related to these volume variations. Thus, the slope of ICP vs. MAP as calculated in PR does not describe an autoregulatory response in the same time domain as described by PRx . PR is bIn summary, PR seems to be correlated to the cerebral interstitial glycerol level, which has been suggested to be a measure of membrane degradation in the brain. This association is not observed in the prostacyclin group. One may speculate that interstitial cerebral glycerol levels, in fact, mirror vascular integrity. We suggest that, by individualizing the treatment of the injured patient, in order to normalize the interstitial cerebral glycerol levels, the vascular pressure reactivity may improve. This might protect the brain from abnormal fluctuations in cerebral blood flow and thus counteract ischemic and/or edema propagation.


Resistant hypertension remains an important cause of heart failure. In thisarticle, we describe a case of resistant hypertension in a 63-year-old womanleading to heart failure and marked morbidity. Her clinical course wascharacterized by chronic pleural effusions and recurrent hospitalizations withrespiratory failure and flash pulmonary edema associated with heart failure withpreserved ejection fraction. Her transthoracic echocardiogram showed severeconcentric left hypertrophy and diastolic dysfunction. The clinical phenotypewas secondary to resistant hypertension due to bilateral renal artery stenosis,and her blood pressure and heart failure resolved after successful renal arteryangioplasty. This case demonstrates how heart failure with preserved ejectionfraction due to renal artery stenosis can easily go unrecognized especially inpatients with multiple comorbidities. The potentially curable nature of thiscondition clearly warrants consideration especially in patients with multiplerisk factors for atherosclerotic vascular disease. She was intubatedshortly after arrival and responded to diuresis with the resolution of her pulmonaryedema. She was extubated after 2 days and had unchanged small pleural effusions. Herelectrocardiogram on presentation  showed sHer past medical history was significant for multiple hospital admissions with flashpulmonary edema and chronic pleural effusions since December 2016. Her previousinvestigations included a pleural biopsy that did not show any pathology, andfollowing an episode of acute kidney injury, she underwent a renal biopsy, which wasinconclusive. She also had a whole-body positron emission tomography scan that didnot show any evidence of malignancy. She was known to have hypertension, chronickidney disease, mild chronic obstructive pulmonary disease, schizoaffectivedisorder, and mild cognitive impairment. Her social history was significant foractive smoking but no alcohol or illicit drug use. She was worked up for a possibleinflammatory condition to explain her chronic pleural effusions. Her serum ANA(antinuclear antibody), anti-dsDNA, rheumatoid factor, erythrocyte sedimentationrate, and C-reactive protein were all negative. She had a positive pANCA and wasreferred to the rheumatology consult team. Her positive pANCA was felt to benonspecific for any rheumatologic condition. She was also seen by the neurology teamfor a possible neurodegenerative disorder causing recurrent aspirations given herrecurrent hospitalizations with respiratory failure. However, her swallowingassessment was completely normal, and she only had mild cognitive impairment onformal cognitive testing.During her hospital stay, she was noted to have elevated systolic blood pressureabove 190 mm Hg with diastolic blood pressure in 100 to 110 mm Hg range despitebeing on maximum doses of 5 antihypertensive medications . She developed anuric acutekidney injury shortly after starting the ACE inhibitor, ramipril. This wasreversible with stopping the new medication, and her kidney function returned tobaseline (creatinine level of 120 µmol/L) but her blood pressure was still elevated.At that point, bilateral renal artery stenosis (RAS) was suspected. A computedtomography angiogram of the renal arteries confirmed the diagnosis ofatherosclerotic bilateral RAS . She theVideo 1, available in the online version of the article.).She was followed closely as an outpatient and had no recurrent pulmonary edema. Herfollow-up echocardiogram 8 months later showed normalization of the left ventricularmass, and reduction in the left atrial size and right ventricular systolic pressure was heart failure with preserved ejection fraction (HFpEF) secondary toresistant hypertension due to bilateral RAS. This case demonstrates how HFpEF due toRAS  can easily go unrecognized especially inpatients with multiple comorbidities if a high index of suspicion is notmaintained.3 Although the presence ofdiastolic dysfunction alone on echocardiogram is not enough to make the diagnosis ofHFpEF, it is an independent risk factor for heart failure hospitalization and death.4 HFpEF compromises at least one third to half of heart failurecases,5 is moreprevalent in women, and is often associated with hypertension.5 It is not uncommon for HFpEF togo unrecognized especially in patients with multiple comorbidities in part due tothe lack of a gold standard test to diagnose it. Our patient’s chronic pleuraleffusions were only part of her whole clinical picture and drove clinicalinvestigations away from the underlying diagnosis. She underwent numerous invasiveinvestigations including a pleural biopsy, a kidney biopsy, and a whole-bodypositron emission tomography scan.HFpEF is defined as signs and symptoms of heart failure in the presence of normalejection fraction (>50%) and diastolic dysfunction.6 Atherosclerotic RAS should be suspected in all patients with resistanthypertension over the age of 55 years. Recurrent flash pulmonary edema and bilateralRAS is labelled as a distinct entity, the Pickering Syndrome, after the author whofirst described it in 11 hypertensive patients.7 Severe diastolic dysfunction and elevated LVEDP (left ventricularend-diastolic pressure) are the main pathophysiologic mechanisms to explain thisphenomenon.Renovascular hypertension is a common correctable cause of secondary hypertensionaccounting for approximately 30% of cases.8 By blocking the renin-angiotensin system in renovascular hypertension, thismechanism is disturbed and a reduction in GFR occurs. This is more pronounced inbilateral RAS as opposed to unilateral where the normal kidney compensates byincreasing GFR. Many patients, however, with both unilateral and bilateral RAS,tolerate ACE inhibitors.9 In fact, Chrysochou et al9 showed that reducing intraglomerular pressure with renin-angiotensin blockadehas a protective effect on renal function and a mortality benefit in these patients.10 This is thought to be through the same mechanism that ACE inhibitors delaythe progression of other forms of chronic kidney disease, that is, reducingproteinuria and the vascular protective effect on diseases that usually accompanyRAS like coronary artery disease.Another important clue to bilateral RAS is kidney dysfunction with the institution ofACE inhibitor therapy. Angiotensin II helps maintain or raise the intraglomerularpressure by preferentially vasoconstricting efferent glomerular arterioles resultingin glomerular filtration rate (GFR) autoregulation.10 Other studies observed mortality benefit with renal artery revascularizationin patients with recurrent flash pulmonary edema and heart failure.12 Kawarada et al12 were able to demonstrate an effect of improved left ventricular fillingpressure and pulmonary artery pressure determined by echocardiography in a case ofrenovascular hypertension after revascularization.12Our patient had a more classic response to ACE inhibitor resulting in acute renalfailure with anuria. This may be related to the fact that her left kidney wasatrophied and possibly nonfunctional and her right renal artery was severelystenosed, and the only way for her to have a reasonable GFR was by maintaining asystolic blood pressure above 190 mm Hg. While no randomized controlled trials haveexamined the clinical benefits of renal artery revascularization, a small number ofsmall retrospective observational studies demonstrated significant benefit in heartfailure and blood pressure control and delaying progression of kidney dysfunction inpatients with renal artery sentosis.9 Our patient had a rapid improvement in her blood pressure control within 24hours after her procedure, and it has remained controlled in follow-up. She has hadno further admissions with heart failure and is currently functioning at New YorkHeart Association class I.Revascularization can also enable treatment with renin-angiotensin blockers inpatients with RAS who may derive mortality benefit from these medications if theyare tolerated.In conclusion, bilateral RAS causing resistant hypertension is an important andprevalent cause of HFpEF. A high index of suspicion is required to diagnose thissyndrome, especially in elderly patients with other forms of atherosclerosis.Randomized controlled trials will be difficult to conduct in this patient populationgiven the small numbers, but if ever done, we expect them to better demonstratebenefits of revascularization, especially in the sicker patients with recurrentflash pulmonary edema.


The study is aimed at identifying echocardiographic and circulating biomarkers as well as hemodynamic indices of embolic stroke of undetermined etiology (ESUS) in patients aged <65.  We prospectively investigated 520 patients with confirmed ischemic stroke and selected those 65 patients who were diagnosed with ESUS (age 54 (47-58) years, 42% male). An additional 36 without stroke but with a similar risk profile were included as a control group (age 53 (47-58) years, 61% male). All patients underwent echocardiography, noninvasive assessment of hemodynamic parameters using a SphygmoCor tonometer , and measurements of selected biomarkers. E′) and systolic (S′) mitral annular velocities and a higher ratio of the peak velocity of early diastolic transmitral flow to the peak velocity of early diastolic mitral annular motion . The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in the control group (both p < 0.01). The isovolumetric relaxation time (IVRT) was longer and the mean left atrial volume index (LAVI) was higher in ESUS patients compared to the control group. Parameters of arterial stiffness such as augmentation pressure, augmentation index, and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (p < 0.05). Patients in the ESUS group had higher levels of asymmetric dimethylarginine, interleukin 6, and N-terminal probrain natriuretic peptide  than those in the control group. In multivariate analysis, the following factors were significantly associated with the presence of ESUS: AIx75 (odds ratio (OR) 1.095, 95% confidence interval (CI) 1.004-1.194; p = 0.04), IVRT , LAVI , and NT-proBNP .  ESUS patients and controls were well matched for baseline characteristics including blood pressure and left ventricular ejection fraction (LVEF). Compared to controls, patients with ESUS had lower mean early diastolic (NCT03377465. Increased arterial stiffness and indices of diastolic dysfunction as well as a higher NT-proBNP level are significantly associated with ESUS. These parameters require further scrutiny over time to understand their impact on the development of symptomatic heart failure. The ClinicalTrials.gov identifier is  More than one million inhabitants of Europe suffer from stroke yearly, and ischemic stroke accounts for approximately 80% of all cases. Despite the reduction in stroke mortality, the absolute number of people with stroke-related death has increased greatly in the past two decades , 2. IdenWe prospectively investigated 520 patients with confirmed ischemic stroke hospitalized in the Department of Neurology and Ischemic Strokes, Medical University of Lodz . We enroWe define ESUS as nonlacunar stroke with no major-risk cardioembolic source of embolism and with the absence of extracranial or intracranial atherosclerosis causing 50% stenosis in the arteries supplying the area of ischemia and with no other specific causes of stroke , 5.The exclusion criteria were as follows: unstable hypertension, atrial fibrillation, hyperthyroidism, pregnancy and breastfeeding, dialysis, cancer, autoimmunologic disease, reception of cytostatic, immunosuppression drugs, glucocorticosteroids, antiretroviral drugs, transplant and treatment with hematogenous preparation during the last 6 months, active infection, alcoholism, addiction to medicines, infection with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), surgical intervention or serious injury during the last 1 month, vaccination during the last 3 months, and incapable of giving agreement.All enrolled patients underwent blinded adjudication by cardiologists experienced in adjudication. Detailed clinical, imaging, and biomarker data were collected at the time of enrollment, and echocardiogram and SphygmoCor analyses were performed and interpreted by doctors blinded to biomarker analysis. Central systolic and diastolic pressures were measured using a sphygmomanometer and peripheral pressures using a stethoscope.NCT03377465  [All methods in this study were performed in accordance with the guidelines and regulations approved by the Bioethics Commission of the Medical University of Lodz, and approval from this commission (no. RNN/272/16/KE) was obtained. Written informed consent was obtained from all the patients. The study was registered at ClinicalTrials.gov—identifier number: ognosis) , 12.E) and atrial filling (A) peak velocities, E/A ratio, deceleration time of early filling, and isovolumic relaxation time were measured from the transmitral flow. Peak systolic (S′), early diastolic (E′), and late diastolic (A′) mitral annular myocardial velocities of the left ventricle septal and lateral walls were recorded from the apical 4-chamber view with pulsed wave tissue Doppler, and results were averaged. The E/E′ was calculated as an index of LV filling pressure [All patients were examined following a standardized protocol using an ALOKA Alpha 10 Premier  with a 3–11 MHz probe after inclusion. Quantitative echocardiography was used following current guidelines . Left vepressure .Blood samples for laboratory tests were collected from patients assigned to either group in a hospital setting, thus minimizing the risk of infection in both the subject and the person collecting the sample. Laboratory tests were performed in fasting subjects in a laboratory of WAM Hospital, following a minimum 12-hour period after the last meal. At the initial time point of the study, 19.5 mL of blood was collected with a vacuum blood collection system from the basilic vein into 8.5 mL, 5 mL, and 4 mL clot activator plastic Vacutainer tubes and into 2 mL Vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA), for routine laboratory tests. The blood samples to perform biomarker analysis were taken on the 7th day after stroke. Enzyme-linked immunosorbent assay (ELISA) tests were conducted for quantitative determination of N-terminal probrain natriuretic peptide (NT-proBNP) , interleukin 6 (IL-6) , and asymmetric dimethylarginine (ADMA)  in human serum [72 h Holter ECG was recorded in a 2-channel, 5-electrode paradigm with a GE SEER Light Ambulatory Recorder and analyzed with the GE Marquette MARS Holter System  .The central (ascending aortic) pressure waveform was derived by radial applanation tonometry 7 days after stroke and application of a generalized transfer function to the radial pressure waveform using a commercial device  . CentralCentral arterial stiffness was assessed by aortic pulse wave velocity (PWV) using electrocardiogram-gated sequential tonometry at the carotid and radial sites  . The patThe SphygmoCor heart rate variability system is a sophisticated system for noninvasively assessing the autonomic nervous system (ANS) based on heart rate variability (HRV) analysis. HRV analysis is based on measuring variability in intervals between R waves  .p < 0.05. The Shapiro-Wilk test was used to assess the normality of distribution. Data were presented as mean and standard deviation or median and interquartile range (25%-75%), depending on the data scale and distribution. To compare two groups, Student's t-test for continuous variables with normal distribution and with homogeneity of variance was used. For data with normal distribution but lacking homogeneity of variance, the Welsh test was conducted. The Mann-Whitney U test for nonnormally distributed variables was used.The STATISTICA 13.1 software package  was used for analysis. Results were considered significant if p < 0.05) were used for the construction of a multivariate logistic regression model; logistic regression was conducted among the patients from the ESUS group (n = 65) vs controls (n = 36). The quality of the models and the usefulness of the markers were evaluated using receiver operating characteristic (ROC) curves and tables of reclassification. For quantitative variables (continuous and discrete) to evaluate correlations between variables, Spearman's rank correlation coefficient was used.The dichotomous data were analyzed by the chi-square test or chi-square with Yates correction. Variables significant in univariate analysis (significance level p = 0.02). In the group with ESUS, 23% of patients received ASA  and statin, 28% beta blocker, 37% ACE (angiotensin-converting enzyme), and 20% CCB  and 20% took a diuretic and 8% insulin. In the control group, 9% of patients received ASA, 17% statin, 12% beta blocker, 24% ACE, 9% CCB, and 15% diuretic and none of them took insulin before admission to the hospital. There were no differences between the stroke and control groups in the levels of low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, prothrombin time, or activated partial thromboplastin time. The level of high-density lipoprotein (HDL) cholesterol was significantly lower in the ESUS group than in controls (1.19 mmol/L (0.95-1.46) vs 1.37 (1.19-1.6); p = 0.02). Patients in the stroke group had higher levels of NT-proBNP pg/mL (391 (107-1249) vs 109 (46-236); p = 0.003), IL-6 pg/mL (2.6 (0.8-8.1) vs 0.7 (0.4-1.2); p = 0.002), and ADMA μmol/L (0.44 (0.39-0.55) vs 0.36 (0.32-0.4); p = 0.0002) than the control group (18 congress abstract). Patients in the ESUS group had higher levels of glomerular filtration rate (GFR) mL/min/1.73 m3 (75 (64-89) vs 68 (62-78); p = 0.002) compared to the control group.There were no significant differences between groups in the body mass index (BMI), peripheral systolic and diastolic blood pressures, or additional diseases such as coronary artery disease (CAD), hypertension, and diabetes. Patients with ESUS more frequently were smokers . ESUS patients also had lower mean early diastolic (E′) (median 8.6 cm/s (7.1-10.3) vs 12.5 cm/s (9.6-14); p = 0.0008) and systolic (S′) mitral annular velocities  and a higher E/E′ ratio compared to the control group (median 7.6 (6.1-8.9) vs 6.0 (5.3-6.9), p = 0.0002). The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in controls  vs 89 (77-101); p = 0.0004). Isovolumetric relaxation time (IVRT) was longer in ESUS patients compared to the control group . The mean left atrial volume index (LAVI) was higher in the ESUS group . ESUS patients (25% of them) more frequently had nonhemodynamically significant liquid in the pericardium (p = 0.04) compared to the control group (6%) (11).There were no differences in aortic diastolic pressure (DP) and systolic pressure (SP) between ESUS and control groups. ESUS patients had a lower value of left ventricular ejection fraction (LVEF) than patients from the control group, but in both groups, the values were proper (60 (55-64) % vs 63 (60-66) %; The evaluation of selected echocardiographic parameters in groups is presented in p = 0.001, 27 ± 13 vs 22 ± 13%; p = 0.03, and 25 ± 11 vs 18 ± 12; p = 0.009, respectively). Aortic systolic pressure (SP) was higher in the ESUS group , and the heart rate variability (HRV) index was lower in the ESUS group compared to controls (6.6 (4.7-9) vs 8.7 (5.9-12); p = 0.006). The evaluation of hemodynamic parameters using the SphygmoCor system is presented in The parameters of arterial stiffness augmentation pressure (AP), augmentation index (AIx), and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (11 mmHg (7-18) vs 6 (3-13); p = 0.04), IVRT , LAVI , and NT-proBNP . This analysis is presented in The significantly associated parameters in the univariate logistic regression analysis presented in 2 and NT-proBNP values higher than 99.5 pg/mL were associated with the presence of ESUS. The ROC charts for LAVI and for NT-proBNP are presented accordingly in Figures The value of LAVI more than 24 mL/mIncreased arterial stiffness and indices of left ventricular diastolic dysfunction as well as a higher NT-proBNP level are associated independently with the presence of ESUS. Our results suggest that there may be a role for increased heart rhythm surveillance in patients with indices of diastolic heart failure to prevent stroke. Despite the lack of long-term randomized double-blind controlled therapeutic trials, there is high potential to reduce stroke prevalence through a significant reduction of arterial stiffness. Pharmacological interventions and lifestyle modification that can influence blood pressure, arterial function, or structure in either the short or long term are promising therapies reversing arterial stiffness, which can prevent ESUS strokes.E′) and systolic (S′) mitral annular velocities and a higher E/E′ ratio as well as longer IVRT compared to the control group (11). Also, mean LAVI and the level of NT-proBNP were higher in the ESUS group, which suggests that despite the proper values of LVEF, the indices of diastolic heart failure could be a predictor of this type of stroke. The parameters of arterial stiffness—augmentation pressure (AP), augmentation index (AIx), and augmentation index adjusted to a heart rate of 75 bpm (AIx75)—were also higher in ESUS patients compared to controls. The parameters independently associated with the presence of ESUS were as follows: higher AIx75, longer IVRT, higher LAVI, and higher NT-proBNP levels. The cutoff points for LAVI and NT-proBNP indicating an increased risk of ESUS were lower in our study than those accepted in the standards for the diagnosis of heart failure (125 pg/mL compared to 99 pg/mL in our study) and LAVI (34 mL/m2 compared to 24 mL/m2 in our study). Increased arterial stiffness and indices of diastolic heart failure are associated independently with the occurrence of ESUS (11).The results of this study revealed that ESUS patients had lower mean early diastolic  and prevalence of left ventricular hypertrophy (LVH) as well as LAVI and E/E′ were observed with elevating CHA2DS2-VASc scores (p < 0.05 for LVMI and LVH and p < 0.001 for LAVI and E/E′). LVH (hazard ratio (HR), 3.609; confidence interval (CI), 2.426–5.369; p < 0.001) and E/E′  were independent risk factors for a CHA2DS2-VASc score of 2 or higher. The authors stated that higher CHA2DS2-VASc scores are associated with impaired diastolic function, reflecting high left atrial pressure and increased risk of thromboembolism [2DS2-VASc scores to decrease the prevalence of thromboembolic events in this group of patients [E′) and systolic (S′) mitral annular velocities and a higher E/E′ ratio as well as longer IVRT compared to the control group, which confirms the connection between indices of diastolic heart failure and ESUS stroke. Even slightly increased values of LAVI (cutoff point 24 mL/m2) and NT-proBNP (cutoff point 99 pg/mL) were predictors of this type of stroke [Patients with heart failure with a reduced ejection fraction (HFrEF) are at risk from thromboembolic events originating from both the arterial and venous circulation, which is in part a result of Virchow's triad of risk factors for thrombus formation strictly connected with heart failure syndrome –21. Kodiembolism . Perhapspatients . The incpatients . The levpatients , 35. In f stroke . FurtherArterial stiffness has been regarded as a reliable marker of arterial structural and functional alterations after abundant experimental and clinical studies. Vascular structure, vascular function, and BP are the three major components that are involved in arterial stiffness . Factors


Uncontrolled blood pressure is the leading cause of mortality and disability due to associated cerebral and cardiovascular diseases and kidney failure. More than one-third of the old adult population have hypertension or prehypertension and many of their blood pressure are poorly controlled. We hypothesized that plant extracts-based antioxidants may benefit those with prehypertension/hypertension. One hundred age- and gender-matched healthy older adults were randomly assigned to receive HyperBalance capsules (n=50) or placebo (n=50) at Tang-Qiao Community Health Service Center, Shanghai. Blood pressure and severity scores of hypertension treatment-related symptoms  were evaluated before and after the 12-week intervention. Ninety-eight people completed the study, with 2 dropouts in the placebo group before the end of the study. Forty-one subjects (82%) of the HyperBalance group and 40 subjects (83.3%) of the placebo group had prehypertension (systolic blood pressures (SBP) between 130-139 and diastolic blood pressure (DBP) between 85-89mmHg), and 9 subjects (18%) in the HyperBalance group and 8 subjects (16.7%) in the placebo group had hypertension (≥140/90mmHg) before the intervention. HyperBalance significantly (P<0.01) reduced SBP from 136.18±4.38 to 124.14±3.96 mmHg and reduced DBP from 82.45±2.91 to 80.24±2.41mmHg, respectively, and reversed all 9 hypertension people to normotension or prehypertension state, whereas the placebo moderately reduced SBP from 135.79±4.22 to 132.35±4.656mmHg and reduced DBP from 82.90±3.07 to 82.27±3.01mmHg. All symptom severity scores became significantly lower in the HyperBalance group than in the placebo group after HyperBalance intervention: dizziness ; headache ; ringing/buzzing in ears ; and rapid heart rate and chest tightness . Polyherbal supplementation such as HyperBalance could benefit old adults with prehypertension/hypertension and improve treatment-related symptoms. Further studies are needed to validate the current findings. Uncontrolled high blood pressure is a leading cause of mortality and disability due to cardiovascular disease (CVD) and kidney failure . For exaIndividuals with prehypertension are characterized with either elevated systolic blood pressure (SBP) ranging from 120 to 139 mmHg or a diastolic blood pressure (DBP) from 80 to 89 mmHg and are at a higher risk of developing hypertension  compared to people with normal blood pressure. Individuals with prehypertension and hypertension, although often asymptomatic (without symptoms), can develop treatment-related symptoms such as dizziness, headaches, visual changes, fatigue, or other nonspecific symptoms after current medical treatment.Individuals with prehypertension can significantly increase the risk for cardiovascular disorders and kidney problems . It has Aging, obesity, high salt intake, lack of exercise, stress, depression, and insulin resistance all can contribute to prehypertension/hypertension , 9, 10. 2O2 production is a major causative factor in endothelial perturbation and in the pathogenesis of atherosclerosis. Increased NADPH oxidase activity is also a major source of reactive oxygen species (ROS) in endothelial cells [Recent studies indicate that increased free radical production and diminished activities of antioxidant and nitric oxide (NO) are involved in the development of hypertension , 15. Lowal cells , 17. Simal cells . The supal cells .Prevention is considered the best strategy to lower the risk of prehypertension progressing to hypertension. Modification of lifestyle, including low-sodium, high-potassium diet, increasing physical activity, quitting smoking, reducing alcohol consumption, and maintaining a healthy weight, has been recommended , 20.Alternatively, botanical herbs that have historically been used as an essential diet supplement could be potential agents for the management of prehypertension and hypertension –23. Gastrodia elata (EG) is one of the most common antihypertension ingredients prescribed by TCM doctors for hypertension [γ) in myocardium of spontaneously hypertensive rats (SHRs) [For example,rtension . EG contrtension . Gastrods (SHRs) . EG alsos (SHRs) . Moreoves (SHRs) , 29. EG s (SHRs) –32.Coadministration of multiple medicinal herbal ingredients is a common practice in traditional Chinese medicine. Such practice is to potentiate the bioavailability, activity, and efficacy of the key therapeutic ingredients, and to minimize or antagonize potential toxicities associated with the ingredients.The primary goal of this exploratory, randomized, placebo-controlled observational study was to determine if administration of polyherbal supplement is beneficial to older adults who have high blood pressure and treatment-related symptoms.The experimental design and procedures of this study were similar to what we recently reported , 33, 34.This was a randomized, double-blind, placebo-controlled study. Sample size calculation was obtained by the calculation of the estimated experimental study parameters. SBP was chosen as the main outcome, assuming a baseline SBP at about about 135 mm Hg, and the standard deviation at about 7 mm Hg. It was expected that SBP would drop to 130 mm Hg after the intervention: σ is the estimated SD; d is the difference between two groups of continuous variables mean.α = 0.05 β = 0.1, Zα = 1.96 Zβ = 1.282, the calculated sample size N is 41. Assuming a potential dropout rate of 20%, at least 49 people would be required for each group of the study. We enrolled 50 people each for the test group and control group.According to the two-sided test, The recruitment of the participants into the study was started on December 7, 2011, and completed on December 30, 2011. The last follow-up observation was completed on March 30, 2012, at Tang Qiao Community Health Service Center in Pudong New District in Shanghai, China. Participants were recruited by self-referral in response to media coverage and word of mouth. Witten informed consent was obtained from all participants prior to enrollment into the study. This study was conducted in adherence to CONSORT guidelines (http://www.consort-statement.org/). All study procedures were conducted in accordance with the Helsinki Declaration of 1975 and were approved by the Shanghai Jiao Tong University Medical Center Institutional Review Board. Subjects who met the first and one of the other two following criteria were eligible for the study:Inclusion Criteria. (1) Inclusion criteria were as follows: healthy males or females at least 50 years of age; (2) having current prehypertension (systolic blood pressure 130-139 mmHg or diastolic blood pressure 85-89mmHg); (3) having a history of hypertension (systolic blood pressure 140-159mmHg or diastolic blood pressure 90-99mmHg).Exclusion Criteria. (1) Exclusion criteria were as follows: having diagnosed with any severe medical conditions or complications of the brain, liver, kidneys, heart or lungs, any other organs, or malignant tumors that need medical treatments. The exclusion criteria were to ensure that the study would not be affected by the treatment of other illnesses.Participants were randomly assigned to the HyperBalance treatment or placebo treatment. The randomization was performed using a predetermined randomization code, which was generated by a random number generator.Trial participants and community doctors were both blinded from the treatment . Of the 100 enrolled participants, 98 participants completed the 12-week follow-up, including 50 subjects in the HyperBalance group and 48 subjects in the placebo group. Two subjects of the placebo group withdrew from the study (due to the objection of the family members).The participants received similar-looking capsules in color-coded bottles . Neither the subjects nor the medical doctors, including the study principal investigator, knew the specific color code until the end of the study. Both the HyperBalance capsules and the placebo (which was mainly composed of flour) were manufactured by Robinson Pharma, Inc. . Each participant was instructed to take 1 capsule with a meal, two times per day for 12 weeks, and a new batch of supplements was dispensed every month during follow-up sessions. (Apocynum venetum) leaves, Gou teng (Uncaria rhynchophylla), Eucommia (Eucommia ulmoides), Heal all (Prunella vulgaris), Senna (Cassia obtusifolia), Gastrodia (Gastrodia elata), Wild chrysanthemum (Chrysanthemum indicum L.), and Rauwolfia (Rauvolfia yunnanensis) (anensis) .Changes in blood pressure, treatment-related symptoms including headache, dizziness, ringing/buzzing in ears, rapid heart rate, and chest tightness, and other signs were recorded using a medical questionnaire that included the demographics and medication history of the participants and questionnaire and quality of life evaluation form SF-36) before and after the completion of the intervention. Measurement of baseline blood pressure and the final blood pressure after the completion of the 12-week follow-up observation were repeated twice separated by 1-week interval. Blood pressure measurement of siting position was conducted by well-trained medical doctors of the community health center, using a mercury sphygmomanometer . Hypertension treatment-related symptoms, i.e., dizziness, headache, ringing/buzzing in ears, rapid heart rate, and chest tightness, were scored using a self-administered 5-point scale . The quality of life was evaluated using the SF-36 that contains 8 domains including physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Items were summed per domain and transformed into scores of 0-100, with higher values representing better functioning. Physical composite score (PCS) and mental composite score (MCS) were computed according to each domain score and the data of Chinese adults model . PCS and before aEpiData 3.02 software was used for the establishment of the database. SPSS 20 software was used for statistical analysis. Group data were presented as the mean ± s.d. Differences between the HyperBalance and placebo groups were compared using Student's t-test for quantitative variables with normal distribution, or Chi-square test for categorized variables. Ridit scoring test, which is a nonparametric test for comparing two or more sets of ordered qualitative data, was used for evaluating the changes in the symptom severity scores after the intervention. The alpha level of P>0.05 was chosen as being statistically significant. All p-values reported were 2-sided.χ2=1.97, P>0.05), with females accounting for more than two-thirds of all participants. The average age of all participants was 65.1±7.1, and again no significant difference was found between the HyperBalance group (64.97±7.2 years) and the placebo group (65.28±7.1 years) .The baseline characteristics of age, gender, and histories of alcohol intake, disease, and medication of the participants are shown in χ2=0.06, P=0.804), smoking (16% vs. 10.4%) , proportions of prehypertension (82% vs. 83.3%) , hypertension (18% vs 16.7%) , and antihypertension medication (78% vs. 87.5%) . There were three cases of hyperlipidemia in each group   and diastolic blood pressure (DBP) of both the HyperBalance group and the placebo group before and after the 12-week intervention are shown in There were no baseline differences between HyperBalance group and placebo control in symptom severity scores of dizziness , headache , ringing/buzzing in ears , and rapid heart rate and chest tightness  . HoweverTo better evaluate the overall effects of HyperBalance on hypertension-related symptoms, the combined symptom severity scores of dizziness, headache, ringing/buzzing in ears, and rapid heart rate and chest tightness were analyzed. The baseline values in combined symptoms scores were not significant between the HyperBalance and placebo groups . However, the combined scores became significant between the two groups after the intervention (2.04±1.47 vs. 5.79±1.41) (P<0.001) .The combined scores of the 4 symptoms were further pooled into 3 subgroups based on levels of symptom improvement  for Chi-square analysis. In the HyperBalance group, 48% people showed great symptom severity improvement (5-7 points) and 42% people showed moderate symptom improvement (3-4 points) compared to 2.1% and 14.6% in the placebo group, respectively (P<0.01), whereas 48.0% of the placebo group showed no symptoms improvement (0 point) and 36% showed slight symptom improvement (1-2 points). Ridit scoring test showed a significantly greater improvement in the combined symptom severity scores after the HyperBalance intervention (mean=0.719±0.1.73) than after placebo intervention (0.272±0.183)   contains flavonoids, 1,8-cineole, camphor, borneol, and bornyl acetate as the main active compounds [ompounds , 46. Intompounds . CIL dirompounds . CIL extompounds . Pretreaompounds . Apocynum venetum leaves (AVLE) include apocynin, flavonol glycosides, quercetin, triacontanol, beta-sitosterol, hyperin, and long-chain fatty acids  contains various chemical constituents such as lignans, iridoids, phenolics, steroids, and flavonoids that have multiple antioxidant, anti-inflammatory, antiallergic, antimicrobial, anticancer, antiaging, cardioprotective, and neuroprotective properties [ Eucommia ulmoides lignans are effective in lowering blood pressure, protecting against hypertensive renal injury in spontaneous hypertensive rats, and inhibiting aldose reductase (AR) overexpression in the kidney [ Eucommia lignans inhibit angiotensin II- (Ang II-) induced proliferation of rat mesangial cells via regulating cell cycle-related genes P21 and P27 [operties . Eucommie kidney . Eucommi and P27  and exer and P27 . Cellula and P27 .Prunella vulgaris (P. vulgaris) leaves (PVL) have been widely consumed as a tea ingredient since ancient times for its antiviral, antibacterial, anti-inflammatory, antiallergic, antioxidative, antitumor, antihypertensive, antihyperglycemic, and immunoregulatory properties [ P. vulgaris dose-dependently ameliorated vascular constriction of aortic rings induced by acetylcholine or SNP [operties –71. Tritoperties . P. vulge or SNP . Ursolice or SNP . PVL alse or SNP  and the e or SNP . PVL inhe or SNP  and showe or SNP . PVL exte or SNP . Rosmarie or SNP .Cassia obtusifolia) oral administration of obtusifolin extracts significantly ameliorated high-fat diet-induced changes in body weight, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and malondialdehyde but increased serum superoxide dismutase and nitric oxide [ Cassia obtusifolia have antiallergic effect by inhibiting histamine release [ Cassia obtusifolia are potent inhibitors of platelet aggregation [Senna , ajmaline, aricine, corynanthine, deserpidine, lankanescine, rauwolscine, etc. as the main active compounds [ Rauwolfia is used as a cotreatment of hypertension due to its side effects such as oxidative damage to liver and other organs and depression [ompounds . Rserpinompounds , 83 and ompounds . Now onlpression . Rauwolfia serpentine formulation  in 30 adults with prehypertension or stage I hypertension significantly increased serum potassium (p < 0.05) but significantly decreased systolic blood pressure (p < 0.0001) and diastolic blood pressure (p < 0.0001) [So far, few studies compared single medical herbal ingredients with polyherbal formulation on prehypertension although combination therapy of different antihypertensive agents often results in better efficacy than single-pills therapy . One rec 0.0001) . While n 0.0001) . rauwolfia drugs  showed decrease in arterial blood pressure to normal level and an 8-year increase in mean lifespan compared to the 80 patients who had not received any hypotensive drugs. Furthermore, the number of fatal brain strokes and myocardial infarctions decreased almost 2-fold in the treatment group.One early study examined 295 moderate arterial hypertension patients with the diastolic pressure under 110 mm Hg [ Amlodipine is a calcium channel blocker that dilates (widens) blood vessels and improves blood flow but it may also induce treatment-related symptoms. It is known that antihypertension medicines can induce different side effects such as dizziness, weakness, fatigue, shortness of breath, difficulty breathing, and chest pain induced by beta-blockers, headache, dizziness, fainting, reduced kidney function induced by ACE Inhibitors, and affected muscular function of the heart by diuretics [In this study, a significant proportion (82.7%) or 81 of the 98 participants received the antihypertension medicine amlodipine tablet for a period between 3 and 36 months.iuretics , 86–92. There are limitations of this study. The sample size of this study is too small to reach a conclusion. Because risk factors for prehypertension/hypertension are heterogeneous and potentially affected by a range of genetic and environmental factors including lifestyle, daily activity/exercise, genotype, age, obesity, diabetes, stress, education level, inflammation, alcohol intake, and smoking, it is difficult to know the optimal dose of individual ingredients for a most effective formulation. Further studies could control these factors to allow a better understanding of the mechanism of polyherbal intervention.In conclusion, 12-week supplementation of polyherbal ingredients such as HyperBalance could benefit older adults with prehypertension/hypertension in improving blood pressures and treatment-related symptoms. Further studies of long-term supplementation of polyherbal medicine are needed to validate the current findings.


Acute kidney injury (AKI) may develop during partial nephrectomy due to ischemic reperfusion injury induced by renal artery clamping or surgical insult. The effect of remote ischemic preconditioning (RIPC) on reducing the renal injury after partial nephrectomy has not been evaluated in terms of urinary biomarkers.N-acetyl-beta-D-glucosaminidase, will be compared between groups during the postoperative 2 weeks. Regional oxygen saturation on the skin of the contralateral kidney will be measured to evaluate the association between intraoperative regional oxygen saturation values and renal injury of the operating side.We will conduct a randomized controlled trial enrolling the patients who will undergo partial nephrectomy. In the study group, RIPC which consisted of four 5-min cycles of limb ischemia and reperfusion will be conducted after induction of anesthesia. Postoperative serum creatinine values, the incidence of AKI, and urinary biomarkers, including urinary creatinine, microalbumin, β-2 microglobulin, and 99mTc-DTPA radionuclide scintigraphy to calculate glomerular filtration rate 6 and 12 months after surgery. This data should show the long-term effect of RIPC.We expect that our trial may demonstrate the effect of RIPC on mitigating the immediate postoperative renal injury and improving patient outcomes after partial nephrectomy. Moreover, our patients will undergo NCT03273751. Registered on 6 September 2017.ClinicalTrials.gov, ID: The online version of this article (10.1186/s13063-018-2820-3) contains supplementary material, which is available to authorized users. Remote ischemic preconditioning (RIPC) refers to applying one or more cycles of brief, non-lethal ischemia and reperfusion to a distant organ or tissue, which is known to protect heart and other organs against acute ischemic insult –4. To dePartial nephrectomy has now become a standard treatment for localized renal small cell cancer , 10. ParN-acetyl-beta-D-glucosaminidase (NAG) are also available [99mTc-DTPA) radionuclide scintigraphy. Since AKI can predispose to chronic kidney disease [Theoretically, we assumed that RIPC, which can prevent IRI, may reduce renal ischemic injury in patients undergoing partial nephrectomy. There are only two randomized controlled trials (RCT) which evaluated the effect of RIPC during partial nephrectomy , 16. Altvailable –22, the  disease , the lonTherefore, we hypothesized that RIPC may mitigate the IRI due to renal arterial clamping during partial nephrectomy, thereby, reducing the elevation in serum creatinine and urinary biomarkers of renal injury. We aimed to evaluate the effect of RIPC on postoperative renal function measured by serum creatinine, urinary biomarkers, and GFR measured by scintigraphy.The trial protocol was developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines  Additio. The SPI99mTc-DTPA radionuclide scintigraphy to compare the function of the kidney on the surgery.Eligible participants are adults (≥ 20 years of age) who are scheduled to undergo open or laparoscopic or robot-assisted partial nephrectomy. We included patients with a normal contralateral renal function that will be confirmed as a preoperative split renal function of > 40% by the 2 of body-surface area or preoperative serum creatinine level > 1.4 mg/dl), and hepatic failure .Exclusion criteria are the patients with any of the following disease: clinically significant peripheral vascular disease affecting the upper arms, severe cardiopulmonary diseases , baseline chronic kidney disease . We will conduct this study at Seoul National University Hospital. A Data Monitoring Committee was established by the personnel who are independent of study organizers. This committee will monitor participant enrollment, data management, the accuracy of information on the case report form, and compliance to the trial protocol every 6 months.This study is being conducted in accordance with the Declaration of Helsinki 1964 as revised in 2013 and the International Conference of Harmonization Guidelines for Good Clinical Practice. This study was approved by the Institutional Review Board of Seoul National University Hospital  and was registered at http://www.sealedenvelope.com). Group allocations will be concealed from the investigators using opaque envelopes. The random assignment will be conducted by a third party independent of the study, and the assignment records will not be disclosed until the end of the study. On the day of the surgery, the opaque envelope containing the group allocation will be delivered to an anesthesiologist who is not involved in the study and is responsible for patient care and the RIPC intervention. Participants, urologic surgeons, post-anesthesia care staff, data collectors, and investigators assessing outcome data will be blinded to the treatment allocation to minimize potential sources of bias.After the initial enrollment, participants will be randomly assigned in a 1:1 ratio to either the RIPC or the control group according to Internet-based computer-generated random numbers in block sizes of 4 or 6  using a target-controlled infusion pump . After loss of consciousness, rocuronium 0.6 mg/kg will be administered intravenously to facilitate endotracheal intubation. Anesthesia will be maintained with desflurane or sevoflurane using a concentration of 1–1.5 minimum alveolar concentration.2) under ultrasound guidance [2 will be continuously monitored with NIRS  until the end of the surgery and rSO2 values will be recorded at intervals of 10 min.After the patients are put in a right or left upper lateral position for the surgery, a disposable NIRS sensor  will be applied directly to the flank area that overlies the opposite kidney that is not undergoing surgery to monitor renal regional oxygen saturation , followed by 5-min deflation of a blood pressure cuff. In patients assigned to the control group, a blood pressure cuff will also placed on the upper arm but without cuff inflation during the study period. The intervention will be performed by an anesthesiologist who is independent of this study.2 of the opposite kidney measured at 10-min intervals from the induction of anesthesia to the end of surgery will also be investigated as secondary outcomes. eGFRs will be calculated with the abbreviated isotope dilution mass spectrometry-Modification in Diet and Renal Disease Study equation, which is The primary outcome is serum creatinine level 1 day after partial nephrectomy, as an index of postoperative kidney function. The secondary outcomes include the incidence of postoperative AKI and urinary biomarkers including urinary creatinine, microalbumin, β-2 microglobulin, and NAG measured immediately, and 1 day and 2 weeks after the partial nephrectomy , median (interquartile range) or the number of patients (%). The normality of distribution of data will be tested by the Kolmogorov-Smirnov test. To compare the outcome variables and baseline characteristics between the RIPC and the control group, Student’s P < 0.05 will be considered statistically significant. Bonferroni correction for multiple measurements will be used to reduce type 1 error.Data will be analyzed using SPSS software . G*power  was used to calculate the sample size. A The trial protocol and results will be published in peer-reviewed journals. The results of the trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement and its extension to non-pharmacological interventions , 30. ParThe present study will test the hypothesis that RIPC performed during partial nephrectomy will reduce the IRI caused by renal artery clamping during surgery as well as the surgical insult. Our primary outcome variable will be serum creatinine value measured on the first postoperative day. However, as serum creatinine may be non-specific and insensitive to detect early subclinical renal injury, urinary biomarkers, as well as other secondary clinical outcomes, will be compared between groups. Our study should be able to give a reliable answer to the question of whether RIPC could protect the kidney from IRI during partial nephrectomy.Patients who undergo partial nephrectomy are prone to develop postoperative renal parenchymal injury theoretically. Only a few studies reported the incidence of AKI after partial nephrectomy with currently available criteria including RIFLE , the Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO). To our knowledge, in two previous studies investigating the development of AKI in patients who underwent partial nephrectomy, the incidences of AKI were reported as 39% and 54% according to AKIN and RIFLE criteria, respectively , 31. AnoThe protective effect of RIPC on vital organs against IRI has been reported in previous animal studies –36. RemoThe optimal protocol and regimen of RIPC, including the timing, number of ischemia/reperfusion cycle and duration of each ischemic period, have not yet been established. Important variables in the regimen of RIPC are considered to be the optimal duration of the ischemia, the number of cycles repeated, and the site of application of the ischemia .According to the Cochrane Review of ischemic preconditioning (IPC) for the reduction of renal IRI , the mosRegarding the inflation pressure of the cuff, a threshold of 200 mmHg has commonly been used in previous studies to induce ischemia of the upper extremities. However, a 200-mmHg inflation of the blood pressure cuff might be insufficient to occlude arterial blood flow of the upper limb in patients with chronic hypertension , 44 and Recent studies reported that the use of propofol may inhibit the protective effect of RIPC –48. In tTo our knowledge, there were two studies that evaluated the effect of RIPC during partial nephrectomy , 16. HuaOur protocols have several limitations. First, urinary creatinine, microalbumin, β-2 microglobulin, and NAG were chosen as biomarkers of renal injury. These biomarkers were chosen because they are routinely measured in our clinical practice. However, there are other biomarkers with better performance such as urine tissue inhibitor of metalloproteinase-2 and insulin-like-growth-factor-binding protein 7 . Measuri99mTc-DTPA radionuclide scintigraphy to calculate GFR 6 and 12 months after surgery. This data will provide the long-term effect of RIPC in addition to the outcome variables that will be reported according to this study protocol.In conclusion, our study protocol will test the effect of RIPC on the serum creatinine values after partial nephrectomy. Furthermore, our study will compare the incidence of AKI among the patients who received RIPC and those who did not. The urinary biomarker levels will help us to discriminate the degree of renal injury between the study groups more precisely. If the result of our trial supports our hypothesis, the next step in our research protocol will be to evaluate the long-term effect of RIPC in this surgical setting. Our patients will undergo The study was initiated in September 2017. By June 2018, 46 patients had been enrolled in this study. Enrollment of 86 patients is expected to be completed in the winter of 2018.Additional file 1:Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist. (DOC 124 kb)