Background: In 2009, Belgrade nephrologists and general practitioners from thirteen health centers carried out screening for chronic kidney disease (CKD). Three years later, medical records of patients from four health centers participating in the screening study were retrospectively analyzed in order to check whether general practitioners had continued to control patients at risk for CKD in accordance with the recommendations provided.Methods: The study included 460 patients who visited their doctor at least once in the three-year period. Data on blood pressure, ACEI use, estimated glomerular filtration rate (eGFR) and comorbidities were taken from patients’ medical records.Results: Blood pressure was not recorded in any of the three years in 42.8% and eGFR in 36.7% of the patients, but blood pressure was registered every year in 7.8% and eGFR in 4.3% of them. Over the three years, the relative number of patients with recorded blood pressure decreased from 41.7% to 17.8%, and with recorded eGFR from 41.7% to 21.5%. Multivariate linear regression found that Health Center, systolic and diastolic blood pressure and presence of hypertension were negatively associated with number of years with recorded blood pressure. Health Center, systolic blood pressure and sum of years with recorded eGFR below 60 ml/min/1.73m2 were associated with number of years with recorded eGFR.Conclusions: Under-recording of blood pressure and eGFR in primary care health centers suggests lack of adherence to current guidelines and insufficient care of CKD patients. This implies the necessity for continuous education of physicians. Chronic kidney disease (CKD) is a worldwide public health problem with increasing incidence and prevalence, poor outcome and high treatment costs. CKD affects up to 13% of the adult population . It is eEarly-stage CKD (stages 1–3) in most patients is asymptomatic and therefore active screening is recommended in persons at high risk for this disease . As patiLike many nephrologists throughout the world, Belgrade nephrologists in cooperation with general practitioners from thirteen Belgrade Health Centers carried out screening for CKD in 2009. The screening included adults without previously known renal disease, but at risk for CKD, that is, patients with hypertension and/or type 2 diabetes mellitus and persons older than 60 years. The screening was preceded by educational meetings for primary care doctors on prevention and early detection of CKD, including organization of the screening study. The results of the screening were presented at a joint meeting of nephrologists and general practitioners, where nephrologists distributed prepared recommendations for prevention, screening and management of CKD. The obtained results have been published . In ordeThree years after the screening study, medical records of patients from four health centers participating in the screening study were retrospectively analyzed with the aim of checking whether general practitioners had continued to control patients at risk for CKD in accordance with the recommendations provided in the study and national guideline.The present analysis was conducted in four health centers where one of the authors of this paper was the coordinator-nephrologist in the original study of 2009 (VL). In these four health centers, a total of 684 patients had been examined in 2009. Out of them 195 were lost from follow-up because they changed their place of residence or left their chosen general practitioner and/or health center. In addition, 46 patients who did not visit their general practitioners once in the analyzed three-year period were excluded from the study and 31 patients died. The remaining 460 patients who visited their doctor at least once in the three-year period were included in the present study. These patients were monitored by 13 general practitioners who participated in the study voluntarily. Health Center 4 differed from others in term that only doctors working in the Diabetes counseling service of this health center participated in the 2009 screening study. Therefore, all the patients from Health Center 4 were diabetics.After obtaining permission from the Ethics Committee of each health center, data on monitoring the patients throughout three years were taken from the electronic or paper medical records. Data on blood pressure, use of ACEI, serum creatinine levels, glomerular filtration rate estimated with MDRD4 (eGFR), comorbidities and data on hospitalizations were registered. The comorbidities included cardiovascular , obstructive pulmonary disease, gastrointestinal , malignancies and fractures. Also, data on the number of annual visits of each patient were taken for evaluation. Urine was analyzed in a small number of patients, but the results were not taken into further consideration.2 in the initial study and three years of the present study. All variables found to be significantly (p < .10) associated with the dependent variable were combined in multivariate linear regression analysis. Due to co-linearity between some variables several models were used in multivariate analysis.Continuous variables are presented as mean and standard deviation and categorical ones as frequencies. To assess differences between the examined parameters in the three examined years, the chi-square test and one-way analysis of variance with repeated measurements (ANOVA) was used depending on the variables compared. We applied univariate and multivariate linear regression to detect variables associated with number of years with recorded blood pressure or eGFR in the medical records during the three-year period. In this analysis, the following variables were included as independent ones: selected health centers denoted with serial numbers 1–4, physician (binary variable coded as 0 for physicians who included <15 patients in the present study and 1 for those who included ≥15 patients), patients’ characteristics – age, gender, number of comorbidities, systolic and diastolic blood pressure in the initial screening in 2009 and in each year of the present study, hypertension (defined as blood pressure above 140/80 mmHg) in the initial study, use of ACEI, eGFR in the initial study and in each year of the present one, stage of CKD according to KDOQI guidelines [p < .015).Data on patients at the onset of the study are presented in Comorbidities were more often present in patients from Health Centers 1 and 2, that is, for 59 (72%) patients from Health Center 1 and 75 (87%) patients from Health Center 2. The distribution of patients according to the number of comorbidities differed significantly among the four health centers. Health Center 2 had the highest number of patients with no comorbidity, while Health Center 3 had the highest proportion of patients with two or more comorbidities.2 had significantly more years with recorded eGFR.The distribution of patients according to number of years with recorded eGFR in the three-year period depending on different variables is presented in Trends in the percentage of patients with recorded blood pressure over three years are presented in Similar trends were observed in the relative number of patients with recorded eGFR over three years . There w2 in the initial and present study were positively associated with the dependent variable. Multivariate analysis found health center, systolic blood pressure and sum of years with recorded eGFR <60 mL/min/1.73m2 to be significantly associated with number of years with recorded eGFR  and sum of years with recorded blood pressure >140/80 mmHg in the initial study and the three subsequent years and use of ACEI (positively). In addition to age and gender these variables were combined in a multivariate linear regression analysis that found the following variables to be associated significantly with number of years with recorded blood pressure in the three-year study: Health center, systolic and diastolic blood pressure and presence of hypertension (negatively) . When thded eGFR .In 2009, screening for CKD in at risk population was carried out in Belgrade by primary care physicians and nephrologists in collaboration . The aim2 for more years had it registered more often. The percentage of patients with recorded blood pressure and eGFR declined over the three years.Our results showed that during the three-year period following the initial study blood pressure was not recorded in any year in over 42.8% of patients and every year in less than 7.8% of them. There were significant differences between the health centers evaluated. The number of years with recorded blood pressure was significantly higher in patients using ACEI, those with less comorbidities and those from physicians who included less than 15 patients in the initial study. Patients with blood pressure above 140/80 mmHg for more years had it recorded more often. Similar results were obtained for registering eGFR in the three-year period. eGFR was not recorded in any year for 36.7% of the patients and every year in less than 4.3% of them. The frequency of eGFR records depended significantly on the health center involved, ACEI treatment and the number of co-morbidities. Patients with eGFR below 60 mL/min/1.73 mIt is often pointed out that primary care physicians have a key role in the early detection of CKD as well as in the use of measures for slowing down its progression. Different strategies have been attempted to influence primary care physicians to pay more attention to CKD, most often by direct education. The well-known and very extensive Kidney Early Evaluation Program (KEEP), which was initially directed to screening for CKD in subjects at risk, included education of physicians on risk factors, detection methods, complications and treatment of CKD ,15. In SRecords for eGFR decreased during the three years from 41.7% of the patients to 17.8%. These results are similar to those obtained in a much larger study including 277,111 patients in the USA where at least one laboratory test was performed at the Laboratory Corporation of America during one year. Among the patients examined 19% had at least one measurement of serum creatinine, but in patients at risk for CKD  the proportion varied between 21.4% and 27.9%  reportedHypertension is a well-known risk factor for both CKD and cardiovascular disease, which is the main cause of mortality in CKD patients. Although among the patients included in the present study 92.6% had hypertension (data not presented) blood pressure was not recorded in over 40% of them in any of the three years. Blood pressure was recorded each year in less than 10% of the patents, which is much lower than around 80% found by other authors, although the proportion of patients with hypertension was considerably lower in their studies . NeverthIn the present study, the number of patients for whom both blood pressure and eGFR were recorded, decreased by about half over the three years: that is, from 41.7% to 17.8% for eGFR and from 41.7% to 21.5% for blood pressure. In another retrospective study, eGFR was monitored annually in about 80% of patients ,20. RecoValues for proteinuria in the medical records of patients examined here were scarce, and therefore, it was not included in the analysis. In our primary health centers, measurement of albuminuria is not available and only the semiquantitative urine dipstick test is applied. In addition, at the time of this study, electronic medical records had just been introduced into primary health care centers, so most data were obtained from paper records completed personally by doctors. Also, patients received the results of laboratory analysis on paper and brought them to their doctors. It could be assumed that some serum creatinine measurements were not recorded. Now that primary health centers are computerized the laboratory results are sent electronically directly to the physicians enabling complete registration of all patient data.2 were associated with number of years with recorded eGFR. Thus, recording of both blood pressure and eGFR depended significantly on the health center involved. Comparison of patients’ data at the outset of the present study showed significant differences in mean eGFR and number of comorbidities between the four health centers but the differences could hardly be connected with blood pressure and eGFR recording. It has already been mentioned that all doctors from Health Center 4 worked in Diabetes counseling service and therefore all the patients from Health Center 4 were diabetics. However, although these patients were controlled in a specialized diabetes counseling, blood pressure and eGFR recording was no better than in other centers. Decline in relative number of patients with recorded blood pressure and eGFR over three years was similar in Health Center 4 to some other centers. Even more, in the second year of the study, percentage of patients with recorded blood pressure and eGFR in Health Center 4 was lower than in the other two centers. All this shows that although it is considered that both physicians and patients with DM know the importance of blood pressure as well as kidney function control, it is not implemented in practice.Multivariate linear regression analysis indicated that health center, systolic and diastolic blood pressure and presence of hypertension were negatively associated with number of years with recorded blood pressure in the three-year study, while health center, systolic blood pressure and sum of years with recorded eGFR <60 mL/min/1.73 mBrady and O’Donoghue  also desIn health services where blood pressure and eGFR were determined in the whole population of patients, records of blood pressure were more frequent in those with risk factors for cardiovascular disease , while rOur study has some limitations. First, the present study included data from four out of thirteen health centers included in the initial screening study in 2009. Therefore, the results obtained cannot be generalized in relation to the initial study, and certainly not in relation to all primary health centers. Although it cannot be excluded that data from a larger number of centers might show a different picture, results obtained here shed some light on the quality of care of patients at risk for CKD and these are the first such data from our primary health care. Secondly, data on recording blood pressure and eGFR might be underestimated due to analysis of data personally recorded by physicians. It is possible that blood pressure and serum creatinine were measured but not recorded. On the other hand, the use of routine data from medical records of primary health centers provides a realistic view on how blood pressure and eGFR are recorded in our primary health care. The data obtained represent a starting point for further research, as well as a direction for further action in terms of improving the care of patients at risk for CKD.Under-recording of blood pressure, as one of the main risk factors for CKD, as well as under-recording of eGFR, as a marker of CKD, suggests lack of adherence to current guidelines and therefore insufficient care of CKD patients. Continuous education of primary care physicians is an essential step towards improved prevention, early detection and management of CKD.Ethics Committee of each health center involved in the study has given consent to research.


Based on a compartmental approach individualising the vascular compartment within studied organs, this study proposes a reliable pharmacokinetic (PK) five-compartment model replacing the currently used two-compartment model and constitutes a new direction for further research. This model provides exchange constants between the different tissues, Area Under the Curve of 111In-IT in blood (AUC) and Mean Residence Time (MRT) that have not been reported so far for IT. Finally, the elimination process appears to occur in a compartment other than the liver or the spleen and suggests the metabolism of mAbs may take place mainly on the vascular compartment level.Monoclonal antibodies (mAbs) are key components in several therapies for cancer and inflammatory diseases but current knowledge of their clinical pharmacokinetics and distribution in human tissues remains incomplete. Consequently, optimal dosing and scheduling in clinics are affected. With sequential radiolabeled mAb-based imaging, radiation dosing in tissues/organs can be calculated to provide a better assessment of mAb concentrations in tissues. This is the first pharmacokinetic model of  In spite of their widespread clinical use, literature on mAb clinical pharmacokinetics (PK) remains sparse and little is known about mAb distribution in tissues5, which considerably complicates the defining of optimal mAb dosing and scheduling in clinical practice. Non-compartmental analysis, the most common approach to analysing PK data in drug development, requires a large amount of data and samples per individual to obtain precise PK parameter estimations and is inadequate for studying mAb behaviour6. With compartmental analysis, The mAb standard PK model is a two compartment model , which can assess mAb kinetics in blood but not their distribution in tissues. Fronton et al.7 showed that this model is not compliant with current knowledge. Sequential imaging of radiolabeled mAbs in vivo means that the absorbed radiation dose as well as mAb concentrations can be calculated11. Radioimmunotherapy (RIT) - a targeted therapy using monoclonal antibodies (mAbs) directed to tumor-associated antigens to deliver irradiation from radionucleides to the tumor - is therefore a particularly attractive tool to modelise mAb PK in patients. For many years, two-dimensional (2D) imaging (planar whole-body scintigraphy (anterior and posterior views))12 has been the method of choice for dosimetric studies in RIT despite significant uncertainties in organ volume measurements affecting the accuracy of dosimetric estimates. Nowadays, it is possible to obtain more accurate radiation dose estimation in tissues/organs with three-dimensional (3D) dosimetry using single-photon emission computed-tomography coupled with computed-tomography (SPECT-CT)16, or Positron Emission Tomography coupled with computed-tomography (PET-CT)18.Monoclonal antibodies (mAbs) whether alone or coupled with radioistopes or cytotoxic drugs19 but has not been applied in 3D dosimetric studies so far.Accurate mAb PK modeling requires individualised estimations of antibody concentrations in the vascular compartment within each organ. This individualising appears feasible with dosimetric studieset al.20. It has been approved for the treatment of follicular lymphoma (FL) in case of relapse or refractory disease or to consolidate first-line therapy. The recently reported FIZZ Study showed that fractionated RIT is effective as initial treatment for advanced-stage FL in patients with a high tumor burden21. Following the protocol, a subset of FIZZ patients underwent a patient-specific 3D dosimetric study.Yttrium 90 - Ibritumomab tiuxetan (Y90-IT) is a drug consisting of a murine anti-CD20 antibody (ibritumomab) linked to a chelator (tiuxetan) radiolabeled with 90-Yttrium  according to the method described in the Zevalin monograph  for therapy or 111-Indium for imaging  according to the method described by Ferrer 90Y-Ibritumomab tiuxetan in humans, based on dosimetric and 3D-imaging data obtained from FIZZ patients, coupled with a pharmacokinetic compartmental approach and individualising the vascular compartment within the organs studied. This method allows describing all compartments in which mAb was measured.This is the first description of a pharmacokinetic model of 3 respectively).3D imaging data after the first fraction F1) of RIT was available for 19 patients and after the 2 fractions (F1 and F2) for 13 patients since the second fraction was cancelled for 6 patients due to hematologic toxicity after F1 or the development of HAMA. Baseline characteristics are listed in Table  of RIT wEstimated blood volumes of lumbar vertebrae L2-L4 (8.15 mL), liver (485 mL) and spleen (81.5 mL) are shown in Table The calculation method for mAb amount in blood vessels within organs and tissues is shown in Fig. The model selected with Kinetica® software to best predict the biodistribution of Ibritumomab tiuxetan is shown in Fig. 12 and the AUCcum 7d* (µg.min.mL−1) are higher for F1 than F2) and Spleen compartments .The pharmacokinetic parameters for the various compartments  from Kinetica® software are reported in Table 27. Other studies, investigating the exact amount of urinary excretion through urinary sampling could provide further details on elimination pathways. However, biliary and renal excretions are known to be minimal25.Among the thirty pharmacokinetic models assessed, the best pharmacokinetic model according to the AKAIKE test, validated on both RIT fractions, is a five-compartment model close to a mammalian PK model, except for the spleen. It provides exchange constants between the different tissues, AUC and MRT that have not yet been reported for Ibritumomab tiuxetan. Very little data is available on the elimination pathways of therapeutic mAbs. In our model, which individualises the vascular compartment within organs, the elimination process appears to be performed by a compartment other than that of the liver or the spleen and suggests the metabolism of mAbs may take place mainly on the vascular compartment level. This finding is in keeping with published data suggesting that monoclonal antibodies may be metabolised in the vascular compartment by endothelial cells and, to a much lesser extent (5.9%) urinary excretion111In-ibritumomab tiuxetan is 83.6 and 83.8 hours for F1 and F2, respectively and varies between 20 and 140 hours in the literature28. The volume of blood in the liver (489.61 mL and 459.72 mL for F1 and F2 respectively) and in the spleen (81.22 mL and 65.28 mL) are in keeping with previously published estimates25. The Volumes of distribution (Vd) estimated by our model are 4131.0 and 4064.3 mL for F1 and F2, respectively. These figures are slightly lower than published data (5000–10000 mL29). Nevertheless the calculated volumes of distribution (our results and published data) remain small, suggesting a limited distribution outside the blood30 . These results can be accounted for by mAb properties such as high molecular mass and hydrophilicity/polarity ratio. Other parameters cannot be compared with scientific literature as they are rarely described.The pharmacokinetic parameters of the model concord with data in literature, thereby confirming its reliability. The mean blood half-life of 32, four30, five34 or even fewer35 but this reduced sampling can prove limiting for pharmacokinetic studies. The number of image acquisitions was four  The extrapolation method to determine the amount of blood in organs would have been more precise if imaging had been performed 1 hour after infusion, instead of 4 hours but this is problematic given the possible occurrence of infusion-related reactions to mAb. Also, the dosimetric study was limited to 7 days (taking into account the radioactive period of Indium 111 which is 67 hours). The presence of residual blood activity prevented a precise calculation of the elimination constants since the completed diffusion phase could not be assessed. It has to be acknowledged that 4 samples is already considerable as a whole body SPECT/CT examination is a time/device-consuming procedure (about 1 hour per image) and an inconvenience to patients.Although our 5-compartment model is a step forward compared to the previous 2-compartment model, there are clear limitations. First, in dosimetric studies, the data used to delineate organs is usually obtained with few samples: three3 respectively), as a consequence of tumor reduction after the first RIT fraction36. It should be noted that mAb concentrations were higher in blood and liver and lower in the spleen and lumbar vertebrae at F2 with significant changes in the PK parameters of “L2-L4 vertebrae” and “spleen”. This may be explained by tumor regression during the time between F1 and F2 which would modify the fifth compartment. Another study has revealed baseline metabolic tumor volume influence on mAb exposure37. Evaluating radiolabeled mAb distribution in the tumor compartment is difficult and tedious, in particular for small tumors. PET imaging would yield more precise quantifications due to its better spatial resolution than SPECT and to its more elaborate quantification tools. Major progress has been made in immunoPET since this study was first designed with the development of Zr89 labelled mAbs resulting in PET biodistribution studies39. It should therefore be easier to estimate the volume of tumoral lesions and, their evolution as well as modifications in radiolabeled mAb kinetics from one fraction to the other. A study has shown that CD20 expression can be induced by low dose gamma-radiation which could account for the difference in antibody distribution between the F1 and F2 fractions40. Another explanation could be metabolisation by the internalising41 of surface CD20 receptors following their association with an anti-CD20 antibody or CD20 modulation42.A second limitation is that the compartment representing the tumor was not individualised. Tumor volume was significantly lower before F2 than F1  for certain tissues might be better clarified with further investigations based on immunoPET and broader biological sampling.The PK parameters described in this study are numerous and relevant and constitute a background for further research. The study proposes a reliable pharmacokinetic five-compartment model of 36.Patients with histologically confirmed CD20-positive Follicular Lymphoma were included in the FIZZ study 90Y-Ibritumomab tiuxetan as the initial therapy for follicular lymphoma (FL) in patients in need of treatment according to GELF/BNLI criteria. Briefly, treatment consisted of 2 infusions, termed fraction 1 (F1) and 2 (F2) of 90Y-ibritumomab tiuxetan  given 8–12 weeks apart  and neutrophil count >1.5 × 109/L. Occurrence of grade 3 or grade 4 myelotoxicity after 2 weeks, or a Human anti-mouse antibody (HAMA) reaction led to exclusion from a second 90Y-ibritumomab tiuxetan infusion. Patients with >20% lymphoma infiltration of bone marrow (BM) received 4 weekly infusions of Rituximab (375 mg/m2) (RTX) and proceeded to fractionated RIT only if a repeat BM biopsy demonstrated clearing of lymphoma to <20% involvement. Each 90Y-ibritumomab tiuxetan fraction was preceded by two rituximab infusions (250 mg/m2) given 7–8 days apart, the second infusion given immediately prior to 90Y-ibritumomab tiuxetan in order to saturate the binding sites of circulating anti-CD20 antibodies.The FIZZ study was a multi-centre, non-randomised prospective phase II study of fractionated art Fig.  providedRaw data used to establish a pharmacokinetic model of 90Y-Ibritumomab tiuxetan (IT) was obtained from the patients included in the FIZZ trial at Lille university hospital.111In-ibritumomab tiuxetan (111In–ibritumomab tiuxetan administered intravenously concomitantly with the first rituximab infusion) for both 90Y- ibritumomab tiuxetan fractions21.Following protocol, a subset of FIZZ patients underwent a patient-specific 3D dosimetric study with 138 MBq of 111In for 1.6 mg ibritumomab tiuxetan (specific activity of 138 MBq/mg). The radiochemical purity threshold for injection to the patient was set at 95%.Radiolabeling was performed with 222 MBq of 21. The absorbed bone marrow dose was assessed on the L2-L4 lumbar area according to Shen et al.43.Whole body Single-photon emission computed- tomography (SPECT)/Computed-Tomography (CT)  was performed at 4 hours, 24 h, 96 h and 168 h after infusions. A CT scan was performed to delineate the organs of interest  plus tumor volume. Concentration of radioactivity in each of these organs was determined on SPECT imaging by the count number in the respective volumes21. All patients provided informed written consent. Ethics approval was granted in accordance with French and UK Medical Research Council guidelines and the Declaration of Helsinki (NCT01493479). All methods were performed in accordance with the relevant guidelines and regulations.The accurate processing of 3D images to confirm absorbed-dose calculations (using CT images to estimate patient-specific organ and bone marrow volumes) was centralised in the CRCNA laboratory (Nantes) as previously111In-IT in the whole organ (whole body SPECT/CT performed 4 hours after injection) by the concentration of 111In-IT in peripheral blood (sample taken 1 h after injection). Organ mass was determined using the CT scan.Antibody diffusion was assumed to consist of a vascular phase (from a few minutes until one hour after injection) and a tissue phase. After one hour, when antibody concentration in blood is maximal and before the tissue phase, the blood volume in each organ was extrapolated, by dividing the amount of 111In-ibritumomab tiuxetan in blood was then calculated as follows.111In-Ibritumomab tiuxetan, expressed in milligrams in the blood sample.111In.The amount of radioelement in peripheral blood was calculated through decay correction and correspondence between mass and activity (activity concentration). Blood radioactivity was determined using a well counter  (efficiency = 93.3%). Radiolabeled antibodies were considered to be the only source of radioactivity in blood samples. The amount of At each sampling time, amounts of radiolabeled mAbs in blood in organs were calculated as follows:The amount of mAbs in each tissue was determined by substracting the amount of radiolabeled mAbs in blood from the total amount of radiolabeleld mAbs in organs at each sampling time.The Designer module of Kinetica® software v5.0 (Thermo Fisher Scientific) was used to estimate the PK parameters of Ibritumomab tiuxetan from radiolabeled-mAb blood and organ concentrations. The quality of PK models was assessed by the Akaike Information Criterion (AIC). The best AIC score (43) indicated the most accurate model to describe PK data. The model was built from pharmacokinetic parameters which were evaluated for each patient.1x2 being the order one rate constant from the x1 compartment to the x2 compartment.kx1, x2, x3, x4 and x5 respectively represent blood, L2-L4 vertebrae, liver, spleen and a deep compartment, considered as the other compartments of the organism (including tumor volume).xel is the elimination constant rate from the blood compartment (order one).kd is the distribution volume (Vd).V1/2 is the mAb biological half-life.TT is the total clearance.CL111In-Ibritumomab tiuxetan in blood.AUC is the total Area Under the Curve of These are expressed as111In-Ibritumomab tiuxetan was calculated.Organ blood volumes were measured. The cumulated AUC at four (AUCcum 4d) and seven (AUCcum 7d) days after injection of 111In-Ibritumomab tiuxetan were calculated.For each compartment, the Mean Residence Time (MRT) and maximal concentration (Cmax) of Data obtained after F1 and F2 was not pooled and the pharmacokinetic model was first established on data obtained after F1, followed by that obtained after F2. Parameters are expressed as mean values and standard deviation or mean values and range of variation. They were compared using the bilateral non-parametric Mann–Whitney test (α = 0.05) with XLSTAT® software .


Renal artery denervation (RDN) is a new widely discussed method in treatment of hypertension. Most of the RDN studies assessed BP and arterial changes 3 and 6 months after the procedure, but there is a lack of trials that investigated early changes after RDN. To investigate aortic stiffness 24-48 hours after the procedure and thus to examine whether RDN might have an early additive value for a cardiovascular risk decline beyond the lowering of blood pressure. RDN was performed for 73 patients with resistant hypertension. Arterial stiffness and central haemodynamics were measured before the procedure, the next day after the procedure, and subsequently after 1, 3, 6, and 12 months.p=0.001); reduction was sustained at months 1, 3, 6, and 12. Early changes in the AoPWV value did not correlate with changes in office systolic or diastolic BP . Furthermore, the higher the initial AoPWV value, the greater the reduction of AoPWV observed after 6 months: Q1 8.4±1, Δ0.05±1.6 / Q2 10.1±0.4, Δ1.1±1.4 / Q3 12.2±0.8, Δ1.8±1.7 / Q4 15.3±1.7, Δ2.8±2.1 (p=0.002). Within 48 hours, RDN significantly reduced aortic pulse wave velocity (AoPWV) from 11.3±2.7 to 10.3±2.6 m/s ( Early and sustained effects on AoPWV observed in our study suggest that RDN may have additional effects on reducing arterial stiffness and cardiovascular risk. Arterial hypertension is one of the most common diseases worldwide. According to the PURE study, overall 40.8% of the adult population in 2013 had hypertension .Resistant hypertension (RH) is recognised as a clinical phenotype carrying a high cardiovascular risk . A retroSympathetic nervous system modification, by renal artery denervation (RDN), is a new interventional method in treatment of hypertension. Over the past decade there have been several studies with diverse conclusions on RDN effectiveness. The Symplicity HTN-1 and HTN-2 Trials showed significant blood pressure lowering effect , 10. Unf.By highlighting the relationship between RDN and arterial stiffness as well as central haemodynamics , Brandt Aortic PWV has been assumed as the “gold standard” for measuring aortic stiffness  as an inThe Brandt MC et al. study for the first time revealed aortic stiffness improvement 1 month after the procedure . In addiThe study was authorized by the Regional Biomedical Research Ethics Committee (No. 158200-13-641-205). Prior to formal enrollment in the study, all interested patients signed an informed consent form.Between March 2012 and December 2017, 243 patients (>18 years of age) with suspected RH were referred to a hypertension specialist. They underwent a detail examination using local protocol to rule out secondary hypertension [Renal denervation was performed using Symplicity Flex or Symplicity Spyral (Medtronic) catheter and corresponding radio-frequency generator. Arterial access catheter was inserted after puncturing the common femoral artery using modified Seldinger technique. After the cannulation of the artery, 5000 heparin units were administered to manage anticoagulation. A guiding catheter was then advanced over 0.035-inch wire to cannulate renal artery and an angiography of the renal arteries was performed with manual contrast-media injection. An RDN catheter was then positioned distally in the renal artery. Radiofrequency ablation was initiated if the contact with the arterial wall was proper: a flat impedance curve was displayed on the generator. Then catheter was pulled back proximally towards the aorta and rotated about 90 degrees and radiofrequency ablation was repeated. The number of radiofrequency ablations depended on the vascular anatomy. The complete procedure was then repeated with the other renal artery. If angiography showed accessory renal arteries of >3 mm in diameter, the radiofrequency ablation procedure was repeated in these arteries following the same methodology. After the procedure, all patients received Aspirin or Clopidogrel for at least 1 month.The parameters of arterial stiffness and wave reflection were estimated by applanation tonometry . A high-fidelity micromanometer  was placed on the skin surface to consequently obtain high quality radial, carotid, and femoral waveforms synchronized with ECG R-wave. The distance between the arterial sites was measured manually using a tape measure. Carotid-femoral pulse wave velocity, hereinafter referred to as aortic PWV (AoPWV), was calculated automatically as the distance divided by time (meters per second) and multiplied by 0.8 according to European expert consensus . The aorArterial stiffness and central haemodynamics were measured before the procedure, the next day after the procedure (between 24 and 48 hours), and subsequently 1, 3, 6, and 12 months after the procedure. In addition, office and 24-hour ambulatory blood pressure measurements were performed at 1, 3, 6, and 12 months after the procedure. During each visit, compliance with medical treatment was checked using patient's prescription passport. Our aim was to maintain stable medical treatment during the entire study period. At the time of examination, all patients had a stable cardiac status; there were no significant changes in medications from baseline up to 12 months. p value was <0.05.All analyses were performed using SPSS 20.0. Data were presented as mean ± SD or as proportions. The paired t-test  or Wilcoxon signed-rank test  was used to compare values between time points. The Pearson correlation or Spearman's correlation was used to identify correlations between PWV and MAP changes during follow-up. To identify whether the initial AoPWV value had influence on an AoPWV value after 6 months, the initial AoPWV was divided into the first, second, third, and fourth quartile. Then ANOVA was used to determine whether AoPWV change differs significantly between the quartiles. The results were considered significant whenThe study included 73 patients with resistant arterial hypertension who underwent bilateral RDN. There were 39 female and 34 male patients with mean age of 56.02 ± 7.7 (37-72) years. Obesity was prevalent in the group with an average body mass index of 34.29 ± 5.6. Left ventricular hypertrophy was a frequent finding  as well as family history of hypertension . Prevalence of diabetes was 39.7% (n=29) and prevalence of coronary heart disease was 22.5% (n=16). p=0.568, 5.72 (±1.37), p=0.176. Baseline characteristics of the patients are shown in Average office blood pressure in the study group prior to any interventions was 190/107 (±22/ 13) mmHg, in patients treated with an average of 6.2 (±1.5) antihypertensive drugs at maximal or maximal tolerated doses. There were no significant changes between the numbers of drugs taken 3, 6, and 12 months after the procedure, respectively, 5.65 (±1.37),p<=0.001), aortic pulse pressure from 64±17 to 56±17 mmHg (p<=0.001), and augmentation index HR75 from 27 ± 10 to 23 ± 11% (p=0.001). These measurements remained reduced after 1, 3, 6, and 12 months.Comparing the pre- and postprocedure findings, 24-48 hours after the procedure, there was a significant reduction in aortic mean arterial pressure (MAP) from 128±19 to 116±16 mmHg (p=0.001) and carotid-radial pulse wave velocity from 9.9±1.9 to 9.3±14 m/s (p=0.03). Correlation analysis showed the MAP-independent improvement of AoPWV during 48 hours after RSD (r=0.165), suggesting AoPWV reduction being not limited to the blood pressure response. All recorded data on central haemodynamics and AoPWV changes are shown in Within 48 hours RDN significantly reduced AoPWV from 11.3±2.7 to 10.3±2.6 m/s (p<0.001), 10.3±2.9 (p=0.013), 10±2.6 (p<0.001), and 10.4±2.7 (p=0.013) m/s, as shown in 1 8.4±1, Δ 0.05±1.6 / Q2 10.1±0.4, Δ 1.1±1.4 / Q3 12.2±0.8, Δ 1.8±1.7 / Q4 15.3±1.7, Δ 2.8±2.1, (p=0.002). The quartile analysis for the relationship between the baseline AoPWV values and AoPWV changes at 6 months after the procedure is presented in p=0.45; p=0.33).When analysing the data of the follow-up, we found a significant drop in office blood pressure, seen at month 1, from baseline 190/107 ± 22/13 to 160/95 ± 23/14 mm Hg, which was sustained at months 3, 6, and 12. A significant drop in 24-hour ambulatory blood pressure was observed at month 3 from baseline 163/97 ± 18/14 to 151/89 ± 22/12 mm Hg and was sustained at months 6 and 12. Office and 24-hour ambulatory BP details with regard to other timeframes are presented in The rationale of RDN is that ablation destroys afferent and efferent renal sympathetic nerves. Efferent innervation plays a major role in regulation of renal blood flow, glomerular filtration rate, sodium reabsorption, and subsequent water retention . The modOur positive results on arterial stiffness and central haemodynamics after RDN at months 1, 3, and 6 coincide with those found by Brandt MC et al. . These rIt is also important to mention that the reduction of PWV and central haemodynamics was seen in a study group that consisted of patients with high cardiovascular risk, obesity, and a lot of comorbidities that influenced their PWV to be high at baseline. To add more, our results suggest that patients with high cardiovascular risk might benefit the most; the greater the arterial stiffness before the procedure, the greater the decrease we can expect after RDN. Correlation between baseline AoPWV values and AoPWV reduction by RDN was also observed by Brandt MC et al. .The reduction in AoPWV following RDN observed 24-48 hours after the intervention is new data that shows early cardiovascular benefit from RDN. AoPWV measurements have a great scientific interest, although clinical application is narrow. Our results suggest that it might serve as an early marker of decreased sympathetic innervation. It is known that arterial stiffness is associated with sympathetic innervation. Patients who underwent ipsilateral anaesthesia of the brachial plexus before the surgery for Dupuytren's contracture had a greater decrease in arterial stiffness of the radial artery of the disabled hand, whilst distensibility of the contralateral artery remained unaffected . The samAssessment methods for sympathetic tone modification after renal artery ablation described in previously published studies include renal norepinephrine spillover measurements, microneurography, and peri-procedural high-frequency stimulation. One month after RDN, renal norepinephrine spillover decreased by 47% in a small cohort of the Symplicity HTN-1 trial . Muscle Early and sustained effects on AoPWV observed in our study as early as within 24-48 hours after the procedure for up to 12 months are indicative of an additional RDN effect on reducing arterial stiffness and cardiovascular risk. We also observed a significant blood pressure reduction that sustained for up to 12 months after the procedure.We think that AoPWV could possibly be considered a quality indicator for successfully performed renal artery ablation, with no easily applicable realistic alternatives existing in clinical practice. However, further blinded studies would be needed to confirm the findings.The biggest limitation is the absence of a control group, which consequently makes it not a comparison study, but a cohort study that reports a course of arterial stiffness and central haemodynamics after RDN. Second limitation is unavailability of direct measurement of sympathetic nervous activity by standard methods (microneurography or norepinephrine spillover) because of their complexity and the need for intervention.


How to cite this article: Jain V, Choudhary J, Pandit R. Blood Pressure Target in Acute Brain Injury. Indian J Crit Care Med 2019;23(Suppl 2):S136–S139. Both high and low blood pressure can cause organ dysfunction. Management of blood pressure (BP) is an important part of management of acute brain injury, as this protects the brain from secondary brain injury. Despite recent recommendation regarding blood pressure management, individualized BP and cerebral perfusion pressure (CPP) management remains challenging. This chapter attempts to answer different blood pressure targets in various acute brain injury conditions on the basis of recent evidence.The general formula for cerebral blood flow (CBF) is as follows:CBF = (MAP – ICP) / CVRMAP- Mean arterial pressure, CVR= Cerebral vascular resistanceCPP = MAP – ICP or CVP (whichever is higher) .Since neurons are highly dependent on adequate substrate delivery in order to maintain viability, cerebral blood flow (CBF) is tightly controlled. The brain maintains a constant CBF at approximately 50 mL/100 g/minute despite large changes in BP and CPP. When BP increases, cerebral vessels constrict and CVR increases in order to maintain a constant flow. When BP decreases or ICP increases, the vessels dilate and CVR decreases to keep CBF constant. The cerebral autoregulation is effective in a mean arterial pressure (MAP) range of 50–150 mm Hg in normotensive individuals. The relationship of CBF with systemic arterial pressure remains essentially nonlinear. This is to say the CBF depends on ABP, but does not increase or decrease in proportion to the increase or decrease in ABP. This nonlinear relationship between ABP and CBF is due to several associated factors, like autoregulation of the intracerebral blood vessels, and an intricate relationship between cardiovascular and cerebral vascular systems, ICP, autonomic nervous system and neurohumoral transmitters .When BP falls below the lower limit of autoregulation, CBF becomes completely dependent on CPP and thus, systemic blood pressure. The CBF, in that case, becomes compromised.The three main systems which control CBF are:Cardiovascular system: The CBF depends on the systemic blood pressure which in turn depends on cardiac output as well as systemic vascular resistance. CBF is again related to cardiac output independent of the systemic blood pressure. Although, as already pointed out, the relationship between systemic arterial pressure and CBF remains nonlinear.Intracranial pressure: As the skull is a rigid structure any rise in the pressure in any of the compartments of the brain, like vascular , cerebrospinal fluid  or brain parenchyma , will raise the ICP and can decrease the CPP, which in turn will reduce CBF.Cerebral vascular system: There is a considerable regulation of CVR, mainly at the level of intracerebral arterioles, but also at the level of arteries, veins, and capillaries. This autoregulation allows the brain to maintain satisfactory CBF, over a wide range of ABP. The cerebral autoregulation is mediated by mediators which may be carried by blood  has now become the target.Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial.6 For patients undergoing thrombolytic therapy or endovascular intervention, it is recommended to lower BP to < 185/110 mm Hg at initiation of therapy and to maintain BP, 180/105 mm Hg for first 24 hours after intervention.Higher BP is common after acute ischemic stroke, especially in patients with history of chronic hypertension. ASA/AHA 2018 recommendations do not recommend ideal BP value for AIS patients.7European Stoke Organization recommends to cautiously lower BP when BP is very high (>220/110 mm Hg) or in patients with severe cardiac failure, aortic dissection or hypertensive encephalopathy. Abrupt BP lowering should be avoided as per guidelines .INVEST5 - shows that keeping SBP < 140 mm Hg significantly reduced hematoma progression compared to keeping BP <180 mm Hg. However, there was no difference in mortality or in stroke recurrence.9INTERACT II10 results showed that larger SBP reductions in the acute phase of ICH are associated with the lower risk of a poor outcome, defined by the combination of death or disability.Whereas in 7Given these findings both ASA/AHA guidelines as well as European guidelines recommend that acute lowering of SBP to 140 mm Hg, when SBP is between 150 mm Hg and 220 mm Hg at presentation in ICH patients.11ATACH 2 trial which was released recently compared aggressive BP control (SBP 110–139 mm Hg) vs standard care (SBP 140–179 mm Hg). Trial was terminated early for futility, there were no significant difference in outcome between 2 groups and in aggressive group incidence of renal adverse events were higher.Our pragmatic approach in ICH patients is to aim to control SBP at 140–160 mm Hg within 6 hours, using intravenous anti-hypertensives avoiding to rapid or to extreme BP reduction.9 Additionally, hypotension has been shown to correlate with diffuse brain swelling.10 If autoregulation is not intact, there is dependency on SBP to prevent cerebral ischemia which is the single most important secondary insult.12Systolic blood pressure plays a very important role in contributing secondary injury cascade after severe traumatic brain injury. As early as 1989, Klauber et al. reported a mortality of 35% in patient admitted with SBP <85 mm Hg, compared with only 6% in patients with a higher SBP.13The 4th edition of BRAIN TRAUMA FOUNDATION recommends maintaining SBP >100 mm Hg for age 50–69 years (>110 mm Hg for age 15–49 years) is considered to decrease mortality and improve outcome. Though majority of guidelines target systolic BP, targeting cerebral perfusion pressure (CPP) is more physiological. Brain Trauma Foundation guidelines recommend routine CPP monitoring in severe TBI patients, which is said to decrease 2 weeks mortality. CPP target for survival and favourable outcome is between 60 mm Hg and 70 mm Hg.During initial phase of traumatic brain injury, till bleeding is not controlled one should aim for SBP target of >90 mm Hg. During hyperemic phase there is “luxury perfusion” because of increased cerebral blood flow due to vessel dilatation. During this phase one must target for CPP of around 60 mm Hg. Also, during late phase of TBI, there may be vasospastic phase, so you should be targeting slightly higher perfusion pressures by targeting higher SBP and MAP.14Elevated BP is risk factor for rebleed in unsecured aneurysm. So, BP should be maintained less than 160 mm Hg as per ASA/AHA guidelines before aneurysm is clipped or coiled.Once aneurysm is secured secure induction of hypertension may be recommended for patients with delayed cerebral ischemia (DCI).14Our pragmatic approach is to maintain SBP <160 mm Hg till aneurysm is secured and then monitor for DCI. If patient at high risk of vasospasm or DCI then aim should be to maintain MAP >90 mm Hg or CPP >70 mm Hg.18 Time is important factor to consider along with blood pressure targets. Early control of blood pressure in first few hours of stroke onset is important avenue which needs to look into.In recent metanalysis, lowering BP in 15,432 patients did not change outcome in terms of stroke type, drug class or BP target used. However, there was tread toward less death or dependency and improved outcome, in patients who received treatment in first 6 hours after symptoms onset . Larger BP changes seen in patients who were recruited early while small BP change seen in who were enrolled after 48 hours of onset. Subgroup analysis of ENOS (patients randomised to receive GTN within 6 hours) also showed reduced death or dependency and improved cognition and quality of life.Despite various trials, there are no definitive recommendation regarding BP management targets in acute brain injury. BP management remains mainstay of treatment in acute brain injury patients. In early phase BP lowering may help in reducing hematoma progression and hemorrhagic transformation. In contrast BP management to avoid hypotension may be necessary to avoid secondary cerebral injuries. Various blood pressure targets along with timing of intervention and effect of different drugs is an important factor which needs to investigated to find out its effect of outcome.


Childhood hypertension is associated with higher risks of cardiovascular disease during adulthood. This study estimated the prevalence of hypertension and high blood pressure among children aged 8 to 17 years in the United States per the 2017 American Academy of Pediatrics (AAP) guideline and compared that with the 2004 National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) guideline’s prevalence estimate during 2005–2008 and 2013–2016.This cross-sectional study analyzed the National Health and Nutrition Examination Survey data. High blood pressure included hypertension and elevated blood pressure (per the 2017 AAP guideline)/prehypertension (per the 2004 NIH/NHLBI guideline).The analysis included 3,633 children in 2005–2008 and 3,471 children in 2013–2016. Per the 2004 NIH/NHLBI guideline, 3.1%  had hypertension in 2005–2008 and 1.9%  had hypertension in 2013–2016. Per the 2017 AAP guideline, prevalence was 5.7%  in 2005–2008 and 3.5%  in 2013–2016. About 2.5%  children in 2005–2008 and 1.5%  children in 2013–2016 were reclassified as hypertensive. We observed a similar change in prevalence for high blood pressure after application of the new guideline. The prevalence of high blood pressure also declined from 2005–2008 to 2013–2016 per both guidelines.Although the new guideline would reclassify a small proportion of children as having hypertension or high blood pressure, the prevalence declined from 2005–2008 to 2013–2016. Changing the systolic/diastolic blood pressure cutoffs to define high blood pressure and hypertension in the 2017 American Academy of Pediatrics guideline could reclassify blood pressure levels as high blood pressure or hypertension. About 2.5% children in 2005–2008 and 1.5% in 2013–2016 were reclassified as hypertensive; a similar proportion would be reclassified as having high blood pressure. The overall prevalence of both blood pressure levels declined from 2005–2008 to 2013–2016. Increasing awareness is important to minimize burden and future complications of childhood hypertension. Hypertension is the most common risk factor for cardiovascular disease among adults ,2. AlthoOn the basis of the 2017 AAP guideline, a larger proportion of children and adolescents than previously could be classified as having hypertension . An analThe prevalence of hypertension or high blood pressure could vary according to age, sex, and other sociodemographic characteristics among children and adults ,11,13. IWe used NHANES data collected during 2 periods: 2005–2008 and 2013–2016. NHANES is a biennial cross-sectional survey conducted since 1999 . The surNHANES measures blood pressure among participants 8 years or older. We limited our analysis to children aged 8 to 17 to conform to CDC’s HP 2020 objectives . FurtherThe 2004 NIH/NHLBI guideline defined prehypertension as a blood pressure from the 90th percentile to <95th percentile or if blood pressures were >120/80 mm Hg up to the 95th percentile. This guideline categorized stage 1 hypertension as the 95th to 99th percentile plus 5 mm Hg for systolic blood pressure/diastolic blood pressure and stage 2 hypertension as the >99th percentile plus 5 mm Hg . According to the 2017 AAP guideline, for children younger than 13, the cutoffs for elevated blood pressure were the 90th to <95th percentile or 120/80 mm Hg to <95th percentile (whichever was lower) . In the For children aged 13 or older, systolic blood pressure/diastolic blood pressure cutoff for elevated blood pressure was 120–130/<80 mm Hg, whereas the systolic blood pressure/diastolic blood pressure cutoff was 130-139/80-89 mm Hg for stage 1 hypertension and ≥140/90 mm Hg for stage 2 hypertension in the 2017 AAP guideline . Hypertension included stage 1 and stage 2 hypertension, whereas high blood pressure included both hypertension and elevated blood pressure (per the 2017 AAP guideline)/prehypertension (per the 2004 NIH/NHLBI guideline) ,8,11. A We grouped age into 2 categories: children aged 8 to 12 years and children aged 13 to 17 years. Participants reported their sex . We used the following racial/ethnic categories: Mexican American, other Hispanic, non-Hispanic white, non-Hispanic black, and other. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. We used CDC’s age- and sex-specific BMI categories . We cateWe first tabulated data on sociodemographic and weight-related characteristics  of the unweighted number of study participants. After using the Shapiro–Wilk test and determining that the data were not normally distributed, we described continuous variables as median and interquartile range (IQR). We tabulated categorical variables as number and percentage. We then compared the prevalence of blood pressure according to each guideline among both boys and girls in both survey periods. We also calculated the proportion of participants who would require further evaluation because of higher blood pressure levels per the 2017 AAP guideline in 2013–2016. In addition, we compared the prevalence estimate calculated for each guideline during both survey periods according to demographic and health-related characteristics. For all prevalence estimates, we adjusted for the multistage cluster-sampling design of the survey. We calculated all prevalence estimates and differences with 95% confidence intervals (CIs). All analyses were conducted by using Stata version 14.0 (StataCorp LLC).Our analysis included 7,104 children with blood pressure measurements data: 3,633 from NHANES 2005–2008 and 3,471 from NHANES 2013–2016 . For datAlthough the proportion of boys and girls was similar overall among participants in both survey periods, the proportion of boys was higher among children with hypertension in all groups with hypertension except hypertensive children per the 2004 NIH/NHLBI guideline in 2005–2008 . In 2005The prevalence of high blood pressure and hypertension was slightly higher per the 2017 AAP guideline than per the 2004 NIH/NHLBI guideline in both survey periods among both sexes . The preThe prevalence of both high blood pressure and hypertension decreased from 2005–2008 to 2013–2016 for most characteristics per both guidelines . By charThe prevalence of hypertension was similar across most characteristics per the 2004 NIH/NHLBI guideline in 2005–2008 . The prePer the 2017 AAP guideline, 18.9%  of children could require further evaluation . The proWe investigated the prevalence and trends of hypertension and high blood pressure among the US pediatric population in 2 survey periods with 2 blood pressure guidelines. After comparing the prevalence of the 2017 AAP guideline with the prevalence of 2004 NIH/NHLBI guideline, we found a small proportion of children would be reclassified as having high blood pressure or hypertension among both sexes and across a range of characteristics. About 1 in 5 children would also require additional evaluation because of high blood pressure during the NHANES examination. Furthermore, the prevalence of high blood pressure was lower in the second survey period than in the first survey period.Despite a slightly different age group and different survey periods, the prevalence of hypertension and high blood pressure in our study is similar to the prevalence observed by earlier studies that investigated the prevalence of these conditions among children and adolescents in the United States ,12,20,23According to both guidelines, all children with higher-than-normal blood pressure levels would require further evaluation as well as early intervention ,8. HyperAlthough the prevalence of hypertension per the 2004 NIH/NHLBI guideline (1.9%) was lower than the HP 2020 target of 3.2% in 2013–2016, the 2017 AAP prevalence estimate was higher (3.5%) . PopulatOur study has several notable strengths. First, our prevalence estimates and trends were derived from 4 large nationally representative samples. NHANES used a standardized validated method to report blood pressure levels. We also reported prevalence estimates according to several characteristics.Our study also has several limitations. The true population prevalence of hypertension could be lower than reported in our study because blood pressure was measured on a single day rather than during multiple visits. Some misclassification could also have resulted from “white-coat” hypertension . The smaThis study examined the prevalence of hypertension and high blood pressure among children and adolescents. Although the prevalence was lower in 2013–2016 than in 2005–2008, and the new guideline could reclassify a small proportion of the pediatric population as having hypertension, a significant proportion of children would require further evaluation. Considering the negative consequences of hypertension, it is important to raise awareness among physicians and caregivers about childhood hypertension.


In addition, we observed greater decreases in CBF velocity both at the nadir after standing  and during steady state standing . In contrast, cerebrovascular reactivity was not different between groups. In our sample of Veterans with GWI, dynamic autoregulation was impaired and consistent with greater cerebral hypoperfusion when standing. This reduced CBF may contribute to cognitive difficulties in these Veterans when upright.Neurological dysfunction has been reported in Gulf War Illness (GWI), including abnormal cerebral blood flow (CBF) responses to physostigmine challenge. However, it is unclear whether the CBF response to normal physiological challenges and regulation is similarly dysfunctional. The goal of the present study was to evaluate the CBF velocity response to orthostatic stress  and increased fractional concentration of carbon dioxide. 23 cases of GWI (GWI+) and 9 controls (GWI) volunteered for this study. Primary variables of interest included an index of dynamic autoregulation and cerebrovascular reactivity. Dynamic autoregulation was significantly lower in GWI+ than GWI- both for autoregulatory index (2.99±1.5 vs 4.50±1.5,  More than 25 years after Operations Desert Storm and Shield (Gulf War), deployed Gulf War Veterans continue to report substantially poorer health relative to non-deployed Veterans of the same era, including a higher prevalence of chronic illnesses . ApproxiNeurological dysfunction in the form of cognitive impairment is one of the hallmark symptoms of GWI, and problems with memory , executiHaley and colleagues have studied CBF in Veterans with GWI using both single photon emission computed tomography , as well2) to determine the role of the endothelium and smooth muscle on CBF in Veterans with GWI. The response of CBF to blood pressure changes is accomplished predominately through a myogenic response  of the arterioles in the cerebral vasculature, whereas the CBF response to changes in CO2 occurs through both endothelial and smooth muscle signals [2), we can better understand the disruptions in CBF at the neurovascular unit. We hypothesized that Veterans with GWI would demonstrate impaired CBF in comparison to Veterans without GWI, and that this impairment would be greatest during the CO2 challenge given the contributions of both smooth muscle and endothelium.The objective of the present study was to examine the cerebrovascular response to changes in arterial blood pressure and inspired carbon dioxide  and 9 controls (GWI-). Case status was assigned using the Kansas criteria,  which in2) via capnography (Puritan-Bennett), and 4) heart rate via 3-lead electrocardiogram. Signals were sampled at 1000 Hz and digitized . Offline analyses were performed using custom-written software .Participants arrived at the laboratory for a single testing session having abstained from caffeine and ≥ 2 hours post-prandial. Participants were instrumented to obtain: 1) cerebral blood flow velocity (CBFV) of the middle cerebral artery via transcranial Doppler , 2) beat-to-beat blood pressure (MAP) via finger photoplethysmography , 3) end-tidal carbon dioxide  were calculated while seated (50 s epoch) and standing . The average of 3 maneuvers was used for analysis and the difference between seated and standing values (Δ scores) was also computed. An autoregulatory index (ARI) was computed for each sit-to-stand maneuver using a predicted curve fit model [Following a rest period (≥ 5 min), all participants performed an orthostatic challenge test designed to induce a rapid change in blood pressure as previously described . Mean vait model , and theit model . For thiit model . Two parit model .2, 21% O2, balance nitrogen (hypercapnia), and during mild hyperventilation (hypocapnia) [2 was computed via linear regression for the entire period, and during periods of hyper- and hypocapnia.Cerebrovascular reactivity was assessed while participants breathed at rest (normocapnia), while inspiring 8% COocapnia) , 27. Twoocapnia) , as wellocapnia) , 29. ChaTime- and frequency domain measures were determined as recommended by the task force report  in the l2 (mmHg), and CBFV (cm/s and %) were calculated for GWI+ and GWI- at rest and during orthostatic, hypo- and hyper-capnic challenges. Means (SD) were also calculated for transfer function assessment of cerebral autoregulation, heart rate and blood pressure variability, and baroreflex estimates. Data from all outcome measures were split by group and checked for normality (Kolmogorov-Smirnov test). Between-group comparisons were conducted with a series of independent samples t-tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data (α = 0.05). Equality of variances between groups was checked prior to the analyses. Hedges’ g (g) effect sizes were calculated for independent-samples t-tests and point-biserial r (rpb) was calculated for Mann-Whitney U tests. Effects sizes of 0.8 [g and rpb, respectively. Pearson correlation coefficients were calculated to determine associations between CO2 reactivity and autoregulation. Spearman’s rho correlations were calculated to determine associations between changes in CBFV and transfer function gains.Group means and standard deviations (SD) for arterial blood pressure (mmHg), end-tidal COs of 0.8  and 0.37s of 0.8  were conp = 0.040; however, all other measures were similar between groups. Summary scores for each domain of the Kansas screening questionnaire are also reported for descriptive purposes.Demographics and medication use are reported in p = 0.014), although only ~3 mmHg which was likely not physiologically significant. Similarly, CBFV was lower in the GWI+ group (p = 0.042).Group-averaged responses to the sit-to-stand maneuver are illustrated in Estimated ARI was significantly lower in GWI+ than GWI- ; Fig 2. 2 reactivity was also similar when assessed separately for hyper- and hypocapnic stimulus as well as in combination  may contribute to these results.This is the first study to assess dynamic cerebral autoregulation in Veterans with GWI, which we found was significantly impaired relative to Veterans without GWI  and 3, aPrior studies have assessed the response to orthostatic stress in GWI using tilt-table testing with , 38 and Further support for impaired dynamic cerebral autoregulation in this group is derived from the transfer function analysis of steady state sitting values. Veterans with GWI had higher transfer function gains in both the low and high frequency bands, suggesting they were less effective at minimizing the impacts of changes in blood pressure on CBF . Similar2 [2 reactivity relative to controls, suggesting a decreased capacity to dilate the cerebral vessels. However, we observed similar CO2 reactivity between-groups. This suggests that factors other than CO2 reactivity contribute to the autoregulatory response, most notably cholinergic activation of the cerebral vasculature [To assess the vasodilatory capacity of the cerebral vasculature, we examined changes in CBF velocity of the middle cerebral artery in response to changes in end-tidal CO2 . We hypoculature . In suppculature . An acticulature , and thiculature , 14 whicculature .To measure autonomic function in this group, we examined heart rate and blood pressure variability. We found no evidence of differences in indicators of cardiac parasympathetic control unlike previous works that have demonstrated reduction in high frequency HRV –47. ThisAnother novel finding in this work is the effect of GWI on baroreflex sensitivity. To our surprise we found that baroreflex sensitivity assessed by transfer function was significantly greater in Veterans with GWI. Despite having improved baroreflex, steady state standing blood pressure was significantly lower, although only slightly (~3 mmHg), in the veterans with GWI despite improved baroreflex sensitivity. The reason for this remains unclear and further work on central cardiac function and total peripheral resistance changes when upright is necessary. It is also unclear why baroreflex would be improved in veterans with GWI. One theoretical possibility is that to help maintain CBF when cerebral autoregulation is impaired, tighter regulation of blood pressure is necessary to ensure adequate perfusion of the brain. Several previous studies have found an inverse relationship between baroreflex and cerebral autoregulation in healthy young individuals –50. Base2 [As impairments in dynamic autoregulation were observed upon standing, our findings may also suggest a role for vestibular input to the cerebrovasculature. In support of this possibility, Haley and colleagues  found th2 . Prior s2 , that is2 , and obj2 . Moreove2  and dizz2 , 58, repAn important aspect of this work is that measures of CBF were performed upright. Our recent work demonstrating that cholinergic enhancement was only effective in improving CBF in healthy subjects when upright highlights the importance of orthostatic stress in considering CBF response . FurtherNotwithstanding the limitations of a cross-sectional study, there are other factors that may impact the interpretation of our findings. GWI is a heterogeneous disorder; therefore, our relatively small sample size, poor representation of female veterans, and unequal group sizes are limitations. Human subject research in GWI is challenging as common conditions of advanced age are exclusions for GWI case status. Despite this, we observed a large effect size for a primary variable of interest, ARI. However, we were likely sufficiently underpowered to detect a meaningful change in certain secondary variables. Another possible consideration for differences between groups is due to physical activity. GWI is a fatiguing illness that makes most unable to exercise and thus results in the veterans becoming extremely sedentary. Thus, impaired autoregulation in the veterans with GWI could be the result of deconditioning. While we did not have measures of physical activity or fitness in the two groups previous work examining fit vs sedentary elderly found no difference in cerebral autoregulation .In summary, Veterans with GWI demonstrate dysregulation of CBF during transition from a seated to standing position and when standing. Reasons for the disrupted regulation of CBF are likely multifactorial and may be manifested by disturbances in other physiological systems  and bioenergetics . Future studies are needed to expand on this work, including association of impaired cerebral blood regulation when upright and impaired cognitive function as well as in relation to symptoms at rest and during symptom exacerbation .S1 TableA Effect sizes are reported as Hedges’ g for independent samples t-tests and point-biserial correlations for Mann-Whitney U tests; B Data analyzed with independent samples t-test; C Data analyzed with Mann-Whitney U test.Comparison of measures of heart rate and blood pressure variability among Veterans who screened positive for Gulf War Illness (n = 23) and healthy controls (n = 9) during a 2–3 min steady state period while seated. For time domain measures, mean values of RR Interval (Mean RR) as well as standard deviation (SDNN) and root mean square of successive differences between RR intervals (rMSSD) were obtained. Heart rate variability was derived using the Power Spectrum (Welch) and Power Spectrum (Lomb-Scargle) periodgrams in the low frequency (LF: 0.04–0.15 Hz) and the high frequency (HF: 0.14–0.4 Hz) bands. Values were calculated for power in absolute units as well as % of total power. Ratios of low frequency to high frequency power (LF/HF) was derived. Variability of systolic blood pressure (SBP) was also calculated in the LF and HF bands. (DOCX)Click here for additional data file.S2 TableA Effect sizes are reported as Hedges’ g for independent samples t-tests and point-biserial correlations for Mann-Whitney U tests; B Data analyzed with independent samples t-test; C Data analyzed with Mann-Whitney U test.Comparison of measures of baroreflex sensitivity (BRS) among Veterans who screened positive for Gulf War Illness (n = 23) and healthy controls (n = 9) during a 2–3 min steady state period while seated. Transfer function estimates of gain, coherence and phase were obtained in the low frequency (LF: 0.04–0.15 Hz) and the high frequency (HF: 0.14–0.4 Hz) bands. Spontaneous baroreflex was also estimated from 3 beat segments of systolic blood pressure and RR interval to obtain a mean slope as well as the number of mismatched segments. (DOCX)Click here for additional data file.S1 FigUpper left corner displays low frequency heart rate variability (LF HRV) in the low frequency band (0.04–0.15 Hz) band for Veterans with GWI (GWI+) and controls (GWI-). Lower two panels represent baroreflex sensitivity (BRS) gain derived from transfer function estimates in the low frequency (0.04–0.15 Hz), left panel, and high frequency (0.15–0.4 Hz), right panel, bands. Filled dots are individual values of Veterans with GWI, while open dots are controls. Solid lines represent mean values. *, significant difference between GWI+ and GWI- in that frequency band, p<0.05).(DOCX)Click here for additional data file.


A variety of techniques based on the indirect measurement of blood pressure (BP) by Pulse Transit Time (PTT) have been explored over the past few years. Such an approach has the potential in providing continuous and non-invasive beat to beat blood pressure without the use of a cuff. Pulse Arrival Time (PAT) which includes the cardiac pre-ejection period has been proposed as a surrogate of PTT, however, the balance between its questioned accuracy and measurement simplicity has yet to be established. The present work assessed the degree of linear relationship between PAT and blood pressure on 96 h of continuous electrocardiography and invasive radial blood pressure waveforms in a group of 11 young ICU patients. Participants were selected according to strict exclusion criteria including no use of vasoactive medications and presence of clinical conditions associated with cardiovascular diseases. The average range of variation for diastolic BP was 60 to 79 mmHg while systolic BP varied between 123 and 158 mmHg in the study database. The overall Pearson correlation coefficient for systolic and diastolic blood pressure was −0.5 and −0.42, respectively, while the mean absolute error was 3.9 and 7.6 mmHg. It was concluded that the utilization of PAT for the continuous non-invasive blood pressure estimation is rather limited according to the experimental setup, nonetheless the correlation coefficient performed better when the range of variation of blood pressure was high over periods of 30 min suggesting that PAT has the potential to be used as indicator of changes relating to hypertensive or hypotensive episodes. Arterial blood pressure is one of the four primary vital signs used as an indicator of the health status of the circulatory system that is commonly measured in clinical and ambulatory scenarios. The condition when blood pressure increases persistently above normal values  is called hypertension, a long term medical condition that is associated with coronary artery disease, stroke, heart failure and chronic kidney disease among others  have been proposed as a possible approach in meeting this gap and this is mainly due to the ability of the technique to perform beat to beat measurements non-invasively without the use of a cuff  compared to PTT (R2 = 0.45). Both studies agreed about the influence of PEP as a confounding factor. In the contrary, other studies have elucidated the potential of PAT as a marker of blood pressure. Masè et al.  as a reference and the potential to assess its relationship with PAT over long periods of time under controlled settings. It has been reported that the relationship between these variables deteriorates over time, and periodic recalibration of the parameters of the regression model is needed  from the medical ICU of the Hospital Universitario de San Vicente Fundacion in Colombia were recruited over a period of 6 months for a total of 96 h of recordings of their physiological waveforms. Candidates for the study were selected according to strict exclusion criteria that comprised assisted mechanical ventilation, vasopressors, and vasodilators use prior or during the acquisition time, scheduled surgical procedure within the next 24 h and clinical history with previous cardiovascular diseases in their lifetime. Permission for data acquisition was granted by the Ethics committee of Universidad EIA and Hospital Universitario de San Vicente Fundacion.® to communicate the bedside monitor with a laptop computer over the standard UDP/IP protocol. Acquisition started immediately after the patient was included in the study and stopped only if any of the exclusions criteria were violated during the recording time  or the patient was discharged from the ICU. The invasive arterial blood pressure (ABP) waveform at the radial artery of either arm was obtained at 125 Hz while the Electrocardiography (ECG) lead II featured a 500 Hz sampling rate.Physiological waveforms from the patients were acquired using the Philips MP40 IntelliVue monitors available at each ICU bed. Through a communication interface protocol, data from the Philips monitor can be transferred via the Local Area Network (LAN) or Medical Information Bus (MIB/RS232) Interfaces to an external computer Philips, . The LANFigure ® using a signal quality index based on beat template correlation proposed by Li and Clifford  and Mean Absolute Error (MAE) were calculated for each subject independently to elucidate the overall relationship between BP and PAT in the entire recording time. The ratio between MAE and the variation range of blood pressure was estimated and compared for all subjects. The Mean Absolute Error (MAE) was computed according to equation 1. A second analysis was performed to evaluate how the correlation coefficient changes over time in order to assess the dynamic variation of the relationship between these variables. For this purpose, the CC between PAT and BP was estimated on windows of 30 min with no overlap and the overall results for all subjects are presented. Both analyses were done for systolic and diastolic blood pressure independently and their standard deviations were observed and compared with the corresponding correlation coefficient.PO is the observed pressure  and n the total number of observations in the subject's recording. PE is the estimated Pressure using PAT. The linear regression parameters to compute PE were obtained using all the BP measurements available per subject.Equation 1. Mean Absolute Error (MAE) computation. Of the initial 96 h of recordings from all subjects, 23 were excluded from the analysis because both ECG and ABP were not present simultaneously or the waveforms in certain sections did not meet the signal quality threshold, so a total of 73 h of data were analyzed containing 333,007 beats. Table The second part of the analyses assessed how the Pearson correlation coefficient between PAT and BP varied over time in windows of 30 min for each subject. An example of the systolic-PAT variation for 9 h of recording in subject #1 with the corresponding correlation coefficient at each window is shown in Figure The overall relationship between the standard deviations of PAT and BP with the correlation coefficient in windows of 30 min for all subjects is summarized in Figure The present study analyzed the degree of linear relationship between systolic/diastolic blood pressure and pulse arrival time in a total of 96 h of ICU waveforms from 11 subjects. The choice of strict exclusion criteria was justified in order to obtain a subset of patients exhibiting slightly different characteristics than the average ICU patient that allowed exploring the relationship of the variables in a different fashion. Specifically, the age was restricted from 18 to 50 years since usually the majority of these patients are elderly which is associated with increased arterial stiffness . Pulse arrival time calculated from the ECG to the onset of this signal resulted in values around 400 to 500 ms, which do not match with the expected range reported in previous studies  or alignment issues when estimating PAT (incorrect matching of R-peak to PPG onset) tend always to blur the correlation instead of improving it. The choice of well-known algorithms for calculating the points of interest on each waveform and the use of signal quality indexes are considered an important asset of the present study. As described in the methodology, the raw PAT and BP vectors were filtered using a median moving average filter with a window of 30 s overlapped every 7.5 s. This filter has the advantage of suppressing remaining outliers in the data while providing an even resampled vector that does not depend on the subject's specific heart rate. The selection of such average filter is also in accordance with common monitoring practices considering that vital signs monitors usually display blood pressure estimates as averaged values over short periods of time.The results show that the correlation between pulse arrival time and blood pressure is within a moderate to low range in general. Systolic BP performed better than diastolic BP in terms of the Pearson correlation coefficient (−0.52 vs. −0.42). Although the experimental setup is not identical, our results are in agreement with previous studies that have observed a similar trend using invasive arterial waveforms for the analysis  it would imply that a system measuring BP by PAT is classified grade A only if during validation the BP does not change on a range >29 mmHg (5/0.17). This is in fact a narrow range for normal physiological conditions exposing the weaknesses of the technique.The temporal change of the Pearson correlation coefficient was also assessed in the present work. The motivation relies in previous studies that have showed how the relationship degrades over time and periodic recalibration techniques have to be implemented to maintain the accuracy within acceptable limits (Cattivelli and Garudadri, Another limitation of the analysis presented in the current work is the imbalanced number of cases over the BP range of variation since more cases are found in the lower range. A future study in a larger database like MIMIC would allow an even analysis by providing cases over a balanced range of BPs.The present study demonstrates that the degree of linear relationship between blood pressure and pulse arrival time measured from the ECG to the invasive arterial waveform in a small cohort of ICU patients is within a moderate to low range, hence the ability of PAT for continuous non-invasive blood pressure estimation is questioned. Despite this, it was observed that PAT correlates better with BP when the later exhibits wide variations in short periods, so PAT might have some potential as an indicator of wide trend changes like in hypertensive or hypotensive episodes occurring in this type of patients.BE-R, RT-V, and PK contributed conception and design of the study. BE-R acquired and organized the database. BE-R performed the statistical analysis. BE-R wrote the first draft of the manuscript and prepared tables and figures. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Decreased perfusion in the lower extremities is one of the several adverse effects of placing patients in a lithotomy or Trendelenburg position during surgery. This study aimed to evaluate the effects of patient positioning in lower limb perfusion patients undergoing robotic-assisted laparoscopic radical prostatectomy (RARP) using near-infrared spectroscopy (NIRS).2) was sampled during the following time points: before and 5 min after induction of anaesthesia ; 5 min after establishment of pneumoperitoneum in a 0° lithotomy position (T2); 5 min after a 25° Trendelenburg position (T3); 30, 60, 90 and 120 min after pneumoperitoneum in a Trendelenburg position ; after desufflation in a supine position (T8); and after tracheal extubation (T9).This observation study comprised 30 consenting males with American Society of Anaesthesiologists physical status classes I and II . Regional saturation of oxygen measurements was obtained using an INVOS™ oximeter . A NIRS sensor was positioned on the surface of the skin at the mid-diaphyseal region of the calf muscles (the gastrocnemius and soleus), over the posterior compartment, in the right lower leg. Regional saturation of oxygen  .Lower limb perfusion evaluated by NIRS was maintained during the RARP procedure. Correct patient positioning and careful assessment of risk factors such as vascular morbidity could be important for the prevention of LLCS during RARP. Robotic-assisted laparoscopic radical prostatectomy (RARP) is one of the most commonly performed robotic-assisted surgical procedures worldwide. In RARP, the patient is placed in the lithotomy position and pneumoperitoneum is established, following which the patient is placed in the steep Trendelenburg position. The combination of lithotomy position, pneumoperitoneum, and steep Trendelenburg positioning may cause significant and potentially adverse cardiovascular, respiratory and neuro-physiological changes in the body . The com2) in the lower limbs using NIRS.Lower limb compartment syndrome (LLCS) is a rare but serious complication of surgery in the lithotomy position, with an estimated incidence of one in 3500 cases . Tissue 2) were excluded from the study. Approval for the study was obtained from the institutional review board (registration number 1308010), and informed consent was obtained from the patients. The study was registered with the UMIN Clinical Trials Registry (000032897).Thirty adult males  scheduled for RARP at the Ehime University Hospital, Toon, Ehime, Japan, from September 2013 to May 2014 were consecutively selected. Patients with previous episodes of peripheral vascular disease and those who were morbidly obese (body mass index > 35 kg/m2) was conducted on arrival at the operating room. Anaesthesia was induced with propofol (1.5–2 mg/kg), remifentanil (0.15–0.3 μg/kg/min) and rocuronium bromide (0.8 mg/kg) and maintained using desflurane (4–6%), remifentanil (0.15–0.3 μg/kg/min) and rocuronium bromide (5–7 μg/kg/min). The ventilator settings were as follows: tidal volume, 8–10 mL/kg body weight; inspiratory:expiratory ratio, 1:2 or 1:1.5; inspired O2 fraction, 0.6 with air; and inspiratory fresh gas flow, 2 L/min. The respiratory rate was adjusted to 8–16 /min in order to maintain an end-tidal CO2 (ETCO2) pressure of 30–45 mmHg. After induction of anaesthesia, a 22-G radial artery catheter was inserted for blood sampling and to monitor the continuous arterial pressure and the minimally invasive cardiac output using FloTrac™ . The mean arterial pressure (MAP) was maintained above 60 mmHg.A standard anaesthetic technique was used, wherein routine monitoring of non-invasive arterial blood pressure, electrocardiogram (ECG) and oxygen saturation , over the posterior compartment of the right lower leg. For cerebral oximetry, NIRS sensors were placed unilaterally at least 2 cm above the eyebrow on the right side of the forehead according to manufacturer’s instructions. Both sensors were placed before the induction of anaesthesia during pre-oxygenation with 100% O2. A change of more than 8 percentage points in lower limb rSO2 was defined as clinically relevant [A continuous dual-wavelength near-infrared spectrometer, INVOS™ oximeter , was used to determine the rSOrelevant .For the lithotomy position, devices for vacuum-packed positioning and spreading the legs apart were used to absorb compressive forces, prevent uneven and potentially excessive pressure distribution and prevent excessive stretching or compression. After positioning, the compressive forces were measured using a portable pressure measuring device . The positions were then adjusted and maintained in such a manner that the pressure values in the shoulder, hip and calf were below 30 mmHg.2 gas at a pressure of 12 mmHg, following which the patients were placed in a 25° Trendelenburg position during surgery. The procedure was performed by a surgeon on a control table located away from the operating table, using the da Vinci robot surgical system .The abdominal cavity was insufflated with CO2 were recorded before the induction of anaesthesia. ETCO2, cardiac index and stroke volume variations were monitored after ventilation was controlled. The recorded values were sampled at the following time points: before induction of anaesthesia (T0); 5 min after induction of anaesthesia (T1); 5 min after establishing pneumoperitoneum with the patient in a 0° lithotomy position (T2); 5 min after the patient was placed in a 25° Trendelenburg position (T3); 30, 60, 90 and 120 min after establishment of pneumoperitoneum in the Trendelenburg position ; after desufflation in a supine position (T8); and after tracheal extubation (T9). The levels of haemoglobin, arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2) were measured by arterial blood gas analysis at T1, T2, T3 and T7.MAP and rSO2 of the first five patients (7.3) was used. Twenty-six patients with an error of 0.05 and a power of 80% were required to determine the changes in lower limb rSO2 (8 percentage points) in the current study. Assuming a dropout rate of 15%, 30 patients were recruited in this study.To calculate the sample size, the standard deviation of the baseline rSOp values are two sided, and a p value < 0.05 was considered significant.All statistical analyses were performed using IBM SPSS Statistics 23 . Continuous variables are presented as means and standard deviations. Repeated measured variables were analysed using a linear mixed model, with the patient indicator as random effect and time as fixed effects. Post-hoc analysis was performed with Bonferroni correction to adjust for multiple comparisons when the interactions between times were significant. All of the reported The demographics of the study participants are summarised in Table 2 values (p < 0.01) were observed in the lower limb  in the current study  and was treated with ephedrine  to increase the cerebral perfusion pressure.Changes in cerebral rSO2 (D) increased 60 min after establishment of pneumoperitoneum in a Trendelenburg position when compared to 5 min after induction of anaesthesia. Serum laboratory data related to the compartment syndrome  showed no changes when the preoperative values were compared with those on postoperative day one.MAP (A) decreased after induction of anaesthesia and continued to show a decreasing trend throughout the operation Fig. . CardiacIn the present study, lower limb perfusion evaluated by NIRS was found to be increased after induction of anaesthesia and maintained during the steep Trendelenburg position in RARP patients with no risk of LLCS.LLCS is a rare but serious complication of RARP , 8. The There are several mechanisms for intraoperative LLCS. In RARP procedure, the patient’s legs are above the heart level in the lithotomy position and steep Trendelenburg position, and the blood pressure of the lower limb may decrease if these positions are held for prolonged periods. Decreases in blood flow may result in reduced oxygen supply within the compartment and lead to an inflammatory response, release of cytokines, capillary leakage and interstitial oedema. These responses increase the pressure within the compartment, escalating into a self-perpetuating cascade of worsening swelling. Additionally, direct external pressure from the calf support positioning device can also exacerbate the compartmental pressure. When the pressure rises above critical levels, intra-compartmental structures such as nerves, blood vessels and muscles are damaged. Obesity, peripheral vascular disease, prolonged console time and lack of experienced surgeons are increasing the risk of LLCS during RARP .2. However, instead of this negative physiological change, lower limb rSO2 was increased after induction of anaesthesia and maintained during steep Trendelenburg positions in RARP patients. Volatile anaesthetics such as sevoflurane induced marked changes in muscle microcirculation, increase in tissue blood volume, decreased microvascular resistance and compliance, and decreased muscle oxygen consumption [2 is maintained during the RARP procedure. High inspiratory fractions of oxygen also help in increasing lower limb oxygenation. Moreover, hypercapnia is known to be beneficial for peripheral microcirculation [As reported previously, the cardiovascular factors that affect peripheral perfusion pressure, such as cardiac index, heart rate and stroke volume, were shown to decrease significantly after induction of anaesthesia in RARP patients . Additiosumption . This faculation . Lower l2 during RARP is genuinely conducive for reducing the incidence of LLCS. Further studies are required to explore the perfusion pressure, microcirculation and clinical threshold of rSO2 values. Furthermore, different mechanisms of muscle microcirculation have been reported using different anaesthetics [One of the limitations of this study is that it is not known whether maintenance of lower limb rSOsthetics . TherefoIn conclusion, lower limb perfusion evaluated by NIRS was maintained during the RARP procedure, probably by an increase in microcirculation. Hence, correct patient positioning and careful assessment of risk factors, such as vascular morbidity, might be important for the prevention of LLCS during RARP.