The Poincaré plot is a geometrical technique used to visualize and quantify the correlation between two consecutive data points in a time-series. Since the dynamics of fluctuations in physiological rhythms exhibit long-term correlation and memory, this study aimed to extend the Poincaré plot by calculating the correlation between sequential data points in a time-series, rather than between two consecutive points. By incorporating this so-called lag, we hope to integrate a temporal aspect into quantifying the correlation, to depict whether a physiological system holds prolonged association between events separated by time. In doing so, it attempts to instantaneously characterize the intrinsic behavior of a complex system. We tested this hypothesis on three different physiological time-series: heart rate variability in patients with liver cirrhosis, respiratory rhythm in asthma and body temperature fluctuation in patients with cirrhosis, to evaluate the potential application of the extended Poincaré method in clinical practice. When studying the cardiac inter-beat intervals, the extended Poincaré plot revealed a stronger autocorrelation for patients with decompensated liver cirrhosis compared to less severe cases using Pearson’s correlation coefficient. In addition, long-term variability (known as SD2 in the extended Poincaré plot) appeared as an independent prognostic variable. This holds significance by acting as a non-invasive tool to evaluate patients with chronic liver disease and potentially facilitate transplant selection as an adjuvant to traditional criteria. For asthmatics, employing the extended Poincaré plot allowed for a non-invasive tool to differentially diagnose various classifications of respiratory disease. In the respiratory inter-breath interval analysis, the receiver operating characteristic (ROC) curve provided evidence that the extension of the Poincaré plot holds a greater advantage in the classification of asthmatic patients, over the traditional Poincaré plot. Lastly, the analysis of body temperature from patients using the extended Poincaré plot helped identify inpatients from outpatients with cirrhosis. Through these analyses, the extended Poincaré plot provided unique and additional information which could potentially make a difference in clinical practice. Conclusively, the potential use of our work lies in its possible application of predicting mortality for the organ allocation procedure in patients with cirrhosis and non-invasively distinguish between atopic and non-atopic asthma. In the past, it has extensively been used in the analysis of physiological fluctuations  and has enabled researchers to measure short- and long-term variability separately , rather than between two consecutive data points in the traditional plot Heart Rate Variability (HRV) data from patients with liver cirrhosis: Decreased HRV holds prognostic significance in chronic liver disease . A varie(2)Inter-breath interval (IBI) data from asthmatics: Asthma being a heterogeneous disease in nature, means there is difficulty in distinguishing between atopic and non-atopic as well as controlled and uncontrolled asthma non-invasively. It is of interest in this study to determine whether a strong autocorrelation in IBI time-series is identified in the most pathological form of asthma and of which specific stage of the lag in the extended Poincaré plot is best for diagnosing between the different forms that asthma can present as, as non-invasive tool.(3)Body temperature fluctuations from patients with liver cirrhosis: Temperature is regulated by both circadian and homeostatic processes that intercalate during health and disease. There is evidence to suggest that the pattern of body temperature fluctuation is different in patients with cirrhosis in comparison with healthy individuals . Extendex-axis: An, y-axis: An+1, (r) and an estimation of short- and long-term variability of a time-series. The latter parameters are defined by the standard deviation perpendicular to the line of identity (SD1) and the standard deviation parallel the line of identity (SD2)  .k) when calculating the correlation of a time-series. The extension of the Poincaré plot gives rise to the extended Poincaré plot whereby An is plotted against An+k, where k steps can take any discrete integer Cardiac inter-beat R-R intervals (R-R) recorded from patients with chronic liver disease(b)Respiratory IBI recorded from patients with asthma(c)Body surface temperature (T) recorded from patients with chronic liver disease. Furthermore, three types of stimulated noise  were also assessed using the extended Poincaré plot. All physiological recordings were approved by regional ethics committee and conducted in accordance to the Declaration of Helsinki (Hong Kong Amendment) and Good Clinical Practice guidelines.k) in the extended Poincaré plot, the Pearson correlation coefficient (r), SD1 and SD2 were calculated to produce a series of numbers corresponding to the outcomes in association with the extent of the lag .MATLAB programming language was used for the implementation of all algorithms used in this study . Firstly, gaussian white noise was produced by a MATLAB embedded random generator to be used as negative control for comparing a random memoryless process with human data. Brownian noise, a stochastic process with one step memory, was created by the integration of white noise, to act as a positive control for the presence of autocorrelation in a time-series. Meanwhile, pink noise, a time-series with fractal like 1/f dynamics, was generated by a MATLAB function created by All data recordings were in accordance to the recommendations and approval from the University Hospital of Padova Ethics Committees. Whilst all patients provided a written informed consent, 98 patients with liver cirrhosis [mean (±1 SD) age: 57 (±10.9) years] from the Department of Medicine outpatient clinic of the University of Padova from 29 June 2009 until 2 May 2011 were enrolled. Patient selection was based on their etiology, established through clinical, laboratory, radiological and histological findings. Whereas, severity was characterized by Pugh’s modification of the Child’s grading system (Child-Pugh) and the Model for End-Stage Liver Disease (MELD) scores . EligibiInitially, a 10-min single channel ECG was obtained using conventional ECG electrodes. The data was digitized at a sampling rate of 256 Hz and detected R peaks attained a R-R interval time-series, via an ad hoc computer program . By visual inspection, 8-min artifact-free continuous R-R interval sections were used for analysis.r, SD1 and SD2. In addition, Cox’s proportional hazards ratio was calculated in the survival analysis to statistically analyze if the latter indices predict mortality.From the extended Poincaré plot, the parameters obtained were Pearson’s The study for this cohort was approved by an institutional review board and the ethics committee at Tarbiat Modares University and all participants signed written informed consent prior to data collection. 40 age-matched men, aged between 21 and 39 years, participated in this study during June 2010 to February 2011, in accordance to the eligibility criteria defined by Respiratory IBIs were recorded to create a time series as subjects laid supine for about 70 min, whilst continuous respiratory signals were collected using respiratory inductive plethysmography, as described by r, SD1 and SD2 were attained from the extended Poincaré plot algorithm output. Furthermore, a receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of whether the plots extension, demonstrated by the lag , were appropriate or not for distinguishing between different asthma classifications.Again, the Pearson’s This particular study was approved by Padova University Hospital ethics committee. All participants provided written informed consent. Fifty three patients were recruited, however, 45 subjects were used for analysis based on the exclusion criteria stated by The temperature recordings were as described by r, SD1 and SD2 for this given time-series were calculated.The Pearson’s post hoc test. P-values less than 0.05 were considered statistically significant. Cox’s proportional hazards model was used to assess the prognostic value of the Poincaré plot indices in patients with liver disease. The ROC curve was used to study the diagnostic ability of each step (k) in predication of different classes of asthma . The area under the ROC curve is a measure of how well a parameter can distinguish between two diagnostic groups . When there is a perfect separation of the values of the two groups, i.e., there no overlapping of the distributions, the area under the ROC curve equals 1. When the parameter cannot distinguish between the two groups the area will be equal to 0.5. Area under the curve and its p-value (null hypothesis: area = 0.5) were calculated using IBM SPSS Statistics 24. The ample size for each cohort was calculated based on a 0.05 significance level (error type I) and 0.80 power (1-error type II).Data was statistically analyzed by a two-way ANOVA with Tukey’s Through the extension of the Poincaré plot, the lag affects the elliptical shape of the plot. As the lag increases, the linear correlation generally decreases whilst SD1 and SD2 change in an inversely proportional manner .r correctly identified models of colored noise, proving its reliability . It is clear that the most severe class of cirrhosis (Child C) is distinctly disparate from all other subjects in the study, by shifting toward the Brownian noise spectrum, illustrating a more correlated rhythm across lag-r, also known as the extended Poincaré plot , there was no interaction between patient groups and lag across the range of values for k and thus, Pearson’s r exhibits the same trend across all groups in respect to k.Regarding Pearson’s aré plot . In otheFgroup = 186.3, P < 0.0001) and subsequent steps, k,  for SD1. SD1 could separate different classes of cirrhosis with the lowest value being for Child C and the highest for healthy individuals as shown k, with the greatest gross increase in healthy individuals. However, there is no interaction between lag-k and the subpopulation groups since the variables are parallel to one another (two-way ANOVA).k approaches 20 , however, there is no significant difference between the individual steps  (two-way ANOVA). Moreover, in respect to r, there is no significant difference in trend between the sample groups as k increases.Likewise, SD2 can also separate different classes of cirrhosis from the healthy group of individuals . On the aches 20 . There iStudy participants were followed up for 18-months post-ECG recording to obtain their survival outcomes for use in our mortality studies. Cox’s regression analysis was used to assess whether HRV indices predicated mortality. The hazard ration [Exp(β)] was calculated. In this analysis, Exp(β) = 1, which indicates no effect in predicating mortality, whilst Exp(β) < 1 or Exp(β) > 1 indicate whether the index is either protective or hazardous respectively, when predicating survival.r presented no prognostic capacity, as it did not predict the 18-month survival outcome (P > 0.05) and all the 95% confidence intervals crossed the no effect size. The lowest p-value was 0.089  at k = 5 (Pearson’s at k = 5 .k (P < 0.05). SD2 generally was more significant than SD1 throughout the lag-k. As expected the indices of the severity of liver dysfunction (MELD and Pugh) could robustly predict mortality (P < 0.0001). In order to see whether or not the prognostic value of SD1 and SD2 depend on the severity of liver dysfunction, we used a multivariate Cox’s regression analysis. It appears that the ability of SD1 to predict mortality is dependent on disease severity, across all steps, since P < 0.0001 for the MELD score, but the p-value was insignificant for the sole use of SD1 without consideration of disease severity  , as well as the different classification groups of asthma . As seen in Pearson’s Fgroup > 200, P < 0.0001). However, there is no significant difference between each step, k, and the interaction also presents as significant .Using the area under the ROC curve, Pearson’s r had the best sensitivity and specificity at distinguishing between atopic and non-atopic asthma, at k) for classifying atopic from non-atopic and uncontrolled from controlled asthma  and steps (k) . Yet, there is no interaction between the two since all patient groups follow a declining trend across the lag.For the temperature fluctuation data from subsets of cirrhotic patients, Pearson’s r, there are significant differences between patient groups  and steps (k) , however, there is no interaction between the two .As shown in Fgroup = 272.6, P < 0.0001) but not between steps (k), meaning that the declination trend is not significant. With that being said, there is no interaction between patient groups and steps (k).Nevertheless, the lag-SD2 (which is depicting long-term variability) illustrates a slight declining trend that also separates inpatients from outpatients. Though SD2 uniquely allows for the segregation of cirrhotic inpatients and non-cirrhotic inpatients, across the increasing lag . In factr, the extent of correlation in a given physiological time-series can be quantified, whereby a greater value of correlation conveyed prolonged memory and subsequently impaired homeostasis, as it conveys less adaptable state . Recent investigations in this field are focused on analyzing bronchoalveolar lavage and its specific cellular/cytokine profile or plasma/urinary biomarkers . The correlation coefficient r, appeared to also hold a non-invasive diagnostic value when it comes to differentiating between uncontrolled and -controlled asthma as well as between atopic and non-atopic asthma, especially at greater steps of lag (k > 1). The latter, is very important at supporting the fact that the extended Poincaré plot holds more temporal information, as well diagnostic significance in comparison to the traditional Poincaré plot. Furthermore, SD1 and SD2 showed similar results, by again easily detecting uncontrolled non-atopic asthma from the other subsets of asthma. The diagnostic ability of the extended Poincaré plot across the lag was consistent, and was best portrayed by quantifying correlation to assess the ‘memory’ of the system and its time-series.Secondly, IBI data was analyzed from patients with different classes of asthma to explore the diagnostic capability of the extended Poincaré plot. The extended Poincaré plot indices, Pearson’s omarkers . Our resr had the best sensitivity and specificity at distinguishing between atopic and non-atopic asthma, especially at k = 3. Furthermore, k = 2 and k = 12 had the most significant result in distinguishing between controlled and uncontrolled asthma. These results are promising and also go along with our previous report on the classification of asthma based on respiratory fluctuation analysis . Since hospitals have a temperature-controlled environment and patients spend most of their time at their bedside bed, it is expected to see less short-term and long-term temperature variability in hospitalized patients, in comparison to outpatients and healthy controls. Interestingly both inpatient groups (cirrhotic and non-cirrhotic) exhibit similar SD1 and SD2 parameters, whilst their Pearson’s correlation coefficient is significantly different. This clearly shows that the loss of autocorrelation in cirrhotic inpatients is not related to less variation in their temperature profile.The Poincaré plot has numerous applications in different disciplines and is known by other names such as, return maps, the Poincaré return plot or Lorenz plot in the mathematics and physics community. The classical application of return maps is in detecting non-linearity in deterministic one-dimensional systems . First-rξ is a random noise, and ρ is the parameter of the model and relates to the extent of the correlation (−1 < ρ < 1). In higher order autoregressive processes, we observe more complex behavior. For example, in a second order autoregressive process [AR(2)], the current value is based on the previous two values:Where n+2 might still be correlated with An, as the expansion of Equation 1 gives rise to Equation 3:Interestingly, in an AR(1) process, An+2 and An depends on ρ2 (ρ squared) which is less than ρ itself. Therefore, observing a correlation between An+2 and An does not rule out a first order autocorrelation. A systematic way to determine the order of an autoregressive process is using the partial autocorrelation function (This shows that in an AR(1) process, the extent of correlation between Afunction . We usedfunction  the threThe Poincaré plot provides a simple visual method that can be easily applied to bedside tests to aid diagnosis or treatment . In addition to this classic analytical method, other state of the art visual analytical methods do exist which are used for analysis of physiological time-series such as the recurrence plot . The recr. Another limitation of this study is that, mathematical models and correlation-based approaches do not provide full enlightenment of a system’s behavior, as it oversimplifies critical physiological concepts, by statistically discriminating against stochastic processes. Moreover, Pearson’s r was chosen for the linearity seen in Poincaré plot and its extension as it assumes that the variables in the extended Poincaré plot exhibit a linear relationship, which limits validity if it does not yet, it does nonetheless establish immediate new knowledge, which can potentially be used to solve unmet clinical needs.Our study showed the potential application of the extended Poincaré plot in analyzing various physiological time-series to unravel the resiliency and tolerance of a system that operates against environmental, physiological and pathological challenges. As some variability and plasticity in physiological rhythms are unavoidable, due to the balance between adaptation and memory, physiological controllability can be considered as a critical aspect of homeostasis, to enhance organismal function. It appears that the extension of the Poincaré plot can be applied to current health care challenges, such as the diagnosis of uncontrolled asthma, prediction of survival and assessment of thermoregulation in patients with liver disease. As robust as this present study appears, it lacked multicenter study heterogeneity, such as varying etiology. Even though it is alleged that predictors of mortality derived from HRV are irrespective of the etiology , it woulRS, MB, SM, and AM contributed in work conception. MDR, MR, MG, and MB curated the data. RS and N-U-HA performed the formal analysis. RS, N-U-HA contributed the software. SM and AM supervised the work. RS wrote the original draft. N-U-HA, SM, and AM wrote, review, and edited the manuscript.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.


A living‐donor (adult) kidney transplantation in young children requires an increased cardiac output to maintain adequate perfusion of the relatively large kidney. To achieve this, protocols commonly advise liberal fluid administration guided by high target central venous pressure. Such therapy may lead to good renal outcomes, but the risk of tissue edema is substantial.We aimed to evaluate the safety and feasibility of the transpulmonary thermodilution technique to measure cardiac output in pediatric recipients. The second aim was to evaluate whether a cardiac output‐guided hemodynamic therapy algorithm could induce less liberal fluid administration, while preserving good renal results and achieving increased target cardiac output and blood pressure.In twelve consecutive recipients, cardiac output was measured with transpulmonary thermodilution . The algorithm steered administration of fluids, norepinephrine and dobutamine. Hemodynamic values were obtained before, during and after transplantation. Results are given as mean (SD) [minimum‐maximum].−1 in the first 2 patients to 80 (18) [44‐106] mL kg−1 in the last 10 patients. The latter amount was 23 mL kg−1 less (95% CI = 6‐40 mL kg−1) than in one recent study, but similar to that in another. After reperfusion, all patients received norepinephrine (maximum dose 0.45 (0.3) [0.1‐0.9] mcg kg−1 min−1). Patient and graft survivals were 100% with excellent kidney function at 6 months post‐transplantation.Age and weight of recipients was 3.2 (0.97) [1.6‐4.9] yr and 14.1 (2.4) [10.4‐18] kg, respectively. No complications related to cardiac output monitoring occurred. After transplantation, cardiac index increased with 31% (95% CI = 15%‐48%). Extravascular lung water and central venous pressure did not change. Fluids given decreased from 158 [124‐191] mL kgTranspulmonary thermodilution‐cardiac output monitoring appeared to be safe and feasible. Using the cardiac output‐guided algorithm led to excellent renal results with a trend toward less fluids in favor of norepinephrine. Cardiac output increases after adult donor kidney transplantation in small children.Perioperative hemodynamic therapy is currently based on high target central venous pressures leading to liberal fluid administration with the risk of tissue edema.The transpulmonary thermodilution technique for monitoring cardiac output is feasible and safe in living donor kidney transplantation in children under 20 kg.Cardiac output‐guided hemodynamic therapy seems to lead to less liberal intra‐operative administration of fluids in favor of norepinephrine while achieving good renal outcomes.1−1 or 10% of the cardiac output (CO), whereas the CO of a 1‐year‐old child is approximately 2.5 L min−1.Renal transplantation is the therapy of choice for children with end‐stage renal disease. Living‐donor kidney transplantation (LDKT) has benefits including less acute rejection, better catch‐up growth and higher quality of life.It is uncertain how to guarantee sufficient blood flow through the transplanted kidney, as evidence‐based guidelines do not exist. Hemodynamic therapy protocols commonly advise liberal fluid administration guided by high target central venous pressure (CVP) and arterial blood pressure (ABP).In 2012, our center started a special program for LDKT in children under the age of four. Designing the protocol for perioperative hemodynamic support, we aimed at a physiology‐based approach. The high target CVP advocated in literature was abandoned, aiming for less liberal fluid administration. This accords with many reports questioning the use of CVP as a reliable monitor of fluid status in adults.As this is the first report on TPTD‐CO monitoring during LDKT with large donor‐recipient size mismatch, our first goal was to evaluate the safety and feasibility of the technique and analyze the hemodynamic changes. The second goal was to evaluate whether this CO‐guided hemodynamic therapy algorithm induced a reduction in intraoperative fluid administration compared with other reports, while achieving increased target CO and ABP with good renal outcome.22.1All children with a bodyweight below 20 kg who underwent a LDKT between the start of the program in October 2012 and September 2016 were consecutively included in this prospective observational study. Two anesthesiologists dedicated to the program alternately provided the anesthetic care using a standardized anesthesia protocol and a hemodynamic therapy algorithm . After administration of intravenous rocuronium (0.5‐1 mg kg−1) an endotracheal tube was placed and positive pressure ventilation started with a tidal volume of 6‐8 mL kg−1 and positive end‐expiratory pressure of 4‐6 cm H2O. Anesthesia was maintained with sevoflurane  in oxygen/air and intravenous sufentanil. Target end‐expiratory partial pressure for CO2 was 33‐38 mm Hg. Cefuroxim was given before surgical incision as a prophylactic antibiotic. Mannitol 10% (0.5 L 1.73 m−2) was administered 10 minutes before reperfusion of the donor kidney. No diuretics were given.Anesthesia was induced with sevoflurane by face mask or intravenous thiopental , ABP, and CVP were continuously monitored (Philips data monitor). A thermistor‐tipped PiCCO‐catheter  was inserted (ultrasound‐guided) in the left femoral artery to measure TPTD‐CO. This site was chosen as it was as far away as possible from the vascular anastomosis with all transplantations right sided. The catheter was connected to the PiCCO2 device. The device was connected to a laptop computer with PiCCOwin‐software for storage of hemodynamic measurements and curves (Pulsion). The curves were reviewed for quality assessments to assure that they were technically correct.2.4Patients' demographic data, pretransplantation (co‐)morbidities, estimated glomerular filtration rate (eGFR), presence of dialysis, and recipient‐donor weight ratio were recorded. Also, duration of anesthesia, blood loss, vasoactive drug and fluid administration, time to first diuresis, time to creatinine nadir, time to PiCCO‐catheter removal, duration of hospital stay, complications, and eGFR 6 months after transplantation were recorded.−1 m−2 and stroke volume index (SVI), expressed as mL m−2. Extravascular lung water was adjusted for body weight, yielding extravascular lung water index (EVLWI) expressed as mL kg−1. Global end diastolic volume was not used and not studied because of lack of validation in children. EVLWI was not used to guide therapy but was studied with regard to individual changes as a marker of pulmonary edema.TPTD‐CO measurements were performed at time points left to the discretion of the attending physician. However, three measurements were done at fixed moments in time and were used in our study. All measurements were done in a hemodynamically stable period. Stable conditions were defined as variance in hemodynamic variables of <10% and no change in fluids or vasopressor administration in the last 15 minutes. The first measurement was performed after induction of anesthesia, before surgical incision (t0), the second during surgery after reperfusion of the donor kidney (t1), and the third in the ICU just before removal of the PiCCO catheter (t2). The PiCCO catheter was removed when vasoactive medication was no longer necessary to optimize hemodynamics. At t0, t1, and t2 hemodynamic variables were recorded. CO was measured as the mean of three consecutive measurements with central venous injections of 10 mL iced saline 0.9%. To prevent calculation bias by the PiCCO software, only the TPTD measurements with absolute values of CO and extravascular lung water were used. Cardiac output was divided by the mean HR obtained during TPTD measurements to calculate stroke volume. Cardiac output and stroke volume were adjusted for body surface area, thus yielding CI, expressed as L min2.5Basic fluid requirements were calculated according to the 4‐2‐1‐rule of Holliday and Segar. Intravenous fluids, inotropic and vasopressor support were titrated according to the algorithm shown in Figure −1 m−2. This value was a pragmatic choice aiming at a higher than “normal” CI for optimal perfusion of the donor kidney. The target MAP >65 mm Hg was chosen as acceptable lower margin during anesthesia as all donors had normal ABP. Both targets were evaluated for their appropriateness by visually judging the perfusion of the donor kidney at the moment of reperfusion. If needed, target CI and MAP were adjusted to higher values. Only TPTD‐CO measurements were used to guide therapy. Although the PiCCO technology allows to continuously measure CO, using pulse contour analysis, this was not used because it is considered unreliable when frequent changes in hemodynamic support occur.Reference values for normal cardiac index (CI) in children show a wide range.2.6Results for all variables are given as mean (SD) [minimum‐maximum], unless stated otherwise.t‐test for paired data was used to compare CVP measurements.A one‐way analysis of variance (ANOVA) for repeated measurements was used to evaluate the null hypothesis that there is no difference among patients' mean values for hemodynamic physiological variables obtained at the three measuring points t0, t1 and t2. ANOVA used Greenhouse‐Geisser correction for non‐sphericity if needed. If the ANOVA revealed a difference between the values, post hoc analysis using Bonferroni multiple comparisons test was done. Student's t‐test for groups with unequal variances (Welch's test) was used to compare intraoperative fluids given to our last 10 patients with those reported in two recent papers on intraoperative management in pediatric kidney transplantation.A two‐sample P < .05 was considered statistically significant.Data were analyzed using GraphPad Prism V7.0d (GraphPad Software) and IBM SPSS Statistics V21.0. 3Twelve patients entered the study. Table 3.1Table 3.2−1 min−1 and one received dobutamine (3.8 mcg kg−1 min−1). Following reperfusion of the donor kidney all recipients experienced a decrease in ABP of >20%. Patients' target MAP and CI were quickly restored using fluid loading and increasing vasopressor therapy. After reperfusion, all patients received norepinephrine (maximum dose 0.45 (0.3) [0.1‐0.9] mcg kg−1 min−1) and eight received dobutamine (maximum dose 3.4 (1.7) [1.9‐6.3] mcg kg−1 min−1).At t0, four patients received norepinephrine 0.07 (0.04) [0.01‐0.1] mcg kg−1 that included crystalloids, mannitol and the iced normal saline used for the CO measurements. Per protocol, of this total, 20 mL kg−1 were given prior to reperfusion. Fluid administration was 158 [124‐191] mL kg−1 in the first two patients. It decreased to 80 (18) [44‐106] mL kg−1 in the last 10 patients, which is 23 (8) mL kg−1 less than the 103 (61) mL kg−1 of crystalloids found by Michelet and co‐authors−1; P = .01). They also reported 16 (14) mL kg−1 albumin being given apart from the crystalloids. Our patients did not receive albumin.Figure −1 h−1. The first two received 29.8 [25.8‐33.7] mL kg−1 h−1, the last ten 16.7 (3.8) [8.9‐21.9] mL kg−1 h−1. The difference with the amount found by Taylor and co‐authors−1 h−1; P = .87).Figure −1. Considering crystalloids and blood products together, patients received 102 (38) [62‐207] mL kg−1.Eight patients received blood products: 14 (8) [6‐28] mL kg3.3All hemodynamic data could be collected on the three measuring points, except for CVP. CVP was measured in 10 patients at t0 and t1.P‐values. Results of repeated measures ANOVA indicated a statistically significant time effect for HR, SVI, CI and MAP. Follow‐up comparisons indicated that HR, SVI, CI, and MAP increased between t0 and t1. There was a further increase in MAP between t1 and t2, but not for HR, SVI and CI. MAP increased with 66% (95% CI = 34%‐98%) between t0 and t2. At t2 none of the patients received norepinephrine or dobutamine. CVP values did not change between t0 and t1. Also, no statistically significant time effect for EVLWI was found.Table Figure 3.4All donor kidneys displayed diuresis shortly after reperfusion. Early complications were drug‐induced delirium in two patients, septicemia in one and early postoperative hemorrhage in another, necessitating reoperation. In a patient with nephronophthisis  and pre‐existent liver fibrosis, excessive postoperative ascites and lymph leakage were present. Perfusion problems of the leg distal from the PiCCO catheter or complications at the site of anastomosis were not encountered. After ICU admission, vasopressor therapy could be tapered down in all patients. The PiCCO catheter was removed in ICU when inotrope and vasopressor infusions were no longer needed. Time to removal varied substantially 4.2 (2.8) [1‐12] days. In the first patients of the cohort, the catheter stayed in for 5 days after operation. This gradually decreased to 1 day in the last two patients. One patient had PiCCO monitoring up to 12 days post‐transplantation due to an increased need for sedatives leading to hemodynamic instability, excessive fluid administration, pulmonary edema, prolonged ventilation, and delirium. After this, new protocols aimed at cessation of sedation and ventilation within 24 hours after transplantation, consequently reducing the duration of hemodynamic support and monitoring.None of the kidneys showed delayed graft failure or early graft rejection. Patient and graft survivals were both 100% at 6 months after kidney transplantation.4In this pilot study, TPTD appeared a feasible and safe technique to measure CO during LDKT with large donor‐recipient size mismatch. This is also the first report to quantify CO changes in these patients using a method that was recognized as gold standard for children.4.1The TPTD‐CO monitor has shown its feasibility, reliability and safety in pediatric intensive care for many years.4.2Hemodynamic changes after reperfusion of the donor kidney reflect those occurring after suddenly opening a large arterio‐venous shunt as described by Guyton and Sagawa in 1961.−1 m−2. At t2, all hemodynamic support had been stopped. Therefore, CO increase between t0 and t2 can be attributed to the relatively large donor kidney, despite the pharmacological effects of anesthetics and volume loading during transplantation and in the ICU. The absence of general anesthesia at t2 obviously aided the increase in HR. The increase in MAP between t0 and t2 suggests a permanent restoration of systemic vascular resistance, aided by the absence of anesthetics at t2.Our results are concordant with this mechanism. We found a 31% increase in CI between t0 and t2, which is similar to reported values.4.34.3.1Considering the described mechanism, hemodynamic therapy guided only by ABP and CVP lacks physiological grounds. Although an adequate ABP is necessary to prevent acute kidney injury, ABP values alone only provide limited information on renal perfusion and oxygenation.4.3.2Optimal renal blood flow and pressure are of paramount importance to prevent hypoperfusion, delayed graft function, and subsequent loss of renal tissue. Especially in small children, it is a challenge to achieve this as both hypovolemia and excess fluids are detrimental for the renal microcirculation. It would be ideal if renal flow, pressure, and microcirculation could be estimated. Our algorithm uses second bests as CO , MAP  and fluid responsiveness (volume status). With the currently available hemodynamic monitors fluid responsiveness is difficult to assess in children.4.3.3In addition to fluids, we administered dobutamine and norepinephrine to support CO and ABP. Using dobutamine did not result in tachycardia. Norepinephrine was administered to support ABP by counteracting the depressant effects on systemic vascular resistance of (a) anesthetics and anti‐hypertensive drugs, (b) opening the arterial anastomosis and (c) cytokines released after reperfusion of the (ischemic) donor kidney. After an ischemic period, autoregulatory mechanisms in the donor kidney might be disturbed and pharmacological support may be needed to guarantee an adequate perfusion pressure. In the past, concerns existed on the vasoconstrictive aspects of norepinephrine and its possible negative effects on visceral organ perfusion. Recent studies show otherwise: in a vasodilated state norepinephrine can even improve renal blood flow. It is currently the drug of choice to prevent hypotension in septic shock without increasing the incidence of acute kidney injury.4.3.4As CVP and EVLWI did not increase despite fluid loading, we suggest that our hemodynamic strategy did not cause fluid overload. Prolonged time to tracheal extubation can be a sign of pulmonary edema and fluid overload. In our study, the moment of extubation depended on many variables, including potential signs of fluid overload and the sedation protocol. The latter was optimized during the study, which gradually led to shorter time to extubation. Table −1 h−1. However, this disregards the fact that all our patients weighed <20 kg vs 36.2 kg for Taylor's average patient. Our last 10 patients received 4.9 (1.2) [2.8‐6.3] times their basic fluid requirement calculated with the 4‐2‐1‐rule vs 8.1 times for Taylor's average patient. Obviously, prudence is required in judging the validity of this calculation for the average patient.To assess whether our strategy led to less intraoperative fluids, there were only two recent studies to compare our results with, although the cohorts differ in age, weight, and the allograft source.4.4Although the TPTD‐CO monitor uses a validated and reliable technique, it is invasive and requires experience. Echocardiography is less invasive and can supply the physician with useful information but has several limitations, such as technical problems during surgical procedures, operator dependency, and variability. Non‐ or minimally invasive CO monitors are easily applicable but also require experience while their reliability is questionable in young children and at best may be used as a trend monitor.4.5Our study did not use a control group without CO monitoring. The first 12 patients in our program served as a pilot cohort to test the feasibility and safety of our hemodynamic monitoring and therapy plan. As we considered CO‐guided hemodynamic support as best clinical practice, we omitted a control group. Our cohort was small but consistent in age, weight, type of donor and short cold ischemia times. This consistency and the uniform hemodynamic protocol make our findings rather robust. Other studies show considerable variation in recipients' age and weight, donor characteristics and hemodynamic therapy, which makes comparisons difficult. Nevertheless, the small number of patients should let us refrain from very broad conclusions on safety and risk‐benefit ratio.In conclusion, a kidney transplantation with large donor‐recipient size mismatch implies clinically significant hemodynamic changes, illustrated by a 31% increased CO. The TPTD‐technique proved to be feasible and safe in this cohort. The results suggest that optimizing hemodynamics using a CO‐guided hemodynamic therapy algorithm to titrate inotropes, vasopressors, and fluids may reduce intra‐operative fluid administration compared with a CVP‐guided approach, thus possibly preventing tissue edema. As this is a small cohort, further research is desirable focusing on the most efficient algorithm and outcome effects of CO‐guided fluid therapy in these patients.The authors report no conflict of interest.The Regional Committee for Medical and Health Research Ethics  ethically approved this study. The Committee waived the requirement for written informed consent. Parents were informed of the study and given the opportunity to refuse the use of their child's data.


Heart failure with reduced ejection fraction (HFrEF) is a progressive clinical syndrome commonly associated with left ventricle dilatation and characterized by reduced cardiac output, secondary pulmonary and systemic venous congestion, and inadequate peripheral oxygen delivery. It is common yet complex and requires synthesis of evidence-based guidelines along with strong clinical acumen. The following is a review of an illustrative case that highlights the important clinical considerations in diagnosis, assessment, and management of HFrEF commonly encountered in practice. Explanations provided highlight of the relevant pathophysiology of HFrEF as well as detailed explanations of interpretation of examinations and both noninvasive and invasive assessment in heart failure. The example provided would hopefully serve as a potential point of reference for trainees as well as healthcare practitioners for patients with HFrEF. First, a diagnostic coronary angiogram should be performed to evaluate the presence and extent of coronary atherosclerosis. This will help to determine if the patient's dilated cardiomyopathy is ischemic in nature. After completion of the coronary angiogram and with arterial access already in place, the aorta can be crossed in a retrograde fashion in order to assess left ventricular end-diastolic pressure.The second objective is to confirm and further define the SVR and presence of pulmonary hypertension and how they respond to drug intervention. For this portion of the study, a right heart catheterization should be performed for assessment of the right atrial, right ventricular, pulmonary artery, and pulmonary capillary wedge pressures. These assessments will allow calculation of the TPG, demonstrated below. Furthermore, during the right heart catheterization, measurement of the mixed venous blood saturation and the arterial saturation should be obtained as well as measured assessment of oxygen consumption so that the cardiac output may be calculated via the Fick equation and subsequently the pulmonary vascular resistance (PVR) determined.If the patient's PCWP is elevated as is suspected, then the final step will be to determine the response to acute systemic arterial vasodilator therapy such as nitroprusside. The presence or absence of a decrease in pulmonary capillary wedge pressure and ultimately TPG suggests an improved prognosis particularly in heart transplant candidates.The clinical history, physical examination, and noninvasive assessment do not suggest an etiology that would both be readily identifiable on endomyocardial biopsy and that would alter therapeutic strategy. Therefore, in accordance with ACC/AHA guidelines, an endomyocardial biopsy was not pursued .There are several critical points to consider when assessing both HF and pulmonary hypertension. The first issue to consider is appropriate method for determining cardiac output. As will be demonstrated in the following section, cardiac output is utilized to determine PVR and the degree of PVR impacts prognosis. There are several methods utilized to determine cardiac output in the invasive hemodynamics laboratory. The thermodilution method analyzes the change in blood temperature over time after a cooled injectant has been introduced to the system. This method has the potential to underestimate cardiac output in patients with markedly low output states or severe tricuspid regurgitation. If the cardiac output were to be underestimated, then the pulmonary vascular resistance would be overestimated. The Fick equation utilizes oxygen consumption to determine cardiac output (equation noted below). Oxygen consumption can be measured in the laboratory or can be “assumed” based upon body weight. However, the assumed oxygen consumption value is often inaccurate and should be avoided as its potential inaccuracy can result in a misleading PVR.Second, the assessment of PCWP as a surrogate for left ventricular end-diastolic pressure (LVEDP) has been shown to underestimate the true LVEDP. If the operator relied solely on PCWP, then the patient could be misclassified as type I PAH when indeed they had type II PH and be initiated on a drug therapy that would be ineffective and possibly even deleterious. A prior investigation has demonstrated that 53% of cases classified as type I PH based upon a low PCWP were reclassified as type II PH when LVEDP was measured and was demonstrated to be greater than 15 mmHg [Lastly, caution should be utilized when considering the appropriate agent to administer during the drug study. In type I PAH, a pulmonary vasodilator agent such as nitric oxide is administered to determine if the mean pulmonary arterial pressure can be lowered while maintaining or improving cardiac output. Pulmonary vasodilating agents increase preload, and in type II PAH where the LVEDP is already elevated, this can lead to acute volume overload resulting in pulmonary congestion. The correct agent to use in postcapillary PH (type II PH) is an afterload reducing agent such as nitroprusside. This will allow the investigator to determine if better systemic blood pressure control would alleviate the elevated LVEDP and in turn improve the patient's symptomatology.Venous and arterial access was obtained via a 7-French right femoral vein sheath and a 6-French right femoral arterial sheath. Judkins left 4 and Judkins right 4 catheters were utilized to engage the left and right coronary system, respectively. Coronary angiography noted mild diffuse disease. The catheter was then advanced into the left ventricle where an end-diastolic pressure of 24 mmHg was recorded.The catheter was withdrawn into the aorta, and the blood pressure was measured, noted below. Hemoglobin was drawn and noted to be 12.4 g/dL.   Aortic blood pressure (mmHg): 144/75    Right atrial pressure (mmHg): 14/11, mean = 10   Right ventricular pressure (mmHg): 73/8, end-diastolic pressure = 16   Pulmonary artery pressure (mmHg): 72/32, mean = 49. Oxygen saturation = 45%   Pulmonary capillary wedge pressure (mmHg): mean = 26. Oxygen saturation = 95%    Cardiac output: 3.9 L   Pulmonary vascular resistance : 5.96Next oxygen consumption was measured at the bedside to be 305.00 ml/min. Arterial oxygen saturation was 92%, and mixed venous blood saturation was 45%. Subsequently, a 7-French 110 cm balloon wedge pressure catheter was introduced through the femoral sheath, and the following measurements were obtained:μg/kg/min, and the following data were recorded:   Aortic blood pressure (mmHg): 92/47   Arterial oxygen saturation: 97%   Oxygen consumption: 340.00 ml/min   Pulmonary artery pressure (mmHg): 46/15, mean = 26. Oxygen saturation: 73%   Pulmonary capillary wedge pressure (mmHg): 10  Cardiac output: 8.3 L   Pulmonary vascular resistance : 1.5A nitroprusside drip was administered at 2 The changes in systemic, MPAP, and PCWP are demonstrated in Figures The coronary angiogram demonstrates no obstructive coronary disease consistent with the diagnosis of nonischemic dilated cardiomyopathy.The measurements prior to nitroprusside administration confirm markedly elevated filling pressure and low CO consistent with HF. Type II pulmonary hypertension is also present.To better assess the pulmonary hypertension, the transpulmonary gradient should be calculated:The TPG is ≥12 mmHg which is consistent with postcapillary reactive pulmonary hypertension whereas nonreactive postcapillary PH is ≤12 mmHg. Increased vasomotor tone with accompanying pulmonary artery remodeling underlies the pathophysiology of reactive PH . It is uaO2 is the oxygen content of arterial blood, and CvO2 is the oxygen content of venous blood. Oxygen consumption is given at 305 ml/min, hemoglobin is given at 12.4 g/dL, arterial oxygen saturation was 92%, and venous oxygen saturation was 45%. Entering these data, CO can be solved for:Next, cardiac output should be calculated using the Fick equation as follows:CO can then be utilized to determine pulmonary vascular resistance as follows:Normal PVR is ≤3 WU. This patient's elevated pulmonary vascular resistance is consistent with reactive type II PH.Note that with the administration of nitroprusside, the systemic blood pressure fell from 144/75 mmHg to 92/47 mmHg. With this acute afterload reduction, there was a marked drop in the MPAP to 26 mmHg, the PCWP to 10 mmHg, and the PVR to 1.5 WU. These findings are reflected in the hemodynamic tracings noted in Figures 2 (from 305 ml/min to 340 ml/min) as well as the increase in mixed venous oxygen saturation from 45% to 73%. The arterial oxygen also increased from 92% to 97%. The postnitroprusside cardiac output is therefore calculated as follows:Also of critical importance is the more than twofold increase in CO from 3.9 to 8.3 L/min. This increase is attributable to the increased VOThe left ventricular hemodynamic tracing  is consiThe right ventricular systolic pressure is markedly higher with invasive assessment (73 mmHg) compared to noninvasive assessment (39 mmHg). This may be due to an inability to obtain an optimal continuous-wave Doppler signal or due to daily variation in right ventricular systolic pressure. Continuous daily invasive monitoring of right ventricular systolic pressure in PH type I patients has shown significant fluctuations , and we The patient was gradually initiated on a heart failure regimen consisting of carvedilol 25 mg twice daily, lisinopril 20 mg daily, furosemide 40 mg daily, and spironolactone 25 mg daily. The diltiazem was discontinued as it is a negative inotrope. The patient's blood pressure remained elevated, so hydralazine 50 mg three times daily and isosorbide mononitrate 30 mg daily was added to the regimen. Three-month follow-up demonstrated improved blood pressure control correlating with increased exercise tolerance.


To determine whether an innovative, motorized, wellness device that effortlessly produces physical activity (JD) can mitigate the hypertensive effects of prolonged sitting or lying down.Twenty-two normotensive and hypertensive adults of both genders gave informed consent to participate in a randomized controlled crossover study of a passive simulated jogging device (JD) in both supine and seated postures. Each study participant was monitored with a continuous non-invasive arterial pressure monitoring device (CNAP) over 60 min. The initial 10 min served as baseline for each posture. The subjects were randomized to begin with either JD or SHAM control for 30 min, and monitoring was continued for an additional 10 min in one posture; three days later posture and order of JD or SHAM were changed.In both seated and supine postures, SHAM was associated with a significant rise in blood pressure (BP) which was observed within 5–10 min; it continued to rise or remain elevated for over a 40-min observation period. In contrast, JD produced a significant decrease in both systolic and diastolic blood pressure in both postures. During recovery in seated posture JD decreased systolic and diastolic BP by − 8.1 and − 7.6 mmHg, respectively. In supine posture, a similar decrease in BP occurred.There is rapid onset of increase in systolic and diastolic BP with physical inactivity in both supine and seated postures. Administration of JD significantly decreased BP in both postures. Further studies are needed to assess long-term effectiveness.The online version of this article (10.1007/s00421-018-4016-7) contains supplementary material, which is available to authorized users. Prior to 2017, hypertension was diagnosed if systolic blood pressure exceeded 140 mmHg. Using such criteria, it was estimated that hypertension affected more than 1.2 billion individuals worldwide and became the leading risk for cardiovascular morbidity and mortality. It comprised 40% of the worldwide population over the age of 40 years and accounted for approximately 50% of deaths from stroke, myocardial infarction, peripheral arterial disease, and renal disease among others  encompassing 55,000 persons and 204,000 patient-years. In this study, maintaining systolic blood pressure below 120 mm Hg produced a significant decrease in the occurrence of stroke and myocardial infarction. Serious adverse effects with pharmacotherapy accompanied systolic pressure less than 120 mm Hg. Therefore, the diagnostic threshold for treatment of hypertension was set as greater than systolic blood pressure of 130 mm Hg to achieve optimal efficacy and safety of management  , Study Number: 11172318 and WIRB: 20170208374 . The study is registered at ClinicalTrials.gov (NCT03426774). This investigation is a sub-study of the larger protocol in which multiple study postures and two different devices are being studied. Our study was designed as a randomized crossover trial. In this protocol, subjects were randomized to begin in either supine or seated postures and 3 days later crossing over with the starting posture reversed  on day 1 and on day 3 crossed over to the opposite posture of day 1  placed approximately 120 cm from a sound meter during operation of run speed was mean 59 db, SD 2.5 db which is equivalent to conversations in a busy restaurant. The maximum acceleration forces in seated posture from a triaxial accelerometer during run speed operation of JD was ± 5.4 m/s2 over tibia, ± 5.1 m/s2 over femur, and ± 1.0 m/s2 over forehead. The maximum acceleration forces in supine posture from a triaxial accelerometer during run speed operation of JD was. ± 2.9 m/s2 over tibia, ± 6.3 m/s2 over femur and ± 3.6 m/s2 over the forehead.The noise level of JD  is a commercially available arterial pressure monitoring system composed of the CNAP Monitor 500, the CNAP double finger cuff, and the CNAP controller, which is attached to the patient’s forearm that connects the finger cuff, and an upper arm cuff for oscillometric-determined arterial pressures measurements at the brachial artery. The latter is the reference blood pressure used for calibration of the finger cuff-arterial pressures. CNAP technology is based on the principle of the vascular unloading technique. Infrared light is sent through the finger and the transmitted light depends on the absorption by the blood in the finger artery. Pressure from the outside finger cuff is applied to keep the blood volume in the finger artery constant in accordance to the transmitted light. This corresponding pressure needed to keep the diameter and volume of the finger artery constant throughout the arterial pressure cycle correlates with arterial pressure. To achieve constant volume in the finger arteries, the controller on the forearm makes multiple adjustments per second. The systolic pressure and diastolic pressure values are calibrated to the values obtained by oscillometric, upper arm cuff determination using a proprietary transfer function and mean arterial pressure is adjusted accordingly. Prior to beginning the current investigation, the CNAP device was sent to the factory for recalibration. For each session, an oscillometric arterial pressure measurement was obtained at its beginning and at 1 h at the time of the completion of the session for quality control. Only the initial value for blood pressure was used for calibration of CNAP.A three-lead electrocardiogram was employed for recording of heart rate using a sampling rate of 1000 points per second LabChart 7 (upgraded to heart rate variability measures), ADInstruments, Colorado Springs, CO 80906.Participants were instrumented with the CNAP system and ECG electrodes in the seated or supine postures and feet with stockings strapped with Velcro strips onto the pedals of the JD with a Velcro strip (JD), CNAP was calibrated to oscillometric determined blood pressure. This procedure took a total of about 15 min while the participant assumed the selected posture. Then 10 min of baseline arterial measurements were recorded on the CNAP device as well as ECG waveforms. All waveforms were transferred to LabChart 7 software  on a PC for data processing. The mean values of the final 5-min recording were taken as baseline. Following 30 min operation of JD or SHAM, the JDs were powered off. Recording of CNAP and ECG signals continued for approximately 10 min into recovery and CNAP was recalibrated as a measure of quality control. Participants could stand and walk to a restroom before beginning a second session. Either one or two sessions were done on a given participant on a single day. The total duration of the session for CNAP and ECG recordings was 60 min.p < 0.001.Data from LabChart 7 were inputted into an Excel Spreadsheet for analysis of beat by beat blood pressure and heart rate throughout the study period. Mean values of systolic and diastolic blood pressures were computed every 5 min along with standard error of the mean. All systolic and diastolic arterial pressure values were normalized to change in mm Hg from individual baseline values. Differences for age, BMI, posture, and baseline blood pressure, between JD and SHAM were assessed with ANOVA. Statistical analysis was performed using Statistica software . Data are expressed as Mean ± SEM. Differences in blood pressure measures obtained with ANOVA were considered significant at Table Since no statistical differences for blood pressure changes in SHAM and JD related to age, BMI and hypertensive status at baseline were apparent using ANOVA, all values were grouped to ascertain differences between seated and supine postures on the one hand and SHAM and passive simulated jogging device on the other hand. Because of small number of subjects in the trial multivariate regression analysis to tease out differences in subject characteristics was not employed and should be considered as a limitation in the aforementioned grouping.p < 0.001). Differences remained statistically significant during interventions and throughout recovery where for SHAM, peak change of systolic pressure was 7.5 mm Hg above baseline and for JD, peak change of systolic pressure was 8.1 mm Hg below baseline. Diastolic pressures showed similar findings to a lesser extent (Table p < 0.001). During SHAM, peak change of systolic pressure was 10.4 mm Hg above baseline and during JD, peak change of systolic pressure was 11.2 mm Hg below baseline. These differences remained statistically significant during interventions and recovery period where peak change of systolic pressure for SHAM was 9.9 mm Hg above baseline and peak change of systolic pressure was 8.1 mm Hg below baseline. Diastolic pressures showed the similar findings to a lesser extent (Table p < 0.001). There were no statistical differences in values for systolic and diastolic pressures between seated and supine for both SHAM and JD . This increases total cardiac antioxidant capacity along with an increase in the antioxidant response element transcription factor Nrf2 translocation to the nucleus  , and pharmacologic therapy  is an effective, effortless, technology to acutely lower elevated blood pressure present during physical inactivity such as uninterrupted sitting or bed rest. Long-term studies of JD are necessary to demonstrate effectiveness in states of chronic physical inactivity.Below is the link to the electronic supplementary material.Supplementary material 1 (PDF 994 KB)


Background and objective: Hypotension and bradycardia are the most common hemodynamic disorders and side effects of spinal anesthesia (SA) on the cardiovascular system. SA-induced sympathetic denervation causes peripheral vasodilatation and redistribution of central blood volume that may lead to decreased venous return to the heart. The aim of the study was to evaluate the changes of inferior vena cava collapsibility index (IVC-CI) during SA in spontaneously breathing patients during elective knee joint replacement surgery to prognose manifestation of intraoperative hypotension and bradycardia. Materials and methods: 60 patients (American Society of Anesthesiologists (ASA) physical status I or II, no clinically significant cardiovascular pathology) of both sexes undergoing elective knee joint replacement surgery under SA were included in the prospective study. Inspiratory and expiratory inferior vena cava  diameters were measured using an ultrasound device in supine position before and immediately after SA, then 15 min, 30 min, and 45 min after SA was performed. The heart rate, along with systolic, diastolic, and mean arterial blood pressures were collected. The parameters were measured at the baseline and at the next four time points. Results: There were no significant changes in IVCin, IVCex, and IVC-CI compared to baseline and other time point measurements in hypotensive versus nonhypotensive and bradycardic versus nonbradycardic patients (p > 0.05). Changes in IVC diameter do not prognose hypotension and/or bradycardia during SA: the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for IVC-CI at all measuring points was <0.7, p > 0.05. Conclusions: Reduction in IVC diameters and increase in IVC-CI do not predict hypotension and bradycardia during SA in spontaneously breathing patients undergoing elective knee joint replacement surgery. Spinal anesthesia (SA) is an effective and safe method of providing intraoperative analgesia during various surgical procedures. This anesthetic technique is important and widely used for operations on the lower abdomen, pelvis, perineum, and lower limbs. Hypotension and bradycardia are the most common hemodynamic disorders and side effects of SA on the cardiovascular system . AccordiThe mechanism of SA-induced hypotension and bradycardia is still unclear . During The aim of the study was to evaluate the changes of IVC-CI during SA in spontaneously breathing patients during elective knee joint replacement surgery to prognose manifestation of intraoperative hypotension and bradycardia .The study took place at the Department of Orthopaedics and Traumatology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, from March 2016 to January 2017. Ethical approval for this study was provided by the Kaunas Regional Biomedical Research Ethics Committee (No. BE-2-5 issued on 18 February 2016).The inclusion criteria of the patients were as follows: Age ≥ 18 years; written consent to participate in the study; patients undergoing elective knee joint replacement surgery under SA; patients conformed to American Society of Anesthesiologists (ASA) physical status I or II in preoperative assessment; no severe cardiac pathology.The exclusion criteria were as follows: patients' refusal to participate in the study; other type of anesthesia; ASA III and above; severe cardiovascular pathology; severe intraoperative blood loss requiring blood transfusion; impossible to measure IVC diameter.3–4 intervertebral space. After identification of the subarachnoid space, 15–17 mg of levobupivacaine was administered. After completing the subarachnoid injection, patients were positioned in supine position with one leg bended, as this position is needed for the surgery. All doses of medications were adjusted according to the individual patient’s needs. To determine the level of SA, a cold test with alcohol wipe was performed.The following demographic characteristics of the study were collected: population gender, age, body mass index, body surface area, and ASA status. Routine monitoring of electrocardiography (ECG), noninvasive blood pressure and pulse oximetry were initiated upon arrival to the operating room. Premedication of midazolam 2.5–5 mg was given to all patients and a slow fluid therapy of crystalloids was started once an intravenous cannula was placed. SA was performed in the lateral decubitus position. A 27-G spinal pencil type needle was inserted in the LAll measurements of IVC were performed in supine position with one leg bended. The curvilinear probe  was used. The measurements of IVC diameter were taken in M-mode 1–2 cm below the level of the hepatic vein in the long axis subcostal view ,14,15,16HR, systolic (BPs) and diastolic (BPd) arterial blood pressures were recorded. Hypotension was considered as BPs value drops below baseline by more than 30%. Bradycardia was considered as HR lower than 50 bpm. Mean arterial blood pressure (MAP) was calculated using the following equation: MAP = (2 × BPd + BPs)/3. Decreased circulating blood volume was considered as IVC-CI higher than 50% . The parp < 0.05.The statistical analysis was performed using IBM SPSS 22.0 software. The data are presented as mean with standard deviation or median with a range. Kolmogorov–Smirnov test was used to determine normal distribution of the data. Normally distributed variabilities were analyzed using ANOVA test to compare multiple dependent groups  and Student t test for analyzing the differences in means between two independent groups . Non-normally distributed variabilities were analyzed using the Friedman test to compare multiple dependent groups . The data on the nominal scale were compared using Chi-square test . Pearson correlation coefficient was used to demonstrate correlation between the variables. A receiver operating characteristic (ROC) curve was plotted to determine the threshold value of IVC-CI which provided the prediction of hypotension and bradycardia. We assumed IVC-CI to be clinically relevant if the area under the curve (AUC) was >0.7. Statistical significance was determined as To detect the significant difference in mean values of variability of IVC-CI more than 40% for hypotensive versus nonhypotensive and bradycardic versus nonbradycardic patients assuming significance level alpha = 0.05 and power of the test = 0.8, we should have at least 6 patients in each group. Sixty ASA I–II class patients who were scheduled for elective knee joint replacement surgery and underwent SA were included in the prospective study. There was no significant difference in demographic data between hypotensive versus nonhypotensive and bradycardic versus nonbradycardic patients. Demographic data of the patients is presented in p < 0.001). The hemodynamic parameters at different time points during SA are shown in n = 15) of the patients, and bradycardia <50 bpm was seen in 18.3% (n = 11) cases.There was a statistically significant decrease in BPs, BPd, MAP, and HR immediately after the infusion of local anesthetic and all the other time points compared to baseline measurement (p > 0.05). The variations of ultrasonography indices are shown in p > 0.05). The variations of collapsibility of IVC between the groups are shown in There were no significant changes in IVCin, IVCex, and IVC-CI compared to baseline and the other time point measurements ; time point 2 ; time point 3 ; and time point 4 . The same results were comparing relations between BPd and IVC-CI: time point 1 ; time point 2 ; time point 3 ; and time point 4 . We found no statistically significant correlation between MAP and IVC-CI at any time point: time point 1 ; time point 2 ; time point 3 ; and time point 4 . The same was found comparing the relations of HR and IVC-CI: time point 1 ; time point 2 ; time point 3 ; and time point 4 .There was no correlation between BPs and IVC-CI at any time point: time point 1 . The results are shown in IVC-CI does not predict hypotension or bradycardia associated with SA: the AUC of the ROC curve for IVC-CI at all measuring points for prognose severe hypotension was less than 0.7 and Hypotension and bradycardia are not rare during SA ,4. It isWe hypothesized that the development of hypotension and bradycardia during SA might be related to increased collapsibility of IVC which suggest the patients as fluid responder due to relative decreased intravascular volume caused by vasodilatation. Ultrasonography is a noninvasive diagnostic technique that provides continuous information of the hemodynamic status of the patient ,18. It iWe found the reduction of arterial blood pressure after the injection of local anesthetic to subarachnoid space in all time points compared to the baseline. However, the rate of significant hypotension during SA is lower in our study compared to the literature ,4 and isWe failed to find statistically significant correlation between ultrasonography indices of IVC and hemodynamic parameters while others show opposite results . Some stZhang et al.  state thThe present study shows that variations of IVC-CI do not predict hypotension and bradycardia in spontaneously breathing patients during SA in elective knee replacement surgery, as the AUC of the ROC curve for IVC-CI was <0.7. Furthermore, it is important to mention that, in spontaneously breathing patients, respiratory variations of IVC diameter are highly variable from one cycle to another in a particular patient and between different patients . The valn = 60) it was sufficient for statistical calculations. Even though blood loss was not recorded, the patient was eliminated from the study if there was a need for intraoperative blood transfusion due to severe bleeding. Large-scale prospective studies in patients undergoing SA for surgery will be needed to confirm and expand on the finding of the present study, including the use of other methods and clinical parameters in a variety of patient subgroups.Although the sample size was small (Reduction in IVC diameters and increase in IVC-CI do not predict hypotension and bradycardia during SA in spontaneously breathing patients undergoing elective knee joint replacement surgery.It seems SA does not affect circulating blood volume and heart preload by increasing variability of IVC.


The associations between reduced eGFR and individual PFAAs and UA in the healthy control and hypertension groups were explored by logistic regression analyses adjusted for potential confounding variables. Results show that UA had a significant positive association with reduced eGFR in both healthy control and hypertension groups (P < 0.001). Among the PFAAs, citrulline, glycine and phenylalanine showed significant positive associations with reduced eGFR in both healthy control (P < 0.01 to 0.001) and hypertension (P < 0.001) groups. Moreover, alanine, asparagine and methionine achieved significant positive associations with reduced eGFR only in the hypertension group (P < 0.01 to 0.001). Conversely, serine showed significant inverse associations with reduced eGFR in the hypertension group only (P < 0.001). Our findings provide first evidence for a strong relationship between distinct patterns of PFAAs and elevated UA with reduced eGFR in hypertension. The findings may appear useful in developing effective strategies for the prevention or early detection and treatment of declined kidney function in hypertension.The potential association between altered levels of plasma free amino acids (PFAAs) and uric acid (UA) with estimated glomerular filtration rate (eGFR) remains unknown among patients with hypertension. A total of 2804 healthy controls and 2455 hypertensive patients were included in the current analysis. eGFR was defined as reduced when it was <60 ml/min/1.73 m Kidney diseases with kidney function decline pose very high risks for morbidity and mortality and also enormous burdens and challenges to the global public health care system3. Published evidence suggests that kidney diseases have multidirectional relationships with hypertension and these two global health problems are projected to get worse5. For the prevention and/or better management of kidney function decline and hypertension, efforts directed towards an improved understanding of potential determinants of these two associated conditions should be of utmost importance.Kidney function decline has consistently been found to be a strong independent risk factor for adverse clinical outcomes in a broad spectrum of patients6. Also, published research works suggest the possibility of the changes in amino acid metabolism in the pathogenesis of hypertension8. Existing evidence also indicate a clear relationship of an elevated level of circulating uric acid (UA), known as hyperuricemia (HU) with the accelerated decline in kidney function10. Obermayr et al. suggested HU as a causal risk factor for the development and progression of chronic kidney diseases11. Conversely, the kidneys play major roles in the regulation of circulating UA level as they reabsorb around 90% of filtered urate and eliminate approximately 60–70% of the total UA produced in the human body12. On the other hand, we recently showed a clear relationship of HU with hypertension7; and the role of HU might be causal in the development of hypertension13.Published data suggest that in chronic kidney diseases, alterations in the levels of plasma free amino acids (PFAAs) appear early and are more pronounced in advanced stages of it14. A better understanding of reduced eGFR in hypertension and its association with PFAAs and UA might contribute to better apprehension of the disease pathophysiology, and also help in the prevention or early detection and treatment of acute and chronic kidney diseases with declined kidney function in hypertension.From the findings of various clinical, epidemiological and experimental studies, both altered levels of PFAAs and UA appear to be independently and significantly associated with impaired kidney function which may be of particular importance among patients with hypertension. However, any such potential relationship remains unknown as no study have hitherto investigated it in the general population. Measurement of estimated glomerular filtration rate (eGFR) has long been considered the best available indicator of the overall function of the kidneysThe purpose of the current study was to examine the differences in the concentrations of PFAAs and UA amongst apparently healthy control subjects versus hypertensive patients without and with reduced eGFR. Furthermore, we investigated the association between PFAAs and UA with reduced eGFR in both groups of subjects in an attempt to explore the existence of any relationships between alterations in PFAA and UA levels with reduced eGFR in hypertension.A total of 2804 subjects  in the healthy control group and 2455 subjects  in the hypertension group were eligible for inclusion in the analysis of this study ; hypertension, men 12.9% versus women 4.8% . Also, as shown in Table 2 test, P < 0.001). In the latter group, 56.7%  of patients were taking medications for hypertension.Table We further divided both group of subjects into 2 categories each with preserved and reduced eGFR Table . As reveThe concentrations of of PFAAs for the healthy control and hypertension groups are depicted as median and IQR values in Table The crude association of UA and individual PFAAs with reduced eGFR (no versus yes) using the logistic regression analysis has been presented in the supplementary table , who demonstrated that such patients, whether treated or untreated, are insulin resistant, hyperglycemic and hyperinsulinemic18.In our study, significantly higher values for age and BMI for hypertensive patients simply represent the fact that the prevalence of hypertension progressively increases with age and that higher BMI is positively and significantly associated with an increased risk of hypertension19. Also, our finding of a significantly depressed eGFR in hypertension is in agreement with the findings of other reports showing the association of kidney function decline with an increase in blood pressure22.In this study, the prevalence of reduced eGFR among the apparently healthy control population was 3.4%. The presence of low glomerular filtration amongst general population is not uncommon. A study conducted among adult Italians applied the same criteria for reduced eGFR as in our study and reported the age-adjusted estimates of prevalence of it as 5.7% among men and 6.2% among women7, and this has been reflected in our finding of a significantly higher level of UA among hypertensive patients. HU-induced endothelial dysfunction with impaired NO production, activation of the renin–angiotensin system with an increase in sodium resorption, promotion of vascular smooth muscle cell proliferation and arterial stiffening, increased generation of free radicals and oxidative stress, platelet adhesion and aggregation play important roles in the development of hypertension25.HU has a clear relationship with hypertension8. As observed in our study, the concentrations of Ala, isoleucine (Ile), leucine (Leu), Phe, proline (Pro), tyrosine (Tyr) and valine  persisted to be significantly higher, and Gly and Ser, significantly lower in the hypertensive group than in the healthy control group, when the PFAAs were further compared among subjects with declined kidney functions. In the literature, such alterations in the concentration of PFAAs have been extensively investigated among patients with renal impairments. Chuang et al. (2006) compared PFAAs including all amino acids investigated in our study between pre-hemodialysis patients and age- and sex-matched healthy controls, and observed a significant increase for majority of the PFAAs including Gly in the former group (P < 0.05)26. In another study, compared to normal values, patients with moderate renal failure  showed a significant increase in Ala, Cit, Gly, Lys, Orn, Phe, Pro and Val (P < 0.005 to 0.001); conversely, Arg and Ser showed a decreasing trend although not significant27. Ceballos et al. (1990) compared the patterns of PFAA concentrations between healthy controls and patients with mild renal failure (creatinine clearance >25 ml/min) and exhibited significantly raised concentrations of Cit and Orn and low level of Ser (P < 0.001) amongst the patients28. Overall, our findings for alterations in PFAAs among subjects with reduced eGFR corroborate with those of other relevant studies. However, we compared PFAAs between the hypertensive group without any diagnosed kidney diseases and the control group, both with reduced eGFR; conversely, other studies included patient groups with advanced kidney diseases and the control group with preserved kidney functions. All these might have led to the observed differences in PFAAs between the studies.Our results show that compared to the healthy control subjects, patients with hypertension had significant elevations in almost all PFAAs except for Gly and Ser (significant reductions), and Asn and Thr (non-significant changes). In a recent Japanese study, the authors found similar alterations in PFAA profiles as observed in our study when the subjects developing hypertension were compared with the subjects not developing it over a period of 4 years29. Therefore, it might be possible that reduced kidney function causes diminished renal uptake of Cit, Gly and Phe and decreased production of Arg, Ser and Tyr, and thus leads to a higher level of former amino acids in plasma. On the other hand, significant positive associations of Ala, Asn and Met, and a significant inverse association of Ser with reduced eGFR were revealed in hypertension only  via accumulation of asymmetric dimethylarginine (ADMA), a competitive inhibitor of the latter, and thereby cause an elevation in blood pressure31. Also, a prior study demonstrated that intakes of Ala and Met were positively associated with higher blood pressure among patients with prevalent cardiovascular diseases32. In animal experiments, intracisternal injections of L-Asn produced pressor responses in the freely moving rat33. In contrast, Ser was negatively associated with declined eGFR in hypertension. The amino acid Ser is produced from Gly in the kidneys29. As our results show, the existing concentration of Gly was significantly lower in hypertension causing less availability of it for the production of Ser. Furthermore, persistent reduced ability of the kidneys to produce Ser probably made its plasma concentration low.In the present study, we confirmed the association between PFAAs and UA with reduced kidney function in healthy control subjects and hypertensive patients after adjustments for potential relevant confounders. However, compared to the healthy control group, the modest attenuation in OR for the positive association of UA with reduced kidney function in hypertension was probably caused by the fact that UA level represented a similar dimension (higher levels of UA) for both preserved and declined categories of patients in hypertension. Furthermore, as revealed in this study, Cit, Gly and Phe were positively associated with reduced eGFR in both healthy control and hypertensive groups  and Yamaguchi University (H25-26-2) approved the study protocol which was conducted in accordance with the Declaration of Helsinki. The study participants were briefed verbally about the detailed protocol and provided written informed consent to participate in this study.7. Figure The subject selection procedure has been described elsewhereDuring the check-up, venous blood samples were collected from the cubital vein of seated subjects after an 8-hour overnight fast. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were determined using the hexokinase method and latex agglutination immunoassay, respectively. The concentrations of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and triglyceride (TG) in the serum were measured enzymatically. Plasma UA level was measured using the uricase-HMMPS method by L-type UA.M kit . Serum concentration of creatinine was measured by using the creatininase-HMMPS method following the manufacturer’s instructions .8. Measurements of PFAA concentrations were performed by high-performance liquid chromatography–electrospray ionization–mass spectrometry (HPLC–ESI–MS) followed by precolumn derivatization which allows such measurements with high accuracy. For this, we followed the protocol as described elsewhere41. Briefly, 5 ml of blood samples were collected into tubes containing ethylenediaminetetraacetic acid , which were put on ice immediately and kept for about 15 min. Then the tubes were centrifuged at 4 °C  and the plasma was separated into tubes. These tubes were stored at −80 °C for a period 2 weeks to 2 months until the analysis for PFAAs was performed.In this study, we determined the absolute concentrations (in μmol/L) of 19 amino acids: Ala, Arg, Asn, Cit, Gln, Gly, His, Ile, Leu, Lys, Met, Orn, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. We did not attempt to measure other genetically encoded amino acids like glutamate, aspartate, and cysteine due to their known instability in the bloodet al. 2017]. We defined HU as a plasma UA ≥ 7 mg/dL in males and ≥6.0 mg/dL in females43.We defined hypertension as a systolic blood pressure (SBP) ≥ 140 mmHg or a diastolic blood pressure (DBP) ≥ 90 mmHg and/or the use of antihypertensive medication/s; DM as a FPG ≥ 126 mg/dL, a HbA1c ≥ 6.5%, and/or the use of medication/s for DM [Mahbub 2) = 194 × Serum creatinine (−1.094) × Age (−0.287) × 0.739 44. Subsequently, eGFR was classified into two categories: (1) preserved eGFR (eGFR ≥ 60 ml/min/1.73 m2) and (2) reduced eGFR (eGFR < 60 ml/min/1.73 m2)46.In this study, eGFR was calculated using the serum creatinine data for each subject, applying the following equation recommended for the Japanese population by the Japanese Society of Nephrology: eGFR (mL/min/1.73 m2) test for the categorical variables. We explored the association between reduced kidney function and individual amino acids and UA in each group by the logistic regression analyses. At first, we investigated the crude association between the independent variables and the outcome variable by the logistic regression analyses. For this, the values of all PFAAs and UA were scaled to multiples of 1 IQR calculated separately for males and females as significant sex-differences exist for these values47. Next, we adjusted the logistic regression models for the potential confounding factors showing significant group differences with additional inclusion of use of antihypertensive medications  in the hypertension group. Furthermore, to clarify the direction of the relationships between the PFAAs showing significant associations with reduced kidney function, the former variable were divided into quartiles and logistic regression analyses were conducted with adjustments for the same potential confounders. From the logistic regression analyses, we obtained the odds ratios (OR) for UA and individual amino acids with corresponding 95% confidence interval (CI) and P-values. A two-tailed P < 0.01 was considered significant. The statistical analyses were performed with the software package SPSS version 22 for Windows .The continuous variables of this study were presented as the median and interquartile range (IQR). The differences for demographic and clinical variables between the two groups were assessed by the Mann-Whitney U-test for the continuous variables, and by the Chi-square (χSupplementary Information


Intraoperative hypotension increases 30-day mortality and the risks of myocardial injury and acute renal failure. Patients with inadequate volume reserve before the induction of anesthesia are highly exposed. The identification of latent hypovolemia is therefore crucial. Ultrasonographic measurement of the inferior vena cava collapsibility index (IVCCI) is able to detect volume responsiveness in circulatory shock. No current evidence is available regarding whether preoperative measurement of the IVCCI could identify patients at high risk for hypotension associated with general anesthesia.A total of 102 patients undergoing elective general surgery under general anesthesia with standardized propofol induction were recruited for this prospective observational study. The IVCCI was measured under spontaneous breathing. A collapsing (IVCCI≧50%) (CI+) and a noncollapsing (CI-) group were formed. Immediate postinduction changes in systolic and mean blood pressure were compared. The performance of the IVCCI as a diagnostic tool for predicting hypotension (systolic pressure < 90 mmHg or a ≥ 30% drop from the baseline) was evaluated by ROC curve analysis.P = 0.0001). The relative mean arterial pressure change medians were 34.1% (IQR 23.2–43.0%) and 24.2% (IQR 17.2–30.2%), respectively (P = 0.0029). The ROC curve analysis for IVCCI showed an AUC of 64.8% (95% CI 52.1–77.5%). The selected 50% level of the IVCCI had a sensitivity of only 45.5% (95% CI 28.1–63.7%), but the specificity was high at 90.0% (78.2–96.7%). The positive predictive value was 75.0% (95% CI 50.9–91.3%), and the negative predictive value was 71.4% (95% CI 58.7–82.1%).A total of 83 patients were available for analysis, with 20 in the CI+ and 63 in the CI- group, we excluded 19 previously eligible patients due to inadequate visualization of the IVC (7 cases), lack of adherence to the protocol (8 cases), missing data (2 cases) or change in anesthesiologic management (2 cases). The mean decrease in systolic pressure in the CI+ group was 53.8 ± 15.3 compared to 35.8 ± 18.1 mmHg in CI- patients  contains supplementary material, which is available to authorized users. Maintaining hemodynamic stability is essential for reducing the rate of postoperative complications. Although intraoperative hypotension has no universal definition, it has a serious impact on myocardial injury, acute kidney injury, septic complications , the risHypovolemia is probably the most common factor provoking postinduction hypotension, despite worldwide improvement in preoperative optimization and changing practices promoting the avoidance of unnecessary fasting and mechanical bowel preparation, optimized fluid therapy remains the cornerstone of treatment with excellent effectiveness . The ideSeveral invasive devices  are available for evaluating preload among other elements of hemodynamic status, but their universal use is not a reasonable option due to financial constraints, relatively high complication rates, known limitations and unnecessary invasiveness compared to most surgical procedures .The use of noninvasive ultrasound examination by anesthesiologists is a widespread and useful aid in the safe application of anesthesia. In a recent meta-analysis, Ferreira et al. reported an approximately 31% change in anesthesia management when ultrasound was used. Thirty-five percent of the performed ultrasonographies were transthoracic echocardiographies . A standIn the present study, we aimed to characterize the collapsibility index of the IVC as a potential screening tool to identify patients who were candidate for hypotensive events related to general anesthesia in an otherwise hemodynamically stable population.This prospective, observational study was conducted between 26/07/2016 and 30/10/2018 in the 1st Department of Surgery, Semmelweis University, Budapest, Hungary. Ethics approval for this study was provided by Semmelweis University Regional and Institutional Committee of Science and Research Ethics, Budapest, Hungary . Informed consent was obtained from each subject. Patients aged ≥18 years who were scheduled for elective general surgery under general anesthesia on predetermined weekdays were included if they met the eligibility criteria and all necessary data were available. The inclusion and exclusion criteria are shown in Table Eligible patients were screened using ultrasonography. The inferior vena cava was identified, and characteristics were recorded in the dorsal recumbent position under light sedation (RASS 0- -1) and spontaneous breathing. The collapsibility index (IVCCI) was calculated, and two groups were formed according to the measured IVCCI: the collapsing group characterized by IVCCI≥50% (CI+) and the noncollapsing group (CI-) (in whom the IVCCI was< 50%). This level was arbitrarily set with regard to the results in previously published literature, verifying that IVCCI values between 40 and 50% measured in spontaneously breathing patients are predictive for volume responsiveness in different clinical settings –16.Vital signs were recorded, and protocolled anesthesia induction was performed. Two minutes after drug administration but before intubating the trachea, the vital signs were measured again. The hemodynamic response was characterized in each group with the change in systolic blood pressure as the end point. Anesthesia-related hypotensive events were recorded if the systolic blood pressure dropped below 90 mmHg or a ≥ 30% drop in initial systolic pressure was observed.Patients in the surgical ward were evaluated before transportation to the operating room. Ultrasonographic scans were performed by one of four adequately trained independent anesthesiologists who had undergone institutional training for ultrasound use in anesthesia and who had at least 2 years of experience in the field. One of two ultrasound machines was used . Both machines were equipped with a curvilinear transducer (5 MHz). The inferior vena cava was visualized in B-mode from a longitudinal paramedian subxyphoid view; when a good echographic window was not available, an intercostal, transhepatic lateral view was used. The last section of the vein, which was proximal to the hepatic vein inflow and 0.5–3 cm from the right atrium, was selected for the M-mode, and measurements were performed as recommended in the consensus document of the American and European Cardiologic Societies . The maxRoutine premedication using alprazolam was given 1 hour before surgery. Regular cardiovascular medication of the patients was maintained on their established routine, except for diuretics and angiotensin-converting inhibitors, which were withdrawn. All patients were monitored continuously using ECG, pulse oximetry and capnography starting from the beginning of manual ventilation. Noninvasive blood pressure monitoring by oscillometry and invasive arterial blood pressure monitoring were used at the discretion of the anesthesiologist according to the details of the planned surgery and the risk level of the patient. Noninvasive measurements were obtained at 5 min intervals, and an additional measurement was obligatory 2 min after induction drug administration. This step preceded the intubation of the trachea. If invasive monitoring was used, an arterial cannula was inserted before induction, and postinduction vital signs were registered at the same time points as above. To induce general anesthesia, our institutional standard practice of using fentanyl (1–2 μg/kg), propofol  and nondepolarizing muscle relaxants (rocuronium or cis-atracurium) according to age, weight, chronic organ function and the needs of the surgery was not changed for study purposes.To calculate the sample size, the change in systolic blood pressure after induction drug administration was the variable of interest. A minimum difference of 15 mmHg was considered clinically important, and that in combination with a standard deviation of 25 mmHg coming from our pilot data of 103 patients not involved in the study were used for the calculations. A type one error of 0.05 and a required power of 0.80 were set. Assuming unequal study groups with a 1 to 3 ratio of patients having collapsing (CI+) and noncollapsing (CI-) IVC, we used corrected sample sizes . A minim2 and Fisher exact test were used for contingency table analysis as appropriate. Two-sided p-values are shown, and the limit of statistical significance was set to p < 0.05.Data were pooled for analysis in Microsoft Excel 2013 , a lack of adherence to the protocol (8 cases), a lack of data (2 cases) or a change in anesthesiological management (2 cases). Finally, 83 patients who matched all inclusion criteria were enrolled. Twenty patients were evaluated in the CI+ group and 63 in the CI+ group. The list of surgical operations performed is provided in Table P = 0.0001). The same phenomenon was present in the case of a relative decrease in systolic pressures: CI+ patients had a mean of 36.4 ± 9.1%, while this was 24.7 ± 11.3% in the CI- group (P < 0.0001). The results are shown in Fig. P = 0.0029) (data not graphed). Meanwhile, no difference was detectable in heart rate decrease, as CI+ patients presented a median of only 4 bpm (0 bpm–9.5 bpm), and 1 bpm (− 3 bpm–7 bpm) was observed among CI- patients (P = 0.1901).The mean postinduction decrease in systolic pressure in the CI+ group was 53.8 ± 15.3 mmHg, which was significantly higher than the 35.8 ± 18.1 mmHg observed among CI- patients , demonstrating a poor to fair diagnostic accuracy Fig. . As we pOur prospective observational study compared the hemodynamic consequences of the induction of general anesthesia by propofol in patient groups defined on the basis of having collapsing (IVCCI ≥50%) or noncollapsing (IVCCI< 50%) IVC, and we evaluated the diagnostic value of a high IVCCI value in the prediction of postinduction hypotension. We detected important differences between the two groups, verifying that a high IVCCI value was associated with a more profound change in systolic blood pressure and mean arterial pressure. This remarkable phenomenon is consistent with the general concept that the IVCCI is able to detect volemic changes. The IVCCI had high specificity and low sensitivity in experiments by Mueller et al. when a cutoff level of > 40% was used to predict volume responsiveness . HoweverOf note, most previous data are from intensive care settings in which IVC diameter and the IVCCI were used to identify volume-responsive patients in circulatory shock –16. Our Second, contrary to the results of the abovementioned articles, the IVCCI was evaluated in an otherwise hemodynamically stable patient population. Despite our systematic screening of the relevant literature, we were not aware of a similar study at the preparation of our study protocol. However, Zhang et al. reported the use of the IVCCI for the prediction of hypotension attributable to general anesthesia . Some imOur observational trial has limitations. First, we had to exclude 19 patients despite a slightly better visualization rate compared to that in the previously cited study with a similar approach , but adhWhen we focus on IVCCI’s diagnostic performance, our AUC of 64.8% together with the sensitivity and specificity levels should be evaluated in the context of the models currently available for the prediction of hypotension associated with general anesthesia. A recent multicenter observational study identified age, degree of high blood pressure prior to surgery and type II diabetes as risk factors . As thesAs a clinical interpretation of our results in spontaneously breathing preoperative noncardiac surgical patients, preoperative IVCCI measurement is feasible and can predict postinduction hypotension with high specificity but low sensitivity. Despite its moderate performance, IVCCI is an easy, noninvasive and attractive option to identify patients at risk of postinduction hypotension and should be explored further. The potential involvement of the IVCCI in multifactorial models can be a field of future studies.Additional file 1:Dataset of the study. Categorical questions were marked with 1 (yes) or 0 (no). (XLSX 26 kb)


Epidemiologic studies have demonstrated that systolic blood pressure (SBP) is the most important factor influencing cardiovascular risk. The results of clinical studies including the Systolic Blood Pressure Intervention Trial (SPRINT)  precededOngoing analysis of SPRINT findings has indicated that the increased cardiovascular risk in for participants with a low DBP may be explained by factors other than simply the DBP, such as higher age and higher prevalence of cardiovascular or chronic kidney disease. This suggests that a low DBP is not an independent risk factor for cardiovascular events ,4. This The results being highlighted here do not apply to all age groups. Only 28.2% of the patients in SPRINT were ≥75 years, and the mean age of participants in ONTARGET and TRANSCEND with a low DBP (<70 mmHg) did not exceed 70 years . ElderlyIt is tempting to answer the question posed in the title positively. We have convincing evidence that a low DBP should not stand in the way of intensive blood pressure reduction. On the other hand, as clinicians, we are aware that some of our older patients faint while on hypertensive treatment, so we cannot stop asking question, “Aren’t we going too low?” Thus, there is a need for more studies specifically among elderly patients focusing on the effect of a low DBP. In a superb review concerning the J curve, Messerli and Panjrath present a figure showing that subjects with coronary artery disease who have undergone revascularization tolerate a lower DBP better than those who have not been revascularized . KeepingDBP, diastolic blood pressure; SBP, systolic blood pressure; CI, confidence interval; composite clinical endpoint: myocardial infarction, acute coronary syndrome without infarction, stroke, acute decompensated heart failure, or cardiovascular death. DBP was included in the model at discrete variable thresholds of 60 mmHg and 70 mmHg and was not an independent risk factor.