Chronic kidney disease is associated with disruption of the endocrine system that distorts the balance between calcitriol, calcium, phosphate and parathyroid hormone in the calcium regulation system. This can lead to calcification of the arterial tree and increased risk of cardiovascular disease and death. In this study we develop a health metric, based on biomarkers involved in the calcium regulation system, for use in identifying patients at high risk for future high-cost complications.This study is a retrospective observational study involving a secondary analysis of data from the kidney disease registry of a regional managed care organization. Chronic kidney disease patients in the registry from November 2007 through November 2011 with a complete set of observations of estimated glomerular filtration rate, calcitriol, albumin, free calcium, phosphate, and parathyroid hormone were included in the study (n = 284). Weibull regression model was used to identify the most significant lab tests in predicting “waiting time to hospitalization”. A multivariate linear path model was then constructed to investigate direct and indirect effects of the biomarkers on this outcome.The results showed negative significant direct effects of phosphate and parathyroid hormone on “waiting time to hospitalization”. Base on this result, the risk of hospitalization increases 16.8% for each 0.55 mg/dl increase in phosphate level and 13.5% for each 0.467 increase in the natural logarithm of parathyroid hormone. Positive indirect effects of calcitriol surrogate , free calcium, albumin and estimated glomerular filtration rate were observed but were relatively small in magnitude.Variables involved in the calcium regulation system should be included in future efforts to develop a quality of care index for Chronic Kidney disease patients. Kidney disease is the ninth leading cause of death in the United States . ChronicThe main purpose of this study is to develop a health metric, based on variables involved in the calcium regulation system , a kidney function indicator (eGFR), and a set of kidney function associates , that is related to the risk of future high-cost complications. We test the significance of estimated direct and indirect effects of these kidney function measures and serum chemistry values on waiting time to hospitalization in CKD patients with widely varying severity of disease.m2 for 3 or more months [The National Kidney Foundation (NKF) defines CKD as either kidney damage or a sustained kidney glomerular filtration rate (GFR) of less than 60 ml/min/1.73 e months . An estie months . Age, die months .D3 , parathyroid hormone (PTH) and their influence on kidney function play an important role in controlling the level of phosphate and calcium in the bloodstream. Healthy kidneys are rich with 1-alpha hydroxylase enzyme, which plays a major role in turning vitamin D into its active form, calcitriol. Calcitriol acts on vitamin D receptors, which control calcium channels and therefore is an important component of the calcium regulation system. Secondarily, it controls the absorption of phosphate and in turn regulates PTH levels. When kidneys fail, their ability to activate vitamin D is diminished. Without the activated vitamin D to facilitate calcium and phosphate absorption, PTH will increase, which results in calcium and phosphate resorption from the bone [Phosphate (PO4), calcium, activated vitamin D 1,25-dihydroxyvitamin the bone ,13  as a surrogate for serum calcitriol. There is a significant biphasic relationship between serum calcitriol and serum calcidiol. This relation is positive at normal calcidiol levels, because of the effect of substrate deficiency on calcitriol production, but negative at low calcidiol levels, because secondary hyperparathyroidism simulates the synthesis of calcitriol [The data set analyzed contains blood test results: eGFR, calcidiol, albumin, Ca lcitriol . About 9The data set were drawn from the kidney disease registry of a managed care organization (MCO) during the 4 year period from Nov. 2007 through Nov. 2011. The data set also included age, gender, service date and a complete financial profile for all medical claims that were paid for these patients over that same time period. Service date is a date that medical services were provided. A service constitutes lab tests, procedures, hospital services, physician services, office visits, or other services for which claims were submitted. Charges for services were matched with corresponding date of service. This data was obtained after review of the study protocol by the university at Buffalo’s Health Sciences Institutional Review Board (HSIRB) and permission from the regional MCO.m2 for 3 or more months.) 284 of those had complete observation (see subsequent paragraphs). We compared the 284 selected patients (study group) to the remaining 5,515 CKD patients to check the representativeness of the sample analyzed. For each individual, we calculated the average lab tests over the entire time period and then used PROC TTEST in SAS software. Table α=0.05/7=0.007, using the Bonferroni correction, the means are not significantly different. Thus, we have no significant evidence that the sample of 284 patients analyzed in this study are not representative of all CKD patients in the registry.The registry contained records of 14,264 patients who were treated for kidney disease during this time period. 5,799 of those had confirmed CKD  is a more useful index than total calcium and provides a better indication of calcium status [It is generally agreed that the ionized (or free) calcium is the form that is biologically active. Because of this, free calcium , we considered the hospitalization interval in which a complete set of lab tests was observed and then defined the waiting time to hospitalization by the time from the left of that interval until the next hospitalization. For individuals with no hospitalization, we selected the first lab tests in the time interval from 3 weeks after first service date until the last service date. For these individuals with no hospitalization, waiting time to hospitalization is censored at C, where C is the time from 3 weeks after the first service date until the last service date. Also for individuals with at least one hospitalization and with a complete set of lab observations only after the last hospitalization, waiting time to hospitalization is also censored at C, where C is the time from 3 weeks after the last hospitalization until the last service date. . If a variable was non-normal a normalizing transformation was applied. We used the natural log transformation of the non-normal variable PTH to normalize it. No transformation was required for other lab variables because they appeared to be normally distributed, based on normal probability plot. The normal limits for lab test scores studied are given in Table z-Ca++denote the z-scores of the corresponding variables (transformed variable in the case of PTH).Using the normal limits in Table We first used a censored regression model ,19 to esln(Y)=μ+γ′Z+σ.ε with Weibull distribution for Y, σ is the scale parameter and ε is the error term. Z is vector of covariates and γ is the vector of regression coefficients, which represent the associations of each covariate with ln(Y). The values of a Weibull random variable range over the interval  and WTH >21 is garanteed given its definition in section ‘Definition of variables’, WTH is 21 days greater than the length of the hospitalization interval. Therefore, we used the transformation Y = WTH-21, which ranges from zero up, to better fit the Weibull model. Plot of the log of the negative log of the estimated survival function against log time (LLS plot) provided a visual check of the appropriateness of the Weibull model for Y.In the censored regression model We chose the Weibull model for the following reasons: • empirical evidence that it is reasonable; • the ability to calculate MSE and R-square type statistics that are analogous to those calculated for multivariate linear regression models;• the greater efficiency one can expect to achieve when using a fully parametric model versus the nonparametric Cox model;• and, because if fits when the parametric model assumptions are satisfied a linear mean function and, thus is a convenient choice for multivariate linear path modeling. (Multivariate linear path models involve linear mean function specifications.)kthvariable for a Weibull model is given by exp(−βk/σ) where βkis the corresponding regression coefficient for the kthvariable and σ is the scale parameter.The Weibull model also has a proportional hazards interpretation. We used residuals to investigate the proportional hazards assumption, using martingale and deviance residuals for the Cox proportional hazards regression analysis. There is no indication of a lack of fit of the model to individual observations. We also created plots of the cumulative martingale residuals against the values of the each covariate and computed the p-value of a Kolmogorov-type supremum tests based on a sample of 1,000 simulated residual patterns. There was no evidence to reject the proportional hazard assumption. With the Cox proportional hazards model, the regression coefficients correspond directly to the log of hazard ratios. The hazard ratio corresponding to the Path analysis is a statistical technique used to examine direct and indirect relationships among a set of causally ordered variables. Such relationships, if linear, can be described in a system of linear equations with random variables of interest and unknown parameters. Path analysis was first developed by Sewall Wright in the 1930s for use in phylogenetic studies ,21. ClasX→W→Z, can be examined. Indirect effects can be calculated by multiplying the corresponding direct effects. For example, indirect effect of X on Z in the pathway X→W→Z is product of direct effect of X on W and direct effect of W on Z. The p-value for testing the indirect effects can be found using the Intersection Union Test (IUT) [In linear path analysis direct effects, which are the corresponding regression coefficients, and indirect effects; i.e., those acting through an intermediate variable W, in the pathway st (IUT) . Total eIn this study not all of the variables of interest can be causally ordered in a unidirectional fashion. Sets of variables, however, can be ordered. Thus, we use multivariate linear path modeling, which requires only partial ordering; i.e., an ordering of sets of variables. The models then involve multivariate regression models in place of the univariate regression models associated with the classical path analysis. In the multivariate setting causal ordering is not necessary within each set of variables and the errors in the model for those variables are not required to be independent. In this application we assume the following causal ordering.Considering age as the exogenous variable and ln(Y) as the endpoint endogenous variable, we assume the following casual ordering of the variables, illustrated above. Note that we do not assume any causal ordering between z-eGFR, z-albumin and z-calcidiol, thus making our problem one that is conducive to MLPM.The assumption of casual ordering of variables, illustrated above, is based on the review of the literature presented above. Low eGFR, low calcitriol and low albumin can be manifestations of underlying kidney damage. Calcitriol has effects on calcium levels in the bloodstream. Low calcitriol inhibits absorption of calcium more than phosphate from the intestines, while resorption from the bone is equal, thus contributing to high serum phosphate levels. Low calcium induces high PTH, which causes calcium and phosphate resorption from bone. This bone resoption raises calcium to its proper level while raising phosphate above its desired level.Estimation of the multivariate path model parameters is achieved by the ordinary least square method ,25 appliR2, to measure the predictivity of the model outcome variable in terms of explained variability of the dependent variable [R2can not be calculated due to censoring. So for the measure of explained variation by this model, we used the Kent and O’Quigley [ln(Y)=μ+γ′Z+σ.ε, we have For the measures of goodness of fit, in the simple linear regression models, we used the squared coefficient of multiple determination, variable . We note’Quigley  product-σ is the scale parameter and  where γ and σ from the Weibull regression analysis. where Statistic calculations were performed using the SAS software. For the sample of 284 patients, the mean age was 66.3 years with standard deviation 12.8  years). There were 34 patients in stage 5 (kidney failure with eGFR ≤15), 85 patients in stage 4 (kidney damage with severely low eGFR 16-29), and 165 patients in stage 3 (kidney damage with moderately low eGFR 30-60).There were 70 individual with no hospitalization out of the 284 patients in our study and, hence, had censored observation. From the 214 individuals with hospitalization only 137 patients had a complete set of observed lab tests prior to the next hospitalization and 77 patients had a complete set of observed lab tests only after the last hospitalization. We had 147 (70 + 77) right censored values out of the 284 observations.Table ++, which is In Table σε where σ is the scale parameter of the Weibull distribution, with estimated value ε is an error with variance R2is presented for each other equation.We note that the error term in the censored regression model for ln(Y), Y = WTH-21, is α=0.05 for each linear model to obtain the most parsimonious model that includes only significant effects.The primary purpose of path modeling is to propose a plausible interpretation of the observed data and to describe effects in terms of significant direct and indirect effects. To find the best fitted model we used backward selection with significance level Table Figure X→W→Z is product of direct effect of X on W and direct effect of W on Z. The p-value for testing the indirect effects can be found using the Intersection Union Test (IUT) [++through z-PTH is 0.0414=(−0.37)(−0.113) with p-value = max{0.0002,0.011}=0.011. Total effects are defined as the sum of direct and all possible indirect effects.Indirect effects can be calculated by multiplying the corresponding direct effects along the indirect path from a variable to ln(Y). For example, indirect effect of X on Z in the pathway st (IUT) ,21,24. FFrom the result of the parsimonious path model, the direct and indirect effects of variables on ln(Y), Y = WTH-21, are as follows: • z-PTH and z-PO4 had significant direct effects of -0.112  and -0.137 , respectively.++had significant positive indirect effect through z-PTH of 0.0414 • z-Ca++of 0.0043. The total effect of z-Calcidiol is 0.0255.• z-calcidiol  had a significant positive indirect effect through z-PTH of 0.0212  and a positive indirect effect through z-Ca++of −0.0145. Thus, its total effect on ln(Y) was 0.0774.• z-albumin had a significant positive indirect effect through z-PO4 of 0.0293, a significant indirect positive effect through z-PTH of 0.0626 and a significant indirect negative effect through z-Ca++ of 0.00364. Thus, its total effect onln(Y) was 0.0549.• z-eGFR had a positive significant indirect effect through z-PO4 of 0.02918, a significant positive indirect effect through z-PTH of 0.02217 and a significant positive indirect effect through z-Ca++and z-PTH  for the total effect of 0.00043. This effect is clinically insignificant.• Age had a significant second order indirect effects, one through z-calcidiol and then through z-PTH  and a third order indirect effect through z-calcidiol, z-CaFrom the result of the censored regression model, we identified that PTH and PO4 are the most significant predictors of high-cost hospitalization and, along with albumin, they have the largest effects =1.135. The hazard ratio of 1.135 indicates that the risk of hospitalization will increase 13.5% for each 1 standard deviation increase in z-PTH. A one standard deviation increase in z-PTH corresponds to an approximate 0.467 increase in the natural logarithm of PTH level  or, equivalently a 60% increase in PTH.The negative significant effect of PTH on waiting time to hospitalization indicates patients with higher PTH are at higher risk of hospitalization. With Weibull model for ln(Y), the regression coefficients correspond directly to the log of hazard ratios so that a negative coefficient for a particular covariate corresponds to a higher risk of hospitalization occurring. The estimated hazard ratio corresponding to the effect of PTH is The negative significant effect of phosphate indicates higher risk of hospitalization for patients with higher phosphate levels. A hazard ratio of 1.168 associated with this effect indicates that the risk of a hospitalization will increase 16.8% for each 1 standard deviation increase in z-PO4. A one standard deviation increase in z-PO4 is approximately 0.55 mg/dl increase in PO4 level. Thus, the risk of hospitalization is estimated to increase by 16.8% for each 0.55 mg/dl increase in PO4.Extreme elevations of PTH levels along with hyperphosphatemia could result from an abnormal form of plasma PTH. The latter could result from an abnormal conversion of the pro-hormone to its secreted form .++on ln(Y), and hence on WTH, they are the most significant predictors of PTH and PO4. Therefore they had significant indirect effects on WTH through PTH and PO4. These effects are small, however, relative to the direct effects of PTH and PO4 on WTH.Although, we did not find significant direct effects of eGFR, albumin, calcidiol  and Ca++) was not observed directly in this study. Instead a derived version [++) and obtained essentially the same results. Since Ca++is what is regulated [++in this paper.Free calcium  levels predict mortality independent of bone metabolism parameters and liver function tests in CKD and chronic hemodialysis patients , we did R2for the ln(Y) equation is low, however, more work is needed to identify additional lab results that are also predictive. The potential role of Fibroblast growth factor FGF-23 should be considered as candidates for addition. Fibroblast growth factor FGF-23 is a recently discovered regulator of calcium-phosphate metabolism. In CKD patients, FGF-23 levels rise in parallel with declining renal function long before a significant increase in serum phosphate concentration can be detected [The current results provide a calcium regulation based health metric for identifying patients who are at high risk for future high-cost complications and that can be used as an outcome variable in assessing quality of care. Since the O’Quigley detected . UnfortuRace is known to be associated with both CKD progression and outcomes and is believed to have effects on PTH and calcium-phosphate metabolism. Our data, however, was provided without a race variable. It should be noted that the MCO calculated race specific eGFR’s and that those analyzed in this study are race adjusted. Further study should include race as a factor in addition to using it in the calculation of eGFR.From 14,264 patients in the registry of the MCO only 5,799 had confirmed CKD. 546 of them had observed lab test scores of interest during the 4 year period of study. Out of 546 patients 284 had observed lab scores in at least one hospitalization interval. Work to develop methods of imputation in the context of longitudinal data analysis is ongoing. Once completed, the method developed will allow more complete utization of data in the kidney registry.Additional work with data rich in lab scores is needed to identify the additional risk factors for use in predictive models to develop a health metric for assessing the quality of care of CKD patients, while adjusting for the illness severity of their case mix. Such a metric, if highly predictive of hospitalization, ESRD or death outcome could serve as the foundation of a reimbursement system that fairly rewards physicians for quality of care. The results of the current study are encouraging and justify a similar prospectively designed investigation.Variables involved in the calcium regulation system should be included in future efforts to develop a quality of care index for Chronic Kidney disease patients.The authors have no competing interests to declare.RLC and RWB designed research; RLC and MG performed and analyzed the data and wrote the paper; RLC and RWB edited the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/154/prepub


The European Society of Hypertension has recently published its recommendations on prevention, diagnosis and treatment of high blood pressure in children and adolescents. Taking this contribution as a starting point the Study Group of Hypertension of the Italian Society of Pediatrics together with the Italian Society of Hypertension has conducted a reappraisal of the most recent literature on this subject. The present review does not claim to be an exhaustive description of hypertension in the pediatric population but intends to provide Pediatricians with practical and updated indications in order to guide them in this often unappreciated problem.This document pays particular attention to the primary hypertension which represents a growing problem in children and adolescents. Subjects at elevated risk of hypertension are those overweight, with low birth weight and presenting a family history of hypertension. However, also children who do not present these risk factors may have elevated blood pressure levels. In pediatric age diagnosis of hypertension or high normal blood pressure is made with repeated office blood pressure measurements that show values exceeding the reference values. Blood pressure should be monitored at least once a year with adequate methods and instrumentation and the observed values have to be interpreted according to the most updated nomograms that are adjusted for children’s gender, age and height. Currently other available methods such as ambulatory blood pressure monitoring and home blood pressure measurement are not yet adequately validated for use as diagnostic instruments. To diagnose primary hypertension it is necessary to exclude secondary forms. The probability of facing a secondary form of hypertension is inversely proportional to the child’s age and directly proportional to blood pressure levels. Medical history, clinical data and blood tests may guide the differential diagnosis of primary versus secondary forms. The prevention of high blood pressure is based on correct lifestyle and nutrition, starting from childhood age. The treatment of primary hypertension in children is almost exclusively dietary/behavioral and includes: a) reduction of overweight whenever present b) reduction of dietary sodium intake c) increase in physical activity. Pharmacological therapy will be needed rarely and only in specific cases. Before reference nomograms for blood pressure in childhood were available, the diagnosis of hypertension was made only in the presence of highly elevated blood pressure levels. Practically only the most severe secondary forms were diagnosed. Through the publication of the first reference values is has bth percentile of the distribution of the systo-diastolic blood pressure values, according to gender, age and height. In order to conform to the adult terminology pre-hypertension or high-normal pressure hypertension is defined as blood pressure values consistently above or equal to the 90th percentile, but lower than the 95th..14].Hypertension is one of the main risk factors for the development of cardiac, cerebrovascular and renal diseases. It represents an important pathophysiological substrate for the development of atherosclerosis and consequent organ damage. Once hypertension has been diagnosed it is important to determine the presence of organ damage for the stratification of cardiovascular risk. Major attention should be paid to heart, arteries, kidney, nervous system and retina.2.7 for the presence of ventricular hypertrophy in childhood[2.7 have been proposed that have been derived from 2273 normal weight subjects aged between 0 and 18 years[Left ventricular hypertrophy which is associated with cardiac disease and mortality in adults is the organ damage that has been most documented in hypertensive children and adolescents. There are little data regarding the relationship between childhood hypertension and adult cardiovascular risk,16. It hhildhood. Recentl18 years.Many data have been published concerning early arterial lesions in hypertensive children. The most precocious change of the arterial wall that can be shown by ultrasound techniques is thickening of the intima-media layers-30. In tth percentile) progression of renal failure was delayed more compared to subjects with higher BP target (50th-90th percentile)[The kidney plays a central role in the development of many forms of hypertension. For this reason it is often difficult to determine the cause-effect relationship between increases in blood pressure and renal abnormalities. The prevalence of end-stage renal disease due to hypertension in adults is a well-known and worsening phenomenon. It is not entirely clear however to what extent rises in blood pressure contribute to the progression of renal alterations towards end-stage renal disease. Generally children and adolescents do not develop clinically evident renal abnormalities in response to increases in blood pressure. So the important question if there are any renal alterations in children with mild-moderate hypertension remains to be answered. The observation of contemporaneous hypertension and reduced glomerular filtration rate in children probably suggests the presence of a secondary form of hypertension. This also holds for the presence of proteinuria (>300 mg/day). The matter is more complex concerning microalbuminuria ; in adult hypertension microalbuminuria is a consolidated marker of cardiovascular risk, whereas in children more studies would be necessary to define its significance in the presence of elevated blood pressure values. In pediatric subjects with chronic kidney disease it has been shown that high blood pressure and proteinuria are the two main predictive factors for progression to chronic renal failure. To vericentile).A reduction in baroreflex sensitivity has been shown in children with hypertension and high-normal blood pressure when compared to normotensive children. While aCurrently there are few data in literature regarding the effect of blood pressure on the retinal circulation in children. Fifty-one percent of hypertensive children are supposed to have retinal alterations that can be detected by direct ophthalmoscopy. It has Hypertensive emergencies are defined as situations in which increases in blood pressure are accompanied by acute symptoms of organ damage: hypertensive encephalopathy  and congestive heart failure which expose the patients to life-threatening risks or to severe complications within minutes or hours. Hypertensive emergencies require immediate pharmacological treatment, while bearing in mind to avoid blood pressure reductions that are too abrupt. For this reason marked increases in blood pressure without symptoms of hypertensive encephalopathy or acute heart failure should be preferably treated with oral agents. As in children this condition is always due to secondary forms of hypertension specific tests should be performed-41.The Italian Health System guarantees the assistance of the vast majority of children by a Family Pediatrician. This resource should allow the activation of prevention strategies for the most important chronic and degenerative diseases, starting immediately at young ages. Among these conditions hypertension plays a major role due to its high prevalence, especially when combined to overweight. For this reason the physician who follows children during the developmental age should:•Collect an accurate family history to identify primary and secondary forms of hypertension.•Use standardized methods and suitable instruments for a correct measurement of blood pressure in the child and interpret the values according to the most extensive and updated tables.•Monitor blood pressure during annual control visits from the age of three.•Repeat the blood pressure measurement on at least three different occasions when values are observed that could indicate hypertension or high normal blood pressure.•Learn to make a first differential diagnosis between primary and secondary forms of hypertension on the basis of clinical history, physical examination, targeted examinations.•Send patients with suspect secondary hypertension to referral centers.•Apply the principles of the dietary and behavioral interventions in the treatment of the primary forms.•Send patients with suspect secondary hypertension and cases of primary hypertension who do not respond to dietary and behavioral therapy to specialist centers.•Cooperate with the specialist centers in the follow-up of the hypertensive child.th percentile, there should be a distinction between those who have values above the 99th percentile and those who do not present such high values (95-99th percentile). In the first case it is suitable to send the patient to a specialist center because of the high probability of secondary hypertension, whereas in the second case the presence of peripheral pulses and negative results of simple diagnostic tests  would direct towards the diagnosis of essential hypertension. In the latter condition, the Family Pediatrician can start dietary-behavioral therapy and send the child to a specialist center if no satisfactory improvement in blood pressure values is achieved. Once hypertension has been diagnosed it is advisable to search for other cardiovascular risk factors, such as total and HDL cholesterol, triglycerides, fasting glycemia and insulinemia. Figure National and international screening programs have identified a prevalence of 4% of children with high blood pressure, but theThe specialist centers have the duty to guarantee a multidisciplinary approach to the hypertension problem in children. They should provide pediatric, cardiologic, nephrologic, endocrinologic, dietary and in some cases psychological expertise. These centers should obtain ample experience in the evaluation of organ damage, interpretation of 24 hour ambulatory blood pressure monitoring and self-measurement of blood pressure at home. They should also have access to laboratory techniques and instruments necessary for the diagnosis of different forms of secondary hypertension. It is important that the specialist centers build communication channels between pediatricians and family doctors with the aim of outlining the therapy and monitoring the hypertensive child.Prevention should aim at avoiding the onset of hypertension both in children and in adults. Therefore the pediatrician should identify the main risk factors:•Family history of hypertensionA lot of international studies show that children coming from hypertensive families have a greater risk to present with elevated blood pressure values,8.•Low birth weightEpidemiological studies have shown that intrauterine growth delay and low birth weight are risk factors for hypertension and cardiovascular diseases in adulthood,44. A la•Overweight and obesityOverweight represents over 50% of all the causes of hypertension in children. The rel•Sedentary behaviorAdequate physical activity lasting 40 minutes for 3–5 times a week causes a reduction in blood pressure values,53. A du•Substances that increase blood pressureSalt rich diets already affect blood pressure in childhood, while pSome drugs increase blood pressure . Alcohol and excessive licorice consumption may increase blood pressure. Some psychoactive drugs and particularly cocaine and amphetamines raise blood pressure as well.•Cigarette smokeInfants whose mothers smoked during pregnancy have higher blood pressure than babies born from non-smoking mothers and they•Non sustained form of hypertensionThe finding of elevated blood pressure values at a control visit that is not confirmed at subsequent measurements could represent a risk factor for later development of hypertension. A recenTable The first blood pressure measurements in newborns with reliable techniques go back to the 1970’s. In those years Menghetti published mean systolic blood pressure values in 6.000 Italian full-term newborns between 43.1 mmHg on the first day and 62.0 mmHg after 6 days of life using ultrasound techniques. GeneralHypertension is defined secondary when causes can be found that can be treated with specific interventions. The causes of hypertension vary according to different periods in childhood. Secondary hypertension is more frequent during the first years of life whereas the prevalence of essential hypertension increases with age. The attention that has to be given in finding secondary causes of hypertension should be inversely proportional to age and directly proportional to the severity of the hypertension. The evaluation of children with hypertension should always be aimed at excluding secondary forms. In children hypertension due to renal causes (chronic kidney disease or renovascular hypertension) and aortic coarctation accounts for 70 to 90% of the secondary forms,69. EndoDietary-behavioral therapy is indicated in children with hypertension or high-normal blood pressure and should be advised to those with transiently elevated blood pressure values or with positive family history for hypertension. This therapy should be maintained even if pharmacological treatment is adopted as well-75. Non-•Reduction of overweight2 in m) depending on age and gender. Goals of the treatment are: maintaining a normal height-weight growth in normal weight children; trying to improve BMI by a greater increase in height compared to weight in overweight subjects up to 8 years of age; pursuing gradual weight loss in older children and adolescents with excess weight. In obese hypertensive subjects the aim is achieving weight loss, 1–2 kg a month in adolescents, through the adoption of a moderately hypocaloric diet. In all cases varied dietary schedules are advised which include all food groups and offer a correct division of the meals , having the best possible distribution of caloric  and non-caloric nutrients  according to the indications by LARN[th percentile according to the parameters of the American Academy of Pediatrics[As increased blood pressure is often associated with overweight,76,77, w by LARN and obse by LARN. In the diatrics), the di•Reduction of salt intakeTrials on the relationship between sodium intake and blood pressure in children are limited. In adults it has been demonstrated that moderate salt intake restriction reduces blood pressure in sodium-sensitive subjects, i.e. 50-60% of all hypertensives. A meta-•Increase in physical activityForty minutes of aerobic-based physical activity 3–5 days/week are required to improve cardiovascular function and reduce blood pressure in children. It is aPharmacological therapy, when needed, should not in any condition exclude dietary and behavioral therapy as the latter may allow dose reduction of drugs, better therapeutic control and more effective prevention of other cardiovascular risk factors.th percentile unless non-pharmacological interventions and in the case of initial organ damage (particularly increase in left ventricular mass). Drug therapy should be considered in the presence of severe obesity with concomitant diseases, and may later on be interrupted following a positive response to the dietary-behavioral interventions. The drugs that are currently recommended for the treatment of hypertension in adults are also prescribed for children and adolescents  reni sartans-95  calc sartans; d) diur sartans. Both re sartans,100.1-receptor blocker candesartan do not have any flavor and therefore they can easily be administered in little children. Treatment should start with a single drug. If the blood pressure goal is not reached within 4–8 weeks the dose should be increased or a second drug should be added. Not all drug combinations are rational: an R drug  can reasonably be associated with a V drug . In clinical practice fixed drug combinations are often used, the most frequently employed combination being an ACE-inhibitor plus a thiazide diuretic. The intervention of a specialist is always necessary when the patient weighs less than 10–15 kg, when the blood pressure goal is not reached after two drug treatment and in the presence of impaired renal function (in this situation thiazide diuretics are ineffective and should be replaced by loop diuretics such as furosemide).In practice it would be advisable to use drugs with prolonged effects (retard formulations should be avoided as they are badly absorbed by children and loose their prolonged effect once the tablets are split) and also to prescribe drugs with the least side effects. Adverse side effects are most frequent with diuretics, followed by beta-blockers, calcium antagonists, ACE-inhibitors and finally sartans. Almost none of the drugs used for treating hypertension has specific pediatric formulations. When tablets are divided or pulverized for use in children they often assume a distasteful flavor. The thiazide diuretics hydrchlorothiazide and chlorthalidone, the calcium antagonist lercanidipine and the ATThe present document endorses the recent recommendations of the European Society of Hypertension and represents their translation into the Italian clinical reality. Two specific aspects characterize our country regarding the hypertension problem among the pediatric population. On the one hand Italy, and especially the southern regions, is one of the leading European countries for prevalence of overweight. On the other hand there is a widespread organization of the primary health care of children and adolescents in the whole country. The increase of excess weight in children and adolescents may cause a rise in hypertension and other risk factors that are associated with overweight and obesity. The important increase of cardiovascular diseases that will arise once the present young generations will become adults is of great concern. Sufficient resources could become available to avert this phenomenon, provided that the entire society together with physicians and pediatricians in particular become aware of the severity and the urgency of the problem. For this reason preventive strategies such as promoting healthy lifestyle and nutrition as well as limiting salt and alcohol intake and quitting cigarette smoking are necessary. However, these general measures should be assisted by procedures aiming at revealing specific and individual cardiovascular risk factors. Blood pressure measurement of children and adolescents is definitely the most simple and economic of these procedures. This practice will reveal an important number of subjects with increased blood pressure values thus stimulating both the institutions that take care of children’s health  and scientific research workers. According to the recommendations of the European Society of Hypertension, the fut•Development of accurate non-mercury sphygmomanometer for auscultatory blood pressure measurement and accurate automatic devices for oscillometric blood pressure measurement and careful comparison of the two methods in children and adolescents•Implementation of reference values for office, 24h ambulatory and self-measured blood pressure in children and adolescents•Increase the knowledge of the use of out-of-office blood pressure measuring systems in children and adolescents•Collect data on early organ damage in order to allow risk stratification and to define treatment goals•Conduct large, long-term randomized therapeutic trials on the onset of early organ damage  to obtain information about when to start pharmacological therapy and about the blood pressure goals to achieve•Conduct controlled studies to define the advantages and disadvantages of antihypertensive treatment and establish adequate doses in children and adolescentsAll authors declared that they have no competing interests.All authors have been involved in drafting the manuscript and revising it critically for intellectual content and have given final approval of the version to be published. All authors read and approved the final manuscript.


The monitoring of the cardiac output (CO) and other hemodynamic parameters, traditionally performed with the thermodilution method via a pulmonary artery catheter (PAC), is now increasingly done with the aid of less invasive and much easier to use devices. When used within the context of a hemodynamic optimization protocol, they can positively influence the outcome in both surgical and non-surgical patient populations. While these monitoring tools have simplified the hemodynamic calculations, they are subject to limitations and can lead to erroneous results if not used properly. In this article we will review the commercially available minimally invasive CO monitoring devices, explore their technical characteristics and describe the limitations that should be taken into consideration when clinical decisions are made. The need for the precise quantification of cardiac output (CO) in high-risk surgical patients, both in the operative room and the intensive care unit, is vital in modern medical practice. While up to 20 years ago CO had to be estimated from the PAC, nowadays new, less invasive techniques are available. When used together with perioperative protocols aiming at improving CO and oxygen delivery (DO2), their use is referred to as hemodynamic optimization or goal-directed therapy (GDT) .Much has changed since the introduction of the pulmonary artery catheter (PAC) by Swan and Ganz in 1970 for the measurement of CO using the thermodilution method. Although in the context of moderate and high-risk surgery the beneficial effect of the PAC combined with goal directed therapy (GDT) has been established in a recent meta-analysis , the invThe term ‘minimally invasive cardiac monitoring’ encompasses all the methods and devices that calculate the cardiac output without the need of inserting a PAC, ranging from methods almost non-invasive to marginally less invasive than the PAC. These include the pulse pressure analysis, the transpulmonary thermodilution, the indicator dilution, the esophageal Doppler, the thoracic electrical bioimpedance, the carbon dioxide rebreathing, and the echocardiography. Since each one of these devices utilizes a different method of estimating the cardiac output, the clinician should be aware of their distinct features, their limitations but also the sources of potential error that stem for their use.The pulse pressure analysis uses the arterial waveform, obtained either from an arterial catheter or a finger probe, in order to calculate the stroke volume (SV) and the systemic vascular resistance (SVR).Its principles first described by Erlanger and Hooker in 1904 , pulse pThis and the fact that the compliance is also age-related, prevented any straightforward correlation of the pressure to the volume . Only inOne should always keep in mind that the pulse pressure method relies heavily on an optimal arterial pressure tracing, making an under- or over-damped arterial waveform a potential source of errors in calculation. Moreover, the pulse pressure systems necessitate an arterial wave that is purely reflective of the forward SV. As a consequence, situations in which the arterial wave is distorted either by artifact or a physiologic phenomenon  will lead to inaccuracies . FinallyA variety of commercial systems that make use of the pulse pressure analysis method are available and they are divided in two groups, depending on the way that they are calibrated. Monitors that are ‘autocalibrated’ consist of the FloTrac/Vigileo, the Pulsioflex, the LidCO rapid, and the recently introduced Nexfin and esCCO monitors. On the other hand, there are devices that are externally calibrated: the PiCCOplus and the recently developed EV1000 use the transpulmonary thermodilution method, while the LidCO plus utilizes the lithium dilution technique for the same purpose. Moreover, apart from being useful tools in CO calculations, these monitors can also help predict the fluid responsiveness, as will be discussed later in this review article.Connected to a standard indwelling arterial catheter, the FloTrac sensor  uses an upgraded algorithm that derives the SV from the pulse pressure (PP) of the arterial waveform, after correcting for the compliance and the resistance of the arterial system.A similar pulse pressure analysis method is used by the ProAQT sensor which is incorporated in the Pulsioflex monitor . Utilizing an existing peripheral arterial catheter and analyzing the arterial waveform 250 times per second, a start value for CO trend monitoring is determined after the patient’s characteristics are inserted to the system. To increase accuracy, a CO value measured by another method (for example by echocardiography) can be entered and thus the system can be externally calibrated.As for the LidCO rapid system , it is based on the same algorithm as the LidCO plus monitor (which will be described later), but instead of thermodilution it relies on nomograms for the calculation of the CO.2I) is derived.One of the latest additions to the field of minimally invasive CO monitoring is the Nexfin monitor . Rather than a minimally invasive monitor, it is a completely non-invasive method of determining the patient’s hemodynamic parameters, as the need for an invasive arterial catheter is obviated. The monitor is connected to the patient by wrapping an inflatable cuff around the middle phalanx of the finger. The pulsating finger artery is ‘clamped’ to a constant volume by applying a varying counter pressure equivalent to the arterial pressure resulting in a pressure waveform. The finger arterial pressure is then reconstructed into brachial arterial pressure waveform using a transfer function and a level correction based on a vast clinical database. The resulting brachial pressure waveform serves as the basis for determining continuous CO. Real-time continuous CO and other hemodynamic parameters are derived by a novel pulse contour method (Nexfin CO-Trek®), which is based on the systolic pressure area and a physiological three-element Windkessel model individualized for each patient. Moreover, the presence of a co-oximeter enables the non-invasive calculation of hemoglobin, from which the oxygen delivery index . Also being a non-invasive monitor, it uses a new technology that derives the CO using the Pulse Wave Transit Time (PWTT), which is obtained by the pulse oximetry and the ECG signals of each cardiac cycle. The rationale behind this is that animal studies have shown a strong correlation between the SV and the PWTT. The only up-to-date validation study has demonstrated a clinically unacceptable performance of the device when compared to the CO values obtained with transthoracic echocardiography .The accuracy of the pulse pressure analysis method in estimating CO has been extensively investigated against CO calculations by the thermodilution method using the PAC. This holds true particularly for the FloTrac/Vigileo monitoring. In one of the most recent meta-analyses, Mayer et al.  showed iGiven its straightforward setup and use, it seems that the FloTrac/Vigileo is a useful tool correlating well with the gold standard of the thermodilution method with the PAC, in patients with a regular rhythm and stable respiratory pattern and mechanics, hospitalized in an environment with less abrupt hemodynamic changes as is the intensive therapy unit (ITU). While awaiting for further studies to assess this relationship, a more cautious approach should be adopted when it is used to assess the CO in patients that rely on substantial inotropic or vasopressor support or in environments and settings with rapid dynamic changes, as in the operating room (OR).Despite its relatively short presence in the market, the non-invasive Nexfin monitor has also been validated against the traditional methods of CO calculation, yielding positive results so far. Two different research groups demonstrated a reasonable correlation of CO values obtained by the Nexfin when they were compared with those calculated by transpulmonary thermodilution, both in the setting of cardiac surgery ,14. The The PiCCOplus monitor , which is based on the pulse pressure analysis to provide continuous real-time assessment of the CO, uses the transpulmonary thermodilution for intermittent calibration, being until recently the only device to incorporate this method in a commercial application. This method is based on the same principle as the traditional thermodilution but spares the need for a PAC insertion. The technique starts with the injection of a cold injectate in the superior vena cava (SVC) via a central venous catheter (CVC) which mixes with the ambient blood and travels through the right heart, the pulmonary vasculature and the left heart before reaching the aorta. A thermistor in the aorta or a major arterial branch measures the blood temperature and a thermodilution curve of temperature over time, similar to that from the PAC-based method but having a delayed peak temperature change, is plotted. The CO is measured by the thermodilution equation:B=blood temperature, TI=injectate temperature, and K=−computation constant  , which iSince a pulse contour method is used for continous CO display, the same limitations as in the FloTrac/Vigileo monitor apply for the PiCCOplus . Sources of potential errors that are specific for the transpulmonary thermodilution come from the fact that the PiCCOplus estimates the CO of the left heart whereas the PAC thermodilution that of the right side. These should be identical in ideal conditions, however a discrepancy is encountered in the presence of intracardiac and intrapulmonary shunts. Moreover, conditions related to indicator loss in the tissues  or recirculation will lead to a discrepancy of the calculated CO compared to the one derived by the PAC thermodilution, although these two phenomena may actually cancel each other .Regarding the reliability of the method, it appears that there is good correlation of the CO measurements obtained with the PiCCOplus compared to other methods. Two studies performed on pediatric animal models by the same scientific team showed a significant correlation when the transpulmonary thermodilution derived values were juxtaposed to those obtained with an ultrasound probe around the main pulmonary artery, both in normal cardiac anatomy and in the presence of a left-to-right shunt ,21.An older study confirms the good performance of the transpulmonary thermodilution even during substantial variations in vascular tone and hemodynamics . Taking The latest entry in the area of minimally invasive CO monitoring using the transpulmonary thermodilution comes from Edwards Lifesciences, which developed the EV1000/VolumeView monitor . Needing, as the PiCCOplus does, a specific to the set central arterial catheter and using a patented for the company algorithm, it also displays volumetric parameters as the EVLW and GEDV but also a new variable named the global ejection fraction (GEF). A recent clinical validation study proved the interchangeability of this new method to the PiCCOplus monitor, with VolumeView scoring better in the calculation of GEDV .+-sensitive electrode attached to the catheter that generates a voltage [The last of the calibrated CO monitors is the LidCOplus  that utilizes the lithium dilution technique. Based on the pulse power rather than the pulse pressure analysis via the PulseCO algorithm, which does not rely on the arterial waveform morphology, and needing only a peripheral arterial catheter, the LidCOplus technology uses the lithium dilution to intermittently calibrate the system. Specifically, boluses of 0.5-2 mL of lithium chloride are each time injected through a peripheral or central line and the lithium concentration is measured through aspiration of blood from the arterial catheter, using a Li voltage . Since t voltage .Apart from the expected lack of accuracy of the LidCOplus technology in a patient already on lithium treatment, the other interference that should be taken into account is the use of bolus doses of muscle relaxant drugs in the operative and intensive care setting. High peak doses of these drugs can cross-react with the lithium sensor as they incorporate a positively charged quaternary ammonia ion that can be detected by the sensor and thus lead to an overestimation of the CO. Muscle relaxant agents which are not compatible with the LidCOplus monitor are atracurium and rocuronium, whereas suxamethonium, vecuronium, and pancuronium can be used provided that a time interval of 15–30 minutes elapses between their bolus administration and the LidCOplus calibration.The consistency of the CO measurement with the LidCOplus technology compared to the traditionally established thermodilution method with the PAC, has been investigated in a number of validation studies. In one of the most recent studies by Mora et al. , the litThe Esophageal Doppler (ED) monitor, which is based on the Doppler effect in order to measure the velocity of blood flow, was first introduced in the 1970s as a non-invasive means to measure CO. The velocity is calculated from the following equation:d is the frequency shift, f0 is the frequency of the emitted ultrasound, and θ is the angle between the ultrasound beam and the direction of the blood flow. If the flow of blood in the descending aorta is known, this figure can be used to estimate the stroke volume and hence the cardiac output. The esophageal Doppler measures the velocity of blood in the descending aorta in centimeters per second (cm/s). In order to convert this figure into blood flow in milliliters per second (mL/s), the diameter of the aorta needs to be known. This is derived from published nomograms based on age, sex, weight, and height  or through direct ultrasound measurement . The ED also has the ability to measure the corrected flow time (FTc) as a measure of cardiac preload. The FTc is the duration of flow during systole corrected for a heart rate of 60 beats per minute. It is unclear as to whether the FTc or SV should be used to guide fluid therapy, but it appears that the ability to respond to a fluid challenge is best determined by FTc. Several studies have compared FTc with other indices such as pulmonary artery occlusion pressure and have found good agreement between the two [where v is the blood flow velocity, c is the speed of sound in tissue, f the two -32.There are some limitations to the usage of ED. First, the ED only measures descending aortic blood flow, which may not always be constant due aortic pathology or compression or due to abnormal upper to lower body blood flow distribution. Also, the aortic cross-sectional area is not constant, due to changes in pulse pressure, vascular tone, aortic compliance, volume status, or catecholamine use. Due to the fact that the radius of the aorta is squared in the final CO equation, even small changes in aortic area can significantly affect CO determinations . Moreoveversus anesthetist-directed fluid therapy in 108 patients undergoing elective colorectal resection. They found that despite both groups of patients receiving the same volume of intraoperative fluids, the group managed with the ED had a shorter hospital stay and lower morbidity rates than the control group. Interestingly, patients in the intervention group also had lower levels of interleukin-6, which suggested an attenuated inflammatory response to surgery, perhaps due to the improved organ perfusion. In a study by Wakeling et al. patients recovered gut function significantly faster and suffered significantly less gastrointestinal and overall morbidity [There have been studies that have compared ED measurements of CO with PAC-derived thermodilution CO. Dark and Singer performed a literature review regarding the validity of ED monitoring as a measure of CO in critically ill adults, concluding that the ED monitor has high validity in tracking changes in CO . In addiorbidity . These oorbidity .A completely non-invasive Doppler technology, the USCOM , is also available which uses Doppler technology to measure CO from a suprasternal Doppler probe. This technology has been studied in a few patient population groups (mostly stable ICU patients) and has shown reasonable correlation with PAC ,43.Variations in the electrical impedance of the thorax to an alternating current which occur synchronously with the cardiac cycle were observed nearly 40 years ago. The first use of this phenomenon to measure SV and CO was described by Nyboer , and KubElectrical bioimpedance involves the analysis of intrabeat variations in transthoracic voltage in response to the applied high frequency transthoracic current. Two commercial devices based on electrical bioimpedance use electrodes attached to an endotracheal tube  or the skin . Pulsatile changes in thoracic blood volume result in changes in electrical impedance. The rate of change of impedance during systole is measured and an estimate of the SV and the CO is derived from a mathematical equation.Sources of potential inaccuracies include motion artifacts, electrical interference, cardiac arrhythmias, heart and lung pathologies , and foreign bodies (as chest tubes). Clinical trials of TEB have been shown to be reliable in young healthy volunteers, but in septic or surgical patients, the results have been inconsistent -48.Recently, bioreactance , a modification of thoracic bioimpedance, has been introduced. Bioreactance refers to the electrical resistance, capacitive and inductive properties of blood and biological tissue that induce phase shifts between an applied electrical current and the resulting voltage signal. In contrast to bioimpedance, the bioreactance technique analyzes the frequency spectra variations of the delivered oscillating current. When blood flows out of the heart, phase shifts occur if alternating currents are applied across the patient’s chest. Such phase shifts are conceptually similar to a frequency modulation as used in radio transmission. The phase shifts are measured continuously and have been shown to relate almost linearly to blood flow in the aorta. This results in less interfering from the electrical noise, patient movement, respiratory effort, lead placement, and body mass index.In addition to cardiac output, mean bioreactance measurements are indicative of the total thoracic fluid content (TFC). TFC is affected by both intravascular and extravascular fluid in the chest cavity and although it does not correlate with pulmonary artery wedge pressure (PAWP), its changes are very reliable indicators of the changes in intravascular or extravascular fluid volume . In a stIt appears that the new generation of devices might be better than the first generation TEB machines, although there are still limitations regarding their accuracy in measuring CO during dynamic conditions.The partial carbon dioxide (CO2) rebreathing technique uses the Fick principle applied to the CO2 in order to estimate CO non-invasively. The NICO monitor  implements intermittent partial rebreathing through a specific disposable rebreathing loop. The monitor consists of a CO2 sensor, a disposable airflow sensor and a pulse oximeter. CO2 production (VCO2) is calculated from minute ventilation and its CO2 content, whereas the arterial CO2 content (CacO2) is estimated from end-tidal CO2, with adjustments for the slope of the CO2 dissociation curve and the degree of dead space ventilation. The partial rebreathing reduces CO2 elimination and increases end-tidal CO2. Measurements under normal and rebreathing conditions allow one to omit the venous CO2 content (CvCO2) measurement in the Fick equation, because CvCO2 does not change during this brief period of rebreathing .While the technique is easy to use, the correlation between the NICO and standard thermodilution has been shown to be adversely affected in spontaneously breathing patients, which limits the number of suitable candidates ,53. Partper se, the ClariTEE uses a monoplane transducer that enables the operator to acquire basic views of the heart  that, combined with a software tool, offer continuous calculations of the ventricular size and systolic performance. Moreover, echocardiography derived measurements of the stroke volume can help in the assessment of fluid responsiveness [Widely used in the cardiac operative and postoperative setting to demonstrate cardiac anatomy and identify pathology, the transesophageal echocardiography (TOE) has been impractical in assisting with continuous CO measurements outside the operative theater because of the size of the probe and the limitations that come with it. However, the recent development of a miniaturized 5 mm TOE probe  that can stay indwelled for up to 72 hours, has enabled hemodynamic management of the critically ill patients . Althougsiveness . ValidatThe assessment of intravascular volume status of an individual has been traditionally performed with static parameters, mainly filling pressures such as CVP and PAWP, which reflect the preload of the right and the left ventricles, respectively. It is now acknowledged that these values correlate poorly with the intravascular volume and the response to a fluid bolus , hence tAll the devices that use the pulse pressure analysis method for CO monitoring, also calculate those two parameters. Based on the effect of the cyclic variation of intrathoracic pressures with respiration on the preload of the left ventricle and using appropriate algorithms, the beat to beat variation of the SV and the pulse pressure (PP) is calculated. Specifically, positive pressure ventilation induces cyclic changes in vena cava blood flow, pulmonary artery flow, and aortic blood flow. During inspiration, vena cava blood flow decreases (venous return decreases) and, according to the Frank-Starling relationship, pulmonary artery flow decreases. Approximately three beats later this decrease in pulmonary artery flow is transmitted to the left ventricle inducing a decrease in SV and aortic PP. As a general rule, values of SVV >10% and PPV >13% are indicative of patients that will probably respond to the administration of fluids, while lower values indicate the opposite. The basic limitation is that the above calculations can only be applied to mechanically ventilated patients, as the correlation in spontaneously breathing individuals is weaker. Moreover, for optimal results the tidal volume (TV) should be >8 mL/Kg of body weight, the patient should be in sinus rhythm, and the chest must be closed   may help with the prediction of fluid responsiveness. The PVI is continuously calculated by the new non-invasive Masimo monitor , a device that resembles the traditional pulse oximeter. The monitor measures first the change during a respiratory cycle of the Perfusion Index (PI), which is the ratio of non-pulsatile to pulsatile blood flow through the peripheral capillary bed, and then calculates the PVI from the following formula:The greater the PVI value is, the more likely the patient will respond to fluid administration . As is tAll the above methods of quantifying the CO have the potential to reduce the morbidity and mortality of the patients if they are integrated into appropriate protocols that guide the therapeutic interventions. The use of CO measurements to guide fluid administration and inotropic therapy, optimizing this way the tissue perfusion and cellular oxygenation has been given the broad term goal-directed therapy (GDT). Its beneficial effects demonstrated as early as the late 1970s by the seminal work of Shoemaker and his team ,64, it iA whole array of minimally invasive devices and monitors that can reliably calculate trends in the CO without the need for a PAC are now available to the clinicians. Needing only peripheral or central arterial catheters or only a finger probe, as is the case in the Nexfin and Masimo monitors, they can give reliable measurements of CO and of dynamic indices such as the SVV and the PPV, provided that their limitations are taken into account.Additional tools in the area of minimal invasiveness are the OD, with its use strongly advocated by recent NICE guidelines, and the less widely used gas rebreathing and thoracic bioimpedance methods. Last, the introduction of a miniaturized TOE probe may revolutionize the management of ITU patients, providing real-time information on cardiac anatomy and function.The integration of these devices into therapeutic protocols enables the clinician to apply GDT and guide the inotropic support and fluid administration in a rational way, reducing this way the mortality and morbidity of the patients.AAA: Abdominal aortic aneurysm; BP: Blood pressure; CABG: Coronary artery bypass grafting; CI: Cardiac Index; CO: Cardiac output; CVC: Central venous catheter; CVP: Central venous pressure; DO2: Oxygen delivery; DO2I: Oxygen delivery index; ED: Esophageal Doppler; EPCI: Ejection phase contractility index; EVLW: Extravascular lung water; FTC: Corrected flow time; GDT: Goal-directed therapy; GEDV: Global end-diastolic volume; GEF: Global ejection fraction; HR: Heart rate; IABP: Intra-aortic Balloon Pump; ITBV: Intrathoracic blood volume; ITU: Intensive Therapy Unit; NICE: National Institute for Health and Clinical Ecxellence; OR: Operating room; PAC: Pulmonary artery catheter; PP: Pulse pressure; PAWP: Pulmonary artery wedge pressure; PWTT: Pulse wave transition time; PI: Perfusion index; PPV: Pulse pressure variation; PVI: Pleth Variability Index; PVPI: Pulmonary vascular permeability index; SV: Stroke volume; SVC: Superior vena cava; TEB: Thoracic electrical bioimpedance; TOE: Transesophageal echocardiography; TV: Tidal volume; VEPT: Volume of electrically participating tissues; VET: Ventricular ejection time.CC and LV declare no competing interests. MH has received lecture fees and expenses from Deltex Medical, Edwards Lifescienses, LidCO. MC has received honoraria, travel expenses, or unrestricted educational grants from LiDCO, Edwards Lifesciences, Deltex, Cheetah, Masimo, and Bmeye; he is part of the medical advisory board of Applied Physiology.CC has drafted the manuscript apart from the sections for the esophageal Doppler, the thoracic electrical bioimpedance, the bioreactance, and the gas rebreathing. LV has written the sections for the esophageal Doppler, the thoracic electrical bioimpedance, the bioreactance, and the gas rebreathing. MH has critically reviewed the manuscript. MC has conceived and critically reviewed the manuscript. All authors have read and approved the final version of the manuscript.


Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.UMIN000010142UMIN-CTR:  It is well established that hypertension complicated with T2DM results in an increased incidence of cardiovascular disease . Hence, Pioglitazone is a diabetic medicine that improves insulin resistance. That pioglitazone directly reduces the incidence of cardiovascular events and stroke was shown by the PROactive Study, a large-scale clinical trial ,6. The pBecause the prevalence of metabolic syndrome has increased worldwide and the number of hypertensive patients with diabetes is also expected to increase, the opportunities for clinicians to use an ARB in conjunction with an anti-diabetic medication are expected to grow. Therefore, verifying the effectiveness of this combination therapy in patients with hypertension and diabetes is of clinical significance. However, the utility of such combination therapy from the viewpoint of their anti-inflammatory effects has not been clarified.In this study, we administered as an ARB candesartan, which is the only sartan approved for use in chronic heart failure patients in Japan, and pioglitazone, an anti-diabetic medicine that improves insulin resistance, for 6 months to hypertensive patients with T2DM of long duration but without a history of cardiovascular events. We evaluated whether there was improvement in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of HbA1c and blood pressure and changes in inflammatory factors. Furthermore, the relationship between pulse pressure and the degree of lowering of HbA1c and changes in inflammatory factors was analyzed. Finally, we analyzed predictors of which patients would benefit from co-administration of candesartan with pioglitazone through their organ protective effects.In this prospective study, patients were targeted for enrollment among hypertensive patients with T2DM , SBP, DBP, HbA1c, fasting plasma glucose (FPG), HMW-ADN, PAI-1, Hs-CRP, VCAM-1, and U-8-OHdG. To evaluate tolerability of candesartan and pioglitazone, all adverse events were recorded. All plasmatic parameters were measured after a 12-h overnight fast. In all cases, venous blood samples were taken between 800 and 900 h. We used plasma obtained by the addition of Na2-EDTA (1 mgml_1) and centrifuged at 3000 g for 15 min at 4°C. All measurements were performed in a central laboratory. BMI was calculated as weight (kg) divided by the square of height (m). Height and weight were determined using a standard scale . Blood pressure measurements were obtained from the right arm while patients were in a seated position using a standard sphygmomanometer  (Korotkoff I and V) with an appropriately-sized cuff. Furthermore, the same investigator measured patients’ blood pressure at each visit, always in the morning and after the patient had rested for at least 10 min in a quiet room. Three successive blood pressure readings were obtained at 1-min intervals, and the mean of the three readings was calculated. HbA1c level was measured by high-performance liquid chromatography (HPLC) , with intra- and interassay coefficients of variation (CsV) of 1%. Plasma glucose was assayed by the glucose-oxidase method  with intra- and inter-assay CsV of 0.8%. Plasma HMW-ADN level was determined using a chemiluminescent enzyme immunoassay (CLEIA) . Plasma VCAM-1 level  was determined using an enzyme-linked immunosorbent assay (ELISA) . Plasma PAI-1 levels  were determined using a latex photometric immunoassay (LPIA) . The U-8-OHdG level  was measured using HPLC . Plasma Hs-CRP level  was measured using the latex agglutination nephelometry method .Statistical analysis of data was performed using the Statistical Package for Social Sciences software, version 19.0 . Data are presented as the mean ± s.e. For all statistical analyses, P<0.05 was considered statistically significant.Of the 41 patients who were enrolled in the study, 39 completed the study. The reason for premature withdrawal was lost-to-follow-up. Characteristics of the patient population upon entering the study and the antidiabetic treatments taken before and during the study are shown in Table Furthermore, significant improvements in baseline values for HMW-ADN and PAI-1 were recorded in all patients after 6 months of treatment . VCAM-1, U-8-OHdG, and Hs-CRP values did not decrease from baseline after 6 months of candesartan with pioglitazone treatment Figure .Stepwise multilinear regression analysis was performed to establish which factors could best predict changes in patients’ inflammatory factors. Co-administration of candesartan with pioglitazone improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with T2DM of long duration independent of blood pressure changes. In addition, the following positive correlations with changes in HbA1c (⊿HbA1c) were revealed: ⊿HbA1c vs. ⊿HMW-ADN  and the following parameters: ⊿SBP vs. ⊿HMW-ADN, ⊿SBP vs. ⊿PAI-1, ⊿DBP vs. ⊿HMW-ADN, and ⊿DBP vs. ⊿PAI-1 Figure A, B.In this prospective trial of patients with hypertension and T2DM, we observed that co-administration of candesartan with pioglitazone had beneficial effects with regard to hypertension, inflammation, and adipose tissue metabolism. In particular, patients receiving treatment with both agents experienced a significant improvement in blood pressure, HbA1c, HMW-ADN, and PAI-1. Furthermore, we analyzed predictive factors in patients who received the greatest benefits from the co-administration of candesartan with pioglitazone.Both candesartan and pioglitazone were clinically proven to provide direct cardiovascular protection through pleiotropic effects -16 not oThat there has been an increase in hypertensive patients with T2DM supports the clinical importance of this research. Our data suggest that this therapy was effective from the viewpoint of inflammatory parameters (HMW-ADN and PAI-1) for hypertensive patients with T2DM with a cardiovascular risk. However, these data were not investigated at the same time for the same purpose, which might be considered a limitation of this study. Large-scale prospective multi-arm studies are expected in the future.A positive correlation was observed in ⊿HMW-ADN and ⊿PAI-1 and changes in HbA1c Figure A, B. Our⊿SBP and ⊿DBP correlation analyses did not indicate patterns of associations with these parameters  and pulse pressure values at baseline. Furthermore, multiple regression analysis showed that pulse pressure was independent of age and BMI Table . In summAmong our study patients, we did not observe increases in body weight, exacerbation of heart failure, and the development of bladder cancer after 6 months of treatment. In France, analysis revealed a significant association between pioglitazone and bladder cancer in men . But in This was a pilot study. It was a single group pre-post study of a small number of patients with unbalanced distribution between men and women. Co-administration therapy for 6 months was less effective with regard to VCAM-1, U-8-OHdG, and Hs-CRP. The precise reason is unknown. Results of larger clinical trials evaluating the anti-inflammatory effects of the co-administration of candesartan with pioglitazone are awaited.In conclusion, the simultaneous co-administration of candesartan with pioglitazone improved inflammatory parameters (HMW-ADN and PAI-1), and improvements in inflammatory parameters were correlated with ⊿HbA1c. Pulse pressure values at baseline can become a key predictive factor for changes in patients’ HbA1c. The co-administration of candesartan with pioglitazone could be an effective therapeutic strategy for treating hypertensive patients with T2DM.BMI: Body mass index; DPB: Diastolic blood pressure; ELISA: Enzyme-linked immunosorbent assay; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin A1c; HMW-ADN: High-molecular-weight adiponectin; Hs-CRP: Highly sensitive C-reactive protein; PAI-1: Plasminogen activator inhibitor-1; SBP: Systolic blood pressure; T2DM: Type 2 diabetes mellitus; U-8-OHdG: Urinary 8-hydroxydeoxyguanosine; VCAM-1: Vascular cell adhesion molecule-1.The authors declare that they have no competing interests.HS and MS conceptualized the research hypothesis and analyses, researched the data, performed all of the statistical analyses and wrote the manuscript. TH, HI, TI, KO, NS and YK reviewed and edited the manuscript. KT, MY and KU assisted in conceptualizing the research question and reviewed and edited the manuscript. All authors read and approved the final manuscript.Inflammatory factors vs. ⊿HbA1c. (A). ⊿VCAM-1 vs. ⊿HbA1c: r=0.318, P=0.058; (B). ⊿8-OHdG vs. ⊿HbA1c: r= 0.215, P=.201; (C). ⊿Hs-CRP vs. ⊿HbA1c; r= 0.239; P=0.203.Click here for fileInflammatory factors vs. ⊿SBP. (A). ⊿VCAM-1 vs. ⊿SBP: r=−0.085, P=0.642; (B). ⊿U-8-OHdG vs. ⊿SBP: r=0.043, P=0.823; (C). ⊿Hs-CRP vs. ⊿SBP: r=−0.278, P=0.170.Click here for fileInflammatory factors vs. ⊿DBP. (A). ⊿VCAM-1 vs. ⊿DBP: r=−0.066, P=0.726; (B). ⊿U-8-OHdG vs. ⊿DBP: r=−0.132, P=0.494; (C). ⊿Hs-CRP vs. ⊿DBP: r=−0.286, P=0.156.Click here for fileCo-administration vs. single candesartan. After adjusted HbA1c in both patients, co-administration arm compared to candesartan administration only arm significantly improved in ⊿HMW-ADN and ⊿PAI-1 (%). *P<0.05 vs Candesartan (Can). Error bars indicate SEM for Can and for Candesartan + Pioglitazone (Can + Pio).Click here for file


In ICUs, fluid administration is frequently used to treat hypovolaemia. Because volume expansion (VE) can worsen acute respiratory distress syndrome (ARDS) and volume overload must be avoided, predictive indicators of fluid responsiveness are needed. The purpose of this study was to determine whether passive leg raising (PLR) can be used to predict fluid responsiveness in patients with ARDS treated with venovenous extracorporeal membrane oxygenation (ECMO).We carried out a prospective study in a university hospital surgical ICU. All patients with ARDS treated with venovenous ECMO and exhibiting clinical and laboratory signs of hypovolaemia were enrolled. We measured PLR-induced changes in stroke volume (ΔPLRSV) and cardiac output (ΔPLRCO) using transthoracic echocardiography. We also assessed PLR-induced changes in ECMO pump flow (ΔPLRPO) and PLR-induced changes in ECMO pulse pressure (ΔPLRPP) as predictors of fluid responsiveness. Responders were defined by an increase in stroke volume (SV) > 15% after VE.n = 13), SV increased by > 15% after VE (responders). The patients' clinical characteristics appeared to be similar between responders and nonresponders. In the responder group, PLR significantly increased SV, cardiac output and pump flow (P < 0.001). ΔPLRSV values were correlated with VE-induced SV variations . A 10% increased ΔPLRSV predicted fluid responsiveness with an area under the receiver operating characteristic curve (AUC) of 0.88 ± 0.07 : 0.69 to 0.97; P < 0.0001), 62% sensitivity and 92% specificity. On the basis of AUCs of 0.62 ± 0.11  and 0.53 ± 0.12 , respectively, ΔPLRPP and ΔPLRPO did not predict fluid responsiveness.Twenty-five measurements were obtained from seventeen patients. In 52% of the measurements (In patients treated with venovenous ECMO, a > 10% ΔPLRSV may predict fluid responsiveness. ΔPLRPP and ΔPLRPO cannot predict fluid responsiveness. In ICUs, fluid administration is frequently used to treat hypovolaemia to enhance cardiac function by increasing preload. Many studies have demonstrated that fluid responsiveness can be predicted by using respiratory derivative indices (pulse pressure variation (ΔrespPP), stroke volume (SV) variation (ΔrespSV) and aortic velocity-time integral variation (ΔrespVTIAo)) -5. From The main goal of this study was to answer the following question: Can PLR be used to predict fluid responsiveness in ARDS patients placed on venovenous ECMO? As ECMO pump flow (PO) is a preload-dependent process, we assumed that changes in PO between baseline and PLR (ΔPLRPO) could reflect a preload-dependent condition. Thus, we analysed the predictive value of ΔPLRPO.We conducted a prospective, observational study at the Amiens Sud University Hospital surgical ICU over a period of 13 months (from November 2009 to December 2010). ARDS patients treated with venovenous ECMO for whom the intensivist recommended volume expansion (VE) were enrolled in the study. Patients with poor cardiac echogenicity were not included. All patients had been sedated and paralysed with continuous infusion of midazolam, sufentanil and cisatracurium. All patients underwent invasive arterial pressure monitoring, central venous catheterisation and echocardiography several times daily because of their various diseases.This study was approved by the Institutional Review Board (IRB) for human subjects at our hospital. Informed consent was waived because the IRB considered the protocol to be part of routine clinical practice.The ECMO circuit consists of an inflow venous line inserted into the right femoral vein and advanced through the inferior vena cava close to the right atrium, an outflow venous line inserted into the right internal jugular vein as far as the right atrium, a ROTAFLOW centrifugal pump  and a QUADROX PLS oxygenator (MAQUET GmbH & Co. AG). Inflow and outflow cannula sizes are reported in Table 2) = (π × AoD2)/4. The aortic velocity-time integral (VTIAo) ratio was measured using pulsed Doppler ultrasonography with a five-chamber apical view. SV was calculated by using the equation SV (in mL) = VTIAo × Aa. Cardiac output (CO) was calculated using the formula CO (in mL/minute) = SV × heart rate (HR). Mean echocardiographic values were calculated from five measurements (regardless of the respiratory cycle) and analysed a posteriori. The reproducibility of aortic area and VTIAo measurements were tested before the study. Intraindividual and interindividual reproducibility were calculated from the mean value of three of ten patients. The mean (± standard deviation) intraindividual and interindividual reproducibility values were 4.4 ± 3.9% and 4.4 ± 3.2%, respectively. The ECMO PO was measured on the monitor screen by a physician at the different steps of the study. Maximum and minimum pump flow  were recorded for one minute. Mean PO was calculated as PO (in mL/minute) = (POmax + POmin)/2. PO variation was called the pulse index (PI) and calculated as PI = (POmax - POmin)/(POmax + POmin/2) × 100. The PO/rotation per minute (RPM) ratio (expressed in mL/rotation/minute) was calculated as (PO/RPM) × 1,000. Central venous pressure (CVP) and blood pressure were measured with a transducer zeroed at the level of the midaxillary line. ΔrespPP was measured on frozen waveforms on the monitor by calculating ΔrespPP = (PPmax - PPmin)/[(PPmax + PPmin)/2)] × 100.The following clinical features were measured: age; gender; weight; surgical, medical and/or clinical problems; and the main diagnosis. Transthoracic echocardiography (TTE) was performed by a single physician using a Philips EnVisor Ultrasound System . The diameter of the aortic annulus (AoD) was measured using a long-axis parasternal view at patient inclusion. Aortic area (Aa) was calculated by using the equation Aa , median arterial pressure (MAP), diastolic arterial pressure (DAP), ΔrespPP, CVP, CO, VTIAo and HR were recorded at baseline with the patient in a semirecumbent position (45° angle). Automatic bed raising from this position raised the patient's lower limbs to a 45° angle while the patient's trunk was lowered from a semirecumbent to supine position . A seconU test. For the overall population and for each subgroup (responders and nonresponders), the nonparametric Wilcoxon rank-sum test was used to assess the statistical significance of changes in PLR-induced haemodynamic parameters or VE and to compare the pre-PLR values of the variables measured at baseline . Spearman's rank correlation coefficient was used to test linear correlations. A receiver operating characteristic curve (ROC) and its corresponding positive and negative likelihood ratios were generated for PLR-induced changes in SV (ΔPLRSV), CO (ΔPLRCO) and PO (ΔPLRPO) [P value < 0.05 were considered statistically significant. Statistical analysis was performed using IBM SPSS Statistics 18 software  and MedCalc 8.1.0.0 software .SV measured before and after VE was used to distinguish responders from nonresponders with changes in SV of > 15% and < 15%, respectively ,9,12. Th(ΔPLRPO) . Area unn = 12), oligoanuria (urine output < 0.5 mL/kg/hour or < 20 mL/hour) (n = 9), skin mottling and/or leg coldness (n = 4).Twenty-five measurements were obtained from seventeen patients. PLR manoeuvres and VE were performed twice on eight patients on different days and under different respiratory and haemodynamic conditions. The patients had acute circulatory failure associated with septic shock and primary or secondary ARDS. The most common cause of heart failure was acute cor pulmonale, defined on the basis of echocardiographic criteria . The patr2 = 0.72, P = 0.0001 . This correlation was not observed for PO .Of the 25 patients who underwent VE, 13 (52%) were responders: SV increased by > 15%. At baseline, the haemodynamic and echocardiographic parameters were similar in both groups. None of these parameters were predictive of fluid responsiveness. Tables 95): 0.69 to 0.97; P < 0.0001) and 0.87 ± 0.07 for ΔPLRCO  . ΔPLRPO had poor sensitivity and specificity, as well as a poor AUC: 0.53 ± 0.12     and 0.83 ± 0.13 for ΔPLRCO . Table In the whole population, the AUCs were 0.88 ± 0.07 for ΔPLRSV  Figure . The ΔPLOur study demonstrates that a 10% increase ΔPLRSV predicts a > 15% increase in SV after VE in ARDS patients placed on venovenous ECMO Figure . ECMO isΔPLRPP cannot predict fluid responsiveness, even among patients with a minimal increase in CVP of 2 mmHg. On the basis of physiological knowledge, the use of PP as a substitute for SV would assume constant arterial compliance. By increasing intrathoracic blood volume, PLR may also induce sympathetic activation; however, our patients were deeply sedated, and their HRs remained unchanged during PLR. In clinical practice, SV, PP and vascular tone can vary with the patient's haemodynamic conditions and can be altered by PLR , which m95: 64 to 100) and 83% specificity (CI95: 52 to 98), and 5% for ΔPLRCO, with 85% sensitivity (CI95: 46 to 95) and 83% specificity (CI95: 52 to 98)  failed to predict fluid responsiveness in ARDS patients placed on venovenous ECMO.• A > 10% increase of ΔPLRSV may predict fluid responsiveness in patients treated with venovenous ECMO.• ΔPLRPO cannot be used to predict fluid responsiveness.95: 95% confidence interval; CO: cardiac output; CVC: central venous catheter; CVP: central venous pressure; DAP: diastolic arterial pressure; ECMO: extracorporeal membrane oxygenation; IRB: Institutional Review Board; LVEF: left ventricular ejection fraction; MAP: median arterial pressure; PI: pulse index; PO: pump outflow; PLR: passive leg raising; ROC: receiver operating characteristic; RPM: rotation per minute; SAP: systolic arterial pressure; SD: standard deviation; SV: stroke volume; TTE: transthoracic echocardiography; VE: volume expansion; VTIAo: aortic velocity-time integral ratio.ΔPLRPO: passive leg raising pump outflow change; ΔPLRPP: passive leg raising pulse pressure change; ΔPLRSV: passive leg raising stroke volume change; ΔrespPP: respiratory pulse pressure variation; ΔrespSV: respiratory stroke volume variation; ARDS: acute respiratory distress syndrome; CIThe authors declare that they have no competing interests.PGG conceived, designed and coordinated the study and drafted the manuscript. EZ, MD and TC participated in the coordination of the study. MM, VH, LB and EB participated in the coordination of the study and helped in drafting the manuscript. HD performed the statistical analysis and helped in drafting the manuscript.