The effects of baseline and changes in blood pressure and low density lipoprotein (LDL) cholesterol on the carotid intima media thickness (IMT) have not been well documented.A total of 2572 adults  in a Taiwanese community undertook three blood pressure and LDL cholesterol examinations over 6 years. Latent growth curve modeling was used to investigate the effects of baseline and change in blood pressure and LDL cholesterol on IMT.Greater baseline LDL and blood pressure were associated with an increase in IMT , whilst the association between change in LDL and change in IMT was not statistically significant .Carotid IMT was associated with baseline blood pressure and LDL cholesterol, yet only changes of blood pressure, not LDL cholesterol, were related to carotid IMT during the 6-year observation. It has been suggested that carotid intima media thickness (IMT) is associated with metabolic syndrome components. One cross-sectional study on 2268 Americans showed that the average increase in IMT was 0.52 mm in people with no metabolic syndrome and 0.69 mm in people with 4 metabolic syndrome components . HoweverIMT of the common carotid artery are considered useful indicators of carotid atherosclerosis -5. Al-ShDetails of this cohort have been reported elsewhere -19. BrieBody mass index was calculated as weight (in kilograms) over height (in meters) squared. Blood pressure was measured twice on the right arm supported and positioned at the level of the heart with a mercury sphygmomanometer, after participants were seated comfortably for ten minutes. All participants were asked to refrain from smoking cigarettes for at least 30 minutes and from drinks with caffeine before examination.Hypertension was defined according to the criteria established by the Seventh Joint National Committee : systoliRepeated measurements of blood pressure and lipid profiles were collected biannually from 1990, and the procedures for taking blood samples have been reported elsewhere ,22. BrieThe procedures for ultrasound sonography of carotid arteries have been reported elsewhere ,24, and Continuous variables are presented as mean and standard deviation, and categorical variables in contingency tables. We used a linear regression model to test the associations of repeated systolic blood pressure and LDL with the carotid IMT. We used the diagnostic tools for collinearity, namely the tolerance and variance inflation factors, to evaluate the multicollinearity problem in our model .Latent growth curve modeling, a special application of structural equation modeling (SEM), was then used to analyze the associations between changes in LDL cholesterol and systolic blood pressure (SBP) over the 6-year period and final IMT. Separate non-linear latent growth curve model analyses for LDL cholesterol and carotid IMT and for systolic blood pressure were undertaken . Figure P value greater than 0.05 indicated that the proposed model fitted the data relatively well; (2) a comparative fit index (CFI) greater than 0.95 indicated a good model; (3) a Root Mean Square Error of Approximation (RMSEA) value less than 0.05 was considered as a good model; and (4) a Standardized Root Mean Square Residual (SRMR) less than 0.1 indicated a good model fit [Next, a bivariate latent growth curve model was then constructed in which the IMT was regressed on the baseline and changes of both LDL cholesterol and systolic blood pressure. Covariates, including age, gender, and baseline body mass index were also included in the final model. IMT values were multiplied by 100 to prevent rounding errors in the computation. Several statistics were evaluated for the overall model fit: (1) a small chi-square value for model fit relative to the model degrees of freedom with a odel fit . All staodel fit .A total of 2244 adults  were recruited into this study. Table P <0.05). However, due to the problem with high correlations amongst the explanatory variables, the three LDL cholesterol and the third systolic blood values had non-significant associations with the carotid IMT. The regression diagnostic tests, including variance inflation factors and collinearity diagnostic statistics, showed substantial collinearity among the variables.Using a multiple linear regression model Table , we founP = 0.004). However, the positive association between the increase in LDL and carotid IMT was not statistically significant . The final model fit the data well; the chi-square (DF = 15) value was 21.2 with the p-value as 0.13, indicating the relations amongst the variables in the model were consistent with (non-sig different from) the observed data.Results from the bivariate latent growth curve model are shown in Figure In this Taiwanese cohort, we found associations of carotid IMT with blood pressure and LDL cholesterol. When their effects were taken into account simultaneously, the positive association between the increase in LDL cholesterol and IMT became attenuated and non-significant. This indicates that change in systolic blood pressure may be a better predictor or a stronger risk factor for IMT.The effects of blood pressure and lipids on carotid IMT have been reported in previous studies ,32. In oEvidence from randomized controlled trial data also showed differential effects of blood pressure and cholesterol lowering on carotid atherosclerosis. Among 508 combined hypertensive and hypercholesterolemic patients under a randomized control trial for 2.6 years, the progression of the carotid IMT were not significant for patients treated with fosinopril (−0.002±0.004 mm) or those with fosinipril and prastatin (−0.002±0.004 mm) . Adding Latent growth curve modeling is a new tool to biomedical and epidemiological research, while it has been widely used in the social sciences. Using software packages for structural equation modeling, latent growth curve modeling provides a flexible statistical framework for the analysis of repeated measures in clinical practice to investigate the baseline and changes of exposure to outcomes ,42. The Several limitations of our study should be mentioned. First, IMT, rather than plaque status, was the outcome for our investigation. Previous studies have shown that the numbers of plaque were related to cardiovascular complications  and evenIn conclusion, our study found that carotid IMT was associated with baseline blood pressure and LDL cholesterol measurements, but only changes in blood pressure, not LDL cholesterol, were related to carotid IMT in this Taiwanese cohort.All authors declare no competing interests for preparing the draft.KLC carried out the design and data collection and drafted the manuscript. YKT carried out statistical analysis and revised the draft. HCH participated in laboratory data quality control and biochemical analysis. TCS participated in collecting data and maintaining the study. HJL participated in collecting data. MFC and YTL conceived of the study, and participated in its design and coordination and helped to draft 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/1471-2261/12/66/prepubTable S1: Scheme for the recruitment of the study participants in this study.Click here for file


We investigated factors associated with masked and white-coat hypertension in a Swiss population-based sample.The Swiss Kidney Project on Genes in Hypertension is a family-based cross-sectional study. Office and 24-hour ambulatory blood pressure were measured using validated devices. Masked hypertension was defined as office blood pressure<140/90 mmHg and daytime ambulatory blood pressure≥135/85 mmHg. White-coat hypertension was defined as office blood pressure≥140/90 mmHg and daytime ambulatory blood pressure<135/85 mmHg. Mixed-effect logistic regression was used to examine the relationship of masked and white-coat hypertension with associated factors, while taking familial correlations into account. High-normal office blood pressure was defined as systolic/diastolic blood pressure within the 130–139/85–89 mmHg range.Among the 652 participants included in this analysis, 51% were female. Mean age (±SD) was 48 (±18) years. The proportion of participants with masked and white coat hypertension was respectively 15.8% and 2.6%. Masked hypertension was associated with age (odds ratio (OR) = 1.02, p = 0.012), high-normal office blood pressure , and obesity . White-coat hypertension was significantly associated with age  but not with education, family history of hypertension, or physical activity.Our findings suggest that physicians should consider ambulatory blood pressure monitoring for older individuals with high-normal office blood pressure and/or who are obese. In the last few decades, the development of techniques that enable measurement of blood pressure (BP) outside the physician's office using either ambulatory or home BP has allowed individuals to be classified into four BP categories: sustained normotension , sustained hypertension , white-coat hypertension , and masked hypertension  The term masked hypertension (MH) was first coined by Pickering et al in 2002 On the other hand, the clinical significance of white-coat hypertension (WCH) remains debated to this day Increasing research has been dedicated to better understanding the factors associated with MH. However, only a small number of studies using 24-hour ABPM have been conducted on a population-based level All study participants provided written informed consent. The SKIPOGH study was approved by the Human Research Ethics Committee, Lausanne University Hospital and University of Lausanne , by the Ethics Committee for the Research on Human Beings, Geneva University Hospitals , and by the Ethics Committee of the Canton of Bern, .SKIPOGH (Swiss Kidney Project on Genes in Hypertension) is a family and population-based cross-sectional study that examines the genetic determinants of BP. SKIPOGH is part of the larger family-based international EPOGH study (European Project on Genes in Hypertension). SKIPOGH employs the same methodology as that implemented and validated in the EPOGH study SKIPOGH is a multi-centre study with participants being recruited in the cantons of Bern and Geneva, and the city of Lausanne. Detailed methods have been previously described Participants filled in a standardized questionnaire at home. The questionnaire focused on a variety of issues including lifestyle habits as well as medical and drug history. The study visit was performed in the morning after an overnight fast. Electrolytes, kidney-function test, and blood glucose were measured in local laboratories using standard clinical laboratory methods. Participants were also asked to collect a 24-hour urine sample for the measurement of urinary volume, electrolytes, and the excretion of albumin, urea and creatinine. The CKD-EPI formula was used to calculate the estimated glomerular filtration rate (eGFR) BP was measured with a non-mercury auscultatory sphygmomanometer  that has passed the International Protocol for validation of BP measuring devices of the European Society of Hypertension (ESH) Sustained normotension (NT) was defined as office BP <140/90 and daytime ambulatory BP <135/85 mmHg. MH was defined as office BP <140/90 mmHg and daytime ambulatory BP ≥135/85 mmHg. WCH was defined as office BP ≥140/90 mmHg and daytime ambulatory BP <135/85 mmHg 2), overweight (25–30 kg/m2), and obesity (≥30 kg/m2). Physical activity was assessed as a continuous variable by asking participants to report the number of hours per week they spend playing sports. Albuminuria was defined as a urinary albumin excretion ≥20 μg/min High-normal office BP was defined as an office SBP between 130-139 mmHg and office DBP between 85–89 mmHg All statistical analyses were conducted using Stata 12.0 . Complete case analysis was conducted on participants from Lausanne and Geneva, and participants from Bern up until 2011. Differences in baseline characteristics across BP categories were tested using Fisher's exact test for categorical variables and a 3 degrees of freedom likelihood-ratio test from a linear regression model for continuous variables. The ambulatory and office means for SBP, DBP, and heart rate were adjusted for age, sex, BMI, and study centre using mixed linear models, and a likelihood-ratio test was used to test the differences across BP categories, while taking familial correlations into account. Mixed-effect logistic regression was used to examine the relationship of MH, WCH, and SH with associated factors, while also taking familial correlations into account. For the latter analyses, normotension was used as the reference category.Complete case analysis of the data resulted in 652 participants with 51% of the sample population being female. Mean age was 48 (±18) years. 15.0% of individuals had office hypertension (i.e. had an office BP ≥140/90 mmHg) and 28.2% had daytime ambulatory hypertension (i.e. had a daytime ambulatory BP ≥135/85 mmHg). Univariate and multivariable logistic regression analyses were performed to assess the associations between MH and selected factors, with normotensive individuals acting as the reference group . In multThe association between SH and selected factors is presented in We also conducted sensitivity analyses to explore whether the factors associated with MH differed by study centre. Due to the limited number of individuals with MH in our study, we ran the analyses while grouping two study centres at a time . The factors associated with MH were very similar to our findings including all three centres (results not shown). We could not perform similar sensitivity analyses for WCH due to the limited number of participants identified as white-coat hypertensives.Our study is the first to estimate the proportion of MH in a family- and population-based study in Switzerland. We found that one in six individuals in our sample had MH, a finding comparable to other population-based studies A growing body of evidence has found that ABPM is better correlated with target organ damage than office BP measurement Some studies We found that individuals with MH and SH had the highest ambulatory BP whereas individuals with WCH had the highest office BP. Interestingly, the mean ambulatory DBP of masked hypertensives was significantly higher than that of SH individuals. When treated individuals were excluded from the SH category, this was no longer the case. We also found that individuals with MH had the highest ambulatory heart rate. It has been postulated that MH is associated with a sympathetic overdrive, although the exact mechanisms underlying this sympathetic activation have to be further clarified Our study has some limitations. The cross-sectional nature of this study limits inference on causality. There were relatively few participants who were classified as having WCH, limiting the statistical analyses that may be performed on this sub-group. Likewise, we were unable to stratify individuals in the SH category by treatment status due to the low number of participants who had SH and were not on anti-hypertensive medication. Participation rate was relatively low, raising the issue of selection bias and thus limiting the external validity of our results. However, there was no difference in terms of age and sex distribution between the participants to this study and those of the population-based sample from which they were drawn We found that individuals with MH tend to share similar characteristics as patients with SH. Although there is currently a lack of randomized controlled trials that have investigated the benefits of treating patients with MH, it is plausible that by identifying individuals with MH, cardiovascular complications and target organ damage may potentially be avoided if management of hypertension is based on ambulatory BP Table S1Mean ambulatory and office systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) by blood pressure category.(DOCX)Click here for additional data file.


This pilot study  assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.Five adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 200 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.After 14 days, CClonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS . Chronic Fatigue Syndrome (CFS) is a relatively common and disabling condition among adolescents in developed countries ,2. A stuThe pathophysiology of CFS remains poorly understood. However, previous reports have documented enhanced sympathetic nervous activity at rest and during moderate somatic stressors, affecting cardiovascular control . For ins2-receptor. It has a general inhibitory influence on sympathetic nervous activity, in particular due to its effect in the central nervous system, resulting in lower blood pressures and heart rate [To date, only cognitive behavioral therapy and graded exercise therapy have a well-documented beneficial effect in the treatment of CFS ,14. Thusart rate . TherefoAn area of concern, however, is the possibility of adverse effects. In fact, clonidine might worsen rather than improve the orthostatic intolerance among CFS patients, increasing the risk of syncope; this is particularly true if the autonomic alterations are secondary to hypovolemia rather than a primary disease mechanism. Also, CFS patients are generally considered to be sensitive towards adverse pharmacological effects, maybe because of altered pharmacodynamics . TherefoThe Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) is a randomized, placebo-controlled, double-blind trial of clonidine in adolescent CFS . The aim of this pilot study  was to investigate the feasibility and safety of clonidine in adolescent CFS. Specifically, we wanted to assess appropriate dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) reports of possible adverse effects, in particular syncope.Five adolescent CSF patients were recruited from the Pediatric outpatient clinic, Oslo University Hospital, Rikshospitalet, Norway, which serves as a national referral center for children and adolescents with unexplained chronic fatigue. Other disease states that might explain their present symptoms, such as autoimmune, endocrine, neurologic or psychiatric disorders (including depression and anxiety), were ruled out by a thorough and standardized set of investigations.Different case definitions of CFS exist. The frequently used definition from the International Chronic Fatigue Syndrome Study Group (commonly referred to as the Fukuda-definition) requires at least six months of unexplained chronic or relapsing fatigue of new onset, severely affecting daily activities, as well as four or more of eight specific accompanying symptoms  . The valExclusion criteria included supine systolic blood pressure (SBP) < 85 mm Hg, a fall in SBP upon standing > 30 mm Hg, supine heart rate (HR) < 50 beats/min, abnormal ECG, permanent bed-rest, regular use of pharmaceuticals, other chronic diseases and a positive pregnancy test.Patients were invited to two clinical encounters at our institutions, separated by a time period of 14 days. At the first encounter, a head-up tilt-test was performed. The subjects were positioned horizontally on a-table with foot-board support  and attached to the Task Force Monitor® , a device for non-invasive recording of cardiovascular variables . We obtaThe participants were instructed to take 50 μg clonidine twice per day (BID) until the second clinical encounter, which consisted of blood samples (for assays of clonidine concentration) and a repeated head-up tilt test. Also, participants were questioned about possible side-effects of clonidine treatment . At discharge from the second clinical encounter, they were instructed to take 25 μg clonidine BID for another week, after which the treatment was discontinued.Two days in advance of both encounters, all participants were instructed not to drink beverages containing alcohol or caffeine, not to take any drugs, and not to use tobacco products. They were requested to fast overnight prior to the first clinical encounter, and apply an ointment of the local anesthetic lidocaine (Emla®) in the antecubital fossa one hour before venous puncture. Blood samples and HUT were carried out between 8 and 10 am at both occasions in a quiet, warm room.Written, informed consent was obtained from all participants and their parents. The study was approved by the Regional committee for ethics in medical research (REK Sør-Øst C) and The Norwegian Medicines Agency.et al. with some modifications [The blood samples for clonidine determinations were collected in 4 mL heparin tubes. After centrifugation for 12 minutes at 1000 g at room temperature, the plasma fraction was frozen at −20°C until analysis within 2 weeks. Plasma concentrations of clonidine were assayed by the method of Müller ications . The samAll data were exported to Microsoft Excel for further analyses. From each experimental run of HUT, we calculated the median of all variables in two epochs: From 270 to 30 seconds prior to tilt (Baseline) and from 30 to 270 seconds after beeing tilted (Tilt). We also computed delta values (Tilt – Baseline). Cardiac output was computed as stroke volume times HR, whereas total peripheral resistance was calculated as mean arterial blood pressure (MBP) divided by cardiac output. Relevant hemodynamic variables were indexed against body surface area. This method of analyzing results from HUT has successfully been used in previous projects from our institution ,6.Results are displayed as median and total range. Due to the low number of participants, we did not carry out statistical tests.Five patients  were screened; they all adhered to the inclusion and exclusion criteria, and were therefore enrolled in the project (Table max) in all patients; median (range) value was 0.26 (0.14 - 0.29) μg/L. After 14 days of clonidine treatment, median trough concentration (C0) was 0.21 μg/L, rising to a median level of 0.41 μg/L (Cmax) two hours after administration of the regular dose .AD/HD, Attention deficit/Hyperactivity disorder; CFS, Chronic fatigue syndrome; CI, Cardiac index; DBP, Diastolic blood pressure; HF, High-frequency heart rate variability; HR, Heart rate; HUT, Head-up tilt-test; LF, Low-frequency Heart Rate Variability; LF/HF, Low-frequency: high-frequency heart rate variability ratio; MBP, Mean arterial blood pressure; NorCAPITAL, The Norwegian study of chronic fatigue syndrome in adolescents: pathophysiology and intervention trial; SBP, Systolic blood pressure; SI, Stroke index; TPRI, Total peripheral resistance index.The authors declare that they have no competing interests.EF, DS and AW carried out the clinical investigations, head-up tilt-tests and data analyses. EF drafted the manuscript; DS and AW helped to draft the manuscript. AMA and NTV carried out the laboratory investigations and helped to draft the manuscript. JPS, ET participated in study planning and design, and helped to draft the manuscript. VBW conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors have read and approved the final version of the manuscript.


Fever is a dangerous secondary insult for the injured brain . We inve2) and Temp. were recorded at the start of paracetamol infusion (T0) and after 30 (T30), 60 (T60) and 120 (T120) minutes. Interventions for the maintenance of CPP >60 mmHg or ICP <20 mmHg were recorded.The i.v. paracetamol (1 g in 15 minutes) was administered to NICU patients with a body temperature (Temp.) >37.5°C. Its effects on mean arterial pressure (MAP), heart rate (HR), intracranial pressure (ICP), cerebral perfusion pressure (CPP), jugular venous oxygen saturation (SjVOP <0.001), MAP , CPP  and HR  with respect to the starting value (ANOVA for repeated measures), whereas ICP and SjVO2 remained unchanged .Fifteen NICU patients  males, median GCS 7) were prospectively studied. We analyzed the administration of one dose of paracetamol for each patient . After infusion of paracetamol we found a decrease of Temp. (from 37.8 ± 0.3 to 37.4 ± 0.4°C, Use of i.v. paracetamol is effective in the maintenance of normothermia in acute brain-injured patients. However, adverse hemodynamic effects, which could represent a secondary insult for the injured brain, must be rapidly recognized and treated.


Proper blood pressure control during surgical procedures such as total joint arthroplasty (TJA) is considered critical to good outcome. There is poor understanding of the pre-operative risk factors for poor intra-operative hemodynamic control. The purpose of this study is to identify risk factors for poor hemodynamic control during TJA.We performed a retrospective cohort analysis of 118 patients receiving TJA in the Dominican Republic. We collected patient demographic and comorbidity data. We developed an a priori definition for poor hemodynamic control: 1) Mean arterial pressure (MAP) <65% of preoperative MAP or 2) MAP >135% of preoperative MAP. We performed bivariate and multivariate analyses to identify risk factors for poor hemodynamic control during TJA.Hypertension was relatively common in our study population (76 of 118 patients). Average preoperative mean arterial pressure was 109.0 (corresponding to an average SBP of 149 and DBP of 89). Forty-nine (41.5%) patients had intraoperative blood pressure readings consistent with poor hemodynamic control. Based on multi-variable analysis preoperative hypertension of any type  and an increase in BMI  were significant risk factors for poor hemodynamic control.Preoperative hypertension and being overweight/obese increase the likelihood of poor blood pressure control during TJA. Hypertensive and/or obese patients warrant further attention and medical optimization prior to TJA. More work is required to elucidate the relationship between these risk factors and overall outcome. Overall, 20 patients had no history of hypertension and did not have hypertension preoperatively, 21 patients had a history of hypertension but did not have preoperative hypertension, and 76 patients presented to the preoperative clinic with hypertension. Of these 76 hypertensive patients, 55 patients had a prior diagnosis of hypertension and 21 had no prior history of hypertension (undiagnosed). There were 76 patients in total with a prior diagnosis of hypertension. Of those with a prior diagnosis of hypertension 39 patients were taking 2 or more anti-hypertensive medications and 6 were not taking any medications. Nine patients presented in a state of hypertensive urgency [SBP >180 or DBP >120] (TableForty-nine (41.5%) patients had intraoperative blood pressure readings consistent with poor hemodynamic control. Six patients (5.1%) required intra-operative blood products and 5 patients had an intra-operative rhythm disturbance Table. Results of bivariate analysis Table suggest Obese patients [BMI≥30] had a moderately increased risk of poor hemodynamic control relative to normal weight patients [BMI < 25] . An increase of 5 BMI points conferred a significantly increased risk of poor hemodynamic control . Patients with rheumatoid arthritis (RA) had a non-statistically significant decreased risk for poor hemodynamic control .Patients with duration of surgery greater than 3 hours were at increased risk for poor hemodynamic control . The vast majority of cases over 3 hours were bilateral (17/18).In the bivariate analysis, gender, BMI and preoperative hypertension reached the criterion for inclusion in a multivariable model (relative risk > 1.5 or < 0.67). Using multivariable analysis we found that preoperative hypertension of any type  and an increase in BMI  were statistically significant risk factors for poor hemodynamic control. Women had a moderately increased risk of poor hemodynamic control compared to men , but this finding was not statistically significant.In this study we sought to identify the risk factors for poor hemodynamic control during TJA. We found that preoperative hypertension and being overweight/obese were significant risk factors. The medical optimization of orthopaedic patients has received very little attention in the literature; however, our findings suggest that the hypertensive obese patient warrants further attention preoperatively.Intra-operative hemodynamic control is considered an important driver of surgical outcome. Poor hemodynamic control has been reported in the cardiovascular literature to be associated with death, stroke, cognitive and renal dysfunction, perioperative myocardial infarction, and increased mortality,12,16,17The risk for complication due to poor intra-operative blood pressure control during TJA is under-appreciated by the orthopaedic community. There is evidence in the orthopaedic literature that poor intra-operative blood pressure control is associated with increased risk for complication after TJA. One prior study found that systolic blood pressures above 150.6±9 mmHg significantly increased the risk of myocardial infarction in a cohort of patients undergoing a variety of non-cardiac procedures (orthopedic procedures represented greater than 50% of procedures in this study). AnotherOur study highlights several key findings. First, we found that being overweight/obese was independently associated with an increased risk for poor hemodynamic control. The pathophysiologic cause of this association is unclear. Autonomic dysfunction in the obese patient could provide a plausible explanation. Prior sOur study also demonstrates that preoperative hypertension is a major risk for poorly controlled hemodynamic control during total joint arthroplasty. This finding is congruent with prior work in this area. In particular, a landmark randomized multicenter study involving over 17,000 patients found that preoperative hypertension was associated with perioperative bradycardia, tachycardia and hypertension. DespiteOur results suggest that duration of surgery increases the risk for poor hemodynamic control. However duration of surgery also appears to be strongly related to procedure performed and 17/18 surgeries greater than three hours in duration were bilateral in nature. Understanding the potential risks associated with bilateral and/or lengthy procedures is important and should be addressed in future investigations.This study was set in the Dominican Republic, among patients with limited financial means who had a high prevalence of preoperative hypertension. Most of the patients with hypertension documented at the preoperative visit had history of hypertension but were not well controlled. Our data document the importance of attempting to optimize preoperative blood pressure control in patients such as the Operation Walk population who have a high burden of inadequately controlled hypertension. The data also indicate that mission trips such as Operation Walk Boston should coordinate with local physicians to ensure that patients selected for total joint arthroplasty are carefully optimized prior to admission for surgery. These efforts should include assessment of adherence to prescribed pharmaco-therapeutics as well as attention to non-pharmacologic approaches .A potential limitation of the present study is that the small sample size precludes stable peri/postoperative outcome data such as deaths and cardiac and other complications. As such we do not report a complication rate. The literature suggests that poor hemodynamic control during surgery leads to adverse outcome;,11,18,29This study focused on intra-operative blood pressure assessment during TJA. An area of further investigation is the perioperative blood pressure changes associated with TJA. In certain patient populations blood pressure control can be difficult immediately after the procedure and in the post-anesthesia care unit.Preoperative hypertension and being overweight/obese increase the likelihood of poor blood pressure control during TJA. Intraoperative blood pressure variability is an important determinant of perioperative outcome. We emphasize the need for careful preoperative assessment of the hypertensive and/or overweight/obese orthopaedic patient. We also highlight the importance of preoperative blood pressure monitoring and optimization for orthopedic mission programs performed in settings where hypertension is prevalent.The authors declare that they have no competing interests.Conception: BUN; MC; TST JNK, Design: BUN; JEC; EPN; MC; TST; JNK, Data collection: BUN; EPN; MC, Data analysis: BUN; JEC; JNK, Manuscript draft & revision: BUN; JEC; EPN; MC; TST; JNK. All Authors have approved the final version of this manuscript in its entirety.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/20/prepub


Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.NCT00970931.Clinical Trials  High blood pressure is the major risk factor for cardiovascular disease. The risks start at blood pressure values as lower as 115/75 mmHg, but increase exponentially and confer increased absolute risks with blood pressure higher than 140/90 mmHg . CardiovA meta-analysis of 61 cohort studies, with more than one million of subjects (12.7 million persons-year at risk), presenting more than 56,000 fatal cardiovascular events, demonstrated that the risk for cardiovascular events starts with systolic blood pressure higher than 115 mmHg or diastolic blood pressure higher than 75 mmHg, doubling at each 20 mmHg in the first case or 10 mmHg in the second [The raising of blood pressure with age is not inexorable and does not occur in populations that do not consume large amounts of salt. Under the contemporary and unnatural overload of dietary sodium, kidneys had to reset their primary sodium handling function from retention to excretion. Subjects with familial predisposition to hypertension require higher renal flow and consequently higher blood pressure to eliminate the sodium overload, resulting in extracellular volume expansion, increase in cardiac output and peripheral resistance. With long-standing high blood pressure, loss of glomeruli and renal arterioles may further shift pressure natriuresis and exacerbate blood pressure elevation. The recurrence of this phenomenon along the years leads to arteriolar hypertrophy and sustained blood pressure rise -11. AfteThe worldwide prevalence of hypertension in individuals older than 70 years was 70% of women and 59% of men . The incThe risk factors for hypertension, such as the excessive dietary sodium intake, low potassium consumption, excess of adiposity, insulin resistance, abuse of alcoholic beverages, and low consumption of fruits and vegetables are well-known. Many nutritional and behavioral interventions are efficacious to reduce blood pressure, but outside the strict experimental conditions their effectiveness has been inconsistent. The mean weight of populations is not stable but has increased in recent years worldwide. Randomized controlled trials with long follow-up periods have shown that the efficacy of weight control interventions is lost with time. In the TOHP-II trial, weight, salt consumption and blood pressure returned to the baseline values after 36 months of intervention . The DASTwo large clinical trials showed that the prevention of hypertension by drug treatment is feasible and well tolerated. In the TROPHY study , 772 indThe expectation that BP agents have beneficial effects independent of the blood pressure-lowering one (pleiotropic effects) is still deep-rooted in physician's minds, but it has been repeatedly dismissed by independent clinical trials and by a large meta-analysis  The effiThe early use of blood pressure-lowering drugs may prevent cardiovascular events and the incidence of hypertension. The very low absolute risk of pre-hypertension in young individuals free of diabetes or cardiovascular disease precludes the launching of clinical trials with the aim to prevent hard outcomes. The blood pressure-lowering effect and the prevention of the incidence of full hypertension may be valid surrogate endpoints that could be investigated in feasible randomized clinical trials. The PREVER prevention trial study will test if a low dose of an association of chlorthalidone with amiloride prevents hypertension at an acceptable safety in a nationwide large sample of individuals with pre-hypertension . Other intermediate outcomes, such as microalbuminuria and left ventricular hypertrophy, are going to be investigated. Diuretics were chosen in face of their cost-effectiveness, since they are at least as efficacious as other blood pressure agents , at very1. Does an association of low doses of chlorthalidone and amiloride reduce the incidence of hypertension in individuals with pre-hypertension?2. Does an association of low doses of chlorthalidone and amiloride reduce the incidence of target-organ damage in patients with pre-hypertension?3. Does an association of low doses of chlorthalidone and amiloride reduce the incidence of cardiovascular events in patients with pre-hypertension?4. Is the association of low doses of chlorthalidone and amiloride safe to be used on a population-based perspective?randomized, double-blind, clinical trial, controlled by placebo.individuals with 30 to 70 years of age with pre-hypertension.low life expectancy, other indications for the use of diuretics, such as cardiovascular disease, intolerance to the study drugs, pregnancy.will be generated by a computer, using a validated software , with variable block sizes and stratified by center.Chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. Figure Primary:1. Incidence of hypertension.2. Adverse events.3. Development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG.Secondary: fatal or non-fatal cardiovascular events.th, 9th, 12th and 18th months. Figure consultations for evaluation and enrollment and thereafter consultations at the third, 6Incidence of hypertension: the diagnosis of hypertension will be signaled at any of the follow-up visits by average blood pressure  ≥ 140/90 mmHg. The diagnosis will be confirmed by a new visit soon afterwards, with the average of blood pressure measurements of both consultations within hypertensive levels.Adverse events: adverse events will be investigated by open questions and by a semi-structured questionnaire including general symptoms and the presumed adverse effects of the drugs used in the trial. The incidence of adverse effects will be determined by the incidence of adverse events more frequent in the drug arm than in the placebo arm. Laboratory adverse events, such as hypokalemia, hyperuricemia and diabetes (glycated hemoglobin and fasting glucose) will be investigated at the final visit of the participants.Target-organ damage: Microalbuminuria will be determined by nephelometry. Left ventricular hypertrophy will be investigated by electrocardiogram, using the Sokolow-Lyon voltage and the Cornell voltage-duration product. These examinations will be carried out at the baseline evaluation and the final visit.Cardiovascular outcomes: from a statistical point of view they will be secondary events, in face of the sample power calculated for the trial. Figure assuming an incidence of hypertension of 14% in two years in the control group, a size effect of 40% of reduction in the incidence in the treated group, for a power of 85% and P alpha of 5%, it will be necessary to study 568 individuals per group, rounded to 625 per group to compensate for losses in follow-up.the cumulative incidence of hypertension and adverse events will be tested by Chi-square. Survival curves (Kaplan Meyer) will be compared by log-rank test, and Cox hazard regression models. Blood pressure will be compared by ANOVA for multiple repeated measurements and factors, testing for the time-group interaction.this is a nation-based trial, with 24 clinical centers distributed in nine States. A Coordinating Committee was responsible for the elaboration of this proposal and for the main decisions regarding the trial. The organizational study chart will include an executive Committee, a safety committee, outcome committee, data, lab and EKG centers, and the research unitsThe early use of blood pressure-lowering drugs in individuals with pre-hypertension may prevent cardiovascular events, target-organ damage and the incidence of full hypertension. Non-drug treatment (life-style changing) has had low long-term effectiveness and blood pressure drugs can circumvent such limitation. Diuretics may be particularly efficacious in this regard, since they act on the main mechanism of blood pressure rising with ageing. The association of chlorthalidone with amiloride combines the efficacy of chlorthalidone with the potassium-sparing effect of amiloride, preventing electrolyte and metabolic abnormalities induced by chlorthalidone. If this association shows to be effective and well-tolerated on a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.the Ministry of Health, Division of Science and Technology (DECIT), and Ministry of Science and Technology, FINEP and CNPq, Brazil, funded the study.The project was approved by the Ethics committee of the Hospital de Clínicas de Porto Alegre, which is accredited by the Office of Human Research Protections as an Institutional Review Board, and by the Ethic Committees of all participating centers. All participants will sign an informed consent to participate.The authors declare that they have no competing interests.FDF conceived the study; all authors participated in the trial design and methodological considerations, contributed to the draft of this manuscript for intellectual content and approved its final version. They are the coordinators of the clinical centers that will enroll the trial participants.BP: blood pressure; NNT: number needed to treat; ACE: Angiotensin converting inhibitors; EKG: Electrocardiogram.


Venoarterial extracorporeal membrane oxygenation (VA ECMO) provides mechanical support to the patient with cardiac or cardiopulmonary failure. This paper reviews the physiology of VA ECMO including the determinants of ECMO flow and gas exchange. The efficacy of this therapy may be determined by assessing patient hemodynamics and device flow, overall gas exchange support, markers of adequate oxygen delivery, and pulsatility of the arterial blood pressure waveform. Cardiopulmonary bypass (CPB) was used successfully for the first time in 1953 when Dr. John H. Gibbon repaired an atrial septal defect in an 18-year-old woman. Since then, technological improvements in extracorporeal life support have allowed for the development of a type of partial cardiopulmonary bypass called extracorporeal membrane oxygenation (ECMO). Not only has the technology of ECMO been brought out of the operating room into the bedside allowing clinicians to aid in the care of critically ill patients requiring pulmonary or cardiopulmonary support, but EMCO has also become remarkably portable and has allowed for intra- and interhospital transport of otherwise unstable patients. While ECMO support can be venovenous (VV) or venoarterial (VA), this paper aims to focus on the functional mechanics and the monitoring considerations in a patient with VA ECMO.VA ECMO provides both respiratory and hemodynamic support, in contrast to VV ECMO, which provides only respiratory support. VA ECMO is ideally placed in a patient with a reversible pathological process and is commonly placed in those with cardiogenic shock as well as those with other causes of hemodynamic instability refractory to medical management . In the VA ECMO provides partial hemodynamic support and can provide ventricular decompression, augmentation of perfusion pressure, and oxygenation and removal of carbon dioxide in the blood; however, it also increases the afterload against which the left ventricle (LV) works. The balance of the beneficial effect of decompression against the detrimental effect of increased afterload depends on the level of support and the state of the myocardium. Those on VA ECMO must be anticoagulated, the requirement of which must be weighed against the risk of bleeding. In addition, VA ECMO cannot be maintained on a long-term basis. Although there is no set time frame for device therapy, correction of physiologic derangements should occur within the first 24–48 hours. Recent studies have published durations of support ranging from 1.4 days to 11.5 days . VA ECMOCannulation for VA ECMO can be described as either peripheral or central  3]. Per. Per3]. 2), a flow probe that clips onto to the arterial cannula to directly assess flow in liters/minute, a pre- and postoxygenator pressure monitor, a console whereby the speed of the pump can be adjusted, various access ports through which medications can be infused and blood samples withdrawn, a heat exchanger by which temperature can be controlled, and a bridge between the venous and arterial lines. Such a bridge allows blood to continue to circulate through the circuit after proximal clamping, which can be performed to test the effects of temporarily suspending ECMO support. The ability to circulate blood during clamping decreases the risk of stasis and thrombosis. An ECMO circuit may also include a venous reservoir or bladder located on the venous line prior to the pump to serve as an air bubble trap as well as a volume buffer. Centrifugal pumps (see following section) can generate substantial negative pressure at the venous inlet; thus, the presence of a reservoir can provide extra preload reserve to prevent cavitation of the cannulated vessel with resultant hemolysis. The bladder also allows for noninvasive monitoring of venous inlet pressure, although certain consoles may allow for pressure monitoring without the presence of a reservoir. Venous inlet pressures should not exceed negative 50 mm Hg.The fundamental components of a VA ECMO circuit include a venous inflow cannula, a pump, a membrane oxygenator/lung, and an arterial outflow cannula. The venous cannula withdraws blood at the level of the right atrium/vena cava. The blood is pumped through the membrane oxygenator allowing for oxygen uptake and carbon dioxide removal, and this arterialized blood is returned to the systemic circulation through an artery. Other components of the circuit may include a saturation sensor on the venous cannula to assess the mixed venous saturation  is accomplished with one of two types of pumps—centrifugal or roller. This paper will focus on centrifugal pumps, which are more commonly used than roller pumps in the adult population. Centrifugal pumps like the CentriMag  propel blood forward with a magnetically levitated impeller that spins like a top.The flow of blood through a VA ECMO circuit may be thought of as being governed by the modifiable variables of preload, afterload, and revolutions per minute (RPM) of the impeller as well as by the static variables of cannula length and diameter. Centrifugal pumps are preload dependent and afterload sensitive. The preload dependency of the centrifugal pump manifests as decreased flows with significant hypovolemia or with mechanical obstructive processes such as tamponade or tension pneumothorax. The centrifugal pump is also afterload sensitive. Decreased flows can occur with postpump obstructions such as thrombus in the oxygenator or kinks in the arterial cannula, as well as with excessive systemic vascular resistance (SVR) or mean arterial pressure (MAP). A decrease in the RPMs decreases flow through the circuit, while an increase in the RPMs, when not limited by preload, afterload, or circuit components, should cause an increase in the flow. Resistance to blood flow increases directly with cannula length and inversely with cannula diameter. Hence shorter and larger bore cannulas promote greater flow, while longer and smaller bore cannulas tend to limit flow. Circuit components are chosen to allow for at least 50–75 cc/kg/min of flow in adults (compared with 80 cc/kg/min for pediatric patients and 100 cc/kg/min for neonates). Larger patients may require additional inflow or outflow cannulas if adequate flows cannot be achieved with a given set of circuit components.DO2) and the blood flow rate. A gas blender attached to the oxygenator mixes air and oxygen and allows for a range of FDO2. Increases in FDO2 will increase the partial pressure of oxygen in the blood (PaO2). In addition, increases in blood flow will also increase oxygenation as a greater volume of blood is exposed to the surface of the membrane. Augmentation of oxygenation only occurs up to a certain point after which the time for oxygen transfer becomes too short. Oxygenation is independent of sweep gas flow rate. In contrast to oxygenation, carbon dioxide elimination is dependent on sweep gas flow rate and is independent of blood flow (2). Carbon dioxide diffuses faster than oxygen because it is more soluble. As a result, it transfers approximately 10 times more efficiently than oxygen, sometimes necessitating the use of carbon dioxide enriched fresh gas in order to prevent hypocarbia. A comparison between pre- and postoxygenator blood samples should reveal an increase in PaO2 and a decrease in PaCO2. If such a change is not seen, membrane malfunction should be suspected.Gas exchange occurs in the membrane oxygenator  4]. Ext. Ext4]. ood flow . A flowmTogether, the blood flow and gas exchange of VA ECMO act as a surrogate heart and lung that supports end-organ function.2 and lactate—should be tracked to ensure adequate perfusion and oxygen delivery to the end-organs. And finally, the hemodynamic effects of VA ECMO upon the myocardium—beneficial or detrimental—may be gauged by following the pulsatility of the arterial waveform  as well as a rise in lactate dehydrogenase (LDH). Spillage of free hemoglobin into the urine may result in a pink tinge to the urine. In addition, hypovolemia may also result in chattering— a low-frequency jerking or shaking movement of the cannulas due to a physical interaction between the inflow cannula and the vessel from decreased space. Hemolysis and chattering can occur independently of hypovolemia due to patient or cannula positioning or from excessive centrifugal pumps speeds (>3000 RPM) . InadequWhile maintenance of flows are crucial to the care of the patient on VA ECMO, attention must also be paid to the mean arterial pressure, as the end-organs require both a cardiac output as well as a perfusion pressure for optimal function. A goal MAP > 65 mm Hg may be used as a starting point but can be adjusted either lower or higher given individual circumstances. MAP should not exceed 90 mm Hg in order to limit afterload and to promote forward flow. Recall that2. As a partial cardiopulmonary bypass circuit, VA ECMO creates a separate circulation system parallel to the native circulation by siphoning a certain portion of venous return and reinfusing it as a contribution to the overall cardiac output of the body. The body's net oxygenation and ventilation depends on the interaction between the body's own capacity to oxygenate, ventilate, and perfuse (native lung function and cardiac output) and the contribution from VA ECMO in doing the same (membrane lung function and flow). The accurate interrogation of net gas exchange support depends on where the two systems converge. The location of the arterial ECMO cannula determines the point of convergence and the suitability of a particular arterial site for blood sampling or monitoring of SpOCannulation of the right common carotid artery flushes well-oxygenated and ventilated blood down the right upper extremity. Thus, blood gases drawn from the right radial artery will not be reflective of net gas exchange support. Blood gases obtained distal to the location of mixing  will be more accurate. Right radial arterial gases will not be accurate in right axillary artery cannulation, as well, due to its location relative to the ECMO cannulation site. Similarly, left radial arterial gases should be avoided in patients with left axillary artery cannulation. Direct aortic root cannulation allows for accurate blood gas analysis from any artery regardless of heart or lung function.The preferred site of blood gas sampling with femoral artery cannulation is the right radial artery. When heart function is poor (with or without good lung function), retrograde ECMO flow should provide the vessels of the aortic arch with arterialized blood and allow good oxygen delivery to the coronary and cerebral circulations. Recovery of myocardial function pushes the mixing point of the two circulations more distally along the aorta causing native cardiac output to take over perfusion of the coronary and cerebral circulations. With good lung function, the coronary arteries, the innominate, and the right carotid artery will receive well-oxygenated blood. However, poor lung function in the setting of good myocardial function may cause these circulations to receive poorly oxygenated blood. In extreme cases, the patient's head may appear blue, while the lower extremities appear pink. Placement of a right radial arterial catheter, which interrogates oxygenation to the heart and brain, will allow for the detection of coronary and cerebral hypoxemia. This phenomenon is known by several descriptors including upper body hypoxemia, North-South Syndrome and Harlequin Syndrome.2) and/or positive end-expiratory pressure (PEEP). Depending on the etiology, inadequate lung function may be addressed by performing recruitment maneuvers to decrease atelectasis, diuresing to decrease pulmonary edema, instituting antibiotic therapy for pneumonia, or utilizing thoracentesis or bronchoscopy for significant pleural effusions or secretions and mucous plugging. Upper body hypoxemia may also be remedied by manipulating aspects of VA ECMO support. VA ECMO flows can be increased in an attempt to better perfuse the aortic root with retrograde arterialized blood. In addition, the arterial outflow cannulation site can be switched from the femoral artery to the axillary or carotid artery. As they are in closer proximity to the aortic arch, these cannulation sites may be more effective in washing the root with oxygenated blood. However, cannulation of these smaller vessels will require a smaller cannula, which will decrease the maximum achievable flows. A VA-V ECMO circuit can also be created where a portion of arterialized blood from the arterial outflow cannula is diverted via the right internal jugular artery to the right heart. This enriches the blood traveling through the pulmonary circulation and to the left ventricle to provide better oxygen delivery to the coronary and cerebral circulations. Finally, if cardiac function has recovered sufficiently, VA ECMO can be converted to VV ECMO to provide only gas exchange support until the lungs fully recover function.Upper body hypoxemia may be addressed in several ways. The oxygen content of pulmonary venous blood may be augmented by adjusting ventilator settings, such as increasing the fraction of inspired oxygen  by increasing the extraction ratio (ER) of oxygen from the blood. Recall that2 is oxygen consumption. Simplification of this equation results in the following:2), this equation reflects the inverse relationship of ER with SvO2. Assuming a SaO2 of 100%, a normal extraction of 25–35% results in a normal SvO2 of 65–75%. A state of high extraction will result in a low SvO2 of <65–75%; once oxygen extraction reaches a maximum of 50–60% and the SvO2 decreases to 40–50%, the body will begin to produce lactate due to the initiation of anaerobic metabolism.SvO2 due to inadequate oxygen delivery may be secondary to inadequate ECMO support. Recall that2 is oxygen content. Given that the main components of CaO2 are hemoglobin (Hb) and SaO2 the equation may be simplified to2 and may improve a suboptimal SvO2. Oxygen delivery can also be increased by red cell transfusion as well as by ensuring adequate arterial saturation. Because the anemic patient requires higher ECMO flows to achieve the same oxygen delivery, optimization of Hb prior to manipulation of flows may be desirable. A high ER or low SvO2 may also be caused by an increase in oxygen consumption; thus, interventions to decrease VO2  can also be made concomitantly. A more complete description of oxygen delivery on VA ECMO may be delineated with this equation:A high ER or low SvO2 cannot be measured because venous return is split between the native and ECMO circulations. However, because the majority of blood flows through the VA ECMO circuit, it can be reasonably estimated by interrogating the venous cannula leading towards the membrane oxygenator either by blood gas analysis or a saturation probe to obtain a premembrane saturation. The minority of blood flows through the native pulmonary circulation. Hence, measurement of SvO2 from a pulmonary artery catheter may not be accurate.A true SvO2 renders another equation for the variables that affect SvO2:Rearrangement of the equation for VOVA ECMO provides rest to the myocardium by decreasing venous return and subsequently the volume work and wall tension of the heart. In addition, the decrease in preload decreases left ventricular end-diastolic volume (LVEDV) and pressure (LVEDP), thus promoting better coronary perfusion pressure due to a greater pressure gradient (coronary perfusion pressure = diastolic pressure – left ventricular end diastolic pressure). However, the return of blood into the arterial system increases afterload and the pressure work of the myocardium. The overall effect of the decrease in volume work and the increase in pressure work depends on the level of ECMO support as well as myocardial function and its response to these phenomena.The ejection of blood flow out of the left ventricle generates a stroke volume and its arterial correlate, a pulse pressure. The absence of pulsatility in the arterial waveform in the setting of an appropriate level of support  may be a sign of poor contractility and the heart's inability to overcome the increase in afterload despite the decrease in preload and volume work. Without pulsatility, blood within the left ventricle and at the aortic root may stagnate. In this situation, the risk of thrombus formation and subsequent embolic complications is increased. In addition, without the adequate ejection of blood, persistent venous return from thebesian and bronchial veins into the left atrium (LA) and ventricle will result in overdistension of the LV. This increase in LVEDV will cause an increase in LVEDP, which can compromise coronary perfusion pressure and cause additional ischemic damage to the myocardium. Finally, an increase in afterload in the setting of severe mitral regurgitation may result in left atrial hypertension and the transmission of pressures to the pulmonary system resulting in pulmonary edema and hemorrhage. Such a complication may occur even without preexisting valvular pathology, as the stasis of blood may cause left ventricular dilation and a functional mitral insufficiency due to dilation of the annulus. In this scenario, a pulmonary artery catheter may demonstrate an increase in the pulmonary capillary occlusion pressure. While assessment of the heart in a partially bypassed state can be challenging, transesophageal echocardiography may aid in confirming aortic valve opening as well as by providing an assessment of the left ventricular end-diastolic dimension.VA ECMO flows can be reduced in an attempt to reduce afterload. However, this maneuver may not be possible if it compromises oxygen delivery and end-organ perfusion due to the inability of the heart to produce a compensatory increase in native cardiac output. Inotropic support can be instituted or escalated to increase contractility of the myocardium. In addition, afterload reduction with a vasodilator or intra-aortic balloon pump (IABP) may be implemented. An IABP brings the added benefit of improving coronary perfusion with balloon inflation during diastole. If these maneuvers fail to promote left ventricular ejection, decompression of the left ventricle may be necessary. Decompression may be accomplished by a percutaneous left atrial septostomy, which allows blood from the LA to drain down its pressure gradient into the right atrium (RA) to then be drained via the venous cannula. A catheter may also be placed into the LA through a transseptal puncture to facilitate drainage . In addiPulsatility is a dynamic property. Loss of pulsatility may signal worsening myocardial function, while the appearance of pulsatility or an improvement in pulse pressure may signal recovery. The differential diagnosis for loss of pulsatility also includes: VA ECMO Flows That Are Too High. The greater the ECMO flows, the more blood that drains into the circuit causing a greater decrease in LV preload, stroke volume, and pulse pressure. Total bypass, where the ECMO circuit takes over 100% of the cardiac output, creates a flat, nonpulsatile arterial tracing and signifies the lack of ejection of blood from the left ventricle.Hypovolemia/Mechanical Obstruction. A decrease in intravascular volume or a mechanical cause of decreased venous return may result in a decrease in LV preload that leads to a decreased stroke volume and pulse pressure.RV Failure. VA ECMO decreases RV preload and the volume work of the ventricle. However, pulmonary edema, lung collapse, or other parenchymal disease may cause hypoxic pulmonary vasoconstriction and may result in clinically significant pulmonary hypertension and an increase in RV pressure work. If this occurs to a significant extent, the right ventricle may be unable to deliver volume to the left side of the heart, resulting in a decrease in stroke volume and in pulsatility. In this scenario, pulmonary afterload reduction with nitric oxide or with inodilators such as milrinone and dobutamine  may be beneficial. If systemic pressures allow, nitroglycerin or nitroprusside may also be utilized.While it may be possible to maintain adequate hemodynamic and gas exchange support with VA ECMO during dysrhythmias that would otherwise be fatal, nonsinus rhythms such as ventricular fibrillation should be rectified due to the ineffective ejection of blood flow from the LV. Such arrhythmias should be addressed with direct current cardioversion, antiarrhythmics, pacing, or ablation.Pre- and Postmembrane Oxygenator Pressures. Exposure of blood to nonbiologic surfaces results in contact activation of the coagulation system resulting in a propensity to develop clot in the VA ECMO circuit. Premembrane pressures should be followed to assess for increases greater than 300–400 mm Hg. The postmembrane pressure can give useful context to the pre-membrane pressure. An elevated premembrane pressure in the setting of a normal post-membrane pressure suggests that the source of the increased resistance lies within the oxygenator. This scenario produces an increase in the difference between pre- and post-membrane pressures  and may be indicative of thrombus on the membrane lung. If thrombus is suspected and is accompanied by a deterioration in gas exchange, the oxygenator may need to be replaced. An elevated pre-membrane pressure in the setting of an elevated post-membrane pressure suggests that the source of increased resistance is located downstream to the oxygenator, perhaps as a clot or kink in the cannula. Partial Thromboplastin Time/Activated Clotting Time. Heparinization is used to decrease the risk of developing clot. Adequate anticoagulation is monitored by partial thromboplastin time (PTT) and/or the activated clotting time (ACT). Heparin levels and antithrombin III levels may also be followed.Distal Ischemia. Ipsilateral distal pulses as well as limb color and warmth should be assessed routinely with peripheral cannulations such as the axillary artery (arm ischemia) and the femoral artery (leg ischemia). In the case of femoral cannulations, a dorsalis pedis (DP) or posterior tibial (PT) distal perfusion cannula can be placed to promote perfusion to the lower extremity. Ischemic brain injury may occur as a consequence of carotid cannulation.Central Venous Pressure. The CVP is altered by venous drainage during VA ECMO support; however, a rise in CVP in the setting of stable settings may be indicative of a mechanical obstructive process.Myocardial recovery on VA ECMO support is suggested by an increase in pulse pressure and by improved contractility on echocardiography. The ultimate test of myocardial recovery, however, is accomplished by assessing hemodynamic stability on minimal or no support. The RPMs can be decreased to achieve ~1 liter/min of flow or the VA ECMO cannulas can be briefly clamped. The native ventricle must be able to handle the full load of native cardiac output. If the myocardium has recovered, a decrease in or the temporary withdrawal of VA ECMO support should result in acceptable contractility on echocardiography and a stable MAP and CVP. Hypotension, a rising CVP, and a poorly contractile myocardium on echocardiography suggest inadequate recovery.VA ECMO, a form of mechanical circulatory support, had its origins in the operating room as cardiopulmonary bypass and has evolved for use in the intensive care unit and beyond. Its purpose is simple—to replace some of the function of a failed cardiopulmonary system and to provide some rest to the myocardium. The successful achievement of such an aim, however, requires a thorough understanding of basic physiologic principles so that the weaknesses inherent to this therapy can be identified and rectified. As this technology continues to improve and becomes more accessible, knowledge of the principles underlying VA ECMO will only grow in importance to those involved in the care of the critically ill.


Although many predictors have been evaluated, a set of strong independent prognostic mortality indicators has not been established in children with pediatric pulmonary arterial hypertension (PAH). The aim of this study was to identify a combination of clinical and molecular predictors of survival in PAH.This single-center, retrospective cohort study was performed from children with PAH between 2001 and 2008 at Children's Hospital Colorado. Blood samples from 83 patients (median age of 8.3 years-old) were obtained. We retrospectively analyzed 46 variables, which included 27 circulating proteins, 7 demographic variables and 12 hemodynamic and echocardiographic variables for establishing the best predictors of mortality. A data mining approach was utilized to evaluate predictor variables and to uncover complex data structures while performing variable selection in high dimensional problems.Thirteen children (16%) died during follow-up  and survival rates from time of sample collection at 1 year, 3 years and 5 years were 95%, 85% and 79%, respectively. A subset of potentially informative predictors were identified, the top four are listed here in order of importance: Tissue inhibitors of metalloproteinases-1 (TIMP-1), apolipoprotein-AI, RV/LV diastolic dimension ratio and age at diagnosis. In univariate analysis, TIMP-1 and apolipoprotein-AI had significant association with survival time . Patients grouped by TIMP-1 and apolipoprotein-AI values had significantly different survival risks (p<0.01).Important predictors of mortality were identified from a large number of circulating proteins and clinical markers in this cohort. If confirmed in other populations, measurement of a subset of these predictors could aid in management of pediatric PAH by identifying patients at risk for death. These findings also further support a role for the clinical utility of measuring circulating proteins. Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease, characterized by remodeling of small to medium-sized pulmonary arteries, leading to elevated pulmonary vascular resistance and ultimately to progressive right heart failure and death Recently, inflammatory processes have been highlighted in various types of PAH and circulating inflammatory proteins and progenitor cells may play a significant role in the development of PAH. Evidence of inflammation in the PAH population is supported by production of proinflammatory cytokines, including interleukins (IL) The study was approved by the Colorado Multiple Institutional Review Board (COMIRB). Written informed consent and HIPPA Authorization were obtained from all patients over the age of 17 years or from parents or legal guardians of participants younger than 18 years. Assent was obtained from all participants 7 years of age and older.This single-center, retrospective cohort study was performed using clinical data from children with PAH between May 2001 and October 2008 at Children’s Hospital Colorado. Patients included in this study had diagnoses of idiopathic - primary pulmonary hypertension or congenital heart disease and had a banked blood sample available. All patients were being treated with appropriate therapies to manage their PAH during sample collection Exercise capacity was assessed by 6-minute walk distance during follow-up. We measured peak oxygen consumption during the cardiopulmonary test and calculated a ratio of minute ventilation to carbon dioxide output as ventilatory efficiency. Six-minute walk distance was most often performed the day before the catheterization; however, measurements from within 90 days of the blood draw were included. Right ventricular (RV) and left ventricular (LV) diastolic dimension are standard measurements by m-mode echocardiography By right heart catheterization using a flow-directed Swan-Ganz catheter and a systemic arterial line for monitoring, we measured mean right atrial pressure (mRAP), mean pulmonary artery pressure (mPAP), mean systemic blood pressure, and pulmonary capillary wedge pressure (PCWP). Accordingly, we calculated pulmonary vascular resistance index (PVRI) and pulmonary vascular resistance/systemic vascular resistance ratio. Cardiac output was obtained using thermo-dilution and cardiac index (CI) was calculated. If a significant intra-cardiac defect remained, cardiac output was obtained by the Fick method using the LaFarge estimation Blood samples were obtained from the femoral vein during right heart catheterization, but in rare instances were instead collected using venipuncture within 5 days of the procedure. Twenty-seven protein levels were measured in the blood samples . CirculaThe limit of detection value for each assay was used for those values reported below this limit. Descriptive statistics were calculated using medians and inter-quartile range (IQR) for continuous variables and percentages for categorical variables. The outcome used for analyses was all-cause mortality. Cox survival models were used to assess univariate associations between each marker and survival performed using SAS version 9.3 software . Random survival forests (RSF) are a popular method commonly employed in problems where the numbers of predictors outnumber a small number of events and have been shown to have good statistical properties when a large number of predictors are present. This study included 83 PAH children with a median age of 8.3 years old (IQR 4–13.8 years-old) with 41(49%) female patients and average growth . The difAll the proteins measured, with the exception of Interleukin-1 beta, were detected in greater than 50% of samples. A description of all the circulating protein levels is included in Table S2 in In total, there were 46 predictors analyzed, which included 27 circulating proteins, 7 demographic variables and 12 hemodynamic and echocardiographic variables. The most predictive molecular markers when investigated in a univariate manner, were uric acid (Hazard ratio (HR) [95%Confidence interval]: 1.6  per 1 mg/dl), APO-AI , TIMP-1 , and hemoglobin , whereas the most predictive clinical markers were RV/LV diastolic dimension ratio , pulmonary vascular resistance index , peak oxygen consumption , VE/VCO2 slope , pulmonary artery pressure , age at diagnosis , body surface area , and WHO FC  with a small number of events. Therefore, clinical findings regarding the prognostic impact of predictors remain to be confirmed in a larger multi-site study. Second, children were individually treated with various vasodilator therapies according to their conditions. The variety of treatments might be potentially associated with their prognosis. Additionally, patients with complex heart disease can have other cardiovascular risk factors on the risk of mortality which may not be captured in this study.In conclusion, using a novel data mining approach we identified potentially important predictors of mortality in this cohort. If confirmed in other populations, measurement of a subset of these predictors could aid in management of pediatric PAH by identifying patients at risk for death. These findings also further support a role for the clinical utility of measuring circulating proteins. Higher TIMP-1 was associated with mortality in pediatric patients with PAH and was the best predictor among various clinical data.File S1This contains Figures S1–S4 and Tables S1 and S2. Figure S1. Test statistics evaluating the association between molecular markers and demographic variables. Figure S2. Heatmap displaying the magnitude of the correlation between measured circulating proteins. Figure S3. The points correspond to the intraclass correlation coefficient (ICC) for each molecular marker listed and the lines denote the 95% confidence intervals of the estimates. The higher the ICC value, the more similar the protein levels were within a patient. Figure S4. Functional form of top predictor variables. Plots for top 4 predictors from RSF are displayed. Table S1. Detailed Diagnosis of heart disease diagnosis in congenital heart disease patients. Table S2. Description of circulating protein levels in pediatric PH patients.(DOCX)Click here for additional data file.


Introduction. Noninvasive blood pressure (NIBP) monitoring methods are widely used in critically ill patients despite poor evidence of their accuracy. The erroneous interpretations of blood pressure (BP) may lead to clinical errors. Objectives. To test the accuracy and reliability of aneroid (ABP) and oscillometric (OBP) devices compared to the invasive BP (IBP) monitoring in an ICU population. Materials and Methods. Fifty adult patients (200 comparisons) were included in a randomized crossover trial. BP was recorded simultaneously by IBP and either by ABP or by OBP, taking IBP as gold standard. Results. Compared with ABP, IBP systolic values were significantly higher . Both diastolic  and mean  IBP were instead lower. Compared with OBP, systolic  and mean  IBP were higher, while diastolic IBP  was lower. Bland-Altman plots showed wide limits of agreement in both NIBP-IBP comparisons. Conclusions. BP measurements with different devices produced significantly different results. Since in critically ill patients the importance of BP readings is often crucial, noninvasive techniques cannot be regarded as reliable alternatives to direct measurements. Arterial blood pressure (BP) is one of the most frequently measured parameters in clinical practice, as many diagnostic and therapeutic decisions are based on this measure. The reliability of BP measurements is particularly important in critically ill patients, who often need frequent or continuous BP monitoring to establish or reassess their treatments. Different systems derive systolic (SAP), diastolic (DAP), and mean (MAP) arterial pressure parameters based on different physical events. These events are the Korotkoff tones for aneroid manometers (ABP), the maximal oscillations of a cuff pressure curve for oscillometric devices (OBP), and direct electronic measurement for invasive arterial blood pressure (IBP).In some clinical settings the ABP technique with manual aneroid manometers (mercury manometers having been banned a few years ago) remains the method of choice for BP measurement , despiteUnfortunately, NIBP monitoring is influenced by factors related to the procedure, to the instruments themselves, and to interobserver variability . BecauseThe objective of this study is therefore to compare invasive arterial blood pressure with noninvasive blood pressure measurements, considering that the measurements with invasive method reliably reflect the actual value of BP.This is a randomized crossover clinical trial performed to test the accuracy and reliability of ABP and OBP compared with invasive arterial blood pressure (IBP) monitoring. The study was carried out from July to December 2012 in the General ICU of the “Azienda Ospedaliero-Universitaria” Hospital of Trieste, Italy. The ICU has 13 beds and admits about 800 patients a year. During the study period, 50 patients aged between 18 and 92 years with a radial artery catheter were included in the study. The caregivers took the decision to place an intra-arterial catheter without any influence from the researchers. Because the other trial interventions were noninvasive and did not interfere with usual patients care, no informed consent was required according to the hospital authorities.Exclusion criteria were the presence of a different arterial line , any contraindication to cuff application/inflation , Glasgow Coma Scale ≥12, and the presence of arrhythmias. For every patient, main diagnosis and ongoing infusion of vasoactive drugs were also recorded.BP measurements were performed by 3 critical care nurses. In order to obtain accurate and consistent readings, each nurse had been trained to follow a standardized BP recording method  before sDuring the study, the BP was measured 4 consecutive times per patient on the same arm , twice bζ.A strict study protocol prescribed that the IBP-designated nurse calibrated the arterial line by (1) positioning the transducer at the level of the patient's 4th intercostal space at the midaxillary line, (2) regulating the pressure reading to zero, (3) inspecting the tubing and transducer to ensure absence of kinking or air bubbles, and (4) flushing the tube and performing a “fast flush” test to verify the presence of a normal arterial waveform, a natural frequency between 16 and 25 Hz, and a damping coefficient between 0.5 and 0.9Given that the current literature reports risks of inaccuracy of auscultatory BP measurement related to both observer and methodological errors, the following precautions were taken. We avoided digit preferences, and SAP and DAP values were rounded to the closest 2 mmHg. Cuff deflation was standardized at 2 mmHg per second. An appropriately sized cuff was chosen following a measurement of arm circumference . The nurse was positioned so as to be able to see the dial of the manometer perpendicularly and at eye level. In case of persistence of the fifth Korotkoff tone, attenuation of the fourth tone was acquired as a measure of DAP. To prevent possible bias resulting from “white coat hypertension” effect, we included only patients sedated or with reduced level of consciousness . To calculate the MAP from the values obtained by the sphygmomanometer we used the formula (SAP + 2DAP)/3.t-test was used for comparisons between means. The correlation between the SAP, DAP, and MAP values of the ABP/IBP and OBP/IBP comparisons was investigated with linear regression, Pearson's correlation coefficient, and a Bland-Altman chart [P < 0.05.Statistical analysis was performed using the statistical software Stata SE version 10. Continuous variables  are displayed as mean ± standard deviation (SD) and median. Nominal variables  are displayed as number and percentage and analysed using 2 × 2 contingency tables and Fisher's exact test. Paired an chart . The accan chart  and the t-test), a between-technique minimum difference in mean SAP of approximately 6 mmHg, in case of an SD of ±15 mmHg, and a 4 mmHg difference in case of an SD of ±10 mmHg .The sample size was determined to detect, with a probability of a type I error of 0.05 and a type II error of 0.2  and 18 males (36%). Their mean age was 65.3 ± 16 years (median 73). The causes of admission to the ICU were acute ischemic or haemorrhagic stroke , severe sepsis or septic shock , major polytrauma , respiratory failure , postoperative complications , and postcardiac arrest syndrome . Twenty-six measurements for each comparison were collected while vasoactive drugs  were administered.P < 0.001) . Based on all measurements the correlations between ABP and OBP devices and IBP measurements were highly significant  .Accuracy was defined as the agreement between the concomitant IBP and ABP/OBP measurements using the method of Bland-Altman . The BlaThe averages of all systolic, diastolic, and mean blood pressure measurements obtained in the study population by the noninvasive devices and by IBP monitoring are reported in We also compared the two methods in terms of percentages of readings that varied by ≤20, ≤15, ≤10, and ≤5 mmHg . AccordiTo date, there are different methods available to measure arterial systolic, diastolic, and mean BP, which rely on the detection of different physical events. IBP monitoring is commonly used in the ICU and normally consists of a column of fluid directly connecting an arterial catheter to a pressure transducer, which converts the pressure waveform into an electrical signal. This signal is processed, amplified, converted, and displayed as BP value and graphic waveform. In the absence of technical errors  IBP is considered the golden standard for BP measurement in the ICU. IBP provides several advantages over less invasive methods: it allows quick and easy blood sampling, it ensures close monitoring through continuous beat-to-beat BP measurement, its readings remain reliable in obese, neonate, burned, haemodynamically unstable, or arrhythmic patients, and it generates waveforms that allow pulse contour analysis.The auscultatory method prescribes instead that a cuff be placed around the upper arm, inflated above systolic pressure to occlude the brachial artery, and subsequently slowly deflated. The restoration of blood flow is associated with the detection of Korotkoff sounds by a stethoscope over the artery. The first clearly audible sound corresponds to SAP (Korotkoff's phase 1) and the last audible sound (phase 5) to DAP. In situations in which the fifth sounds are audible even after complete deflation of the cuff, the fourth sound can be used as DAP. Previous research has found that this method tends to give lower values of SAP and higher of DAP when compared with the true intra-arterial pressure [Oscillometric devices record the oscillations of pressure in a sphygmomanometer cuff during its progressive deflation; the maximal detected oscillation corresponds to MAP, while SAP and DAP are estimated according to various empirical algorithms usually not disclosed by manufacturers that may result in dramatically different accuracy levels . MoreoveHowever, noninvasive methods are still widely used in the ICU . Our stuOverall, according to the BHS criteria, we found a large percentage of readings outside the range of acceptable agreement. This may result in greater risks of erroneous clinical decisions—for example, unnecessary use of inotropic support and blood transfusions in hypotensive patients or, conversely, delayed antihypertensive treatment in hypertensive patients , 19, 28.In accordance with previous studies , 20, 28,P < 0.05), while no statistically significant difference was shown for normal or high pressure values. Holt et al. [In a study from Takci et al.  where IBt et al.  comparedt et al. . In our The differences we reported may depend on the site where BP was measured. NIBP measurements were performed on the brachial artery, whereas IBP measurements were performed on the radial artery. It is known that IBP monitoring provides different BP values according to the site of detection and that brachial BP tends to be closer to central BP than radial BP –32. HoweThis study has some limitations. First of all, the patients included in this study differed in terms of their main diagnosis. However, data from previous studies have demonstrated that underlying diseases do not contribute to the differences between different methods . Second,ABP, OBP, and IBP are not based on the same physiological observation and measurement with different devices may not produce the same results. So it is very difficult to establish what is the “true” blood pressure, that is, the one on which to base clinical choices and derive data for calculating various scores. Even standardizing the technique and limiting interobserver variability, we found that both studied noninvasive methods (auscultatory and oscillometric) can be inaccurate among critically ill patients. Since in critically ill patients the importance of BP readings is often crucial, noninvasive techniques cannot be regarded as reliable alternatives to direct BP measurements. In settings where IBP monitoring is not possible and only noninvasive techniques are available, BP values detected by noninvasive methods may be randomly and unpredictably very different from the real one. In these cases, according to our findings, SAP values should be considered less reliable, while MAP appears to be the most reliable parameter, especially if assessed by the auscultatory method.Since NIBP monitoring is normally available in every ICU, its use should be recommended in addition to IBP monitoring. If the data obtained by the two methods differ markedly and/or are not consistent with the patient's clinical condition, the operator should maintain a suspicious eye and check the reliability of the instruments, especially before undertaking any treatment. When IBP is not measured in the ICU for any reason, a comparison of ABP and OBP values is recommended.