Oxygenation-sensitive (OS) Cardiovascular Magnetic Resonance (CMR) is a promising utility in the diagnosis of heart disease. Contrast in OS-CMR images is generated through deoxyhemoglobin in the tissue, which is negatively correlated with the signal intensity (SI). Thus, changing hematocrit levels may be a confounder in the interpretation of OS-CMR results. We hypothesized that hemodilution confounds the observed signal intensity in OS-CMR images.Venous and arterial blood from five pigs was diluted with lactated Ringer solution in 10 % increments to 50 %. The changes in signal intensity (SI) were compared to changes in blood gases and hemoglobin concentration. We performed an OS-CMR scan in 21 healthy volunteers using vasoactive breathing stimuli at baseline, which was then repeated after rapid infusion of 1 L of lactated Ringer’s solution within 5–8 min. Changes of SI were measured and compared between the hydration states.r = -0.67, p < 0.0001) and venous blood  were negatively correlated with the changes in hemoglobin (Hb). SI changes in venous blood were also associated with SO2  and deoxyHb concentration . In healthy volunteers, rapid infusion resulted in a significant drop in the hemoglobin concentration . Baseline myocardial SI increased by 3.0 ± 5.7 % (p = 0.026) following rapid infusion, and in males there was a strong association between the change in hemoglobin concentration and % changes in SI . After hyperhydration, the SI response after hyperventilation was attenuated , as was the maximum SI increase during apnea (p = 0.012). The extent of SI attenuation was correlated with the reduction in hemoglobin concentration at the end of apnea  for all subjects and at maximal SI  and the end of breath-hold  for males only.The % change in SI from baseline for arterial (In dynamic studies using oxygenation-sensitive CMR, the hematocrit level affects baseline signal intensity and the observed signal intensity response. Thus, the hydration status of the patient may be a confounder for OS-CMR image analysis. Oxygenation-sensitive (OS) Cardiovascular Magnetic Resonance (CMR) is a promising tool to assess myocardial oxygenation changes . In contHowever, many factors influencing the technical aspects of the underlying T2*-sensitive sequences remain confounders. The hydration status of an individual may be such a confounder . Lin et The aim of this study was to assess the differences in oxygenation-sensitive signal intensity free of vasoactive effects in an in-vitro setup and during vasoactive breathing maneuvers in healthy subjects. We hypothesized that hemodilution results in an increase in baseline signal and leads to an attenuation in signal intensity changes after hemodilution during dynamic breathing maneuvers.Venous and fully oxygenated arterial blood samples from five pigs ventilated with 100 % oxygen were used to assess hemoglobin-dependent changes in oxygenation-sensitive (OS) signal intensity (SI) independent of vasomotor effects. The blood was obtained immediately after euthanasia of five animals used for another experiment . The stuThis study protocol was approved by the local research ethics board of the Institut de Cardiologie de Montréal (ICM #13-1447). In order to examine the relevance of hemodilution to clinical studies, 21 healthy volunteers were recruited to participate in this study by public advertisement. Inclusion criteria were age >18 years and ability to give informed consent. Participants with any history of cardiovascular, respiratory, cerebral or renal disease, pregnancy, smoking within the last 6 months or any contraindication for MRI scans were excluded. The subjects were required to refrain from the consumption of caffeinated beverages 12 h prior to the scan.An 18-Gauge i.v. line was placed in a cubital or ante-cubital vein for the initial measurement of the baseline hematocrit and hemoglobin concentration. After acquisition of baseline images, 1 L of Ringer’s Lactate solution was rapidly infused over 5–8 min with a pressure bag (300 mmHg). Immediately after rapid i.v. hydration, a second blood sample was acquired before a second set of images was acquired (hyper-hydration) using the identical protocol as that used for baseline scans. Non-invasive blood pressure was measured before and after hemodilution, heart rate was continuously recorded during the scans and rate-pressure product was calculated by multiplying the systolic blood pressure with the heart rate. A vasoactive breathing maneuver according to Fischer et al. was employed as an activation-dependent stimulus analogue to fMRI scans at baseline and after hemodilution .Images were acquired in a clinical 3 T MRI system  using a 30-channel coil setup with body and spine coils. For the in-vitro study, the samples were scanned with a simulated 60/min heart rate immediately after localization, after being placed in the scanner to minimize sedimentation. For healthy volunteers, all images were acquired during a breath-hold at end-expiration. Left-ventricular (LV) function was assessed using a standard ECG-gated balanced steady-state free-precession (bSSFP) sequence in six LV-centered radial long-axis slices .One mid-ventricular slice was acquired during all oxygenation-sensitive scans using a retrospective ECG-gated bSSFP prototype sequence . After acquisition of baseline images for both the normo- and hypervolemic state during a short breath-hold, the subjects performed 60 s hyperventilation (35 breaths/min) with constant cine acquisition during a maximal consecutive breath-hold as a dynamic vasoactive maneuver at both levels. A metronome was used to ensure consistency of the respiratory rate. Volunteers were instructed to use the alarm bell to signal the break-point of the voluntary apnea and to immediately recommence breathing.Image analysis was performed using certified CMR evaluation software . In the in-vitro samples, SI was measured after defining a contour in the long-axis (LAX) orientation of the syringes. For the assessment of left-ventricular function, parameters in the volunteers endo- and epicardial contours were traced in end-systole and end-diastole.In OS-CMR images, manual endo- and epicardial contour tracing was completed in end-systolic frames. Mean myocardial SI was automatically generated by the software following contour tracing. All SI values were expressed as percent change (ΔSI[%]) between two images.max), as well as after 30 s apnea (SI30s) and end-breath-hold SI (SIend) changes were examined. A second reader, blinded to the hydration status, the maneuver and the subjects’ demographics, read 39 out of 220 images (18 %) to assess inter-observer reproducibility. For the in-vitro samples, the same equation was used to calculate the %change in SI from the undiluted blood samples (100 %) to the LRS-diluted samples , respectively.The change in signal intensity between the baseline and hyper-hydration images was calculated, and the relative SI changes during the vasoactive breathing maneuvers were compared between the two hydration states. Specifically, differences between end-hyperventilation (HV), peak . All variables were checked for normal distribution using the D’Agostino-Pearson omnibus normality test. Student’s t tests were performed for those values with normal distribution, otherwise Mann-Whitney or Wilcoxon tests were used. To test correlation between quantitative variables, Pearson correlation coefficients or Spearman rank test were determined. Differences in blood levels to baseline in the in-vitro data was analyzed with a one-way ANOVA (Friedman test) with a Dunn post-hoc test for multiple comparisons. Variables are presented as means ± standard deviation. Images of nine participants (39 readings) were replicated by a second independent reader, and inter‑observer reliability was assessed using a two-way intraclass correlation (ICC) test with SPSS version 23 . p < 0.001). Arterial blood had no detectable deoxyHb. In the venous blood, the absolute deoxyHb concentration (p < 0.001) and the fraction of deoxy-Hb fell with increasing dilution (p < 0.001), while oxygen saturation showed a small increase (p < 0.001). Actual hemoglobin concentration for the same dilution of venous and arterial samples did not differ.The changes in hemoglobin concentration, hemoglobin saturation, absolute deoxy-hemoglobin (deoxyHb) concentration and the deoxyHb fraction of arterial and venous blood samples are shown in Table r = -0.55, p = 0.002) and arterial blood  were negatively correlated with the changes in hemoglobin concentration, respectively  and weight (p < 0.001) were significantly higher in males. All variables passed the D’Agostini-Pearson Test for normal data distribution.The participants’ demographics are displayed in Table p < 0.0001) and hematocrit . There was no difference in relative hemoglobin  or hematocrit  changes between male and female participants.Rapid infusion of 1 L Lactated Ringer’s solution resulted in a significant drop in the hemoglobin concentration . There was a weak but significant correlation between hemoglobin concentration and breath-hold time Maximal voluntary apnea was shorter after hemodilution  indicated a strong agreement between readers.In oxygenation-sensitives images 18 out of 680 (2.65 %) end-systolic image frames had to be excluded due to poor image quality mostly due to breathing artifact at the transition from hyperventilation to apnea. In all other images image quality was good to excellent. There was no difference in image quality between the hydration states (2.47 % vs. 2.86 % exclusion rate). A strong intra-class correlation coefficient (ICC) of 0.924  following rapid infusion. Figure p = 0.56) or in females (p = 0.19), however in the eleven males there was a strong association between absolute changes in hemoglobin concentration and %changes in SI  and at the maximal SI increase during apnea  of the breathing maneuver. At 30 s (SI30s) into the breath-hold, there was only a trend (p = 0.057) for an attenuated SI increase at hyperhydration  during apnea .SI decreased after hyperventilation and increased during apnea at both hydration states. However, an attenuation of signal intensity response to the breathing maneuvers was observed after hyperventilation  but not in females , resulting in only a trend for a correlation for the entire cohort ,  in the entire collective . Looking at gender differences this was also true for the male subgroup .With increasing reduction in hemoglobin concentration (∆Hb), we found a stronger attenuation in SI  for SI8), Fig. . Figure Our results demonstrate for the first time that hemodilution may increase baseline signal intensity in oxygenation-sensitive images but also attenuate the observed signal response to vasoactive breathing maneuvers. The understanding of this relationship is important for the clinical applications of OS-CMR . PatientIn the in-vitro data, the concentration and fraction of deoxyHb were negatively correlated to the signal intensity of the sample and positively correlated to the hemoglobin saturation. Interestingly, both the hemodilution of arterial and venous blood resulted in an increase in signal intensity of the sample. Although there was no significant difference in the slope of the regressions, the less pronounced increase observed in venous blood can be explained by the signal-attenuating effects of the deoxyHb.During the dilution of deoxyHb, the T2* effect based on the paramagnetic properties of deoxyHb is reduced, which augments the relative impact of T2 effects, leading to a higher signal intensity. Establishing this relationship in vitro is an important step to distinguish the SI effects of the simple hemodilution of deoxyhemoglobin from the more complex SI-changing effects by the vasoactive breathing maneuver in the participants during hemodilution.The in-vitro data corresponds to the increase in baseline signal intensity after rapid infusion of crystalloids in healthy volunteers, leading to an attenuation of the T2* effect, which explains the observed rise in signal intensity. This effect was also observed in neurologic fMRI studies by Lin et al. , 18. TheThe linearity of the regression lines in our results suggests that the baseline signal intensity can be normalized for a known deviation of hemoglobin concentration. Interestingly, the change in hemoglobin concentration was only related to changes in signal intensity in male subjects.Levin et al. 2001) performed repeated photic-stimulation functional MR experiments before and after hemodilution  in male 01 perforYet, the observed sex differences in our study may be explained by a higher total vasodilatory capacity which had not been exhausted by the intravascular hypervolemia. A larger sample size might have detected a weaker yet still existing relationship in female participants.The increase in baseline SI and the attenuation in SI response during vasoactive breathing maneuvers were already observed at a mean drop in hemoglobin concentration of 13.7 g/L (corresponding drop in HCT 3.8 %) in our study. Such a relatively small change is easily encountered in clinical settings. In some patients, the drop in hemoglobin concentration during volume substitution after blood loss can exceed such change by far. Conversely, diuretic therapy may significantly increase in hematocrit level. Thus, our data have clinical relevance for the future use of OS-CMR in non-invasive cardiac testing.The changes in ventricular volumes and function data are explained by the increase in preload and consecutive improvement in contractility, based on the Frank-Starling mechanism. The increase in blood pressure leads to an elevated rate-pressure product, with an increased myocardial workload and thus higher oxygen extraction. While this may suggest an explanation for the decreased signal intensity response as well, the blood pressure remained within the auto-regulation range for myocardial blood flow and therefore, a decreased myocardial oxygen supply would result in a consecutive compensatory increase in blood flow to maintain a constant tissue oxygenation. Thus, an increase of the myocardial oxygen extraction less likely explains the observed hemoglobin-dependent changes in OS-CMR.A study of Zheng and colleagues on brain functional connectivity in hemodialysis patient with end-stage renal disease  showed tThe precise execution of breathing maneuvers may have varied between participants and between breathing maneuvers within subjects. To minimize variations, we paced the respiratory rate for the subjects with a metronome during hyperventilation and visually monitored it by a camera installed in the scanner room. If breathing appeared insufficiently deep or too slow, we immediately intervened to correct that. As breath-hold duration during maximal tolerable apnea is highly variable, we used standard time points for comparison between fluid states. The 30 s time point was reached by every participant. Further, we used the peak signal intensity change during apnea and the signal intensity change at the end of the maneuver, when participants had the urge to breathe again for comparison. However, these time points vary in the time point of acquisition during the maneuver between participants and between runs. The primary reader of the exams was not blinded to the fluid state during which the images were acquired. However, the second reader, who analyzed 18 % of the images, was blinded to the fluid state, and there was an excellent agreement between the readers. Results may be very different in a patient cohort with a more chronic systemic fluid overload. Although our data opens up the potential for normalizing the measured signal intensity response to hemoglobin changes, there needs to be further research, especially in patients with coronary pathologies present in patients with heart failure that can be scanned before and after re-compensation. Larger sample sizes may allow for a more precise determination of the relationships and thus correction factors.In dynamic studies using oxygenation-sensitive CMR, the hematocrit level affects baseline signal intensity and the observed signal intensity response. Thus, the hydration status of the patient may be a confounder for OS-CMR image analysis.max, delta (difference) in maximal oxygenation-sensitive signal intensity; A, arterial blood sample; ANOVA, analysis of variance; BH, breath-hold; BMI, Body Mass Index; BOLD, Blood Oxygen Level-Dependent; bSSFP, balanced steady-state free-precession; CI, confidence interval; cm, centimeter(s); CMR, Cardiovascular Magnetic Resonance; Conc., concentration; CT, Computed Tomography; deoxyHb, deoxygenated hemoglobin; ECG, electrocardiogram; FHHb, fraction of deoxyhemoglobin of total hemoglobin; fMRI, Functional Magnetic Resonance Imaging; g, gram(s); h, hours; Hb, hemoglobin; HCT, hematocrit; HR, heart rate; HV, hyperventilation; i.v., intra-venous; ICC, intra-class correlation; ICM, Institut de Cardiologie de Montréal; kg, kilogram(s); L, Liter; LAX, long-axis; LRS, Lactated Ringer’s solution; LV, left-ventricular; m, meter(s); ml, milliliter(s); mmHg, Millimeter Mercury; MR, Magnetic Resonance; MRI, Magnetic Resonance Imaging; OS, oxygenation-sensitive; s, seconds; SAX, short-axis; SI, signal intensity; SI30s, signal intensity at 30 s into the breath-hold; SIend, signal intensity at the end of the breath-hold; SImax, maximal signal intensity during breath-hold; SO2, oxygen saturation of hemoglobin; SvO2, venous oxygen saturation of hemoglobin; T, Tesla; TE, Echo time; TR, Repetition time; V, venous blood sample; vs., versus∆, delta (difference); ∆OS-SI


Patients with chronic kidney disease, especially those undergoing dialysis treatment and having secondary hyperparathyroidism, have a high risk of bone fracture. The renin-angiotensin system (RAS) is associated with osteoclastic bone resorption. We aimed to examine whether the use of RAS inhibitors reduces the incidence of fracture in hemodialysis patients.This was a multicenter, 3-year, prospective, observational study. From 2008 to 2011, maintenance hemodialysis patients with secondary hyperparathyroidism  treated with angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) at baseline were followed for a mean of 2.7 years. The association between the use of ACEI/ARB and hospitalization rate owing to fracture was examined by using Cox regression models. Effect modifications by the severity of secondary hyperparathyroidism (intact parathyroid hormone [iPTH] level), sex, and systolic blood pressure were also examined. The incidence proportion of fracture-related hospitalization was 5.42% throughout the observation period. ACEI/ARB use was associated with a lower rate of fracture-related hospitalization . This association was not significantly affected by sex (P = 0.56) or systolic blood pressure levels (P = 0.87). The hazard ratios adjusted by iPTH levels were qualitatively different, but not statistically significant (P = 0.11): 0.77 , 0.38 , 0.59 , and 1.29  for the first, second, third and fourth quartiles of iPTH, respectively.Use of RAS inhibitors is associated with a lower rate of fracture-related hospitalization in hemodialysis patients with secondary hyperparathyroidism.NCT00995163ClinicalTrials.gov  Patients with chronic kidney disease (CKD), especially those undergoing dialysis, have poor survival and increased risk of cardiovascular disease (CVD) due to hypertension. To control blood pressure and preserve cardiac function, inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is used widely in patients with CKD–3.Mineral and bone metabolic disorders are other common complications of patients with CKD. This disorder contributes to the development of bone fractures, and increases the risk for all-cause and cardiovascular mortality owing to vascular calcification.–13 The KSeveral clinical studies on the general population have suggested that ACEIs decrease the risk of bone fracture–24. The The MBD-5D study is a multicenter, 3-year, prospective, observational study involving maintenance hemodialysis patients with secondary hyperparathyroidism. Details of the study design have been published elsewhere, 27. BriEligible patients comprised all those who were receiving hemodialysis at a participating facility as of January 1, 2008, and who satisfied any of the following inclusion criteria: intact PTH (iPTH) level of ≥180 pg/mL or treatment with intravenous vitamin D receptor activator or oral active vitamin D receptor activator. Patients undergoing hemodialysis for <3 months were excluded.The primary outcome of this study was the time to incidence of hospitalization owing to fracture, regardless of the type of fracture. We examined the period from the initiation of the observation to the occurrence of the initial event. A participant was censored after the initial event. The exposure of interest was ACEI/ARB use at baseline.To describe patient characteristics, continuous variables are shown as medians (interquartile range: IQR), whereas categorical variables are shown as percentages. For comparisons between the groups with and without ACEI/ARB use, Wilcoxon and chi-square tests were used, respectively.In the primary analysis, the association between ACEI/ARB use and the incidence of hospitalization owing to fracture was examined. The cumulative incidence of hospitalization owing to fracture between groups with and without ACEI/ARB use was analyzed by using the Kaplan–Meier survival curve and log-rank test. Non-adjusted, case-mix-adjusted, and multivariate-adjusted Cox regression proportional hazard models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). Deaths (n = 506), losses during the follow-up period (n = 143), renal transplantation (n = 5), changes to peritoneal dialysis (n = 2), and termination of the observation were considered censored data. The proportional hazards assumption was visually checked by using a log negative-log survival plot.In the case-mix adjusted model, age, sex, duration of dialysis, and causes of end-stage kidney disease were adjusted. In the multivariate-adjusted model, the following covariates were adjusted in addition to those in the case-mix model: body mass index; Kt/V; comorbidity of CVD and/or diabetes mellitus, smoking, history of parathyroidectomy, prescriptions of anticoagulants, vitamin D receptor activators, and phosphate binders, and serum levels of albumin, calcium, phosphorus, PTH, alkaline phosphatase, and blood hemoglobin, in addition to systolic and diastolic blood pressure and the use of antihypertensive drugs .To reinforce the results of the primary analysis, a sensitivity analysis was performed: blood pressure and use of each antihypertensive drug were removed from the covariates of the multivariate-adjusted model to confirm whether the analysis was robust if these blood pressure-related data were intermediates rather than confounders.In the secondary analysis, effect modifications by some factors clinically relevant to fractures were examined, such as the severity of secondary hyperparathyroidism , sex, and systolic blood pressure. The iPTH and systolic blood pressure were categorized into quartiles. We applied Cox regression models in which the main predictor was defined as a categorical combination of one of the factors mentioned above and the use of ACEI/ARB, with the same covariates as those used in the multivariate-adjusted models in the primary analysis. The statistical significance of the effect modification was tested by using a likelihood ratio test.All statistical analyses were performed with SAS 9.2 . A P value of <0.05 was considered significant.The median age of the patients was 63  years. Women accounted for 38.5%. The median duration of dialysis was 8.3  years. Patients with diabetes mellitus and CVD accounted for 31.6% and 60.0%, respectively.A higher proportion of men than women had diabetic nephropathy as the primary disease among patients using ACEI/ARB compared with those not using ACEI/ARB  hospitalizations owing to fractures within the observation period. Of these, 58 hospitalizations were because of hip fractures. Patients using ACEI/ARB had a lower fracture incidence rate (1.48 vs. 2.33 per 100 person-years) and a lower incidence (3.64% vs. 6.60%) throughout the observation period than those not using ACEI/ARB.On the basis of the Cox regression analyses, ACEI/ARB use was associated with a lower incidence of hospitalization owing to fracture in non-adjusted , case-mix-adjusted  and multivariate-adjusted  models . SimilarThe results of the analysis of effect modifications by iPTH levels, sex, and systolic blood pressure for the association between ACEI/ARB use and hospitalization owing to fracture are shown in This study showed that treatment with ACEI/ARB was associated with a lower rate of hospitalization owing to fracture in hemodialysis patients with secondary hyperparathyroidism Figs  and 2. T.[In vitro studies have shown that angiotensin II directly enhances multinuclear osteoclast differentiation from bone marrow-derived mononuclear cells, and induces the expression of receptor activator of nuclear factor-κB ligand in osteoblasts; in contrast, these effects are inhibited by ARBs[In the general population, use of ACEIs decreases the risk for fracture. A population-based, pharmaco-epidemiological, case-control study showed that the risk of any fracture was reduced by 9% in patients who received ACEIs during the 5-year observation period. The RAS.. In a mu.. In vitrd by ARBs. Taken tIn the analysis of the effect modification by the severity of secondary hyperparathyroidism, the effect of ACEI/ARB on the incidence of fractures was obvious in patients with the second (196–265 pg/mL) quartiles as compare to in those with the first (≤195 pg/mL), third (266–391 pg/mL) and fourth (≥392 pg/mL) quartiles of iPTH . It is pThis study has several limitations. The MBD-5D data were obtained from patients at dialysis facilities in Japan. Our cohort had far lower competing risks such as deaths and renal transplantations than those in Western countries, which made it suitable to examine bone fractures as an outcome. However, these results may not be applicable to dialysis patients worldwide. We could not obtain detailed data about fractures such as site, severity, and cause of fracture as well as on bone mineral density. While the events evaluated in this study required hospitalization, we could not obtain data for activities of daily living that may have influenced the outcome. Furthermore, this was an observational study and could not escape from confounding by indication bias, although the sensitivity analyses showed consistent results.The use of RAS inhibitors is associated with a lower rate of hospitalization owing to bone fracture in hemodialysis patients with secondary hyperparathyroidism. To the best of our knowledge, this is the first study to report a significant reduction of the fracture risk in patients with severe CKD. RAS intervention may be an appealing preventive therapeutic strategy in addition to conventional treatments available for patients with CKD-associated mineral and bone disorder.


Renal artery stenosis is frequently associated with resistant hypertension, which is defined as failure to normalize blood pressure (BP) even when combined drugs are used. Inhibition of PDE5 by sildenafil has been shown to increase endothelial function and decrease blood pressure in experimental models. However, no available study evaluated the baroreflex sensitivity nor autonomic balance in renovascular hypertensive rats treated with sildenafil. In a translational medicine perspective, our hypothesis is that sildenafil could improve autonomic imbalance and baroreflex sensitivity, contributing to lower blood pressure. Renovascular hypertensive 2-kidney-1-clip (2K1C) and sham rats were treated with sildenafil (45 mg/Kg/day) during 7 days. At the end of treatment, BP and heart rate (HR) were recorded in conscious rats after a 24-h-recovery period. Spontaneous and drug-induced baroreflex sensitivity and autonomic tone were evaluated; in addition, lipid peroxidation was measured in plasma samples. Treatment was efficient in increasing both spontaneous and induced baroreflex sensitivity in treated hypertensive animals. Inhibition of PDE5 was also capable of ameliorating autonomic imbalance in 2K1C rats and decreasing systemic oxidative stress. Taken together, these beneficial effects resulted in significant reductions in BP without affecting HR. We suggest that sildenafil could be considered as a promising alternative to treat resistant hypertension. Even though arterial hypertension is the most common modifiable risk factor for cardiovascular diseases, it is still an important health problem worldwide. It is predicted that its prevalence will reach 1/3 of global population by 2025 , the enzyme responsible for degrading cyclic guanosine monophosphate (cGMP). Thus, the main mechanism of action for this drug is the increase in nitric oxide (NO)/cGMP signaling pathway  weighing 150–200 g were used. Animals were bred and housed in a temperature and humidity-controlled room set to a 12/12 h dark/light cycle with access to water and regular chow  ad libitum. Experimental procedures were performed in accordance with National Institutes of Health (NIH) guidelines and protocols were approved by Institutional Animal Care and Use Committee (CEUA-UFPB protocol #042/2015).Thirty eight Wistar rats (n = 9): animals were submitted to sham surgery and received vehicle during 7 days; (2) Sham + sildenafil (n = 7): animals were submitted to sham surgery and received sildenafil citrate during 7 days (45 mg/Kg/day) by gavage; (3) 2K1C + vehicle (n = 11): animals were submitted to renal artery clipping to induce renovascular hypertension and received vehicle during 7 days; and (4) 2K1C + sildenafil (n = 11): animals were submitted to renal artery clipping to induce renovascular hypertension and received sildenafil citrate during 7 days (45 mg/Kg/day by gavage). Sildenafil dose was chosen based on previous studies and on the difference on pharmacokinetics for sildenafil in different species  Sham + vehicle , rats were anesthetized with a mixture of ketamine and xylazine  for catheters implantation and direct hemodynamic measurements. The surgical procedures were executed only after the absence of withdraw and corneal reflexes. Polyethylene catheters were inserted into the femoral artery and vein though a small inguinal incision in order to allowing blood pressure (BP) recordings and drug administration, respectively. Pulsatile arterial pressure was recorded using a pressure transducer  coupled to an amplifier and to an acquisition system  using a specific software . Systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and heart rate (HR) were derived from the pulsatile arterial pressure online.Baroreflex sensitivity was evaluated after a 24-h-recovery from the catheter implantation surgery. After 40 min of blood pressure and heart rate baseline recordings, reflex responses were obtained using vasoactive drugs as previously described using the modified Oxford method  assay. The concentration of malondialdehyde (MDA), an end product of lipid peroxidation, was measured as an indicative of oxidative stress. In this assay, MDA reacts with thiobarbituric acid to produce a red-colored complex. Briefly, 400 μL of perchloric acid (7%) was added to 250 μL serum, mixed and centrifuged at 600 g, 4°C, during 20 min. The supernatant was collected, added to 400 μL of thiobarbituric acid (0.6%), heat at 60°C during 1 h and read at 532 nm. A standard curve of MDA was constructed and the results were expressed as nmol of MDA/mL.After the experiments animals were euthanized with an overdose of thiopental (200 mg/Kg). Kidneys and heart were collected, cleaned from connective tissue and weighed.t-test or one-way ANOVA followed by Tukey's post hoc when appropriate. Statistical analyzes were performed using Prism 6 and the differences were considered significant when p < 0.05.All results are expressed as mean ± SEM. Statistical comparisons among groups were performed by As shown in Table p < 0.01; Figure p < 0.01; Figure The results of mean arterial pressure (MAP) and heart rate (HR) are summarized in Figure p < 0.01; Figure p < 0.01). These results were similar in SBRS  and the treatment restored SBRS . In both spontaneous and drug-induced baroreflex activation, treatment of normotensive rats did not modify baroreflex sensitivity . Values for SBRS and drug-induced baroreflex gain were not different within groups.The representative tracings of changes in blood pressure and heart rate after the administration of vasoactive drugs and baroreflex gain are shown in Figures S Figure . Hypertep < 0.01). Moreover, cardiac vagal tone was reduced in hypertension . Treatment with sildenafil during 7 days normalized sympathetic  and vagal tone  in 2K1C hypertension. No differences were found in sham + sildenafil group when compared to sham + vehicle. Changes in MAP after adrenergic blockade with propranolol followed the same pattern as HR . No differences were observed in sham + sildenafil. Regarding muscarinic blockade with atropine, no differences were found in ΔMAP in all groups. In addition, SBRS was evaluated before and after autonomic blockade, as presented in Table To test whether the treatment was efficient in correcting autonomic imbalance in 2K1C animals, sympathetic, and vagal tone to the heart were measured as the ΔHR after pharmacological blockade with propranolol and atropine Figure . Cardiacp < 0.05). Sildenafil treatment given to 2K1C rats for 7 days was able to reduce MDA levels when compared to non-treated hypertensive rats . Treatment of sham animals with sildenafil did not modify this parameter.The quantification of MDA, a final product of lipid peroxidation, is summarized in Figure In this study we aimed to investigate whether oral treatment with a specific PDE5 inhibitor would improve baroreflex sensitivity in renovascular hypertensive rats. This study is part of a series of studies conducted by our research group, which evaluate the effects of sildenafil administration in animal models of cardiovascular diseases in a translational medicine perspective. Our novel findings are that 7 days of oral sildenafil administration to 2K1C rats were efficient in improving baroreflex control of HR and reestablish autonomic balance to levels of non-hypertensive animals. Furthermore, the treatment decreased serum lipid peroxidation, which is an indicative of oxidative stress. Taken together, these favorable effects of sildenafil treatment were accompanied by a significant reduction in BP in treated hypertensive rats. We propose that sildenafil could be considered as a potential alternative pharmacological approach to treat resistant hypertensive patients.The efficacy of sildenafil treatment in reducing mean arterial pressure in 2K1C rats is remarkable Figures . This obPrevious studies in hypertensive rats found a slight decrease in total peripheral vascular resistance after chronic PDE5 inhibition, with no changes in HR. This suggested that the blood pressure-lowering effect of this drug did not trigger a reflex heart rate response (Ferreira-Melo et al., One important finding from the present work is that sildenafil was efficient in restoring both spontaneous and drug-induced baroreflex sensitivity Figure , which wNowadays, it is well-accepted that the mechanisms underlying impaired baroreflex control of blood pressure in hypertension involve, at least in part, Ang II-mediated increase in oxidative stress along the axis formed by subfornical organ, paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla (SFO-PVN-RVLM; Braga et al., Interestingly, Aboutabl and colleagues showed that chronic inhibition of PDE5 reduced blood pressure in NO-deficient rats and increased plasma nitrite/nitrate and cGMP levels, suggesting that sildenafil treatment could restore, at least in part, NO/cGMP pathway in this model (Aboutabl et al., In the present study we found that PDE5 inhibition decreased serum lipid peroxidation, a marker of systemic oxidative stress. Increase in serum MDA is associated with increased oxidative stress in RVLM and PVN in 2K1C rats (Campos et al., Our findings suggest that right renal artery clipping was efficient in inducing renovascular hypertension Figure . The redIn conclusion, this is the first study to show that inhibition of PDE5 is capable to improve baroreflex sensitivity in renovascular hypertensive rats. This improvement is associated with correction of autonomic imbalance in 2K1C rats. It was also documented that sildenafil treatment was efficient in reducing systemic oxidative stress and reducing blood pressure in treated animals. This study reinforces the concept that chronic administration of PDE5 inhibitors could be useful in normalizing blood pressure in resistant patients.CC, RA, and AO carried out the experiments, acquisition and analyses of data and drafted the manuscript. JC and MF participated in the supervision of the experiments and critically revised the manuscript. VB participated in the study's design and supervision and in the critical revision of the manuscript. CB conceived the study, supervised and participated in the acquisition and analyses of data and drafted the manuscript. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


P < 0.05) decrease in HR immediately after inserting and stimulating the needle at the left and the right Quchi acupuncture point. In contrast, total HRV increased immediately after inserting the needle, but this increase was significant only towards the end of the stimulation phase and after removing the needle. There were some differences between stimulation of the left and right Quchi acupoint, but they remained insignificant. This study provides evidence that there is a beneficial effect on heart rate variability in patients with hypertension and that there are some effects of laterality of the acupoint Quchi.Hypertension is one of the major risk factors for cardiovascular disease worldwide. Over 70% of the patients use antihypertensive drugs, so nonpharmacological treatments in addition to the medication are important. Our goal was to investigate acupuncture treatment on the Quchi acupoint using heart rate (HR) and heart rate variability (HRV) and to find out whether there is a laterality in acute effects. Sixty hypertensive patients  were randomly assigned to two manual needle acupuncture groups (group A: left Quchi (LI11) acupoint, group B: right Quchi acupoint). There was a significant ( Hypertension is known to be one of the major risk factors for cardiovascular disease all over the world. High blood pressure increases the risk for heart disease and stroke, which are the leading causes of death in the United States of America. Hypertension was a primary or contributing cause of death for more than 348,000 Americans in the year 2009, which means about 1000 cases of death each day , 6. MoreThe English word “left” comes from the Anglo-Saxon word “lyft,” which means “weak” or “useless,” and the English word “right” is derived from the Anglo-Saxon word “riht,” meaning also “straight” or “correct.” Similarly, in many cultures “right” also means “correct.” In medicine in general and especially in brain research, many studies and reviews deal with the topic laterality of motor and sensory control . HoweverThe goal of our study was to investigate basic mechanisms of acupuncture treatment on the Quchi acupoint in patients with hypertension using heart rate (HR) and heart rate variability (HRV). Within this investigation we wanted to find out whether there is a laterality in acute effects using needle acupuncture. Previous investigations from China indicated such laterality-related effects , 10.At the Heilongjiang University in Harbin, 60 patients  suffering from hypertension were investigated. They were randomly assigned to two intervention groups; group A received manual needle acupuncture at the left Quchi (LI11) acupoint and group B received manual needle acupuncture at the right Quchi acupoint. Randomization was performed by chance by a medical doctor who was not involved in this study otherwise. The demographic data of the two groups can be seen in The duration of RR-intervals is measured during a special time period (5 min), and on spectral analysis basis HRV is determined. Electrocardiographic (ECG) registration is performed using three adhesive electrodes  which are applied to the chest.The following quotes are taken from .The duraThe researchers in China used a medilog AR12 HRV  system from the TCM Research Center at the Medical University in Graz for the joint investigations. This system has a sampling rate of 4096 Hz and can therefore detect R-waves extremely accurately. The raw data are stored digitally on a CompactFlash (CF) 32 MB memory card. After removing the card from the portable system, the data were read by a card reader connected with a standard computer in China and then transferred to the TCM Research Center Graz via internet. With a new software the biosignals were analyzed and HRV was displayed in a way to help to judge the function of the autonomic nervous system. Viewing this innovative kind of analysis helps to show how well the human body reacts to sport, stress, recovery, and also acupuncture.Similar to previous studies, mean HR, total HRV, and the LF (low frequency)/HF (high frequency) ratio of HRV were chosen as evaluation parameters, as such being recommended by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology .All patients received manual needle acupuncture at the Quchi acupoint (LI11) on the arm . With thP < 0.05.The data were analyzed using SigmaPlot 12.0 software . Graphical presentation of results uses box plot illustrations. Testing was performed with repeated measures ANOVA on ranks and Tukey test. The criterion for significance was P < 0.05) decrease in HR immediately after inserting and stimulating the needle at the left (group A) and the right (group B) Quchi acupuncture point. HR remained on that level during the whole experiment.The results of mean HR from the ECG recordings before, during, and after acupuncture of the 60 patients with hypertension are shown in P < 0.05). There were some differences between stimulation of the left and right Quchi acupoint, but they remained insignificant.In contrast to this decrease in HR, total HRV increased immediately after inserting the needle . HoweverNo significant changes could be seen in the LF/HF ratio during acupuncture see .There was no significant change in systolic or diastolic blood pressure (BPsys and BPdia) before and after acupuncture.Laterality in acute effects after needle acupuncture stimulation has not been studied extensively in the past. One pilot study on the topic, which is also based on evidence from HRV like our present study, was published by Wang et al. last year . The autHRV can be used as a globally reliable indicator of the state of health. It could be demonstrated in previous investigations that in special syndromes like stress or burnout one can counteract this process using different preventive methods like acupuncture .n = 30, so that the comparison of the two groups (A and B) is representative. Anyway, similar to previous investigations, we are not sure at the moment whether this phenomenon can change under different brain activities because we did not measure other specific brain neuromonitoring parameters concerning central nervous system regulation.The results of our present investigation also did not show significant differences in laterality with regard to HR; however, similar to the pilot study by Wang et al. , there wn = 30) received western medicine (nicardipine). The effective rate 66.7% in the electroacupuncture group was similar to that of 70.0% in the medication group. The authors concluded that also electroacupuncture on Quchi is able to beneficially regulate blood pressure of patients with essential hypertension through adjusting blood plasma catecholamines [The same acupoint (Quchi) was also used to investigate the mechanism of acupuncture on blood pressure and blood plasma catecholamines in patients with essential hypertension . Therefoolamines .A further article on the topic deals with an animal experimental study . Quchi aAn effect of acupuncture at Quchi and also at Taichong (LR3) on blood pressure was observed not only in older patients, but also in younger patients with hypertension . Again, In our present study, no side effects appeared. We had no elbow soreness, as described in other articles . Every eAs mentioned in the introduction, lifestyle is associated with HRV and blood pressure , 20. HowIn conclusion, this study provides evidence that there is a beneficial effect on heart rate variability in patients with hypertension and that there are some effects of laterality of the acupoint Quchi, although these effects did not reach the level of significance. The question of laterality of acupoints still needs further investigations.


Psychosocial stress leads to altered neuroendocrine functions, such as serotonergic dysfunction, as well as alterations of the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA)-axis activity resulting in an imbalance between inhibitory and excitatory neurotransmitters. Poor dietary intake of L-tryptophan as a precursor of serotonin increases sensitivity to stress.This randomized, double-blind, placebo-controlled study investigated the effect of a specific amino acid composition with micronutrients on neurovegetative disorders and the cardiometabolic risk profile in psychosocially stressed patients. 32 patients (18–65 years) were eligible for protocol analysis. Points in the Psychological Neurological Questionnaire (PNF), clinical and blood parameter, in particular the serotonin level, salivary cortisol levels, and dietary intake were evaluated at baseline and 12 weeks after supplementation.The intervention in the form of either verum or placebo resulted in both groups in a significant decrease of neurovegetative symptoms. However, patients of the placebo group achieved significantly less points in the PNF compared to the verum group. But the rate of responders (≥10 points loss in PNF) was not significantly different between the groups. The macronutrient intake did not differ between verum and placebo group. On average, the HPA-axis was not disturbed in both groups. Blood serotonin indicated in both groups no significant correlation with dietary tryptophan intake or PNF.Daily supplementation of a specific amino acid composition with micronutrients in psychologically stressed patients resulted in no improvement of neurovegetative disorders as measured by the PNF when compared to the placebo group.NCT01425983)Clinical Trials.gov (The online version of this article (doi:10.1186/s12937-015-0030-3) contains supplementary material, which is available to authorized users. According to the WHO, psychosocial stress is one of the important health risks of the century; resulting cardiometabolic consequences are enormous ,2. AffecPhysical or psychological stress leads to an increased secretion of corticotropin-releasing hormone (CRH), which affects two important stress systems: the sympathoadrenal medullary system acts by the hormones epinephrine and norepinephrine on cardiovascular functions, thereby increasing resting heart rate and blood pressure; the enabled hypothalamus-pituitary-adrenal (HPA)-axis goes along with a cortisol secretion ,4. SomatThe elevated activity of serotonergic neurons in stress diminishes during psychological stress and is associated with mood disorders and depressive symptoms . This isThe essential amino acid L-tryptophan is the least available amino acid in human nutrition and a precursor of serotonin. In particular, a high protein supply constitutes also the large neutral amino acids (LNAA), which compete with L-tryptophan for the blood brain barrier transporter -10. CentThe effects of micronutrients on mood, mild psychiatric symptoms and stress were discussed in a recently published meta-analysis . The autThe aim of this study is to investigate, if daily oral administration of an amino acid mixture in combination with micronutrients, specifically designed to decrease neurovegetative disorders, will target these neuroendocrine and metabolic alterations in adults with psychological stress.Psychologically stressed women n = 21) and men (n = 13) with cardiological disorders were recruited from a cardiological outpatient practice in Berlin, Germany. Psychological stress was defined by neurovegetative disorders determined by a standardized Psychological Neurological Questionnaire (PNF) [ and men During 12 weeks of the prospective, controlled, double-blind trial, participants were required to take one serving of supplement . The self-reported symptoms were assessed as total points, as well as for individual categories, ranging from “not at all” (0 points) to “often” (3 points).Prior to dietary intervention and after 12 weeks saliva and blood samples, clinical and biochemical data were collected. After a 10 min resting period, blood pressure and resting heart rate were measured under standardized conditions. The average of three simultaneous measurements was determined. Anthropometric data and venous blood samples were obtained after an overnight fasting period of at least 12 h.Laboratory Schottdorf MVZ GmbH, Augsburg, Germany, conducted all laboratory analyses  and morning (30 min after awakening) at baseline and week 12. Therefore, Salivette® sterile cotton swabs were chewed for nearly 1 min until saturation and deposited in collection tubes, subsequently stored in a refrigerator. Measurements were performed by using microtiter plate reader Sunrise  and Cortisol ELISA .Three-day food records were reviewed with each participant at baseline and week 12, the average of 3 days was assessed. PRODI 5.5 software  with database BLS II.3 was used for the analysis.U test, nonparametric Wilcoxon test was used for data comparison at different time points within groups. Differences in classified variables were tested by Chi2 test. All statistical tests were based on per protocol population and two-sided. Differences were considered significant at p < 0.05. Data are reported as mean ± standard deviation (SD). All analyses were conducted using SPSS® for Windows (version 22.0).Statistical comparisons were made between groups using nonparametric Mann–Whitney-The study was approved by the Freiburg Ethics Commission International and was registered with the U.S. National Institutes of Health Clinical Trials.gov (NCT01425983).A total of 34 patients were randomized into verum and placebo groups, 32 patients were left for protocol analysis Figure . Two patThe patient’s characteristics at baseline are shown in Table Additionally, the HPA-axis was not disturbed as shown by saliva cortisol measurement and a serotonin deficiency was not detectable in the blood Table . Blood sp = 0.154).After 12 weeks of supplementation, patients of both groups indicated a significant improvement of neurovegetative disorders. Patients of the placebo group achieved significantly less points in the PNF compared to the verum group (Table Absolute values of energy- and macronutrient-intake did not significantly differ between verum and placebo group Table . OverallThe present study investigated whether daily supplementation of an amino acid mixture with micronutrients specifically decreases neurovegetative disorders in psychologically stressed adults as compared to a placebo. After 12-week dietary intervention both groups demonstrated a significant reduction of characteristic symptoms. Surprisingly the patients of the placebo group reported significantly less points than the patients of verum group.The PNF could be discussed as a tool for establishing chronic stress . Here, wThe assumptions of a disturbed HPA-axis and a serotonin deficiency were not met for most patients. Therefore, the diagnosis of psychological stress was merely confirmed by the PNF and in a diminished manner by elevated resting heart rate. Although another clinical study showed that there seemed to be no correlations of blood serotonin and central serotonin in humans . ConsideMany unpredictable effects such as changes in nutritional behaviour over time, which are difficult to control for, bias results even in carefully designed studies . The nutAlthough there were no significant differences in nutritional intake between the groups, the SFA-intake was remarkable. Other authors stated that the impact of a self-medication by eating palatable foods during chronic stress, leads to a high-fat diet in these patients, thereby protecting against stress-induced effects ,31. It hAlthough considering the protective effects of a high-fat diet in short-term, the increased fat-intake will become habitual ,37 and tAs a study limitation, there would be to mention the small sample size, which decreases the statistical power, in particular for the comparison of subgroups but also for the detection of marginal changes. The low participation could be attributed to the impacts of chronic stress and should be recognized as a non-participation bias. Concurrently, the selection of participants was locally limited, and most of them were handicapped by cardiological therapy, although significant impairment by antihypertensive drugs was excluded.The connection between a high-fat diet and chronic stress exposure is widely examined in studies with rodents ,33. In tDaily supplementation of a specific amino acid composition with micronutrients in psychologically stressed patients resulted in no improvement of neurovegetative disorders as measured by the PNF when compared to the placebo group.


Acute asthma is a chronic condition affecting people of all ages around the world and hence, is one of the leading causes of emergency department (ED) visits and hospital admissions globally. Most of them are related to poor patient practices and a weak healthcare system. The aim of our study was to assess the reasons for the increased usage of the ED by asthmatic patients in Pakistan.A cross-sectional study was conducted on 600 asthmatic patients reporting to the ED of Civil Hospital Karachi over a 6-month period. The consenting patients were given a questionnaire to fill and the following data was collected: demographic information, duration of the disease, medications prescribed the, frequency of and reasons for outpatient clinic and ED visits for issues related to asthma.According to our results most of the participants visited the ED to obtain a nebulized bronchodilator (90 %) or oxygen (79.5 %). Moreover, 44.8 % of the people visited the ED to get treatment without any delay and 24.0 % considered that the severity of asthma does not allow the patient to wait for clinic visits. Strikingly, 92.8 % claimed that inhaled corticosteroid therapy treatment should be stopped when patients feel better. Irregular follow ups with clinics, low education about asthma and an education level higher than a Bachelors degree were the most important factors associated with three or more ED visits per year, p values = 0.0289, 0.0110 and 0.0150 respectively.This study identifies several preventable risk factors responsible for recurrent visits to the ED by asthmatic patients in Pakistan. Asthma is defined as a chronic inflammatory disorder of the airways that leads to symptoms like wheezing, coughing, breathlessness and tightness of chest, especially at night or in the morning . It is aAcute asthma is one of the leading causes of ED visits and hospital admissions globally –7. PreviThe increased use of the ED as first-choice of care by asthmatic patients’ needs to be discouraged because they are an unnecessary and preventable burden on resources that could be better utilized elsewhere. It is therefore important to identify the factors and problems in our healthcare system that are responsible for this trend so that we can address them and save valuable resources. The aim of our study is to assess the reasons for the increased usage of the ED by asthmatic patients in Pakistan.This cross-sectional study was conducted from September 2014 to February 2015 on 600 patients reporting to the ED of Civil Hospital Karachi. It was approved by the Institutional Review Board of Dow University of Health Sciences (DUHS). The inclusion criterion was such that patients with a reported diagnosis of asthma and on prescribed inhaled corticosteroids (ICS) for a minimum of 5 months were recruited for the study. Patients not having a reported diagnosis of asthma by a physician, not on ICS therapy or suffering from any illness that they were seeking medical care for or other chronic respiratory illnesses, like chronic obstructive pulmonary diseases (COPD), were omitted from the study. The consenting patients were given a questionnaire to fill in the ED by the co-investigators. It had questions pertaining to their demographic information and socioeconomic status. Also, their education about the disease was evaluated from the following questions—duration of the disease, the medications prescribed and adherence to them and the method of use of inhaler devices. They were also asked about the frequency of outpatient clinic and ED visits for issues related to asthma. Their files were cross-checked to compare the information that they provided with documented visits and confirm its validity.The data was entered using Social Sciences (SPSS) software program for Windows (version 19.0) and the same software was used for statistical analysis. Descriptive statistics, such as means, standard deviations, or median were employed to outline age and duration of asthma disease. Percentages were also used to indicate gender, ICS use, follow up with clinics, general education level, education about medications, education about asthma, and reasons for visiting the ED. Moreover, in order to compare the distributions of asthma disease duration across number of asthma-related ED visits (<3 versus ≥3), Mann–Whitney test was applied. The associations between gender, ICS use, follow up with clinics, general education level, education about medications, and education about asthma across asthma-related ED visits were determined by Chi square test. Multiple logistic models were also employed to assess the risk factors that were linked with three or more asthma-related ED visits. p values less than 0.05 were considered significant. The odds ratios (ORs) with 95 % CIs were further considered to report the strength of these associations.A total of six hundred (N = 600) asthmatic patients were selected by non-probability convenience sampling in this cross sectional study. Out of 600 participants, 186 (31.0 %) were males and 414 (69.0 %) patients were females. Table Furthermore, asthma-related ED visits were stratified on the basis of whether the asthma patient visited the ED thrice or more for asthma treatment. Table Mann–Whitney test shows there was no connection between the duration of the disease and the number of ED visits p  =  0.546). An education level higher than a Bachelors degree  and irregular follow up with clinics  were highly associated with three or more asthma-related ED visits, after being controlled for gender, ICS use, general education level, education about medications, and education about asthma. Our study also indicated that patients with a Bachelors degree or higher were twice as more likely to visit the ED than the patients with Intermediate (grade 12) education or less than it . Moreover, this finding is consistent with patients having education about medications . It was further revealed that patients who were not educated about asthma also had greater number of visits to the ED for the treatment of their condition . Table 6. An eduThe results of this study showed that a large percentage of the Pakistani population used the ED as a first-choice option instead of keeping follow up appointments with physicians. These findings are in line with previous studies conducted in Saudi Arabia, New Zealand and the United States –19. We aFurthermore, these results highlight major flaws in our healthcare system and show that there is a desperate need for better training of doctors, better education of and easier access to clinics for patients and generalized awareness programs related to asthma for the community. A huge problem that we do face is that asthma patients do not respond to follow ups with the figure an astounding 70 %. Out of the remaining 30 % who do, around 22 % visit the primary care clinic where the guidance is unsatisfactory as indicated by work of Abudahish A et al.  This stuMoreover, it is a well-known fact that individuals with higher education level have a higher socioeconomic levels. As a result they have a better health status due to the reason that they have greater access to healthcare services. Interestingly, we found that the more educated patients reported three or more visits to the ED, results that were consistent with a previous study in Saudi Arabia . HoweverAccording to our understanding, this study is a first of its kind to be carried out in Pakistan. It was a very extensive process involving direct communication with the patients and then confirming the information received with the patient files. It is an important step in the right direction because it identifies the frailties in the healthcare system. Further studies are required in this field so that we can improve the framework for asthma care in this country.This study was carried out only in one hospital so our sample size was a bit restricted and these results do not tell the story of the situation in the whole country. The patients that we got were mostly from a low socioeconomic and relatively illiterate background so we cannot generalize these results to other patients who might have a different knowledge of asthma. Other factors, like access to primary care, may have affected the recurrent use of the ED but we could not take them into consideration due to the unavailability of relevant data. The data was also collected in written form via questionnaires and it might have affected the results as the patients, some of whom were not very educated, might not have comprehended some of the questions. Therefore, verbal questioning could be added for better results. We could also only quantify the education received by the patients regarding asthma and not really judge the quality of it. We also did not take into account other environmental factors in the daily routine of the patient responsible for exacerbation of the disease, leading to ED visits. Furthermore, we could not accurately judge the socioeconomic status of the patients because we only used profession and level of education as indicators. Also, a previous study has indicated that people tend to downplay their level of economic disadvantage when reporting it .This study identified several factors responsible for recurrent visits to the ED for asthma care. The important ones were patient misconceptions about the use of the ED in treating asthma, the lack of education regarding asthma, the lack of adherence to follow up appointments with exclusive asthma clinics and the decreased adherence to asthma medication. These factors need to be addressed by healthcare workers and there needs to be an overhaul at the highest level in order to improve the healthcare system. The government also needs to focus more on the education part in primary healthcare rather than giving all their attention to the tertiary sector. It is the only way to decrease the load on the tertiary care system and prevent the drainage of important resources.


During the last few years, due to medical and surgical evolution, patients with increasingly severe diseases causing multiorgan dysfunction are frequently admitted to intensive care units. Therapeutic options, when organ failure occurs, are frequently nonspecific and mostly directed towards supporting vital function. In these scenarios, the kidneys are almost always involved and, therefore, renal replacement therapies have become a common routine practice in critically ill patients with acute kidney injury. Recent technological improvement has led to the production of safe, versatile and efficient dialysis machines. In addition, emerging evidence may allow better individualization of treatment with tailored prescription depending on the patients’ clinical picture . The aim of the present review is to give a general overview of current practice in renal replacement therapies for critically ill patients. The main clinical aspects, including dose prescription, modality of dialysis delivery, anticoagulation strategies and timing will be addressed. In addition, some technical issues on physical principles governing blood purification, filters characteristics, and vascular access, will be covered. Finally, a section on current standard nomenclature of renal replacement therapy is devoted to clarify the “Tower of Babel” of critical care nephrology. Therapeutic options in the setting of multisystem organ failure are mostly aimed at supporting vital functions. The kidneys are almost always involved in such a syndrome, and dialytic techniques are routinely used in the ICUs to treat severe acute kidney injury (AKI)2.Critically ill patients with severe diseases and multisystem organ failure are currently frequently admitted to and treated in the intensive care unit (ICU). Although the identification and management of multisystem organ failure has improved, the incidence has increased over the last half-centuryCurrent practice in renal replacement therapy (RRT) for adult critically ill patients, with specific details on technical features and clinical applications, will be reviewed.3. In CAVH, blood flow in the circuit was driven by a spontaneous arterio-venous pressure gradient and spontaneous ultrafiltration (UF) occurred depending on the transmembrane pressure (TMP) gradient. The arterio-venous pressure gradient was dependent on the mean arterial pressure of the patient and the intrinsic resistance of the circuit (determining the blood flow); the UF was determined by the hydrostatic pressure drop inside the filter and the negative suction provided by the UF column from the patient level to the ground. As a consequence, patients with low blood pressure and/or low cardiac output achieved the lowest clearances but were able to self-limit UF. When peristaltic pumps were added to the extracorporeal circuit, veno-venous hemofiltration became feasible. Subsequently, fluid delivery systems and UF control mechanisms were implemented allowing dialysate and replacement solutions to be delivered with acceptable accuracy. Higher clearances were finally possible because of the ability to provide increased flow rates. Although clearly improved, RRT machines were still inaccurate, and safety and performance were still a challenge. It soon became evident that an ideal extracorporeal circuit requires continuous pressure measurements at different levels 4.Peter Kramer in 1977 described the first continuous form of dialysis specifically dedicated to critically ill patients: continuous arterio-venous hemofiltration (CAVH)5. Contemporary devices, equipped with 4 to 5 roller pumps, 3 to 4 scales and pressure sensors, allow a fluid load from 20 to 40 kg in order to reduce nursing workload. In addition, maximal flow rates have increased up to about 450 mL⁄min for the blood pump, 8–10 L⁄hr for the dialysate⁄replacement pumps, and 20–25 L⁄hour for the effluent pump. Mechanical implementation has been associated with a huge electronic evolution: interfaces have been implemented with wide screens and clear alarm signals and warnings, and circuit pressure trends are now visualized. Furthermore, during continuous RRT (CRRT), now flexible and safe, modalities can be switched in order to tailor them to the patients’ need. Modern RRT filters, a key component of the system, are composed of groups of hollow fibers with a range of surface areas (from 0.1 to over 2 m2) in order to meet the need of differently sized patients. Such fibers have a generally high porosity (30–50 A°) with a pore cutoff size of 30 kDa and are used for both diffusive and convective treatments. Polyacrylonitrile, polysulphone and poly(methyl methacrylate) (PMMA) are the most commonly used membranes and allow a high UF coefficient (over 20 ml/h/mmHg) and high diffusive and convective performance. Biocompatibility (the change in blood factors induced by membrane/blood contact) is considered the most important quality of these RRT membranes.Currently, third/fourth-generation machines are designed to meet the dialysis dose requirements and the strict safety features that are recommended in every modern ICURenal replacement consists of blood purification by semi-permeable membranes. Blood flows into hollow fibers composed of porous biocompatible synthetic material. A wide range of substances  can be transported across such membranes, from the blood to the effluent side of the hollow fibers, by the mechanism of diffusion (solutes) and convection (water and solutes) .Dialysis is based on the diffusion principle: a dialytic solution flows through the filter counter current to blood flow in order to maintain the highest solute gradient from inlet to outlet port. Diffusion is the solute transport method applied during intermittent hemodialysis (IHD) and continuous veno-venous hemodialysis (CVVHD) . During During convection, solutes are transported across a semi-permeable membrane by UF (water transfer across the membrane). In other words, as the solvent (plasma water) is pushed (ultrafiltered) across the membrane according to the TMP, solutes are carried with it, as long as the porosity of the membrane allows the molecules to be sieved from the blood. Convection is applied during continuous veno-venous hemofiltration (CVVH) while the combination of both convection and diffusion configures continuous veno-venous hemodiafiltration (CVVHDF) .UF) in CAVH systems was governed by the membrane UF coefficient (Km) and the TMP gradient generated by the pressures on both sides of the hollow fiber according to the following formula:The UF rate  or clogging (in which case a progressive secondary increase of TMP is observed). In fact, as molecules cleared during convection are physically dragged to the UF side, the protein layering that progressively clogs the fiber pores significantly limits solute transport6. A peculiar membrane capacity, defined as adsorption, has been shown to play a major role in higher molecular weight toxins7; however, membrane adsorptive capacity is generally saturated within the first few treatment hours. This observation explains the minimal impact of the adsorption component on solute clearance8. An exception on this rule is made by high-mobility group box 1 protein (HMGB-1), as this major sepsis key mediator can be significantly removed (more than 90%) by adsorption through an acrylonitrile-treated surface (AN69-ST) and PMMA membranes9. However the clinical relevance of this molecule clearance remains to be ascertained. As UF proceeds and plasma water and solutes are filtered from blood, hydrostatic pressure within the filter declines and the effect of oncotic pressure increases because blood concentrates and hematocrit increases. The fraction of plasma water that is removed from blood during UF is called the filtration fraction and should be kept in the range of 20–25% in order to avoid equalization of the oncotic pressure to the TMP and filtration/pressure equilibrium. Finally, replacing the plasma water removed through the filter with a substitution solution completes the hemofiltration process and purified blood is returned to the patient. When the substitution fluid is administered after the filter it is referred to as post-dilution HF. When the substitution solution is infused before the filter it is referred to as pre-dilution HF. While post-dilution allows a urea clearance equivalent to therapy delivery (see below), pre-dilution, in spite of theoretical reduced solutes clearances, allows prolonged circuit lifespan by reducing hemoconcentration and protein caking effects within filter fibers. The difference between the volume of ultrafiltered plasma water and reinfused substitution solution gives the net UF, which is the fluid that is eventually removed from the patient for fluid control. Net UF prescription is based on patient needs and can range from more than 1 L/h (pulmonary edema in a patient with congestive heart failure and diuretic-resistant AKI) to zero (sepsis with catabolic state increased creatinine levels and conserved diuresis). A net UF rate must be added to diffusion-based CRRT modalities in order to achieve fluid balance control since diffusion does not allow for water exchanges.In modern RRT machines Q8, no study so far has shown that the application of hemofiltration, with respect to hemodialysis, improves hard outcomes 11.Interestingly, apart from the demonstration of different clearances of middle molecular weight solutes (i.e beta-2 microglobulin) provided by CVVH when compared to similar CVVHD doses12, urea and creatinine, due to their significant accumulation during AKI and the ease of their routine daily blood determination, are generally used as reference solutes for measuring renal replacement clearance during either chronic or acute dialysis.RRT dose is a measure of the quantity of blood purified by “waste products and toxins” and is generally expressed as clearance (K). Clearance is defined as the amount of blood purified by a single solute in the unit of time and it is expressed as volume over time, as it represents the flow of “cleaned” blood. As these still incompletely known substances “to be purified” are difficult to measure and quantify, the operative view of RRT dose is generally reduced to the measure of the elimination of a representative marker solute. Unfortunately, the marker solute does not represent all the solutes that accumulate during AKI because kinetics and volume of distribution are different for each solute and its removal during RRT is not necessarily representative of the removal of other solutes. However, since single solute marker assessment of dialysis dose appears to be related to patient outcomeDuring RRT, clearance depends upon blood flow rate (Qb), substitution flow rate (Qf) or dialysis flow (Qd), solute molecular weights, and hemodialyzer type and size. Qb is mainly dependent upon vascular access and the operational characteristics of utilized machines in the clinical setting. Qf is strictly linked to Qb, during convective techniques, by filtration fraction. Filtration fraction does not limit Qd, but when Qd/Qb ratio exceeds 0.3, dialysate will not be completely saturated with blood diffusing solutes. When UF is applied, molecules are dragged with plasma water through the filter pores according to their sieving coefficient (SC); the SC is calculated as the effluent/plasma concentration ratio of the target molecule. When the SC is 1, as in the case of small molecules , the same solute concentration is found in the two sides of the hollow fiber. A SC value of 0 means that the molecule is not filtered . K during convection is measured by the product of Qf multiplied by the SC; hence, there is a linear relationship between K and Qf, the SC being the changing variable for different solutes. During diffusion, the linear relationship is lost when Qd exceeds about 1/3 of Qb.One of the crucial merits of specific dose prescription, calculation, and delivery is the avoidance of underdialysis and the improved monitoring and awareness of effective delivered therapy.13 concluded that, based on present scientific evidence, continuous RRT should be considered equivalent to IHD for treatment of AKI. Vinsonneau and colleagues14 conducted a large, prospective, randomized multicenter study in 21 ICUs over a 3.5-year period. The primary end point was the 60-day mortality following the randomization of 360 patients with AKI to either CVVHDF or IHD and no difference was found in 28, 60 and 90-day mortality between the two groups. Hence, according to the results, the study investigators concluded that IHD can be delivered safely to critically ill patients. Unfortunately, delivered dose in both arms was not controlled for in the trial design. The accompanying editorial15 emphasized that the advantages of continuous therapies are particularly significant when therapy downtime is minimized, in order to enhance the low intensity, smooth and continuous effects of plasma K. However, Vinsonneauet al.’s findings have been confirmed repeatedly by other studies17. One of the reasons for the lack of hard outcome differences between intermittent and continuous techniques could be because IHD has become safer and more efficacious18. Alternatively, a liberal application of CRRT (including extended and probably wrong indications) can cause adverse effects as discussed later below.Blood purification can be achieved in the ICU both by continuous and intermittent RRT. In theory, during continuous RRT, the treatment is kept running 24 hours a day, seven days a week. During intermittent RRT renal support is delivered in intermittent sessions lasting  3–6 hours, typically three times per week (or depending on specific needs). Currently, about 80% of critically ill patients are treated with continuous RRT. However, due to the absence of significant differences in outcome deriving from the application of continuous vs intermittent RRT, no specific recommendation is provided by the major critical care societies, and the choice is mainly left to institutional protocols and expertise. Apart from evidence in large clinical trials, more gentle RRT application is generally better tolerated in hemodynamically unstable, critically ill patients with severe AKI. Furthermore, since the occurrence of intradialytic hypotension is proportional to the net Quf rate, it is possible to prescribe a lower net Quf rate when the treatment is applied over 24 hours as compared to a quick 3-hour session. Recently, the Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock22 depending on variations in schedule and type of solute removal (convective or diffusive), they all attempt to provide a gentle, prolonged and more feasible extended IHD, with all the advantages of discontinuous treatment . These techniques generally have shown good results in terms of hemodynamic tolerance and adequacy of dialytic dosage23. Baldwin and coworkers compared 3 consecutive days of CVVH with a similar period of extended daily dialysis with filtration23. No significant difference was found between the two therapies as far as urea or creatinine levels and electrolyte and acid–base control. Interestingly, after 3 days of treatment, there was a mild but persistent metabolic acidosis in the extended dialysis group, but in the CVVH group hypophosphatemia was described. Advantages and disadvantages of IHD, CRRT and hybrid techniques, respectively, are depicted inHybrid techniques, which combine the advantages of both continuous and intermittent modalities, may represent an interesting compromise. Although a variety of names have been given to hybrid techniques (see the nomenclature section)24.In conclusion, intermittent and continuous therapies, when applied by expert centers, may appear similar where hard outcomes are concerned. As far as long-term RRT outcomes are concerned, however, recent reports indicate that RRT survivors treated by IHD might have a lower chance of recovering pre-morbid kidney function and have an increased risk of remaining dialysis-dependent at hospital discharge29. Anticoagulation strategy depends on the type of RRT and is often needed for continuous therapies due to the increased exposure to the blood-artificial surface. Aims of anticoagulation are: maintenance of extracorporeal circuit and dialyzer patency; reduction of downtime that might have a clinical impact in the overall RRT clearance; reduction of treatment cost by the utilization of less material; and achievement of the above aims while minimizing risks for the patient. Several technical features of the RRT circuit are likely to affect the success of any anticoagulant approach: vascular access has to be of adequate size; tube kinking should be avoided; blood flow rate should exceed 100 ml/min; pump flow fluctuations must be prevented; and the venous bubble trap, where air/blood contact occurs, must be accurately monitored. Furthermore, plasma filtration fraction should be kept as far as possible below 20% and, when possible, pre-dilution hemofiltration should be selected. There is evidence that, when circuit set-up is perfectly optimized, anticoagulants are only a relatively minor component of circuit patency. When patients have altered coagulation, thrombocytopenia, or active bleeding (e.g. after trauma or surgery), RRT can be safely performed without anticoagulation25. Lastly, regional citrate anticoagulation (RCA) can be safely used nowadays not only in patients with bleeding risks but also in patients without bleeding risks, according to the current KDIGO guidelines30. Extensive training is needed regarding the metabolic side effects of citrate before embarking upon routine citrate anticoagulation. In recent years, new commercially available citrate solutions together with adapted CRRT machines have rendered the technique safer and easier to use31.The contact between blood and artificial surfaces induces activation of the coagulation cascade, resulting in filter and/or circuit clotting and the need for anticoagulationDifferent methods for anticoagulation are summarized inRegardless of RRT technique used, the following clinical variables are typically compromised in the critically ill patient with AKI: fluid status and tissue edema, hemodynamics, acid–base and electrolyte equilibrium, protein-rich nutritional support, phosphate and calcium balance, and infection control.33. Furthermore, a slow continuous RRT with fluid removal over 24 hours is better able to manage the critically ill patient’s needs; in case of increased nutritional administration, fluids deriving from parenteral drugs or hemoderivates transfusion, QUF can be easily tailored on an hourly base34. Conversely, rapid  ultrafiltration of body water may lead to acute hypovolemia and subsequent hypotension, since refilling from the interstitial compartment is slow and steady due to hydrostatic and osmotic pressures35. Since no effective clinical monitoring is currently available to “measure” fluid overload and the amount of fluid excess to be removed, clinical expertise in critical care nephrology (and possibly a multidisciplinary approach) is essential for adequate management of fluid removal36.Currently, a broader concept of “timely intervention” is generally accepted. When oliguria results in impairment of one or more of the above clinical variables, RRT should be instituted rapidly in order to avoid fluid overload and congestion. The only urgent indications to perform dialysis are pulmonary edema refractory to high dose diuretics, rapidly increasing hyperkalemia, severe refractory acidosis, symptoms/signs of uremia, and specific drug intoxications. Critically ill patients, especially if they are oliguric or anuric, typically gain weight from water accumulation and large volumes of intravenous fluids. In such patients, water removal is indicated for the achievement of a negative daily fluid balance, which has been associated with multiorgan function improvement  in observational and retrospective studies37. Otherwise, timing can be considered as the time elapsed between any established indication to start and the effective inception of the dialytic session. A recent retrospective study38 confirmed that crude 90-day mortality of patients with RRT started after “classic indications”  was significantly higher than in patients with “pre-emptive” RRT : adjusted odds ratio, 2.05; 95% CI, 1.03 to 4.09. Interestingly, also patients with classic RRT but a delayed start (>12 hours from indication) showed higher crude mortality compared with patients with classic RRT that started early due to urgent indications (<12 hours from indication); this association persisted after adjustment for known confounders . Due to the retrospective nature of this study, it is not clear how effectively comparable the two populations (classic vs pre-emptive or early vs delayed) are. The Canadian Critical Care Trials Group recently concluded the first pilot trial aiming to prospectively evaluate the feasibility of a protocol-driven accelerated RRT initiation39. This interesting complex trial showed how difficult it would be to conduct a large multicenter prospective trial attempting to randomize two AKI populations only differing by the time elapsed from RRT indication to treatment start. In fact, in the pilot trial, a large number of patients had to be excluded after provisional eligibility per protocol design: those deemed by the intensivist and nephrologist in charge as requiring urgent RRT or deferral of RRT indication. This excluded cohort might unfortunately represent a sample of patients whose outcomes are potentially affected by pre-emptive or delayed RRT start. However, in the analysis of the enrolled 101 patients, the authors succeeded in their primary outcome. In the accelerated arm, median time to RRT start was 7.4h. In the standard arm, 33 patients started RRT at a median of 31.6h from eligibility, and, interestingly, the other 19 did not receive any RRT (6 died and 13 recovered kidney function). Even though these preliminary results should be interpreted with caution, hard outcomes were not affected by acceleration of RRT start .As for the exact timing for starting RRT, a definition of timing is currently not available. Timing can be considered as a synonym for “indication” and then one can start CRRT early or late depending on how severe  the indication is (e.g. creatinine level or potassium level or the presence of sepsis)40, CVVH dose has been indexed for the first time to patients’ body weight (mL/Kg/h), in order to highlight that this variable is of high importance in AKI patients. Two large, multicenter, randomized controlled studies published in 2009  replacement therapy study41 and in 2008, the VA/NIH Acute Renal Failure Trial Network (ATN) study42) finally clarified the concept of optimal dialysis dose. These fundamental trials were conceived to test the hypothesis concerning the impact of “intensive” RRT on hard outcomes  when compared to “less intensive” renal support. The RENAL study was conducted exclusively with continuous therapies  and compared 25 mL/Kg/h CVVHDF to 40 mL/Kg/h. Using a different approach, the ATN study, conducted in North America, considered 20 mL/Kg/h CVVHDF or thrice weekly intermittent dialysis as the control group and compared it to 35 mL/Kg/h CVVHDF or daily IHD as the intensive arm. Apart from methodological differences, both studies confirmed that “intensive” RRT does not improve patient outcomes, and survival  was similar among compared arms. Based on the results of those trials, the accepted dose of RRT is considered to be within the range of 25–35 mL/Kg/h for CRRT and/or thrice weekly IHD with a Kt/V (see table on nomenclature) of 1.3.From a clinical standpoint, the effects of RRT dose have been systematically evaluated in the last 10 years. After the milestone trial from the group in Vicenza back in 200043: metabolic acidosis is common in both groups and both techniques correct metabolic acidosis; however, the rate and degree of correction may significantly differ between continuous and intermittent techniques. In the same study43 CVVHDF was shown to normalize metabolic acidosis more rapidly and more effectively during the first 24 hours than IHD. IHD was also associated with a higher incidence of metabolic acidosis as compared to CVVHDF during the subsequent 2-week treatment period. Accordingly, continuous RRT could be considered physiologically superior to IHD in the correction of metabolic acidosis. In a comparison between CVVH and peritoneal dialysis, all patients receiving CVVH achieved correction of acidosis by 50 hours of treatment, whereas only 15% of those randomized to peritoneal dialysis achieved such correction (P < 0.001)44. Despite the results of these studies, correction of acidosis by RRT has not revealed any specific impact on outcomes.Clearly, clinical effects of RRT dose are not limited to urea and excess body water control. Oligo anuric patients often suffer from mild acidemia secondary to increased unmeasured anions (strong ion gap – SIG - 12.3 mEq/l), hyperphosphatemia, and hyperlactatemia. This acidosis is attenuated by the alkalizing effect of hypoalbuminemia. The effect on acid–base balance of IHD and CVVHDF has been evaluated45. In fact, as with any type of continuous extra corporeal therapy, CRRT often requires continuous anticoagulation therapy, which can increase the bleeding risk in case of heparin use or metabolic derangements in case of citrate use. Conversely, clotting of the extracorporeal circuit also occurs frequently with CRRT, which might contribute to blood loss and could exacerbate anemia in critically ill patients. The increased solute transfer associated with the use of CRRT might enhance removal of amino acids, vitamins, catecholamines, and other solutes. As alluded to before, therapy downtime (the period when a prescribed CRRT has not run due to unplanned interruptions) should be carefully controlled, possibly limited and eventually compensated, because it might significantly impact dialysis delivery47. Following this path, it might be speculated that the quality of care and the specific dialysis monitoring is likely to be superior when a dialysis nurse is attending the treatment session48. In order to meet the safety requirement, the new generation of CRRT machines has been implemented with a strict safety profile limiting dangerous side effects of dialytic treatments. In any case, ICU staff training is mandatory before starting the routine utilization of such monitors.Although safety features of CRRT machines have evolved, the possibility that CRRT may confer increased risk should not be overlookedA synopsis of RRT prescription is also presented in49. Statistical analysis identified urine output and creatinine as significant predictors of successful cessation. The predictive value of urine output was negatively affected by the use of diuretics. Risk factors for re-dialysis were also analyzed50: the 94 postoperative patients analyzed by these authors were considered free from RRT if after at least 30 days they did not require dialysis. Successful weaning from RRT was correlated with Sequential Organ Failure Assessment (SOFA) score, age, dialysis duration and, again, urine output. Interestingly, out of the patients who remained “RRT-free” for 5 days after RRT discontinuation, more than two-thirds (20) remained RRT-free for up to 30 days.In the specific setting of “weaning from RRT”, no good evidence exists at present and it is unlikely to be the case in the near future. Nevertheless, some insights may be gleaned from recent available literature. An interesting report from the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) investigators described current practice for the discontinuation of CRRT in order to identify variables associated with successful discontinuation and whether the approach to discontinue CRRT therapy affected patient outcomesAs a general recommendation, before weaning from RRT, physicians should wait for adequate urine output (without diuretic therapy) and optimized creatinine values. Once renal function appears close to the baseline or “pre-AKI” level, it seems reasonable to interrupt the treatment without any specific weaning protocol. Future trials, including the identification of new biomarkers, are needed to design novel weaning protocols.2 clearance, hemoperfusion, plasma-filtration and adsorption responding to different medical needs58. Finally, advances in information technology should allow the fully integrated extracorporeal blood purification system to be connected to all electronic therapeutic devices, from simple syringe pumps to CRRT machines, in order to ultimately lead to an ‘‘artificial organ’’ in a more complete sense59. In such a detailed and diversified technological world it is of utmost importance that communication among practitioners  is homogeneous and widely accepted. In light of this, nomenclature is a crucial aspect concerning RRT (please see60.In recent years, great technological improvements have been made in the manufacturing of extracorporeal circuits, rendering them easier to use, safer and more efficient for long-term support. Modern RRT systems can be managed in the ICU by one bedside nurse who is trained and experienced in circuit management, and it is now possible to treat patients for several weeks, or even months, without major complications. Thanks to technology development, the possibility of removing “waste products” is currently open to several molecules, including middle-sized ones, different from creatinine. It is now becoming a reality to integrate multiple devices into a single user-friendly machine for CO