This study investigated the volume and duration of pleural and mediastinal effusions following extracardiac total cavopulmonary connection, as well as preoperative risk factors and their impact on outcome.A total of 210 patients who underwent extracardiac total cavopulmonary connection at our center between 2012 and 2020 were included in this study. Postoperative daily amount of pleural and mediastinal drainage were collected and factors influencing duration and amount of effusions were analyzed. The impact of effusions on adverse events was analyzed.p = 0.004) and end-diastolic pressure (p = 0.044) were associated with high volume of drainages, and hypoplastic left heart syndrome (p = 0.007), presence of aortopulmonary collaterals (p = 0.002), and high end-diastolic pressure (p = 0.023) were associated with long duration of drainages. Dextrocardia was associated with higher volume (p < 0.001) and longer duration (p = 0.006) of left pleural drainage. Duration of drainage was associated with adverse events following extracardiac total cavopulmonary connection (p = 0.015).Median age at extracardiac total cavopulmonary connection was 2.2  years with median weight of 11.6 (10.7–13.0) kg. Overall duration of drainage after extracardiac total cavopulmonary connection was 9 (6–17) days. The total volume of mediastinal, right pleural, and left pleural drainage was 18.8 (11.9–36.7), 64.4 (27.4–125.9), and 13.6 (0.0–53.5) mL/kg, respectively. Hypoplastic left heart syndrome (Volume and duration of pleural and mediastinal effusions following extracardiac total cavopulmonary connection were related with hypoplastic left heart syndrome, aortopulmonary collaterals, and end-diastolic pressure. The duration of drainage for effusions was a risk factor for adverse events after total cavopulmonary connection. As patient selection, surgical procedures, and postoperative management have been refined over time, today’s early staged Fontan surgery for patients with univentricular heart is linked to excellent early survival –4. NeverOur institution has been performing an extracardiac conduit total cavopulmonary connection (EC-TCPC) as the standard procedure , 11. VarIn general, studies have consistently found that pleural effusions are associated with morbidity and prolonged hospitalization in EC-TCPC patients , 16. KimIn an effort to close the current knowledge gap, we sought to identify risk factors for pleural effusion and evaluate the effects of pleural and mediastinal effusions following EC-TCPC.The Institutional Review Board of the Technical University of Munich approved the study . Due to the retrospective nature of the study, the need for individual patient consent was waived.The retrospective review of medical records including in-hospital and out-patient notes, laboratory data, cardiac catheterization and other non-invasive images was performed for patients who underwent EC-TCPC at the German Heart Center Munich between 2012 and 2020. Patients who underwent TCPC conversion from classic Fontan procedure were excluded. The preoperative variables were measured at the closest time before surgery and postoperative variables were the first measurements when admitted to the ICU. Postoperative daily amounts of right pleural, left pleural and mediastinal effusions from the ICU charts were collected.3 and lymphocyte fraction ≥80%.Following EC-TCPC surgery, all patients were admitted to the intensive care unit (ICU). Extubation was performed several hours after ICU submission. If the drainage of pleural effusion was less than 2 mL/kg/day/tube, the chest/mediastinal tube was removed. The diagnosis of chylothorax was established by fluid analysis through puncture, including the presence of chylomicrons, triglyceride content of ≥110 mg/dl, or a total cell count of 1,000 cells/mm2), pulmonary artery distortion, and elevated ventricular filling pressure (12 mm Hg).Extracardiac conduit total cavopulmonary connection was performed through a median sternotomy on cardiopulmonary bypass with aortic and bicaval cannulation , 11. ConThe patients underwent outpatient follow-up with pediatric cardiologists, and follow-up periods were defined as the time between the EC-TCPC and the time of the final appointment for each individual patient in the study. Adverse events were defined as death, heart transplantation, TCPC take down, symptomatic protein-losing enteropathy, symptomatic plastic bronchitis, thromboembolic events, sustained episode of supraventricular tachycardia, and requirement of permanent pacemaker implantation after EC-TCPC.P-value < 0.1 in the univariable analysis were entered into the multivatiable model, with no subsequent removal of variables. Both forward inclusion and backward elimination process was used to generate the final multivariate model. It was confirmed that the risk factors resulting from forward inclusion and backward elimination was identical. P-values < 0.05 were considered significant. Data analysis and graphing were performed with the Statistical Package for the Social Sciences (SPSS) version 28.0 for Windows .Categorical variables are presented as absolute numbers and percentages. Continuous variables are expressed as medians with interquartile ranges (IQR). Associated factors for excessive volume of drainage after EC-TCPC were identified using a logistic regression analysis. A cut-off value of 75 IQR was used in this analysis. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Cox proportional hazard models was used to identify the variables that are associated with the duration of drainages. Hazard ratio (HR) with 95% CI were estimated. Impact of the duration as well as the amount of effusions on late adverse events after EC-TCPC were analyzed through Cox regression model. Risk factor analysis was tested by a univariable regression model and later as a multivariable model. For the multivariate model, those variables with a n = 79, 38%) and dominant right ventricle (RV) was observed in 127 (61%) patients. Dextrocardia was present in 19 patients (9%), and heterotaxy syndrome in 17 (8%). All patients had previous BCPS at the median age of 0.3 (IQR = 0.3–0.5) years and median interval between BCPS and EC-TCPC was 1.8 (IQR = 1.4–2.2) years. Pre-TCPC catheter data is shown in A total of 210 Patients were identified who underwent EC-TCPC at our center during the study period. Patient’s characteristics are shown in Median total volume of mediastinal, right pleural, and left pleural drainage after EC-TCPC was 18.8 , 64.4 , and 13.6 (0.0–53.5) mL/kg, respectively . Median Overall duration of any drainage was 9 (IQR 6–17) days, and the last drainage needed was right pleural drainage in 136 (64.8%), left pleural drainage in 33 (15.7%) patients, and both right and left pleural drainage in 41 (19.5%). Distribution of the duration of the drainage was shown in p = 0.022), presence of APCs , PAP , SVEDP , and systolic arterial pressure  were associated with volume from drainage with univariable analysis (p = 0.004) and SVEDP  were independent factors associated with high volume of drainages. Winter respiratory viral season of November through March was not identified as a factor influencing volume of mediastinal and pleural effusions .As for the total volume of mediastinal and pleural drainage, HLHS , presence of APCs , and PAP , were associated with volume from drainage with univariable analysis. Multivariable analysis identified HLHS  and presence of APCs  as independent factors associated with high volume of drainages.As for right pleural drainage, HLHS , PAP , SVEDP , systolic aortic pressure , and arterial oxygen saturation  were associated with a large volume from drainage in the univariable analysis. Multivariable analysis demonstrated dextrocardia , PAP , and arterial oxygen saturation  were independent factors associated with high volume of drainages. Results of the analysis using all variables are shown in As for left pleural drainage, dextrocardia , dominant RV , presence of APCs , previous Norwood procedure , PAP , and SVEDP  were associated with total duration of drainage in univariable analysis (p = 0.007), presence of APCs , and SVEDP  were independent factors associated with total duration of drainages. Winter respiratory viral season of November through March was not identified as a factor influencing duration of pleural effusions .As for total duration of mediastinal and pleural drainage, HLHS , dominant RV , presence of APCs , previous Norwood procedure , and PAP  were associated with long duration of drainage in univariable analysis. Multivariable analysis showed that HLHS  and presence of APCs  were independent factors associated with long duration of drainages.As for duration of right pleural drainage, HLHS , PAP , and SVEDP , were associated with long duration of drainage in univariable analysis. Multivariable analysis demonstrated that dextrocardia  and PAP  were independent factors associated with long duration of drainages. The additional surgical procedures did not influence the analyzed outcomes. Results of the analysis using all variables are shown in As for duration of left pleural drainage, dextrocardia  and duration of left pleural drainage  were associated with an increased risk for late adverse outcomes. Need for ascites drainage was also associated with adverse events . Variables which influenced the amount and duration of drainage were not associated with the following variables: HLHS , presence of APCs , previous Norwood procedure , PAP , SVEDP , Dextrocardia , systolic arterial pressure , arterial oxygen saturation , anomalous systemic venous drainage , TPG , dominant RV , and heterotaxy . The total duration of any drainage was an independent factor associated with adverse events following EC-TCPC  as determined by multivariable analysis. The details of adverse events are shown in As for the impact of effusion on late outcomes, the amount of effusion was not identified as an increased risk of adverse outcomes following EC-TCPC . Whereasp < 0.001) and left pleural drainage (p < 0.001). Volume of drainage was higher in patients with chylothorax in the right pleural drainage (p < 0.001) and left pleural drainage (p < 0.001).Chylothorax was observed in 46 patients (21.9%). Patients with chylothorax had significantly longer duration of right pleural drainage . Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.PH, PM, HS, BM, AH, JH, and MO: conceptualization. PH, PM, AH, JH, and MO: methodology. PH, PM, HS, AH, JH, and MO: validation and writing—review and editing. PH, PM, HS, BM, JV, MS, BR, PE, AH, JH, and MO: resources and writing—original draft. PH, PM, HS, JH, and MO: visualization. JH and MO: supervision and project administration. All authors have read and agreed to the published version of the manuscript.


PWV was significantly decreased in SSc patients compared with the controls (p = 0.007). PWV was correlated with age  and BMI . Finally, patients with no specific auto-antibody pattern had greater AIx than those expressing anticentromere antibodies. Our study demonstrated that SSc patients had greater AIx, but lower PWV than the controls. In addition, few variables were correlated to arterial stiffness. Further studies are necessary to validate these findings and to establish medication’s role in modifying cardiovascular risk.Systemic Sclerosis (SSc) is an autoimmune disorder characterized by organ and tissue fibrosis in which the incidence of atherosclerosis and cardiovascular events is increased, although the exact underlying mechanism remains unclear. Arterial stiffness is a marker of vascular damage that can predict cardiovascular events; therefore, this study aimed to assess the augmentation index (AIx) and pulse wave velocity (PWV), markers of stiffness, in a Systemic Sclerosis population and to detect potentially associated variables. Fourteen female Systemic Sclerosis patients and 14 age- and sex-matched controls were enrolled. Demographic, anthropometric, sero-hematological parameters and disease characteristics were collected for each participant. Arterial stiffness was evaluated using an applanation tonometry system. No differences were found between groups, except for BMI, fasting blood glucose, red blood cells count, hemoglobin, and treatment. Patients had increased augmentation index than the controls ( Systemic Sclerosis (SSc) is a connective autoimmune disease characterized by progressive fibrosis of several organs and tissues, more commonly affecting women . GeneticIn the early stage of SSc, cardiac dysfunction is frequently occult. However, structural and functional abnormalities may occur as the disease progresses; indeed, late fibrosis determines diastolic and systolic dysfunction, conduction defects, and pericardial involvement . MoreoveArterial stiffness (AS) is known to be a marker of vascular damage and is associated with an increased risk for CV diseases (CVD), stroke, and renal disease . IncreasFew studies have assessed arterial stiffness in SSc patients and the reported findings are contradictory. Therefore, this study aimed to define the presence of macrovascular damage in a cohort of SSc patients compared with a control group by the non-invasive measurement of arterial stiffness. Further investigations were carried out to identify worthwhile correlated variables with arterial stiffness.We conducted a single-center cross-sectional study analyzing the clinical, laboratory, and hemodynamic parameters of 14 consecutive Caucasian outpatients with SSc, matched for age and sex with 14 controls. Patients attending the Day Hospital of Rheumatology at the University “Magna Graecia” of Catanzaro who met the ACR/EULAR 2013 criteria for the diagnosis of SSc  were enrAll laboratory measurements were performed after a minimum fasting period of 12 h on peripheral blood samples. Serum levels of high-sensitivity C-reactive protein (hs-CRP) were measured by the immunoturbidimetric method with an automated system . Fasting blood glucose was measured using the glucose oxidation method . Triglyceride and total, low- (LDL) and high-density lipoprotein (HDL) cholesterol concentrations were measured by enzymatic methods . Erythrocyte sedimentation rate (ESR) was determined using microphotometrical capillary stopped-flow kinetic analysis . Serum creatinine was evaluated using the Roche Creatinine Plus assay . Renal function, expressed by e-GFR, was obtained according to the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration group equation .®, AESKU Diagnostics, Wendelsheim, Germany); anti-Scl70 by chemiluminescent immunoassay (CLIA) ; anticentromere antibodies (ACA) were detected by IIF , finally, anti-RNA polymerase III antibodies were determined by the ELISA kit . Antinuclear auto-antibody (ANA) levels were determined by indirect immunofluorescence (IIF)  that implies a high-fidelity applanation tonometry (Millar). An integrated software directly analyzed the recorded waves. First, after 30 min of rest, blood pressure was obtained through a non-invasive, automatic recording of the brachial artery at the dominant arm . Measurements were obtained with the patient in the supine position, in a temperature-controlled room. The central pressure wave and pressures were directly derived from the measurement of twenty sequential radial artery waveforms using a validated transfer function . Pulse wThe derived systolic central wave was used to define P1, the first systolic peak due to left ventricular ejection and P2, the second systolic peak caused by pulse wave reflection. AIx was derived using the formula: (AP/pulse pressure (PP)) × 100, where the augmentation pressure (AP) is the difference between P2 and P1 and PP is the difference between the systolic and diastolic pressure. As AIx depends on the pulse wave velocity, heart rate and the amplitude of the reflected wave were recorded. The aortic cf-PWV was calculated using common carotid and femoral artery wave measurements. The following formula: PWV (m/s) = distance/time was used. Distance is the length between the carotid and femoral pulse site, whereas time refers to the wave transit. In detail, the pulse transit time from the carotid to the femoral artery was determined by measuring the R-R’ interval of an ECG performed during the exam. The distance between the sternal notch and the femoral artery was considered to define the path length between the carotid and femoral arteries. The study was approved by the local ethics committee before collecting data from the patients. Written informed consent was obtained from each participant. The Declaration of Helsinki principles were used as a guide to conduct the study. p-value ≤ 0.05 was considered to be statistically significant. IBM SPSS®  version 26 was used for statistical analysis.Continuous variables were summarized as the mean and standard deviation (SD)  or as the median and interquartile range (IQR) , as per the Kolmogorov–Smirnov test. Categorical data were expressed as frequencies and percentages. The Mann–Whitney U, Kruskal–Wallis non-parametric test, and Chi-square test were performed to compare the variables. Among the SSc patients, linear regression analysis was used to assess the correlations between PWV and AIx with the following variables: age, body mass index (BMI), disease duration, arterial hypertension, type 2 diabetes mellitus (T2DM), dyslipidemia, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, ESR, hs-CRP, endothelin receptor antagonists, calcium channel blockers, antiplatelet drug, HMG-CoA reductase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin-II-receptor antagonists, steroids, β-blockers. A p = 0.019). The patients’ median disease duration was 11 [5.0–16] years. Concerning the sero-hematological features, the control group had a higher fasting blood glucose (FBG) than the SSc patients . Moreover, the controls had a higher red blood cell (RBC) count and hemoglobin (HB) than the SSc patients . All 14 SSc patients were treated with iloprost and, among them, nine subjects received endothelin receptor antagonists.At the end of the enrollment period, 14 SSc patients and 14 sex- and age-matched controls, all females, were included in the study . There wRegarding the clinical and autoimmunity features of SSc patients, according to LeRoy classification , three pp = 0.035). Peripheral and central hemodynamic determinations of the study population are presented in p = 0.008). Interestingly, cf-PWV was significantly reduced in the SSc patients compared with the control group .The augmentation index and cf-PWV were evaluated for each participant as previously described, and the results are presented graphically in r = 0.462; p = 0.048) and BMI .The correlation of cf-PWV and AIx with several covariates was assessed by linear regression analysis among the SSc patients . Specifip = 0.885 for each).AIx differed among the disease auto-antibodies . Namely,Arterial stiffness has been widely correlated with aging, but also with arterial hypertension and diabetes. The underlying process includes a complex interplay between factors, among which are collagen-elastin and metalloprotease (MMP) balance as well as endothelial dysfunction .p = 0.019). Our study showed that patients with SSc had increased AIx compared with the controls , but not cf-PWV, which was surprisingly lower .In this cross-sectional study, we evaluated arterial stiffness in a cohort of 14 female Caucasian SSc patients and 14 female control subjects. The groups did not differ for traditional CV risk factors, and only BMI was slightly lower in SSc patients than in the controls  and BMI . The reported data are in line with the current knowledge defining age and BMI as major determinants of arterial stiffness. To our best knowledge, this is the first study to report a decrease in PWV in SSc patients. However, it should be considered that while PWV is a direct parameter of arterial stiffness, AIx depends on three factors: heart rate, PWV, and the amplitude of the reflected wave. Thus, an increased AIx might be the expression of peripheral microvascular disease, a main hallmark of SSc, suggesting that the small arteries are involved earlier than the large ones. Moreover, we found few correlations between PWV and the variables studied. Specifically, PWV was associated with age  for correlation with PWV. It is worth noting that the analysis was conducted solely on the 14 patients enrolled in the study, therefore, a larger sample size may detect the correlations more effectively. In a previous study [No correlations were found with treatment, although calcium channel blockers and ACE inhibitors resulted in being close to statistical significance (us study , CCB treus study , which ius study . It mustus study , the proThe current study has some limitations. The AS parameters were statistically different between the two groups, however, only a few correlations with the demographic and clinical variables were found. This could be explained by the limited number of enrolled subjects; therefore, a larger sample size will be necessary to detect further associations. Moreover, as the cross-sectional design of the study prevented the definition of causality, longitudinal protocols should be carried out to better define and investigate the predictive value of arterial stiffness for cardiovascular events in SSc patients as well as the role of treatment in modifying AS measurements. Finally, this was a single-center study including all-female Caucasian patients, therefore, generalization of the findings remains to be determined.In conclusion, our results support the evidence of an increased AIx, but not PWV, in SSc patients. In addition to the correlations found for PWV with both age and BMI, treatment might have some impact on the AS of these patients, therefore, an in-depth analysis is required. Arterial stiffness measurement may be a reliable and reproducible method for identifying macrovascular involvement in patients with SSc, being relevant in the clinical setting due to its predictive value of CV events.


Inducing general anesthesia (GA) in children can considerably affect blood pressure, and the rate of severe critical events owing to this remains high. Cerebrovascular autoregulation (CAR) protects the brain against blood-flow-related injury. Impaired CAR may contribute to the risk of cerebral hypoxic–ischemic or hyperemic injury. However, blood pressure limits of autoregulation (LAR) in infants and children are unclear.In this pilot study CAR was monitored prospectively in 20 patients aged <4 years receiving elective surgery under GA. Cardiac- or neurosurgical procedures were excluded. The possibility of calculating the CAR index hemoglobin volume index (HVx), by correlating near-infrared-spectroscopy (NIRS)-derived relative cerebral tissue hemoglobin and invasive mean arterial blood pressure (MAP) was determined. Optimal MAP (MAPopt), LAR, and the proportion of time with a MAP outside LAR were determined.The mean patient age was 14 ± 10 months. MAPopt could be determined in 19 of 20 patients, with an average of 62 ± 12 mmHg. The required time for a first MAPopt depended on the extent of spontaneous MAP fluctuations. The actual MAP was outside the LAR in 30% ± 24% of the measuring time. MAPopt significantly differed among patients with similar demographics. The CAR range averaged 19 ± 6 mmHg. Using weight-adjusted blood pressure recommendations or regional cerebral tissue saturation, only a fraction of the phases with inadequate MAP could be identified.Non-invasive CAR monitoring using NIRS-derived HVx in infants, toddlers, and children receiving elective surgery under GA was reliable and provided robust data in this pilot study. Using a CAR-driven approach, individual MAPopt could be determined intraoperatively. The intensity of blood pressure fluctuations influences the initial measuring time. MAPopt may differ considerably from recommendations in the literature, and the MAP range within LAR in children may be smaller than that in adults. The necessity of manual artifact elimination represents a limitation. Larger prospective and multicenter cohort studies are necessary to confirm the feasibility of CAR-driven MAP management in children receiving major surgery under GA and to enable an interventional trial design using MAPopt as a target. Severe critical events occur in approximately >5% of children receiving general anesthesia (GA) , 2, hypoAvoiding inadequate mean arterial blood pressure (MAP) values could contribute to the reduction of perioperative neurological complications because MAP is the driving force for an adequate cerebral perfusion , 4. SeveCerebrovascular autoregulation (CAR) is mediated by cerebral precapillary vasoconstriction or vasodilation occurring in response to changes in slow waves in MAP and aims to ensure a constant CBF over a certain MAP range within the limits of autoregulation (LAR) and protects the brain against injury from hypo- or hyperperfusion. Thus, the concept of CAR is defined by lower limit of autoregulation (LLA) and upper limit of autoregulation (ULA). CAR impairment due to morbid processes or the occurrence of MAP values below or above the LLA or ULA, respectively, can lead to both hypo- and hyperperfusion that increases the risks of brain injury and transient or persistent neurological disability , 6.Maintaining MAP at an optimal point within the LAR leads to the concept of MAPopt, which is the MAP with the highest and best preserved pressure reactivity and thus, the best functionality of CAR to enable optimal CBF , 8. PostHowever, generally applicable MAP values to maintain MAP within LAR in infants, toddlers, and children are unknown and may not even be applicable to all children of a specific age and weight.2) and local relative total hemoglobin level (rtHb)  , 11. Autl (rtHb) , 13.According to Lee et al., non-invasive cerebrovascular autoregulation monitoring with HVx is an excellent alternative to the best established and evaluated CAR index PRx, which is based on invasively measured intracranial pressure (ICP) as a surrogate parameter for cerebral blood volume. Slow changes in the rtHb measured by NIRS are caused by the same blood volume changes that cause slow waves of ICP used for calculating the ICP-derived index PRx .CAR monitoring has been validated in animal models and in adult and pediatric trials , 14–19.In a pediatric swine model, the NIRS-derived index HVx accurately detected the lower limit of autoregulation (LLA) compared to laser-Doppler flow measurements .Impaired CAR results in higher index values, whereas intact CAR is indicated by HVx values approaching zero or even becoming negative , 17, 18.The aims of this pilot study were to describe the feasibility of CAR monitoring using HVx during major elective surgery in toddlers and small children under GA to determine MAPopt and lower and upper blood pressure limits of autoregulation as a guide for blood pressure management.In total, 20 consecutive infants, toddlers, and small children receiving major elective surgery were prospectively enrolled from January 2019 to April 2020. The inclusion criteria were age <4 years and received major elective pediatric surgery requiring GA. Meanwhile, the exclusion criteria were cardiac or neurosurgical interventions. As no intervention was performed, the study was not registered in an international research platform. Data were prospectively collected with institutional review board approval (763/2016BO1), and the study was conducted in compliance with the Declaration of Helsinki. Written parental consent for all the patients was obtained in advance.Demographic data comprised age at surgery, preoperative weight and height, sex, diagnosis, and surgical procedure. Autoregulation monitoring was initiated as part of routine monitoring. Adverse events were documented by the anesthetist in charge.Anesthesia was performed by experienced pediatric anesthesiologists. Two times as total intravenous anesthesia using continuous infusion of propofol and remifentanil, eighteen times as balanced anesthesia using a combination of sevoflurane and continuous infusion of remifentanil.2 monitoring, electrocardiogram, central venous saturation, serum lactate, and diuresis monitoring. Additionally, perfusion status was monitored by standardized capillary refill time. Therapeutic goals were MAP > 40 mmHg in infants <6 months, MAP > 50 mmHg in infants 6–12 months, and MAP > 55 mmHg in toddlers and children aged 1–4 years. Additional therapeutic targets included a difference between arterial oxygen saturation and central venous saturation of 30%, diuresis >2 ml/kg/h, capillary refill time <2 s, and lactate <2 mmol/L.All the patients were subjected to a standardized pediatric anesthetic treatment protocol. Hemodynamic therapy was actively managed using invasive arterial blood pressure, SPOThe attending anesthetists were blinded to the calculations of MAPopt, LLA, and ULA. Thus, CAR monitoring did not have any influence on procedures.2 and relative total hemoglobin (rtHb) with a sensor placed on the forehead, lateral to the midline. Monitoring was performed continuously during GA. The invasive blood pressure monitor and the cerebral oximeter were connected to a laptop running the ICM + software  for data recording at 100 Hz as described previously  was used. OxyAlert™ NIRSensors, with a two-wavelength LED source (730 and 810 nm) and two photodiode detectors with source-detector separations of 30 and 40 mm, were used for measuring rSOeviously . ArtifacU-shaped curve). The LLA was identified as the group with HVx ≥ 0.3 when the bar graph demonstrated increasing index values as MAP decreased. The ULA was defined as the group with HVx ≥ 0.3 when the bar graph demonstrated increasing index values as MAP increased  was used to analyze data and create all charts. Continuous data are presented as mean (±SD), whereas categorical data are presented as percentages. Distribution was tested using an analysis of variance (ANOVA) and Shapiro–Wilk test, including a subgroup analysis. Further, multiple pairwise comparison methods including Dunn's and Holm–Sidak methods were used. Altogether, 20 patients were enrolled, of whom nine were male and eleven were female. The mean patient age and weight were 14 ± 10 months and 9 ± 3 kg, respectively.Preoperatively, 50% of the patients were classified as American Society of Anesthesiology (ASA) 3, 40% as ASA 2, and 10% as ASA 1. The cumulative recording time was 62 h with a mean duration of operation of 186 ± 75 min. Five procedures were endoscopically performed, whereas the others were performed conventionally. None of the recordings had to be stopped or interrupted for technical issues with the sensors or arterial catheter.MAPopt could be determined in 19 of 20 patients (95%). As some patients had not experienced the entire autoregulated blood pressure range, either LLA or ULA could not be determined. LLA could not be identified in 15% and ULA in 20% of the patients. All the obtained autoregulatory parameters are listed in p = 0.014) according to the Kruskal–Wallis analysis. The time until a first reliable MAPopt could be identified showed significant variation. Further analyses revealed an inverse correlation between spontaneous fluctuations in blood pressure, which were operationalized as blood pressure standard deviation and the time required for a first optimal blood pressure. Hence, if patients had volatile hemodynamics, a first value was obtained quicker than in stable patients. For six patients with a blood pressure standard deviation of >10 mmHg, a first reliable MAPopt could be determined after 18 ± 3 min. By contrast, five patients with a blood pressure standard deviation of <5 mmHg required 79 ± 48 min of recording before a first MAPopt could be identified, which was significantly different (p = 0.004).On average, MAP was outside the range of functional CAR (HVx > 0.3) in 30% ± 24% of the operation time, denoted as “time in critical region” TICR, . The TIC2 of >20% from baseline is considered critical . Moreover, the rSO2 TICR value includes a potential outlier who expended 53% of the procedure time and 20% below the baseline range, although it appeared totally stable according to cerebral autoregulation monitoring with only 0.6% TICR.Intraoperative cerebral oximetry monitoring is a standard method for identifying possible critical cerebral hypoxia during pediatric surgery. A decrease in cerebral rSOcritical . AccordiThe identified MAPopt values were also compared to weight adjusted recommendations  Figure . The detAs inducing GA in children can considerably affect blood pressure –30, and A functional CAR mechanism protects the brain against low flow or ischemic injury resulting from transient fluctuations in arterial blood pressure within the LAR , whereasWe performed CAR monitoring in 20 infants, toddlers, and small children receiving major surgery under GA and demonstrated that non-invasive CAR monitoring, using the NIRS-derived HVx provides robust data and can be performed reliably and safely in clinical practice.The key observations in this study are as follows. First, MAP was outside the range of intact autoregulation (TICR) for 30% of the monitoring time. Second, MAPopt could be determined in 95% of the patients. Third, MAP was more often below than above MAPopt. Finally, in ≥50% of the patients, the LLA was higher than the age-adjusted guideline recommendations for MAP.CAR monitoring and determining MAPopt, LLA, and ULA depend on spontaneous fluctuations in blood pressure and sufficient span of blood pressure to acquire the full range of values of the functional CAR. Thus, the blood pressure range must spontaneously exceed both the LLA and ULA at least once intraoperatively. As this was not always the case, the complete blood pressure range with intact autoregulation could be determined in only 11 of 20 patients (55%), whereas in other patients, only one of the limits was determined. In only one patient, blood pressure fluctuations were minimal to such an extent that MAPopt could not be determined at all. Consequently, a MAPopt could be determined in 95% of the patients and could have been used as a target for an active MAPopt-guided hemodynamic management.In those 11 patients where the complete blood pressure range of intact autoregulation could be determined, the span averaged 19 ± 6 mmHg, which is a smaller range than that in adults . FurtherThe intensity of blood pressure fluctuations during anesthesia distinctly influenced the time until the first MAPopt could be determined . In the In more stable patients, the long offset until a first MAPopt can be determined might not be disadvantageous, as their blood pressure may be within the target range of functional CAR  Figures, 3.2 < 35 mmHg) occurred. For this reason and due to the small cohort size, no correlation was made. Whether higher values of pCO2 have a relevant influence should be the subject of subsequent studies.In our cohort no hypocapnia  were identified (Using weight-adjusted blood pressure recommendations or cerebral oximetry with rSOentified . The detentified , and in entified . Cerebraentified . One patentified . This paBy contrast, CAR monitoring by NIRS-derived HVx, enables the determination of individual target blood pressure ranges according to MAPopt determination. This allows actively managing blood pressure guided by HVx during a major surgery under GA to reduce TICR where infants, toddlers. and small children are at risk of hemodynamic brain injury.As low perioperative arterial blood pressure is associated with cerebral hypoperfusion and consecutive neurological injury, actively maintaining blood pressure in the range of intact autoregulation should theoretically contribute to preventing neurological injury; however, perioperative data are limited . EspeciaFirst, the purely observational design and relatively small size of our cohort impair the power of the data generated.Second, the concept of HVx as a surrogate parameter for the status of CAR remains debatable. Correlation with other indices, such as the pressure reactivity index, in clinical practice might be useful, although this parameter is obtainable only with invasive ICP monitoring . NIRS asThird, the necessity of manual artifact elimination that was performed prior to analysis also represents a major limitation for the use of NIRS as a MAP guideline. This could be overcome by pausing the measurement during manipulations on the arterial catheter, thereby making artifact elimination unnecessary. Automated artifact detection algorithms could possibly improve monitoring quality even more.Lastly, although no significant or evident postoperative neurological deficits were identified, neither short-term detailed neurological examinations nor long-term data regarding neurological development were collected. Therefore, no correlations between MAP, distance of MAP to MAPopt, TICR, and neurological outcomes, could be determined.Machine learning-based algorithms for automatic identification of reliable MAPopt and lower/upper limits of CA identification could improve the application during anesthesia.To evaluate a potential beneficial effect of individual autoregulation-guided blood pressure management, a prospective, randomized trial comparing a MAPopt guided blood pressure management against standard blood pressure management is necessary.Monitoring CAR using NIRS and invasive arterial blood pressure can be used intraoperatively when performing major elective surgery in infants, toddlers, and small children under GA in order to identify individual hemodynamic targets to potentially optimize CAR. Individualization of target blood pressure ranges and patient-specific management may be necessary. Therefore, dedicated pediatric clinical trials using non-invasive CAR monitoring should be conducted.


Journal of Ophthalmic and Vision Research (JOVR), two articles are published addressing changes in optical coherence tomography angiography (OCTA) parameters after acute changes in ocular perfusion pressure (OPP). The first article by Ashraf Khorasani et al is a study on changes in vascular density (VD) of the macula and optic nerve after an acute rise in intraocular pressure (IOP), and the second paper is a case report by Mirshahi et al describing OCTA changes in acute systemic hypertension.In this issue of ,4,5,6,7Studies on hemodynamics of the retina and optic nerve microvasculature is an old but still open area of research. With technologies evolving over time, a variety of diagnostic modalities have been used for detection and documentation of blood flow and vascular diameter, including fluorescein angiography, color Doppler ultrasonography, Doppler velocimetry, laser speckle flowgraphy, and Doppler OCT.OCTA is a relatively new technology used for extraction of blood vessels on OCT images by detecting movement of blood. This technology has been extensively used to evaluate circulation in different retinal vascular layers  and choriocapillaris. Evaluation of the peripapillary vascular network and optic disc vessels with OCTA has also become an active area of research in glaucoma.in vivo evaluation of microvasculature, results of studies on this intricate system may not always corroborate with each other. This is due to the complex interplay between blood pressure, intraocular pressure, and retinal/optic nerve autoregulation, where subtle differences in study parameters can affect the response of blood vessels and impact the study results. The difference between ocular arterial pressure and intraocular pressure (IOP) determines the ocular perfusion pressure (OPP). As the ocular arterial pressure cannot be easily measured, brachial artery pressure has been used as its surrogate in most studies, although some corrections may be needed in the upright position. Autoregulation of blood flow is another factor that affects hemodynamics of ocular tissues, especially the retina and optic nerve, and needs to be considered in these types of studies. As autoregulation may need some time to fully take place, timing of measurements after a stimulus/event also seems to be important.While the retina and optic nerve provide a unique target for  Although not as accurate as methods that directly measure blood flow and vessel diameter such as laser speckle flowgraphy and Doppler OCT, VD in OCTA can be considered a useful clinical parameter to reflect changes in blood flow and vascular diameter. When using this parameter to study ocular hemodynamics, some important points need to be kept in mind:Concerning the wide availability of OCTA machines, this modality has been extensively used to evaluate changes in retinal/optic nerve circulation under different conditions. There are two quantitative measures in OCTA that are mostly used to describe changes in retinal and optic nerve vasculature: flux and VD. Flux is the intensity of flow signals while VD is the proportion of flow signals on the en-face OCTA image.OCTA detects blood flow above a certain threshold; above that threshold, the OCTA signal cannot reflect flow rate. Hence, subtle changes in blood flow may not be detected by VD. At the same time, it is very sensitive to changes in small vessels diameter, even below its resolution.VD also depends on the total length and diameter of vessels and will be affected by loss of small vessels in diseases such as diabetic retinopathy and retinal vein occlusions.VD is the sum of flow signals in an image and includes flow from all vessel diameters in the specified area, therefore the study area will define which vessel sizes are included. For example, VD in the parafoveal area will be a better representative of small vessels as compared to VD of a whole 3VD is affected by multiple parameters in addition to blood flow, including low signal strength. So, considering media quality  and excluding low signal strength images is crucial to ensure validity of data. and application of a suction cup. There are also studies investigating changes in vasculature during IOP rise after laser iridoplasty or intravitreal injections. The response of the vascular structure may be different with acute rises in IOP such as when a suction cup is applied, or after intravitreal injections as compared to slower increases in IOP as happens after laser iridoplasty or dark room prone positioning. Therefore, results of different studies may not be readily comparable.Previous studies have used various methods to increase IOP in human eyes, including dark room prone positioning in eyes prone to angle closureThe article by Ashraf Khorasani et al is an interventional study, evaluating the effect of acute IOP rise by application of a suction cup on VD in the DVP and SVP, the peripapillary region and inside the disc in 12 healthy individuals and 12 patients with mild-moderate NPDR. They achieved a mean IOP elevation of 13.93  it may be more affected by changes in intraocular pressure. On the other hand, older patients with diabetes may have stiffer arteries that are less affected by changes in perfusion pressure; hence the SVP, which is closer to the arteries, may be less affected by a moderate amount of IOP rise. In this study, changes in VD in response to IOP rise was not different between the two groups. These results should be interpreted reservedly, as the study may have been underpowered to detect such a difference because of small sample size.The two groups had different baseline OCTA parameters, which can be explained by the difference in age and the presence of diabetes with its associated effect on ocular vessels. As the DVP is considered to be mostly on the venous side of the retinal circulation, it would have been informative if blood pressure readings at the time of IOP rise were available.Another factor to consider is that stress during placement of the suction cup may cause blood pressure to rise and may partially mitigate the effect of IOP rise by increasing ocular prefusion pressure. Also, the degree of blood pressure rise may differ based on age and presence of diabetes. Although blood pressure has been reported to be steady in healthy subjects during application of a suction cup in a prior study, Prior studies have not reported a different response by radial peripapillary capillaries and vessels inside the disc after an acute rise in IOP by intraocular injections. As stated before, the complex interplay of BP, IOP, retinal/optic disc autoregulation and the timing of the measurements after IOP rise affects the results of studies and makes standardization and comparisons difficult.The different response of the optic disc vessels, originating from choroidal arteries, and the peripapillary radial vessels which originate from the central retinal artery, to acute IOP rise can be a confirmation of the previously known fact of different pressures within the retinal and choroidal systems.Although a small study with its limitations, this paper adds to the body of the evidence in this field and the authors should be congratulated for their work. Although an increase in BP increases OPP, autoregulation counteracts it and with vascular leakage and thrombosis happening in acute cases, there may be a decrease in blood flow and ischemia in OCTA contrary to what is expected from an increase in OPP. Ischemia is especially evident in the B scan OCTA images of this case as parafoveal acute middle maculopathy (hyper-reflectivity of the outer plexiform layer), coinciding with locations where capillary loss is visible in the SVP and DVP. Depth-enhanced visualization of blood vessels, a characteristic of OCTA, has enabled better visualization of retinal capillary loss. Better visualization of ischemia in the choriocapillaris in comparison to FA can be attributed to the longer wavelength of infrared light used in OCTA that penetrates better through the RPE as compared to the blue light of fluorescein angiography (FA).The second article by Mirshahi et al is a case report describing OCTA findings in acute hypertensive retinopathy. Acute hypertensive retinopathy can cause various tissue reactions alongside the increase in ocular perfusion pressure: vascular contraction due to autoregulation, vascular leakage, and thrombosis.These two articles remind us of the fact that in biological systems, the response to stimuli may not follow gross physical rules and need to be interpreted taking into account variability of intricate biological responses which may not always be simple to elucidate.


Excess trunk body fat in obese individuals influences respiratory physiological function. The aims of this study were to compare volumetric capnography findings (VCap) between severely obese patients and normal-weight subjects and to assess whether there is any association between neck circumference (NC), waist-hip ratio (WHR) and VCap among grade III obese individuals.  Analytical observational case-matched cross-sectional study, University of Campinas.  This cross-sectional study compared VCap variables between 60 stage III obese patients and 60 normal-weight individuals. 2 production , expiratory tidal volume , CO2 production per breath  and peak expiratory flow . The end-expiratory CO2 (PetCO2) concentration  and the phase 3 slope were normalized according to expired tidal volume  were lower in the obese group.  In comparison with the normal-weight group, obese patients presented higher alveolar minute volume , CO2 production per minute and per breath and expiratory volume; whereas the smaller were the phase 2 slope (P2Slp), phase 3 slope (P3Slp) and pressure drop in the mouth during inspiration. The greater the NC was, the larger were the alveolar minute volume, anatomical dead space, CO Besides these variables, each breath cycle produces a curve called a capnogram that has a shape similar to that of N2 washout.Volumetric capnography (VCap), which consists of plotting the expired CO,,,Our hypothesis was that VCap might help in understanding abnormalities in respiratory patterns and lung function during rest among obese individuals.The aims of this study were to compare the VCap variables between severely obese patients and normal-weight subjects and to evaluate the existence of any correlation between neck circumference (NC), waist/hip ratio (WHR) and VCap variables among obese patients.2) candidates for bariatric surgery at Hospital de Clínicas, University of Campinas (UNICAMP) and normal-weight controls (BMI 18.6-24.9) who were selected from the data bank of the Pulmonary Function Laboratory, UNICAMP. The subjects and controls were aged between 18 and 65 years old and were evaluated between August 2014 and July 2015. The study was approved by the local Research Ethics Committee.This was an analytical observational case-matched cross-sectional study in which the subjects enrolled were grade III obese ; and individuals who opted not to take part in the study. Both the obese and the non-obese participants reported that they did not have any respiratory diseases (current or past) and were not on any respiratory medication.The individuals selected were matched according to age, gender and height and were divided into two groups: obese (group 1) and non-obese (group 2). In both groups, the variables initially collected and analyzed were age, gender and anthropometric measurements  .In the obese group, the variables of NC and WHR were also collected and analyzed. The obese patients also answered the Berlin questionnaire (BQ), which evaluates the risk of development of obstructive sleep apnea syndrome (OSAS). Occurrences of hypertension were assessed in accordance with the Eighth National Joint Committee (JNC 8) criteria, i.e. individuals were considered to present hypertension if at least three different blood pressure measurements were higher than 140/90 mmHg.2SMOS Plus 8100 Dixtal/Novametrix; Respironics, Murrisville, PA, USA).All the participants underwent VCap in the mornings at the Pulmonary Function Laboratory of UNICAMP. The device used was the oxy-capnograph and respiratory profile monitor . After this, a nose clip was put in place to avoid air escape through the nostrils and the subject was asked to breathe room air regularly through a mouthpiece that he or she held with his or her dominant hand, which was connected to the capnograph sensors. The participant was asked to breathe normally for some seconds to adapt to this situation.2 concentration (PetCO2). Furthermore, sequences that showed phases 2 and 3 slopes equal to zero were eliminated, along with outlier values.Online digital recording of respiratory cycles was then started , and this continued for five minutes. A pulse oximetry sensor was installed on the index finger. At the end of data collection, an offline sequence of the subjects’ respiratory cycles was selected to accommodate variation of < 15% for expiratory tidal volume and < 5% for partial pressure of COPhases 2 and 3 slopes equal to zero can occur because, from time to time, the apparatus used removes the humidity from the sensor and, through this, the parameters are cleared. Outlier values occur because patients who are breathing spontaneously may make different respiratory efforts .2 was calculated. The patients were weighed using a digital scale that was appropriate for their size, with a maximum capacity of 300 kg and a resolution of 100 g, and height was ascertained using a wall-mounted stadiometer. From these measurements, BMI in kg/mWaist circumference was determined using a measuring tape around the individual at the natural waist line, i.e. in the narrowest area between the chest and hip, at the midpoint between the last rib and the iliac crest. The readings were made at the end of expiration. Hip circumference was determined in the horizontal plane at the level of the greatest posterior protuberance of the buttocks. The waist/hip ratio (WHR) was calculated using the formula: WHR = waist circumference (cm)/hip circumference (cm). Both of these measurements were made with the patient standing, using a flexible measuring tape. Neck circumference was also measured using a flexible tape at the level of the laryngeal prominence.The baseline characteristics of the sample were presented in frequency tables encompassing the categorical variables, as absolute (n) and percentage (%) frequencies. Continuous variables were presented as mean values with their respective standard deviations (SD). Bivariate analyses on categorical variables were carried out through the chi-square and Fisher’s exact tests. For comparisons of continuous measurements, the Mann-Whitney test was used. To study the relationship between the capnography measurements and, respectively, the neck circumference and the waist-to-hip ratio of the obese individuals, Spearman’s correlation coefficient was used. The significance level used was 5% (P < 0.05). A Bonferroni adjustment was used for pairwise comparisons, to identify the significance within mean differences between correlations for each outcome (Bonferroni adjusted α = 0.0015625 for Mann-Whitney comparisons and α = 0.0045 for Spearman’s correlations). To perform the analyses, the Statistical Analysis System (SAS) software for Windows, version 9.2, was used.Sample size estimation was performed through a single-proportion formula with a 95% confidence interval. Precision was set at 10% and the calculated sample size was determined to be 60.2, NC 44 cm and WHR 0.91. These two last anthropometric parameters were only measured in the group of obese individuals.In the obese group, there were 45 women (75%) and 15 men (25%). Their mean age was 36 years, mean weight 141 kg, mean height 1.66 m, mean BMI 50.9 kg/mIn this group, 27 (55%) had hypertension and 49 (81.7%) were diabetic. In the Berlin Questionnaire, 45 individuals (75%) presented a high risk of having OSAS and 15 (25%) presented a low risk.2. In the non-obese group, 45 (75%) were women and 15 (25%) were men, with a mean age of 36 years, mean weight 67.3 kg, mean height 1.66 m and mean BMI 20.8 kg/m2 per minute (VCO2) (ml/min), partial pressure of end-tidal carbon dioxide (PetCO2) (mmHg), expiratory volume (Ve) (ml), peak expiratory flow (PEF) (l/min), production of CO2 per breath (VCO2/br) (ml/breath) and phase 3 slope normalized according to end-tidal partial pressure of CO2 (P3Slp/Ve) that were statistically different (P < 0.05) from those of the normal-weight controls. After applying the Holm-Bonferroni correction, MV alv (ml) and VCO2 (ml/min) remained significantly higher in the obese group (P < 0.0015625). The capnography variables are shown in The obese patients presented alveolar minute volume  (ml), production of COD), the production of CO2 per minute (VCO2), the inspiratory volume (Vi), the expiratory volume (Ve), the peak expiratory flow (PEF) and the production of CO2 per breath (VCO2/br); whereas the greater the NC was, the smaller were the phase 2 slope (P2Slp), the phase 3 slope (P3Slp) and the pressure drop in the mouth during negative inspiratory pressure (NIP). After applying the Bonferroni adjustment (P < 0.0045), NIP, P3Slp and VCO2/br no longer presented significant correlations, while the other variables remained significant.In the obese individuals, WHR did not present any correlation with VCap measurements. On the other hand, in correlation analyses between NC measurements and capnography variables , there w2 (average per minute) or VCO2. These results  suggest that obese patients possibly have more efficient ventilation during tidal breathing, since the VCap measurements are made during several minutes of quiet breathing. These measurements do not require forced expiration, as spirometry does. Tidal volume and alveolar minute ventilation may be higher in order to match the higher needs of a greater body mass. Nevertheless, the low mean PetCO2 and P3Slp/Ve may indicate that the obese group presented a larger alveolated area. The comparison between the two groups (obese versus non-obese subjects) revealed that there were no statistical differences regarding age and height. The respiratory rate and the dead volume of the airways were similar in the two groups.The obese patients in this study had significantly greater alveolar minute volume  and expired volume of COThe reductions in forced vital capacity that are detected in obese patients through spirometry may, at least in part, be related to the difficulties in using expiratory abdominal muscles due to fat accumulation in this area. The obese patients in the present study did not perform spirometry because this was not part of the study protocol.Wei et al. found that the lungs of obese patients had higher capacity to diffuse carbon monoxide and attributed this result to the higher blood flow to the lungs that obese subjects may have.2) and sulfur hexafluoride (SF6) have been used to study these areas and the elimination curves that they produce during each expiration depict concentrations of the gas at different volumes until all the expiratory volume has been expired. Irrespective of the gas used, all curves have the same shape and, on each of them, three phases can be identified: phase 1, with very low concentrations of the gas, corresponds to the elimination of the air from the anatomical dead space; phase 2, which is generally a steep upward line, represents the growing concentration of the gas that is eliminated from proximal alveolated air spaces; and phase 3, which is almost a plateau line, represents the elimination of the gas from most of the alveoli in the lungs. The phase 3 slope (mmHg/l) is an important feature of gas washout curves and contains information about gas transportation in the alveolated airways of the lung periphery. It varies in many pathological conditions of the lungs.,,,,,,,The peripheral airspaces have been termed the silent lung zone because conventional lung function tests are unable to detect their involvement in disease processes. Inert gases such as helium (He), nitrogen  should therefore be small.Phase 3 (mmHg/l) of the VCap represents the elimination of CO,,,Because of the very small convective velocities in the lung periphery, gas transportation through diffusion is the dominant mechanism in acinar air spaces. Steepened phase 3 slopes may represent increased diffusional resistance in the peripheral lung. These steepened slopes occur when breathing involves a smaller-than-normal maximum interfacial area between the tidal volume and the functional residual capacity (FRC) during a breathing interval. Small tidal volumes produce steeper slopes because the inhaled air penetrates to shallower-than-normal depths in the lung and therefore encounters smaller-than-normal maximum interfacial areas and longer gas-phase diffusion paths.2 washout curves with increasing age was due to an increase in the interface between functional residual capacity (FRC) and tidal volume (VT), with lung growth in children.In a paper on VCap in children, Ream et al.It seems that, taking into account the significantly smaller normalized values of phase 3 slopes in obese patients, a hypothesis can be put forward: obese patients may have larger or more efficient alveolated airspaces than do non-obese subjects. The correlations between NC values and capnography variables that were found to be significant are in agreement with the hypothesis put forward here, i.e. that the greater the body mass was , the larger were the lungs of the obese subjects who participated in this study.,,,Human leptin is a 16-kDa protein of 167 amino acids and was the first fat cell-derived hormone to be discovered.Leptin levels are paradoxically increased in situations of obesity.,,,,The excess leptin present in obese subjects may at least partly explain the apparently larger lungs detected through VCap in these patients. Fat deposits in the neck and abdomen may display a mechanical effect on the chest and may hinder chest mobility during forced expiration and possibly also during spontaneous ventilation, with consequences for lung function. This has also been observed in other studies,None of the obese patients in the present study, whose BMI was greater than 52, had obesity hypoventilation syndrome (OHS), although 45 of them showed a high-risk result from the Berlin questionnaire for obstructive sleep apnea syndrome (OSAS).2 retention. Recent reports have shown that alveolar growth continues from childhood into adolescence in humans and other mammals.The hypothesis that these individuals may have had a larger alveolar-capillary membrane might serve as a possible reason for the absence of COFerreira et al.This study has some limitations. Carbon monoxide diffusion was not performed on the patients of the present study because we did not have the equipment to do this. This measurement could have helped to rule out alterations in carbon monoxide diffusion as the cause of our findings. The NC and WHR data relating to the controls were not available because the data were collected from a database. Spirometry data were not available because the obese patients were in the process of losing weight and would undergo spirometry after achieving a predetermined goal. It was not possible to evaluate whether exposure to toxic agents such as tobacco might have influenced respiratory function in the two groups, since we did not have this information in the database relating to the non-obese group.2 elimination. Knowing the leptin levels in these patients might have contributed towards investigating this hypothesis.Our findings may contribute towards understanding the complex range of alterations to respiratory function that are seen in very obese patients. They also raise the intriguing possibility that some obese individuals may undergo changes to the alveolar-capillary membrane that enable greater efficiency of CO2 production per minute and per breath and expiratory volume; whereas the smaller were the phase 2 slope (P2Slp), phase 3 slope (P3Slp) and pressure drop in the mouth during inspiration. Some of these changes were related to possibly larger lungs in obese patients and others to their larger NC. The combination of larger lungs and absence of hypoventilation makes us speculate that these two occurrences may be linked.Volumetric capnography was capable of detecting particular characteristics of lung structure and function in morbidly obese patients, among which some had not previously been shown. It identified changes to various respiratory parameters, in comparison with a normal-weight control group. The greater the NC was, the larger were the alveolar minute volume, anatomical dead space, CO


Fontan palliation depends on low pulmonary vascular resistance in order to maintain pulmonary blood flow and adequate oxygenation. This physiology results in higher central venous pressures with limited renal perfusion pressure and cardiac output. Positive pressure ventilation with mechanical ventilation increases intrathoracic pressure and raises central venous pressure and can further limit pulmonary and renal perfusion. Fluid removal with intermittent hemodialysis can be challenging in Fontan patients and can cause intolerable hypotension, however the increased abdominal filling pressures during peritoneal dialysis dwells can exacerbate systemic venous hypertension seen in Fontan patients and threaten adequate pulmonary blood flow and cardiac output. Successful transition to peritoneal dialysis in a chronically ventilated patient with hypoplastic left heart syndrome, end-stage renal disease and Fontan physiology has not been described. We present details outlining the successful transition across multiple modalities of renal replacement therapy to assist other teams faced with similar challenges in chronically ventilated Fontan patients with end-stage renal disease. This third stage palliation for those with single ventricle physiology adds the IVC/hepatic blood flow to the PA and follows the second stage  palliation that connected superior vena cava (SVC) blood flow to the PA . Given tgenation . When ungenation , 4.Chronic positive pressure ventilation increases intrapulmonary pressures and thereby reduces the blood flow gradient of systemic venous return through the TCPC and risks adequate oxygenation . PeritonHere we present a case of successful transition from continuous veno-venous hemodiafiltration (CVVHDF) to intermittent hemodialysis (HD) to PD in a chronically ventilated child with HLHS who developed end-stage renal disease (ESRD) following Fontan palliation.A 5-year old 19 kg boy with HLHS  status post Norwood/Sano and bidirectional Glenn, underwent TCPC (Fontan) palliation with a 3.8 mm fenestrated 16 mm polytetrafluoroethylene (PTFE) extracardiac conduit. His pre-Glenn course included diaphragm plication, gastrostomy tube placement and tracheostomy with chronic mechanical ventilation for subglottic stenosis and severe left bronchomalacia until he was 4 years of age. A pre-Fontan cardiac catheterization was favorable with mean bilateral PA pressures of 12–13 mmHg and no branch PA stenosis . His TCPHis post-TCPC course was complicated by a large chylous left pleural effusion confirmed by ultrasound  on POD 6With no response to diuretics, CVVHDF was started POD 20 for fluid overload (+11.4 L) and anuric renal failure. His prior tracheostomy site was re-cannulated for chronic mechanical ventilation. He required epinephrine (0.03–0.07 mcg/kg/min) throughout his CVVHDF course to maintain his blood pressures during that therapy. After 38 days of CVVHDF, he was hemodynamically stable off pressor support with mild tricuspid regurgitation but oliguric acute kidney injury persisted and the decision was made to transition to daily intermittent hemodialysis (HD) eventually spaced to four days a week. Given his Fontan physiology, his hemodialysis was delivered over 4 h at a relatively low blood flow rate of 120 ml/min to allow adequate fluid removal without inciting hypotension. On POD 97, he was discharged home but required readmission to the intensive care unit (ICU) for each dialysis session given his chronic mechanical ventilation and need for hemodynamic monitoring.The patient had multiple repeated admissions for bacteremia [methicillin sensitive staphylococcus aureus (MSSA) and subsequently enterococcus], HD volume removal adjustments, and HD catheter changes. He was evaluated but determined to not be a candidate for cardiac and renal transplant. The burden of four days a week inpatient HD and the difficulties with infections led to the decision to work towards peritoneal dialysis despite the following risks: (1) concern for possible prior breach of pleural and peritoneal membranes risking hydrothorax, and (2) concern that adequate volume dwells could limit his venous return, pulmonary blood flow and respiratory function. After careful consideration between providers and his family, the decision was made to proceed and a laparoscopic PD catheter was placed .After adequate time for healing of the PD catheter incision, continuous cycler-assisted peritoneal dialysis (CCPD) was initiated with slow increases in fill volumes during an inpatient ICU admission where his hemodynamics were closely monitored. Initial hypotension was tolerated and resolved without intervention. His respiratory status was stabilized with no change in his chest x-ray (CXR) or ventilatory requirement. The patient was discharged home on CCPD with fill volumes of 600 ml (about 30 ml/kg), for 12 cycles over 12 h. Details of the patient's transition between modes of dialysis are detailed in Acute kidney injury (AKI) after complex congenital cardiac surgery with cardiopulmonary bypass is common and associated with increased morbidity and mortality , 8. AKI The incidence of RRT in patients with Fontan physiology was 6.2% in a review of 1,166 patients from 1,973 to 2017  found AKI  in 164 (35.3%) that persisted until POD 7–9 in 72 (15.5%). Those with persistent AKI had lower renal perfusion pressure, longer duration of mechanical ventilation and higher rates of RRT. Forty-nine (10.5%) received RRT, initiated when urine output was <1 ml/kg/h and there was no response to furosemide infusion for 48 h . Of the A study of 81 adults with Fontan physiology found a 46% incidence of chronic kidney disease when defined using estimated glomerular filtration rate and albuminuria . An obseAlthough our patient tolerated HD, its requirement to be performed as an inpatient led to the decision to attempt PD. In our patient's case, repeated sternotomies, multiple mediastinal tubes, extensive dissection of adhesions and gastrostomy tube placement were thought likely to have resulted in peritoneal membrane adhesions and fibrosis, potentially compromising the integrity of his peritoneum. This raised concern whether his peritoneum, in the setting of increased intra-abdominal pressure, would sufficiently prevent small solute and free water transport into his pleural spaces as hydrothorax is a rare, but well described complication of PD . WhetherDespite his complex medical challenges, our patient was able to tolerate daily increases in his PD filling volumes with the associated increase in intra-abdominal pressure, central venous pressure and intrathoracic pressure and maintain adequate pulmonary blood flow and therefore cardiac output. Careful coordination of his care by his cardiac intensive care, cardiology, nephrology and surgery provider teams allowed for successful transition across renal replacement strategies that eventually allowed for delivery of care at home. We hope this management outline may assist other care teams when faced with similar clinical situations in these uniquely vulnerable patients.


Crescentic glomerulonephritis (CrGN) usually requires urgent immunosuppressive treatment. However, aggressive immunosuppressive treatment is often difficult because of the patients’ medical conditions or comorbidities. Prognostic markers including urinary cytokines/chemokines as noninvasive biomarkers were explored in CrGN patients. This prospective cohort study included 82 patients with biopsy-confirmed CrGN from 2002 to 2015 who were followed up for 5 years. Urine and serum cytokines/chemokines on the day of kidney biopsy were analyzed in 36 patients. The median age was 65 years and 47.6% were male. Baseline estimated glomerular filtration rate (eGFR) and interstitial fibrosis and tubular atrophy (IFTA) scores were identified as significant prognostic factors. Among patients with cytokines/chemokines measurement, increased IL-10 level was identified as an independent predictor of good prognosis, and increased levels of urinary MCP-1 and fractalkine tended to be associated with good prognosis after adjusting for baseline eGFR and IFTA score. However, semiquantitative analysis of intrarenal leukocytes did not show prognostic value predicting renal outcome or correlation with urinary cytokines/chemokines. This study supports the clinical importance of baseline eGFR and IFTA scores and suggests potential usefulness of urinary IL-10, MCP-1, and fractalkine as prognostic markers for predicting renal outcomes in patients with CrGN. However, some patients develop end-stage kidney disease despite immunosuppressive treatment, and therapy-related complications can seriously impair quality of life and even lead to death, especially in the elderly or patients with serious comorbidities3. Therefore, the risk–benefit profile and potential treatment response should be considered before initiating aggressive immunosuppressive treatment. Previous studies have reported baseline kidney function or pathologic findings at diagnosis as prognostic markers predicting the treatment response of CrGN6. However, predicting renal outcomes in CrGN using noninvasive biomarkers remains challenging.Crescentic glomerulonephritis (CrGN) is often fatal and can progress to end-stage kidney disease. Timely initiation of immunosuppressive treatment following urgent kidney biopsy has been regarded as standard management8. The cellular composition of crescents appears to change over time, with predominant epithelial cells in the early stages and increasing numbers of infiltrating macrophages, lymphocytes, and myofibroblasts in later stages10. Eventually, complex inflammatory processes are involved in the development and evolution of crescents12.Crescent formation, a main feature of pauci-immune GN, anti-glomerular basement membrane (GBM) GN, and aggressive immune complex GN, can be triggered by various underlying disorders. Glomerular microvascular injury and rupture of GBM result in leakage of plasma proteins and inflammatory cells within the Bowman’s space, and subsequent hyperplasia of parietal epithelial cells even in non-inflammatory glomerular injury14, regulated upon activation in normal T cells expressed and secreted (RANTES)15, interleukin (IL)-616, IL-1017, and transforming growth factor-β1 (TGF-ß1)18 in the pathogenesis of CrGN. However, few studies have attempted to determine the clinical value of cytokines/chemokines in urine or serum specimens of patients with CrGN, focusing on prognosis or treatment response, and the clinical relevance of urinary or serum cytokines/chemokines is yet to be determined in CrGN21.Several studies have investigated the roles of cytokines or chemokines, such as monocyte chemoattractant protein-1 (MCP-1)In this study, we aimed to investigate the clinical value of urinary cytokines/chemokines as biomarkers for predicting the prognosis of CrGN.2 and uPCR was 1.97  mg/mgCr. Baseline eGFR was significantly higher in the good prognosis group than in the poor prognosis group. Approximately 70% of the patients showed positive results for anti-neutrophil cytoplasmic antibody (ANCA). Pauci-immune crescentic glomerulonephritis was the most common pathologic diagnosis, followed by immune complex-mediated crescentic glomerulonephritis. Patients with underlying autoimmune disease other than ANCA-associated diseases or who were treated with immunosuppressive therapy prior to the diagnosis of CrGN were not included. The definitions of good and poor prognosis were specified in the "The baseline characteristics of patients with CrGN are presented in Table Among the variables reflecting histologic features, percentages of normal glomeruli, glomerular chronic changes, and tubular chronic changes were significantly different according to prognosis. There was no significant difference in the treatment regimens, and 60 (86%) patients were treated with corticosteroids and other immunosuppressants (mostly cyclophosphamide). There was no difference in the characteristics between the cytokine measurement and non-measurement groups . Tubular chronic changes, IFTA 2 and 3, tended to be associated with poor prognosis .Table P = 0.06), ln(urine IL-10/creatinine) , and ln(urine MCP-1/creatinine)  tended to be associated with good prognosis after treatment (Table P = 0.048) was associated with a good prognosis. Ln  and ln(urine MCP-1/creatinine)  tended to be associated with good prognosis.Ten cytokines/chemokines were measured in the blood and urine specimens of 36 patients. Table P = 0.81; CD3, 8.0% (3.7–10.3) vs. 7.0% (3.7–10.2), P = 0.69, CD20, 2.4% (0.5–4.7) vs. 1.1% (0.5–4.2), P = 0.57]. The degree of infiltration of intrarenal immune cells did not show any correlation with urinary cytokines/chemokines or histologic features, such as chronic glomerular changes  and tubular chronic changes .Immunohistochemistry of CD45, CD3, and CD20 followed by tissueFAXS analysis was performed in 78 patients whose kidney biopsy specimens were available  were identified as independent predictors of poor prognosis. Our study demonstrated that high baseline levels of urinary IL-10, MCP-1, and fractalkine were predictors of good prognosis independent of baseline eGFR and chronic tubular change.22. In 2010, Berden et al.4 incorporated the results of previous studies and proposed histopathologic classification of ANCA-associated glomerulonephritis based on glomerular pathology assessed by light microscopy: focal, crescentic, mixed, and sclerotic; although later validation studies have shown conflicting results regarding crescentic and mixed classes23. In addition to glomerular findings, tubulointerstitial histopathological findings have also been reported as predictors of renal outcome24. In our study, consistent with previous studies, baseline kidney function and tubulointerstitial histopathological findings at diagnosis were important predictors of renal outcome.Previous studies have reported baseline renal function and renal histopathological findings at the time of diagnosis as predictors of renal outcome in CrGN25. IL-10–deficient regulatory T cells lose their capacity to attenuate renal tissue injury in CrGN17 and low intracellular IL-10 levels in remission were associated with a high relapse rate of ANCA-associated vasculitis during the long-term follow-up26. Therefore, the increase in urinary IL-10 at diagnosis may suggest endogenous initiation of immune modulation switching the intrarenal immunologic micromilieu in a favorable direction in which disease will be easily controlled by showing enhanced responsiveness to immunosuppressive treatment.In our study, a high urinary IL-10 level was identified as a significant prognostic factor for good renal outcome, independent of baseline eGFR and IFTA score. IL-10, a representative anti-inflammatory cytokine, is released by regulatory T cells and is associated with immune regulation in CrGN27. Blocking MCP-1 and fractalkine attenuated kidney damage in a murine model of GN28. Cellular crescents can be reversed by appropriate immunosuppressive treatment in the early stages29. Interstitial collagen production and progression to fibrous crescents are common when the Bowman’s capsule ruptures, accompanied by an influx of fibroblasts and macrophages into the Bowman’s space30. Macrophages play a central role in the formation of glomerular crescents by stimulating tissue factor expression and fibrin deposition, and subsequently promote the chronic fibrotic phase in established CrGN31. Ablation of macrophages attenuated kidney injury with reduced glomerular crescents, and adoptive transfer of macrophages aggravated murine crescentic glomerulonephritis33. These previous reports suggest that factors affecting the recruitment or activity of macrophages may be important in the pathogenesis of CrGN33. Both MCP-1 and RANTES were reported to play important roles in the inflammatory phase of CrGN, and blocking of MCP-1 reduced the number of crescents and deposition of type I collagen, whereas blocking of RANTES did not14. In another study, urinary MCP-1 was higher in patients with active renal vasculitis than in those with inactive renal vasculitis and correlated with glomerular macrophage infiltration, and decreased urinary MCP-1 following treatment preceded the improvement in renal function19. Although further studies are needed to confirm our findings, urine MCP-1 may be used as a potential predictor of good prognosis, and urine fractalkine or RANTES may also be considered as candidates for noninvasive biomarkers in CrGN.High levels of urinary MCP-1 and fractalkine also tended to be associated with good prognosis in our study, although not statistically significant, probably owing to the small sample size. Urinary RANTES was high in the good prognosis group, although it was not a significant predictor in the multivariable logistic regression analysis. MCP-1, fractalkine, and RANTES attract T lymphocytes and macrophages. MCP-1 and fractalkine play prominent roles in the recruitment of macrophages, whereas RANTES plays a more significant role in the recruitment of T lymphocytes35. One study showed that intrarenal infiltration of helper T cells and macrophages was correlated with response to methylprednisolone therapy in patients with rapidly progressive GN, except for anti-GBM disease36, and another study reported that intraglomerular total leukocytes infiltration as well as interstitial or intraglomerular macrophage infiltration in patients with ANCA-associated GN was correlated with serum creatinine at the time of biopsy, but not after 1 year35. Although semiquantitative analysis of intrarenal total leukocytes, T cells, and B cells did not predict renal outcome in our study, these results may support the potential importance of urinary biomarkers reflecting the entire intrarenal immunologic micromilieu because it is difficult and time consuming to analyze each immune cell in kidney biopsy tissue.In this study, infiltration of total leukocytes, T cells, and B cells in the kidney tissue of CrGN patients was analyzed semiquantitatively. Studies analyzing leukocyte infiltration in the kidney tissue of CrGN patients through immunohistochemistry showed predominant interstitial T lymphocyte infiltration and predominant intraglomerular monocyte or macrophage infiltration20. However, our study design may have increased relevant in real-world practice as urinary cytokines/chemokines at the time of diagnosis are highly significant in determining immunosuppressive treatment. Third, we included all CrGN patients with various etiologies, although ANCA-associated pauci-immune GN was the main cause of CrGN. Although each subtype of CrGN has a different pathophysiology, CrGN usually requires aggressive immunosuppressive treatment regardless of the underlying etiology. In addition, common processes of disruption of GBM integrity, development of glomerular crescent, and progression to fibrosis and sclerosis are involved in the pathophysiology of CrGN37. Therefore, it is reasonable to assume that common biomarkers can be used to predict overall prognosis including the treatment response in CrGN.Our study has several limitations. First, despite the prospective design of this study, blood and urine samples were collected from only 36 of the 82 patients. However, the strength of our study is that serum and urine specimens were simultaneously collected on the day of kidney biopsy. Moreover, as there were no differences in clinical characteristics between the cytokine/chemokine measurement and the non-measurement groups, we believe that the cytokine measurement group can represent all study subjects. Second, changes in cytokines/chemokines after biopsy were not evaluated. Some studies reported that changes following initial treatment or during the post-treatment follow-up period were associated with prognosisDespite these limitations, our study has some strengths. We reviewed five consecutive years of laboratory data to analyze renal outcomes, and it is a relatively sufficient follow-up period compared with previous studies for prognostic biomarkers. We investigated diverse factors to identify predictors of therapeutic response and prognosis of CrGN, including measurements of serum and urine cytokines/chemokines and immunohistochemistry of biopsy specimens.In conclusion, high urinary levels of IL-10, MCP-1, and fractalkine may be used as potential noninvasive prognostic markers to determine immunosuppressive treatment for CrGN. Further prospective studies with a large cohort are required to validate the clinical usefulness of these biomarkers in CrGN.In a prospective cohort of all patients undergoing kidney biopsy between 2002 and 2015 at the Samsung Medical Center , patients with biopsy-proven “CrGN” were analyzed. We excluded patients younger than 18 years, with CrGN of transplanted kidney, and without available data of 1-year spot urine protein to creatinine ratio or any evidence of clinical response from electronic medical records. A total of 82 CrGN cases were included in the final analysis.The study was approved by the Institutional Review Board of Samsung Medical Center in compliance with the Declaration of Helsinki (IRB numbers: 2010-03-007 and 201707099), and informed written consent was obtained from all participants.38. Baseline total white blood cell counts, erythrocyte sedimentation rate, and C-reactive protein levels were also collected. In addition, titers of anti-proteinase 3 antibody, anti-myeloperoxidase antibody, and ANCA were analyzed. Positive ANCA results without elevation of anti-proteinase 3 and anti-myeloperoxidase antibody levels were considered false positives. Treatment regimens were categorized into steroid alone (treatment 1), steroids with other immunosuppressants (treatment 2), and steroids with other immunosuppressants and plasmapheresis (treatment 3).Clinical data including age, sex, prescription history of immunosuppressants, history of plasmapheresis or hemodialysis, and events necessary for clinical response assessment, such as the beginning of maintenance dialysis or kidney transplantation, were extracted from electronic medical records. Laboratory data, including estimated glomerular filtration rate (eGFR), spot urine protein to creatinine ratio (uPCR), and spot urine albumin to creatinine ratio on the day of kidney biopsy (baseline) and at 1 year after kidney biopsy, were collected. Changes in eGFR up to 5 years after kidney biopsy were analyzed to evaluate long-term renal outcomes. Serum creatinine-based eGFR was calculated using the Modification of Diet in Renal Disease equationThe study outcome was divided into good and poor prognosis groups. A good prognosis was defined as a 1-year uPCR decrement of > 50% and increased or maintained eGFR. The increase in uPCR, decrease in eGFR, maintenance dialysis or kidney transplantation within 1 year, or death within 1 year after initial kidney biopsy were considered a poor prognosis.39.Biopsy reports of all patients with CrGN were thoroughly reviewed. The percentages of global sclerosis and each type  of crescent were scored by a pathologist in a blinded manner. Then, the proportions of normal glomeruli , glomeruli with active crescents (cellular or fibrocellular crescents), and glomeruli with chronic changes  were analyzed. The tubular chronic changes were organized according to the interstitial fibrosis and tubular atrophy (IFTA) scoring system as follows: 0, absent; 1, mild (< 25%); 2, moderate (25–50%); and 3, severe (> 50%) of the total tubulointerstitial area40. Renal tissue sections (4-μm thick) were deparaffinized using xylene, rehydrated in a graded alcohol series, and placed in a citrate buffer solution (pH 6.0). The slides were placed in a pressure cooker and heated with microwaves for 10 min to enhance antigen retrieval. After cooling, the slides were immersed in hydrogen peroxide solution  for 30 min to block endogenous peroxidase. After overnight incubation with serum-free protein block (Dako) at 4 °C, the slides were incubated at 25 °C for 1 h with a 1:100 dilution of monoclonal rat anti-mouse antibody against CD45, CD3, and CD20 . Next, they were incubated at room temperature for 30 min with a mixed solution of dextran coupled with peroxidase molecules and goat secondary antibody molecules (Dako). Then, 3,3′-diaminobenzidine tetrahydrochloride (Dako) was applied to the slides to show a brown color, followed by counterstaining with Mayer’s hematoxylin (Dako). A TissueFAXS workstation  was used to analyze and calculate the percentages of CD45-, CD3-, and CD20-positive cells infiltrated into renal tissues, as described previously40.We performed immunohistochemical staining for cluster of differentiation (CD) 45 (leukocyte common antigen), CD3 (surface marker of T cells), and CD20 (transmembrane protein of B cell surface) using formalin-fixed renal tissue sections, as described previously® MAP Human Cytokine/Chemokine panel , coupled with a Luminex xMAP® platform in a magnetic bead format. These cytokines/chemokines were measured according to the manufacturer's instructions as described in our previous study41. B lymphocyte chemoattractant was measured using a human CXCL13/BLC/BCA-1 Quantikine ELISA kit  according to the manufacturer's instructions. Urine cytokine/chemokine levels were adjusted for urine creatinine levels. The measured values of cytokine/chemokine were logarithmically transformed for statistical analysis owing to skewed distribution.Urine and serum samples were collected from 36 patients on the day of the kidney biopsy. Several cytokines/chemokines, including RANTES, fractalkine, interferon-gamma, IL-10, IL-4, IL-6, MCP-1, tumor necrosis factor-alpha, and vascular endothelial growth factor were measured using the MILLIPLEXt-test to confirm that the cytokine measurement group represented all patients in our study. For immunohistochemistry and cytokine/chemokine data, the Mann–Whitney U-test was performed to analyze the differences according to prognosis. Spearman’s correlation analysis was performed to investigate the associations of immunohistochemistry and cytokines/chemokines with prognosis and other clinical variables. To evaluate the prognostic value of cytokines/chemokines and clinical variables in predicting patient outcomes, univariable and multivariable logistic regression analyses were used. All statistical analyses were performed using SAS version 9.4 . Statistical significance was defined as a two-sided P-value < 0.05.Demographics and baseline clinical data are presented as median (interquartile range [IQR]) or number (percentage), as appropriate. We compared the variables of the cytokine measurement group and the non-measurement group using Pearson’s Chi-square test or Fisher’s exact test and Student’s Supplementary Table 1.