Moreover, the severity of fatigue and depressive symptoms was significantly linked to a deterioration in quality of life. Conclusions: Ferritin deficiency in MS patients is associated with an exacerbation of depressive disorders and a decline in quality of life. Symptoms of fatigue in MS patients are inversely proportional to mood and quality of life.Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin for which there is currently no available cure. In the course of MS, next to neurological disorders, patients often present with chronic fatigue syndrome and depressive disorders, which impact on their daily function and quality of life. The aim of study was to analyse the relationship between serum parameters of iron metabolism and the severity of fatigue, depressive symptoms, and quality of life in MS patients. Methods: The study sample consisted of 90 people with a diagnosis of multiple sclerosis, age range 19–67 years, whose functional status evaluated using the Expanded Disability Status Scale in 90% of the participants did not exceed 3.5 points. Venous blood samples were collected for blood cell count determination and for the purposes of obtaining serum analysed for the concentrations of iron, ferritin, transferrin, transferrin saturation, unsaturated iron binding capacity (UIBC), and total iron binding capacity (TIBC). The participants were also evaluated according to the Fatigue Severity Scale, Beck Depression Inventory, and Functional Assessment of Multiple Sclerosis. Results: Ferritin levels were significantly correlated with the severity of depressive symptoms (r = −0.22;  Multiple sclerosis  is a chronic inflammatory disease of autoimmune origin for which there is currently no available cure. It affects the central nervous system, with multiple focal demyelinating lesions forming over time in the brain and the spinal cord . FatigueThe aim of this study was to analyse the relationship between serum parameters of iron metabolism and the severity of fatigue, depressive symptoms, and quality of life in multiple sclerosis patients.The material used in this study was collected from April to July 2018 at John Paul II Multiple Sclerosis Rehabilitation Centre in Borne Sulinowo, MSWiA Central Teaching Hospital in Warsaw, and the Tomasz Sokołowski Teaching Hospital of the Pomeranian Medical University in Szczecin.Research schedule and research procedures,Voluntary participation in the study and the possibility of resigning from further participation at any time of its duration, or not consenting to the use of their results in scientific works,Anonymity of results that will be used only for scientific purposes.Each of the volunteers qualified to participate in the study was informed in detail about:All participants signed a written informed consent form, and the study was conducted in accordance with the Helsinki Declaration. The protocol was approved by the Bioethics Committee of the Pomeranian Medical University (KB-0012/34/15).Inclusion criteria: Age ≥18 years, diagnosed by a neurologist with multiple sclerosis, functional status assessed on the EDSS scale by a neurologist at <6 points, and no iron supplementation. People who declared iron supplementation and whose functional state did not allow for independent walking  were not included in the study. Women who were in the perimenstrual period on the day of the study were also not included in the research.The study group consisted of 90 people (62 women and 28 men) with a diagnosis of multiple sclerosis, aged 19–67 years. The average duration of disease in the study group was 8.22 (6.21),  years. On average, the women had had the condition for one year longer than the men. Among both women and men, the time since the diagnosis fell in the range of 3–12 years (Me = 7 years for women and 6 years for men). A substantial majority of participants (78%) had the relapsing-remitting form of multiple sclerosis (RRMS) (48 women and 22 men). The secondary-progressive type (SPMS) was found in 14 people (8 women and 6 men), and the primary-progressive type (PPMS) affected only 6 women and not a single man. On the Expanded Disability Status Scale (EDSS), the participants’ median score was 3 points. More than 90% of the participants (57 women and 26 men) scored no more than 3.5 points.In the course of the study, on an empty stomach after a 15-min rest, a single venous blood sample was collected from the antecubital vein in each person, for the purposes of blood cell count determination (8% K3 EDTA solution) and obtaining serum (tubes coated with coagulation activator) using the VACUETTE evacuated blood collection system. The following parameters were determined in blood serum: Iron concentration [µg/dL], UIBC (unsaturated iron binding capacity) [µg/dL], TIBC  [µg/dL], transferrin saturation [%], transferrin [mg/dL], and ferritin [μg/L].Data on chronic fatigue syndrome, depressive symptoms, and quality of life were collected using the diagnostic survey method, with appropriate standardized questionnaire surveys.The severity of fatigue was evaluated using the Fatigue Severity Scale (FSS), which is currently one of the most frequently used inventories for measuring fatigue. The scale contains nine simple statements concerning one’s functioning over the past week, and the patients are asked to rate each one on a scale from 1—“strongly disagree” to 7—“strongly agree”. The statements included in the questionnaire cover the effects of fatigue on various aspects of daily living, related to both mental and physical functioning. The final score is the arithmetic mean of the points scored in individual items. The following classification was adopted in the interpretation of the scores: No fatigue (FSS ≤ 4.0 pts), borderline fatigue (4.0 pts < FSS < 5.0 pts), and fatigue (FSS ≥ 5.0 pts) ,25. CronThe intensity of depression was evaluated using the Beck Depression Inventory (BDI-II), which is designed to measure the severity of depressive symptoms, especially to detect depression in screening studies of larger populations, but it may also be used for assessing the progression of depressive disorders and measuring response in the course of treatment. The majority of symptoms included in BDI-II reflect the diagnostic criteria for depression according to the DSM-IV. The inventory contains 21 items representative of individual symptoms of depression, the severity of which is rated on a 4-point scale. The total score is the sum of points scored for all 21 symptoms. The highest possible score is 63 points. A score of 0–9 points is categorised as no depression, 10–19 points is mild depression, 20–25 points is moderate depression, and 26–63 points is severe depression . CronbacQuality of life was evaluated with reference to the Functional Assessment of Multiple Sclerosis (FAMS). The instrument consists of 59 questions, divided into the principal test (44 items) and miscellaneous items evaluating “additional concerns” (15 items). Questions from the principal test, based on factor analysis, have been divided into six subscales, evaluating: Mobility (7 questions), symptoms related to MS progression and treatment (7 questions), emotional status related to the patient’s mood and feelings (7 questions), contentment in everyday life (7 questions), quality of cognitive function, referred to generally as thinking and fatigue (9 questions), and family and social well-being (7 questions). The other 15 questions referring to “additional concerns” evaluate items like sexual well-being and side effects of MS treatment, and are not included in the overall score . The totAll the surveys were self-administered by the respondents, completed at their own pace, on the on the same day when the blood was collected. If the respondent had any problems understanding a given question or statement included in any survey instruments, they had an opportunity to ask for clarification.p < 0.05.Statistical analysis was performed with STATISTICA computer software . Elements of descriptive statistics and statistical inference were employed. Data distribution was tested for normality using the Shapiro–Wilk test. The significance of differences between groups in terms of selected variables was evaluated using tests for independent samples. With normally distributed data, Student’s t-test was used. In turn, differences between data following a non-normal distribution were tested for significance using the non-parametric Mann–Whitney U test. Correlations between variables with a non-normal distribution were identified using a non-parametric test, namely Spearman’s rank correlation coefficient (rho). The statistical significance level was set at p = 0.02) and transferrin (p = 0.04)  ..A general analysis of the median scores in the FSS questionnaire, with reference to the adopted cut off points, suggests that the severity of fatigue symptoms among the participants does not warrant a diagnosis of chronic fatigue syndrome. Both men and women had scores in a similar range (1–7 points), but the median in both groups was <4 points. Looking at the results in more detail, out of all the participants, 24 people (18 women and 6 men) showed symptoms of fatigue, with FSS scores >5 points. Moreover, 16 people (10 women and 6 men) had scores indicative of borderline fatigue. However, more than half of the participants (34 women and 16 men) were not found to display particularly severe symptoms of fatigue, which could justify a diagnosis of chronic fatigue syndrome (FSS ≤ 4 points) .p = 0.07)  points for all participants, and 7.64 (8.44) points for men. The mean BDI-II scores in the women’s group may be interpreted as indicative of mild depression,10.23 (9.13) points. However, with such a high dispersion of scores, it is advisable to consider the median scores, which both for the group as a whole, and in gender-specific groups, were in the points range suggesting the absence of depression. The differences in the number of points scored by men and women were not statistically significant ( = 0.07) .p = 0.04), suggesting that the quality of life assessment among women was moderate (111 points), and good in men (124 points). The participants’ scores in the respective FAMS subscales were similar and for the most part did not point to gender-specific differences. The scores in the “thinking and fatigue” domain were an exception here, with women’s scores (Me = 19 points) significantly lower than men’s (Me = 24.5 points). Likewise, differences were also observed in the analysis of “additional concerns”, but these are not included in the overall score . Statistically significant differences were observed between the FAMS scores for men and women (ll score .p = 0.04) and quality of life assessment  in the patients. A significant positive correlation was found for the intensity of depressive symptoms vs. the degree of disability and severity of symptoms of chronic fatigue syndrome. This suggests that in the study group, the exacerbation of fatigue symptoms and increasing disability was accompanied by a statistically significant increase in depressive symptoms (p < 0.001). Moreover, the findings show a significant negative correlation between BDI-II scores and FAMS results . It may therefore be concluded that the intensity of depressive symptoms was associated with quality of life impairment across all the domains included in the analysis. It was also observed that impaired mobility and increasing fatigue among the participants co-occurred with lower quality of life scores (p < 0.001). At the same time, the analysis of the results demonstrated that the level of disability did not have a significant effect on the prevalence of the chronic fatigue syndrome among the participants (p = 0.06)  . p = 0.02) and significantly negatively correlated with TIBC . In this study, increased ferritin concentrations were found in SPMS patients (Me = 123 µg/L) compared to RRMS patients (Me = 59 µg/L). However, due to the disproportionate numbers of patients representing the respective types of MS, it was difficult to carry out a robust analysis of the relationship between blood biochemical parameters and disease course. Consequently, this result should be regarded exclusively as an indication of a trend that should be verified in further research. In particular that in the literature, there are some reports of associations between the course of MS and ferritin content in the patients’ blood and/or cerebrospinal fluid. The values are significantly higher in patients suffering from chronic progressive MS compared to the RRMS group [The present study focused on the assessment of iron metabolism in 90 MS patients. The patients’ blood test results were compared to reference ranges adopted for the general population, taking into account age and gender. Despite sizeable individual differences, notably in transferrin saturation and iron levels, it may be concluded that the mean values for all the iron metabolism parameters included in the study fell within the normal range. Findings from this study did not confirm the relationship between iron metabolism parameters in serum and the duration of disease or degree of disability according to EDSS, however the participants’ age was found to be significantly positively correlated with ferritin  and were also found to have lower haemoglobin. The present findings lend themselves to the conclusion that elevated serum ferritin levels in MS patients have a positive effect on mood, showing a positive correlation with lower rates of depression , and at the same time better quality of life , especially in the domain of mental health. There is, however, evidence in the literature that depression is accompanied by alterations in iron metabolism, including decreased levels of iron and transferrin, as well as elevated levels of serum ferritin, reduced number of erythrocytes, and lower haematocrit and haemoglobin [It has been put forward that the key factors contributing to neurodegeneration in MS patients, apart from the activation of microglia, chronic oxidative damage, and mitochondrial alterations in axons, may also include iron accumulation in the human brain with age . Iron remoglobin ,43,44. Zmoglobin  publishemoglobin . Anothermoglobin . HoweverAnother objective of this study was to pinpoint the link between the levels of iron and iron-regulating parameters in the blood of MS patients vs. chronic fatigue, a symptom that appears to be an integral part of the disease. Due to the functions of iron in the body, it was assumed that its deficiency will increase fatigue severity. However, our findings did not confirm this hypothesis. No relationship was identified between the values of blood cell count and biochemical parameters vs. the severity of fatigue symptoms. Please note that the level of fatigue reported by the patients included in the study group was low, and their age range was wide, which may have had a modulating effect on the results. To our knowledge, in the available literature, there are no studies analysing correlations of this nature, suggesting a need for continued research with more numerous study samples, which would allow for a verification of the hypothesis underlying this study adjusted for age, duration of disease, degree of disability, and fatigue. There are valid reasons to undertake research in larger patient groups, taking significant symptoms of chronic fatigue syndrome as an inclusion criterion.The biggest limitation of our research is the lack of a control group of healthy people, but on the other hand, the study was aimed at presenting the relationship between blood biochemical results and the level of fatigue and depressive disorders in a group of patients with MS.Our studies mostly involved people without major symptoms of fatigue and depression, so we would like to continue our study, taking into account the severe chronic fatigue syndrome and depression as the inclusion criteria.Knowledge about the relationship between the values of the parameters of iron metabolism in the blood of MS patients and their mood and the intensity of fatigue may affect the possibility of their regulation and thus improve the quality of life of people with multiple sclerosis.Ferritin deficiency in multiple sclerosis patients is associated with an exacerbation of depressive disorders and a decline in quality of life. Symptoms of fatigue in MS patients are inversely proportional to mood and quality of life.


A good prediction model plays an important role in determining the progression to diabetic kidney disease. We aimed to create a model to predict progression to kidney failure in patients with diabetic kidney disease.We retrospectively assessed 641 patients with type 2 diabetic kidney disease as derivation cohort and 280 patients as external out time validation cohort. We used a combination of clinical guidance and univariate logistic regression to select the relevant variables. We calculated the discrimination and calibration of different models. The best model was selected according to the optimal combination of discrimination and calibration.p value of the Hosmer–Lemeshow, .817). There was no significant difference in NRI among laboratory model, lab-medication model, and full model (p > .05). So, we chose the laboratory model as the optimal model.During the 3 years follow up, there were 272 outcomes (42%) in derivation cohort and 138 outcomes (49%) in external validation cohort. The final variables selected in the multivariate logistics regression were age, gender, hemoglobin, NLR, serum cystatin C, eGFR, 24-h urine protein, and the use of oral hypoglycemic drugs. We developed four different models as clinical, laboratory, lab-medication, and full models according to these independent risk factors. Laboratory model performed well in both discrimination and calibration among all the models (C-statistics: external validation 0.863; We constructed a nomogram which contained hemoglobin, NLR, serum cystatin C, eGFR, and 24-h urine protein to predict the risk of patients with diabetic kidney disease initiating renal replacement in 3 years. Tangri et al. developed the kidney failure risk equation (KFRE) to identify a high-risk population of CKD 3-5 patients who are likely to developing ESRD based on demographic, clinical, and laboratory variables [c values . Howeverc values . It has c values . But thec values . HoweverTherefore, we aimed to develop and validate a model to predict the 3-year risk of progression to kidney failure that could be easily implemented in clinical practice, using the variables routinely measured in patients with DKD.2.2.1.In this population-based retrospective cohort study, patients with type 2 DKD who were hospitalized in the First Hospital Affiliated with Zhengzhou University were screened. A total of 641 patients who were hospitalized from December 2012 to December 2015 were enrolled as derivation cohort, while 280 patients hospitalized from January 2016 to December 2017 were enrolled as external out time validation cohort. The DKD diagnosis was based on the guidelines created by the Kidney Disease: Improving Global Outcomes [2.2.Clinical characteristics, including age, sex, duration of diabetes mellitus (DM), systolic blood pressure, diastolic blood pressure, the main medical history of hypertension, coronary heart disease and cancer, body mass index (BMI) and the use as the drugs such as the oral hypoglycemic drugs, insulin, renin-angiotensin system blocker, and statin were collected. Laboratory parameters, including hemoglobin, neutrophil: lymphocyte ratio (NLR), serum creatinine level, serum urea level, serum uric acid level, serum total protein level, serum albumin level, serum calcium level, total cholesterol level, triglyceride level, serum cystatin C level, serum β 2 microglobulin level, glycated hemoglobin (HbA1c) level, blood glucose level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), estimated glomerular filtration rate , 24-h urine protein level, bicarbonate level and the PH value of urine were initially collected at the time of diagnosis with DKD.2.3.The primary endpoint was kidney failure, as defined by the initiation of dialysis and renal transplantation.2.4.SD) or medians  to express the continuous data, while the categorical data are expressed as the absolute values and percentages. Then, we used the univariate logistic regression to select the potential variables. Before the multiple logistic regression, we calculated the collinearity of the variables and remove the factors, serum urea level and serum creatine level, that exist in collinearity. Then, we used a combination of clinical guidance and univariate logistic regression with the enter method to select the relevant variables and conduct multiple logistic regression. The clinical characteristics, including age, sex and the use of oral hypoglycemic drugs, and the statistically significant biochemical measures, including the hemoglobin level, NLR, serum cystatin C level, eGFR, and 24-h urine protein level, were selected to construct the sequential models. Next, the area under the receiver operating characteristic curve, which is referred to as the C-statistic, was used to assess the discriminatory ability of the models. The calibration was assessed by the Hosmer–Lemeshow (H-L) test and calibration curves. The goodness of fit of the models was evaluated by the Akaike information criterion (AIC). We divided all the derivation patients into five groups and selected one group as the internal validation cohort and the other four groups as the training cohort. We used the training cohort to develop the models and the internal validation cohort to validate the models. We repeated the process 5 times to assess the discriminatory ability and calibration of the models. The C-statistic, the AIC, and the p value of the Hosmer–Lemeshow (H-L) test shown were the averages of 5 repetitions, and the detailed values for each individuals repetition are displayed in the Supplementary Materials. The best model was selected according to the optimal combination of the discrimination and calibration calculated by the fivefold crossvalidation and external validation which is ‘Bootstrapping’. The net reclassification improvement and integrated discrimination improvement of models were also used to evaluate the discriminatory ability of the models. Last, we constructed a nomogram to predict the risk of a patient with DKD initiating renal replacement in 3 years. All analyses involved in the development and validation of the model were conducted with R software, version 3.5.3 .There were some missing data in several variables. Variables that indicated the renal function, such as serum creatine, serum urea, serum cystatin C, serum β2 microglobulin, and serum uric acid, had 3.9% missing values. There were 2.9% missing data in hemoglobin and NLR and 6.1% in serum total protein and serum albumin. The 24-h urine protein had 3.1% missing values and CRP and ESR had 8.4% missing data. We used multivariate multiple imputation with chained equations to impute missing values to maximize the statistical power and diminish bias . First, 3.3.1.The baseline clinical characteristics and laboratory parameters of the derivation cohort and external validation cohort are shown in 3.2.p value of univariate logistic regression were shown in p < .001), higher β2 microglobulin levels , higher 24-h urine protein levels  and higher NLRs  had a higher risk of undergoing renal replacement. In addition, patients who had higher serum calcium levels  and higher serum albumin levels  had a lower risk of renal replacement. There are also other indicators that are statistically significant in univariate analysis (p < .05). We conducted the collinear analysis in p, .007), gender , hemoglobin , NLR , serum cystatin C , eGFR , 24-h urine protein  and the use of oral hypoglycemic drugs  test, and calibration curves were used to depict the discriminatory ability and calibration of the models. A higher C-statistic reflected a good discriminatory ability, while a p value of the Hosmer–Lemeshow (H-L) test close to 1 and a relatively lower AIC suggested that the predicted probability was not significantly different from the observed probability in the models. Clinical model, including age, gender and the use of oral hypoglycemic drugs only, performed poorly in both the training cohort  and the validation cohort . The remaining three models, laboratory model, lab-medication model, and full model, had similar C statistics in both internal and external validation  improvement in full model compared with laboratory model, while the NRI of the two model was not statistically significant . The IDI between the comparison of full model and lab-medication model showed a 1.4%  improvement, but NRI was not significant .To further evaluate the discriminatory ability of the models, we considered the following categories of the risk kidney failure within 3 years: 0% to 24.9% was low, 25.0% to 74.9% was intermediate, and 75.0% or more was high. The cutoff values used to calculate the net reclassification were 25% and 75%. The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) of laboratory, lab-medication, and full models were shown in 3.5.2), higher serum cystatin C level (2.1 mg/L), lower NLR (2.83), and very high urine protein level (7.8 g/d) would have a total of 186 points, indicating a predicted 3-year probability of the onset of renal replacement of 58.6%.Based on the above analysis, laboratory model performed well in terms of both discrimination and calibration. Therefore, we regarded laboratory model, which contained hemoglobin, NLR, serum cystatin C, eGFR, 24-h urine protein as the optimal model. The nomogram to predict the probability of DKD initiating renal replacement in 3 years is shown in 4.p = .817. Our study demonstrated that lower eGFR, higher cystatin C levels, lower hemoglobin, higher NLR level and higher 24-h urine protein significantly increased the risk of renal replacement therapy in patients with DKD.We have developed and validated a set of risk prediction models using laboratory data that are obtained routinely in patients with DKD and could be easily integrated into a laboratory information system to predict the progression to kidney failure among patients with DKD. The laboratory model behaved good performance among the sequential models. The C-statistic for laboratory model was 0.986 in the training cohort, 0.983 in the internal validation cohort and 0.863 in the external validation cohort, showing good discriminatory performance, and the calibration was good, with K-fold crossvalidation is one of the most commonly used methods of evaluating the predictive performances of a model [K-fold crossvalidation, (K − 1) fold is allocated to model development, and the residual fold is adopted for the model validation. Jung suggested the nearest integer value of log(n) as a rule for choosing K [ a model . In K-fooosing K , while Zoosing K . ConsequIn recent decades, risk prediction has gained increasing attention, and several prediction models have been developed to predict CKD in the general population ,11,16–18Proteinuria is a strong prognostic factor for the progression of DKD to kidney failure. In some studies, proteinuria was demonstrated to be a predictor of kidney failure ,11,19. SCystatin C, a cysteine protease inhibitor, has been demonstrated to be an early renal marker in diabetic patients . Our stuIn patients with DKD, the NLR was demonstrated to be associated with the 24-h urine protein level and albumin excretion in 80 Turkish patients with newly diagnosed type 2 diabetes . WheelocHowever, a number of limitations of this study should be considered. DKD was mostly clinically diagnosed from the presence of macroalbuminuria and renal impairment in patients with diabetes. Therefore, there might be other types of kidney disease that were included. It is possible that adding pathological information may have improved the predictive ability of the models. In addition, our study population was limited to Chinese patients with type 2 diabetes and advanced CKD, so our findings may not be widely generalizable. What’s more, the time of follow-up is short. A long term prospective cohort study of multicenter is required in future.Future studies into the prognostication of DKD should aim to optimize the inclusion criteria and stratify renal function to improve the precision of the prediction model. External validation through multicenter studies is also necessary.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted, and were approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2018-KY-82) and conform to the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Participant consent was waived because of the retrospective nature of the study and the anonymous nature of clinical data.Click here for additional data file.


Background and Objective: Cerebral microdialysis (CMD) enables monitoring brain tissue metabolism and risk factors for secondary brain injury such as an imbalance of consumption, altered utilization, and delivery of oxygen and glucose, frequently present following spontaneous intracerebral hemorrhage (SICH). The aim of this study was to evaluate the relationship between lactate/pyruvate ratio (LPR) with hemodynamic variables  and metabolic variables , within the cerebral peri-hemorrhagic region, with the hypothesis that there may be an association between these variables, leading to a worsening of outcome in comatose SICH patients.Methods: This is an international multicenter cohort study regarding a retrospective dataset analysis of non-consecutive comatose patients with supratentorial SICH undergoing invasive multimodality neuromonitoring admitted to neurocritical care units pertaining to three different centers. Patients with SICH were included if they had an indication for invasive ICP and CMD monitoring, were >18 years of age, and had a Glasgow Coma Scale (GCS) score of ≤8.Results: Twenty-two patients were included in the analysis. A total monitoring time of 1,558 h was analyzed, with a mean (SD) monitoring time of 70.72 h (66.25) per patient. Moreover, 21 out of the 22 patients (95%) had disturbed cerebrovascular autoregulation during the observation period. When considering a dichotomized LPR for a threshold level of 25 or 40, there was a statistically significant difference in all the measured variables , but not glycerol. When dichotomized PRx was considered as the dependent variable, only LPR was related to autoregulation. A lower PRx was associated with a higher survival .Conclusions: According to our results, disturbed autoregulation in comatose SICH patients is common. It is correlated to deranged metabolites within the peri-hemorrhagic region of the clot and is also associated with poor outcome. Spontaneous intracerebral hemorrhage (SICH) accounts for almost 15% of all strokes worldwide, with the incidence rates of primary SICH in low- and middle-income countries being twice the rates compared to high-income countries  in 2000–2008, and with case fatality rates of 30–48% in low- to middle-income countries and 25–30% in high-income countries . MonitorCMD, first introduced in 1966, aids clinicians in better understanding brain tissue metabolism in intensive care settings , 8. In pControl of hemodynamic variables after SICH is in fact paramount in avoiding secondary brain injury. There is consensus regarding the fact that the initial dimension and growth of the hematoma can cause both primary and secondary tissue damage. The latter may be the consequence of a series of complications such as ischemia, brain edema, development of apoptotic processes, and toxic effects due to the degraded components of hemoglobin and complement activation . AdditioBased on the above-mentioned hypothesis, this study sought to evaluate the association between LPR and the hemodynamic  and metabolic variables  within the peri-hemorrhagic penumbra region of the blood clot in comatose patients with SICH. Moreover, it explored the association of metabolic and hemodynamic variables with outcome.This was a multicenter cohort study regarding a retrospective dataset analysis of non-consecutive comatose patients who underwent multimodal monitoring following SICH. The study took place between April 2014 and June 2017 within three neurocritical care units: Spedali Civili University Hospital of Brescia, Columbia University New York Presbyterian Hospital Medical Center of New York, and the CHUV-Lausanne University Hospital and University of Lausanne, Switzerland. Patients were included if they: (1) had a diagnosis of SICH; (2) had an indication for invasive ICP and CMD monitoring; (2) were comatose with a Glasgow Coma Scale (GCS) score of ≤8 at enrollment; and (3) were >18 years old.Patients were excluded if there were any contraindications for invasive intracranial catheter placement , moribund patients, and age <18 years.This study was conducted in accordance with the Declaration of Helsinki and approved by the Brescia Ethics Committee. In Brescia, patients' informed consent was waived due to the fact that the Italian legislation lacks a clear definition of what is considered a legal representative of temporarily incapacitated adult patients . InformeThe STROBE  guidelines were followed for reporting the results of this cohort study .All patients were intubated and mechanically ventilated during the entire monitoring period, and arterial blood gas samples were obtained every 2 h in order to maintain a target range of end-tidal carbon dioxide [etCO2] between 35 and 45 mmHg. Intravenous midazolam or propofol and fentanyl were used for analgo-sedation, and, if required, a muscle relaxant was added. Therapy was aimed at maintaining systolic arterial blood pressure (SABP) between 140 and 160 mmHg and a mean MABP <130 mmHg according to current guidelines . For all three centers, the decision to apply the multimodality monitoring [invasive ICP and microdialysis (MD)] was made based on an individual case decision, according to the neurosurgeon, and on intensive discussion. Intracranial pressure monitoring was performed either by means of an intraparenchymal fiber-optic transducer  or through catheter insertion into the brain ventricles and connected to an external pressure transducer and drainage system .The MD catheters  were implanted either through tunneling or following burr hole and bolt insertion and were positioned within the brain tissue surrounding the clot, corresponding to the metabolic/ischemic penumbra. To ensure correct placement of the probes within the peri-hematomal region, a brain CT scan was performed following CMD catheter placement. The catheters were perfused with artificial cerebrospinal fluid at a rate of 0.3 μL/min and the samples were collected in microvials for analysis at 1- to 2-h intervals immediately after collection. The samples were analyzed for glucose, pyruvate, lactate, glutamate, and glycerol using the ISCUS Clinical Microdialysis Analyzer . The first sample obtained following catheter placement was discarded since the measurements may have been altered by tissue trauma induced by the catheter insertion itself.®, Cambridge Enterprise, UK) running on bedside laptop computers. Simultaneous recordings of analog signals from the ICP and ABP signals were digitalized with an analog-to-digital converter, sampled (sampling at 50 Hz) and averaged every 5 s. Artifacts were manually detected and removed. In the Brescia and New York centers, CA assessment was measured continuously through the calculation of the PRx every 60 s as a Pearson's correlation coefficient between 30 consecutive samples of the mean arterial pressure and ICP and was evaluated as a variable index, changing in time along with ICP, CPP, and arterial pressure, as described by Smielewski et al.  score and mortality at 6 months, obtained retrospectively.The data derived from the CMD analyzer were visualized through the LAB Pilot software . For each patient, the consecutive values of pyruvate, lactate, glycerol, glutamate, and glucose were gathered and the LPR was derived. The data obtained were transferred to an Excel spreadsheet containing the registration of MAP, ICP, CPP, and PRx every minute. The hourly mean hemodynamic variables  were compared to the metabolic variables acquired every hour with CMD.We expressed continuous variables as mean  for the normally distributed variables or median  for the non-normally distributed variables. Qualitative variables were expressed as frequencies and percentages.To compare the different collected covariates between centers, a linear mixed-effects model (package lme4 in R) has been used to compare continuous variables in order to take into account the repeated patient measurements nested in each center, whereas ordered logistic regression for repeated measures was used to compare the GOS scores.Concerning the unadjusted analysis, LPR was firstly dichotomized into normal and abnormal values (cutoffs of 25 and 40), as well as PRx , and a generalized mixed-effects model with a single variable was used including both CMD and the hemodynamic covariates. Alternatively, the dichotomized LPR and PRx were considered as dependent variables and each CMD and hemodynamic covariate as independent variables, and patients were considered nested in the center as a random effect (package nlme).p-values for fixed effect were obtained through Satterthwaite's method (lmerTest package).Lme4 R package was used to perform an adjusted analysis using a linear mixed-effects model of the relationship between LPR and MD and CA variables, adjusted for age and admission GCS . An emptFor patients' outcomes , we first dichotomized GOS into unfavorable (GOS ≤ 3) and favorable (GOS > 3). In order to see whether there were any differences in the hemodynamic or CMD covariates, we ran an unadjusted analysis using a linear mixed model. The dichotomized GOS or mortality was used as a fixed effect, each of the hemodynamic or CMD covariates as dependent variables, and patients nested in the center as random effects. Verification of the results was performed with ANOVA for repeated measures with the function aov in R.The multimodal monitoring data were obtained from a total monitoring time of 1,558 h, with a mean (SD) monitoring time of 70.72 h (66.25 h) per patient. There were a total of 1,901 readings and an average of 79 readings per patient.Patients' characteristics are represented in 2 = 517.51, p < 0.0001. The correlation between PRx and LPR showed a significant variance in the intercepts across patients , and visual inspection of the residual plots did not reveal any obvious deviation from homoscedasticity or normality. Worth noting is that, although the LPR difference between PRx <0.2 and >0.2 is statistically significant [33.33 (16.56) vs. 33.08 (19.74)], it is minimal and, therefore, may suggest that the PRx threshold chosen may not be the most clinically relevant in this population.When considering a dichotomized LPR (25 or 40), except for glycerol, there was a statistically significant difference in all the measured variables PRx, glucose, and glutamate . When dip = 0.03). Surviving patients had lower glycerol values, whereas the glucose level and the mean ABP (both higher in surviving patients) were at the limit of significance  and to the glucose and glutamate levels. Patients who survived had a statistically significant lower PRx, spent less time with an altered PRx, and had lower glycerol and higher glucose values. Those who died had a higher LPR, higher ICP, and lower MABP values, although not statistically significant .For spontaneous intracerebral hemorrhage (ICH), there are only limited data available on dynamic autoregulation and CPP management, and so far, there are no data regarding autoregulation-based CPP management , 19. The2), which possibly would have provided further insight toward the understanding of the various interactions between the metabolic and hemodynamic variables. The results from one study where the ICH patients were monitored with both PbO2 and CMD suggest that this type of monitoring can demonstrate local derangements in the peri-hematoma cavity that are not reflected in global indices such as the PRx  patients, but has not been extensively validated in patients with ICH .Only the MABP was available for all three centers and not the SABP. However, MABP was fundamental in order to calculate PRx.Finally, GOS was collected by chart review following telephone interview, therefore representing a retrospective collection of outcome.Although accompanied by its limitations, this study helps set the base from which future large prospective trials may be designed, powered in order to confirm the results obtained. If so, multimodality monitoring which includes the measurement of metabolites and their correlation with CA would represent an important adjunct in avoiding secondary brain injury and help improve the outcomes in patients with SICH.With its limitations, this study demonstrates that disturbed CA in comatose SICH patients is frequent and is associated with deranged cerebral intraparenchymal metabolites. Moreover, a trend toward worse outcomes in patients with altered PRx was observed in our study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Spedali Civili Comitato Etico. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.FR, NL, SPi, and SPa contributed to the study conception and design. FR, NL, SPi, SPa, IM, LG, MO, MM, DC, CR, and FT performed the data analysis and interpretation. FR, SPa IM, LG, and MO enrolled the patients for each corresponding study center. FR, NL, SPi, SPa, MO, MM, DC, CR, and FT revised the manuscript for important intellectual content. FR and NL gave final approval of the version to be published. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version.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.


The heart rate (HR) increased during αCGRP infusion (p < 0.001). In addition, we found a positive relationship between Et-CO2 and vm MCA (p = 0.001) as well as vm PCA (p = 0.043). In our view, αCGRP induces changes in cerebral and systemic circulation in healthy volunteers. It might cause vasodilatation of MCA and PCA and a compensatory decrease of Et-CO2 to αCGRP related hemodynamic changes.It is known that perivascular application of CGRP induces cerebral vasodilatation. However, it is unclear whether intravenous alfa CGRP (αCGRP) induces changes in cerebral and systemic hemodynamics. Therefore, we studied the influence of an αCGRP intravenous infusion at a rate of 1.5 mcg/min in 20 min on mean arterial velocity in the middle cerebral artery (vm MCA) and in the posterior cerebral artery (vm PCA) in twenty healthy subjects using transcranial Doppler (TCD). We found out that αCGRP decreased vm MCA ( Calcitonin gene-related peptide (CGRP) has been proven to play an important role in migraine and it has therefore become a target molecule in headache migraine research and treatment –5. ThereRecently, it has been shown that patients with an excellent response to erenumab are highly susceptible to αCGRP provocation . Therefo2 concentration in exhaled air (Et-CO2) during intravenous αCGRP infusion was observed. The Et-CO2 significantly decreased during αCGRP application, but not when volunteers were treated with a placebo  dilatation and none on the response of the posterior cerebral artery (PCA) on CGRP. It has been shown that endothelium of anterior and posterior cerebral circulation could differ in function . Regardi placebo , 8. Howep = 0.66). The inclusion criteria were age more than 18 years, normal somatic and neurological status, normal laboratory tests , and no atherosclerotic process of the carotid and vertebral arteries excluded by color-coded duplex sonography. The exclusion criteria were migraine and other primary headache disorders, previous cerebrovascular, endocrine, renal or liver diseases, uncontrolled hypertension, daily intake of medication except for contraceptives, pregnancy and breast-feeding.Twenty healthy subjects participated in our study  using the standard protocol. The capnograph was connected to a breathing mask and to the computer. Et-CO2 signals were recorded on the same time scale as other variables. This enabled us to compare the signals and perform correlations between them.The experiments took place at 9:00 am in a quiet and dark room with constant temperature. During the experiment, the participants were resting in the supine position. Transcranial Doppler (TCD) sonography with 2 MHz ultrasound probes was applied to measure the mean flow velocity in MCA (vm MCA) through the left and mean flow velocity in PCA (vm PCA) through the right temporal acoustic window. The signals of the arteries were defined according to the direction of the blood flow, the typical depth of the signal and the response to compression. A mechanical probe holder was used to ensure a constant probe position. During the entire experiment the mean blood pressure (MAP) and heart rate (HR) were continuously measured using non-invasive plethysmography . The Et-CO2) during 5 min intervals. The first interval - point 0 was during the baseline period before starting αCGRP infusion (5–10 min of the experiment). The second interval - point 1 was 5–10 min after the start of αCGRP infusion (15–20 min of the experiment). The third interval - point 2 was 15–20 min after the start of αCGRP infusion (25–30 min of the experiment). The last interval - point 3 was 5–10 min after the end αCGRP infusion (35–40 min of the experiment). The mean vm MCA and vm PCA was calculated for each 5 min interval using the following equation vm∫= vdt/(t0–t5). The mean values of other variables  were also calculated for the same time intervals as the flow velocity using TCD software.The experiment consisted of a 10 min baseline period, a 20 min period during which an intravenous infusion of αCGRP 1.5 mcg/min  was given and a 10 min period after the end of the αCGRP infusion. TCD Multi-Dop X4 software  was used to define average values of all parameters  of differences between chosen points are shown in First, we analyzed the vm MCA, vm PCA, MAP, HR, and Et-COThe vm MCA showed a significant decrease in all points except between points 1–3 and 2–3 because of a slight increase of the signal at the recovery phase, after the end of the αCGRP infusion. The decrease of vm MCA was steady between points 1 and 2. The minimum value of vm MCA was measured at the point 2. The vm PCA changed in a similar way during the αCGRP infusion, except for vm PCA decreasing between points 1 and 3, which appeared to be significant in vm PCA but not in vm MCA .The MAP decreased during the αCGRP infusion and increased after it. The decrease was significant between measuring points 0 and 2, i.e., at the time of the CGRP infusion. The trends between points 0–1 and 1–2 were not significant. However, we observed a significant response of MAP between the points 1–3 and 2–3. There was no difference between points 0 and 3, which showed similar values for the MAP signal before and after the 10 min after the end of the αCGRP infusion . HR sign2 associated with the αCGRP infusion. The signal showed a remarkable and significant decrease during the αCGRP infusion between points 0–2 and 1–2. After the end of the infusion, there was no significant change of Et-CO2, which is between points 2 and 3 . However, we found that during the αCGRP infusion, vm in MCA and PCA decreased. In addition, we found a highly positive correlation between vm MCA and vm PCA. Accordingly, the relationship between cerebral blood flow and arterial cross-sectional area also decreased. This could be due to proximal arterial vasodilatation or a decrease in CBF. In healthy volunteers, αCGRP increased global and regional CBF , but in in vitro and in vivo research in animal and human studies that provide evidence that CGRP is a potent vasodilator and has greater potency compared to prostaglandin, acetylcholine and substance P (133Xe SPECT at the baseline condition and after 15 min of the αCGRP infusion and it did not change during the αCGRP infusion. Petersen et al. in a study comparing efficacy of the CGRP receptor antagonist, BIBN4096BS, and a placebo in healthy volunteers, also found MCA dilatation caused by αCGRP infusion. In fact, their study was not set up to rule out αCGRP effects on MCA; however, the global CBF, rCBF and vm MCA was measured during and after the αCGRP infusion at a rate of 1.5 mcg/min for 20 min. The vm MCA was constant during the αCGRP infusion, but the global CBF and the rCBF increased after αCGRP administration. They calculated the relative percentage change of diameter of MCA and estimated that αCGRP increased the MCA diameter (Our assumption is supported by results of extensive stance P . CGRP prstance P . Our resstance P , 8. LassOn the other hand, the study by Asghar did not show any change in the MCA circumference during an αCGRP infusion . In thisin vitro in humans revealed that perivascular application of αCGRP induces dilatation of cerebral arteries (2 to CGRP in a patient with migraine.At present, the mechanism of the αCGRP vasodilatation effect is only partly understood. Earlier studies in animals and arteries . Howeverarteries . These farteries –9. Furtharteries . The resarteries . TherefoThe next important finding of our study is that intravenous infusion of αCGRP at a rate of 1.5 mcg/min for 20 min significantly decreases MAP. The maximal decrease of MAP was at the end of the infusion. After that, a marked increase in MAP was observed. Changes in HR were also significant and in the opposite direction to the changes of MAP. The linear relationship between the variables was inconclusive. From this, we conclude that intravenous αCGRP decreases systemic blood pressure and causes an increase in HR, which is most probably due to cardiac output compensation of the decrease in MAP. Our results support the systemic effects of αCGRP in humans. In animal and human studies, intravenous administration of CGRP was associated with a decrease in systemic blood pressure and positive inotropic and chronotropic heart responses , 17. Fur2 during the αCGRP infusion decreased significantly and persistently even after the end of the αCGRP infusion. The Et-CO2 decrease was reported in migraine patients during αCGRP infusion but not when treated with a placebo. The peak decrease in Et-CO2 occurred 5 min after the end of the αCGRP infusion (2 decrease does not occur incidentally. We also found positive and significant relationships between Et-CO2 and vm MCA as well as Et-CO2 and vm PCA. According to current knowledge, vm in MCA and PCA largely depends on cerebral arterioles status. Thus, αCGRP provokes important vasodilation at the arterioles' levels with the consequent putative increases in vm MCA and vm PCA. On the other hand, vasodilation/constriction of arterioles by CO2 concentration strongly determinates vm MCA and vm PCA. This is a well-known phenomenon named vasomotor reactivity to hyper/hypocapnia and it is one of the main control mechanisms to ensure constant cerebral perfusion (2 changes or largely proximal, for example the response to nitro-glycerine, or it could be distal and proximal (2 during αCGRP stimulation tends to decrease CBF and consequently arterial velocities in MCA and PCA. The Et-CO2 decrease during the αCGRP stimulation could represent the compensation of an αCGRP-induced increase of cerebral blood flow in order to preserve intracranial pressure in the normal range. We could infer that Et-CO2 acts predominantly on distal resistant cerebral vessels, whereas αCGRP induces vasodilatation in proximal and distal parts of the cerebral arterial tree with a net decrease in arterial velocities in MCA and PCA. In other words, the relationship between blood flow and the cross-sectional area of the insonated artery decreased due to the vasodilatory properties of αCGRP on MCA and PCA. Moreover, we found significant negative relationships between Et-CO2 and MAP as well as Et-CO2 and HR. This could be explained by the common effect of αCGRP on Et-CO2, MAP and HR and not by causal relationships between the variables. Both Et-CO2 and HR seem to have a compensatory role in cerebral blood flow and systemic arterial pressure regulation, which have to be homeostatically preserved during an αCGRP infusion.The interesting finding of our study was also that the Et-COinfusion . It seemerfusion , 19. Thuproximal . Therefoin vivo demonstrated the vasodilatation of cerebral arteries, and the medial meningeal and superficial temporal artery after intravenous infusion of αCGRP. Our study supports the intravascular effects of αCGRP probably via intravascular endothelium. In our study, we showed the effects of CGRP on cerebral and systemic circulation. Therefore, the potential long-term safety issues of CGRP antagonists could be raised in patients with coronary artery and cerebrovascular diseases and could be involved in guideline statements (It is known that CGRP is derived predominantly from perivascular sensory neurons and the CGRP receptor complex was shown to be located on the smooth muscle cells of the cerebral vasculature. In addition, studies have shown that perivascular application of CGRP induced vasodilatation even after endothelial removal . The dilatements , 24.The strength of the present study is the accurate description of the effects of CGRP in healthy human subjects. The potential limitations of the study are the low number of subjects and the lack of a control group.2 decrease might have a compensatory role in preserving cerebral blood flow and intracranial pressure during CGRP stimulation. The αCGRP could be used as a marker for treatment efficacy of anti-CGRP monoclonal antibodies in migraine patients.In conclusion, we found out that an intravenous αCGRP infusion might induce vasodilatation of MCA and PCA. It produces systemic effects with a significant decrease of MAP. The Et-COThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The National Medical Ethics Committee of the Republic of Slovenia. The participants provided their written informed consent to participate in this study.BŽ, MZa, and DV contributed to conception and study design. DV organized database and managed experiments. MZa performed the statistical analyses and wrote the results section. DV wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A critical analysis of the surgical literature provides limited evidence to support this strategy.Insufflation pressures of or in excess of 25 mm Hg COTo determine whether high pressure (≥ 25 mm Hg) compared with lower pressure (< 25 mm Hg) retroperitoneoscopy reduces operating time and complications.A multi-centre retrospective cohort study was performed using data collected over a period of almost one decade (1st November 2008 until 1st February 2018) from surgical centres in Germany. A total of 1032 patients with benign adrenal tumours were identified. We compared patients undergoing PRA with insufflation pressures of < 25 mm Hg (G20 group) versus ≥ 25 mm Hg (G25 group). A propensity score matching analysis was performed using BMI, tumour size and surgeon's experience as independent variables. The main outcomes were (1) the incidence of perioperative complications and (2) the length of operating time.p = 0.335) and operation duration , did not significantly differ between the groups.The baseline patient characteristics were similar in both groups, with the exception of tumour size, BMI and surgeon's experience in PRA. After propensity score matching, perioperative outcomes, especially perioperative complications (3.7% vs. 5.5% in G20 and G25, respectively; Neither patient safety nor operative success was compromised when PRA was performed with insufflation pressures below 25 mm Hg. Prospective studies are required to determine whether an optimal insufflation pressure exists that maximizes patient safety and minimizes the risks of post-surgical complications. Nevertheless, our results call for a careful re-evaluation of the routine use of high insufflation pressures during PRA. In the absence of prospective data, commencing PRA with lower insufflation pressures, with the option of increasing insufflation pressures to counter intraoperative bleeding or exposition difficulties, may represent a reasonable strategy. Since0 mm Hg) . In fact0 mm Hg) , 8. Curr0 mm Hg) , 7, 8, 9Yet, a critical analysis of the literature provides limited evidence to support the use of high insufflation pressures, especially when the disadvantages  are considered , 10. AltFurthermore, clear evidence that high pressures improve the operative field (consequently reducing operation time) and reduce intra-/postoperative complications is limited.2 and end-tidal CO2 and reduced pH; an effect which was seen 30 min after starting the procedure. Unfortunately, the authors did not investigate whether these effects translated into adverse clinical consequences postoperatively. This is at least conceivable given that operating time for PRA usually exceeds 30 min. Therefore, we hypothesized that high retroperitoneoscopic insufflation pressures may negatively impact operation variables and the postoperative course.Recently, the randomized controlled trial by Frazer et al.  reportedfirst to describe a representative series of retroperitoneoscopic procedures performed to treat benign adrenal tumours;second to compare patient characteristics and perioperative outcomes in the following groups of patients: (a) high-pressure retroperitoneoscopy  vs. (b) lower pressure retroperitoneoscopy ;third to determine whether high-pressure (in comparison to low-pressure) retroperitoneoscopy may be linked to significant changes in perioperative outcomes (e.g. hypercapnia);fourth to clarify whether insufflation pressure during retroperitoneoscopy influences operation time and reduces the risk of intra- and/or postoperative bleeding.In a retrospective analysis of prospectively collected data from three university surgical centres in Germany, we aimed:2 insufflation pressures. Retroperitoneal insufflation pressures were defined and applied at the beginning of each procedure, based on surgeon's preference for a given indication or a given patient. The only indication for an increase in retroperitoneal pressure would have been a major intraoperative bleeding. The data of these patients were collected and analysed in an intention to treat analysis.This was a multi-centre retrospective cohort study. Our key aim was to compare perioperative outcomes in patients who underwent PRA for benign adrenal tumours  using low  versus high  COThe study was initiated in 2018, after obtaining an institutional ethics committee approval . The three study centres were located in Germany  and all have certified and extensive experience in both endocrine and minimally invasive surgery  . All cenPatients included in our study were diagnosed with benign adrenal tumours  and underwent PRA. Documented insufflation pressure used to create the retroperitoneoscopic space was mandatory for inclusion in the study. All centres defined a maximum tumour size for retroperitoneoscopic surgery of 6 cm. Follow-up for each patient began on the day of operation. Patients were excluded if (i) they did not complete a standard surgical follow-up of at least 30 days, (ii) they were diagnosed with a malignant adrenal tumour, (iii) there was insufficient documentation of the insufflation pressure which was used.The primary outcomes were: (1) any peri- and postoperative complications and (2) the operation duration. Surgical site infections, wound disruptions, seromas, postoperative bleeding, temporary or definitive hypocortisolism and recurrence were considered surgical complications. Conversion to transabdominal laparoscopy or open surgery were considered as secondary outcomes. Furthermore, we recorded the incidence of procedural interruptions requested by anaesthetists to correct hypercapnia. Pulmonary complications , renal conditions , stroke, cardiovascular conditions , thromboembolic conditions (pulmonary embolism or deep venous thrombosis), and infectious conditions  were considered medical complications.We gathered demographic, clinical, and perioperative  data for all patients included in this study. Data on operation duration, blood loss and perioperative complications , and taking account of the primary endpoints and operation duration,  a minimum sample size of 103 patients for each group  was necessary. In order to address bias linked with the retrospective observational design of our study , we performed a propensity score-matched analysis of collected data (see below).n (%). We did statistical comparisons of quantitative variables with Student's t test or Mann–Whitney test. For categorial variables, we used the Pearson's χ2 test or Fisher's exact test. All statistical tests were two-sided, and p values of less than 0.05 were considered statistically significant.All analyses were done using STATA 15 software . We summarized continuous variables as mean  and median . Categorial variables were registered as A propensity score-matched analysis was performed to minimize selection bias. Propensity scores were calculated using logistic regression. Retroperitoneal insufflation pressure (< 25 vs. ≥ 25 mm Hg) was entered in the regression model as a dependent variable and Age, Sex, BMI, Tumour Size, ASA score, surgeon's experience (< 42 or ≥ 42 procedures) as independent covariates. The cases were matched for their propensity scores using a matching ratio of 1:1, nearest neighbour matching protocol, with a caliper of 0.2. Cases were not reusable after matching.In the 3 participating academic medical centres in Germany, a total of 1.032 patients who underwent surgical treatment for adrenal tumours were identified. 253 patients underwent surgical procedures other than unilateral PRA and were therefore excluded from further analysis. In 174 of the remaining 779 patients there was insufficient data on the intraoperative insufflation pressure used to create a pneumo-retroperitoneum. These cases were also excluded from further analysis. 116 patients did not complete the required 30-day follow-up or had a malignant tumour diagnosed  and 301 (61.6%) had < 25 mm Hg pressure (G20). Both groups were statistically comparable for patient characteristics except for tumour size, surgeon's experience and BMI  had ≥ 25 mm Hg retroperitoneal COPerioperative characteristics, mortality and morbidity were analysed after propensity score matching of the included patients. No deaths were observed in the perioperative period and during the 30-day follow-up. The frequency of cortex-sparing surgery was not significantly different between both groups. Perioperative characteristics are summarized in Table Overall, 10 complications (4.6%) were observed. Perioperative complications were comparable in both groups.Our study convincingly demonstrates that perioperative complications  and mortality, as well as procedure duration are independent of the insufflation pressure used when comparing high (≥ 25 mm Hg) with low pressures (< 25 mm Hg).p = 0.673). This result stands in contradiction to the results of the majority of publications reporting the association between increased insufflation pressure and faster procedures [In our cohort (G20 and G25 together), the median overall operation duration of 47 min, is comparable with other series in the literature where operation time ranges from 51 to 157 min , 19–21. ocedures , where aocedures . Propensocedures . Based oOverall 10 complications (4.6%) were observed in our matched series, one patient having potentially more than one complication. The rate of complications is comparable to other series in the published literature. The groups did not significantly differ in terms of perioperative complications, with the exception of procedure interruption due to intraoperative hypercapnia, which is not a component of the Clavien–Dindo classification. Thus, PRA for benign tumours of the adrenal gland performed under low pressure (< 25 mm Hg) had a safety profile similar to that carried out under high insufflation pressure (≥ 25 mm Hg and above). Subcutaneous emphysema was not systematically recorded in the present series. Thus, we cannot make any comparison between low- versus high-pressure retroperitoneal insufflation. As this emphysema usually resolves within hours of the procedure, we might suppose it does not have a major impact on patient wellbeing or satisfaction.Another intraoperative complication was an unintended pneumoperitoneum during the retroperitoneal procedure. Although this complication was not systematically registered, procedure records did not describe major problems in the completion of the retroperitoneal dissection. Due to the lack of uniformity in retrospective evaluation of its consequences among groups, we were not able to quantify any difference between high- versus low-pressure insufflation with regard to this specific complication. Moreover, we did not register any conversion to open surgery in this matched series.2 retropneumoperitoneum (e.g. ventilatory and metabolic effects) have seldom been systematically investigated [2 insufflation pressures of 12 to 16 mm Hg [. Comparison between CO2 insufflation pressures of 15 and 20 mm Hg showed a statistical but not clinically relevant difference in PaCO2 [Whereas the effects of pneumoperitoneum on ventilatory and metabolic parameters have been well documented and are now well appreciated, the physiological effects of the COstigated , 23, 24.16 mm Hg , not comin PaCO2 . As mostp = 0.455). As the present study was not designed to investigate postoperative consequences of intraoperative hypercapnia, we are not able to definitively draw any conclusions about this effect, which warrants examination in future studies. The prospective randomized study by Frazer et al. demonstrated a direct relationship between retroperitoneal CO2 insufflation pressure, hypercapnia and acidosis [2 , end-tidal CO2  and a lesser pH , results which contradict previous investigations [2 insufflation pressures. However, demonstration of this intraoperative phenomenon in large clinical case series is still lacking. In order to detect significant clinical differences in patient outcome, recovery and complication when using high CO2 pressures and in order to contravene a one-sided assessment of the problem, large sample size is needed. Finally, we concur with Frazer's recommended strategy of start the PRA procedure with lower CO2 insufflation pressures in order to decrease intraoperative PaCO2 and acidosis, and to increase only if the surgeon experiences bleeding or exposition difficulties. Patients with greater comorbidities may require an even stricter control of PaCO2 and pH [2 is therefore essential, as an important part of this procedure [2 insufflation pressures and the associated hypercapnic acidosis. Although we did not design our study to detect any clinically apparent effect of hypercapnia on physiologic outcomes, it is worth noting that clinically important outcomes of these changes may certainly occur.Although postoperative complications did not differ among groups in our analysis, the operative procedure had to be temporarily interrupted due to hypercapnia in 2.8% of cases in G25 and 0.9% of cases in G20  was comparable with previous published series , 26–29. Consistent with the length of hospital stay in published case series , 28, 30,The main limitation is that this study was a retrospective analysis. In addition,retroperitoneal insufflation pressures were documented at the beginning of each procedure and not subsequently modified (see methods section). Therefore, we do not consider this factor to be a source of bias or major limitation in the present study. However, patients were not randomly assigned to each of the insufflation pressure groups; thus, there is a relative weakness in the present study design, which may have impacted on the results.We investigated performance bias by stratifying patients by surgeon and/or surgical centre. As we could not exclude performance bias, we entered surgeon's PRA experience as independent variable in our propensity score matching analysis. Another potential limitation of our study was the statistically significant difference in the tumour size and BMI between both studied patient cohorts. Thus, we treated both variables as independent variables in our propensity score matching analysis.p < 0.001). To assess the severity of this bias, we ran sensitivity analyses that included only patients who strictly met a 2-year follow-up period. We found that there was minimal bias in our analysis.In addition, the variable follow-up periods represent a minor limitation of our study in terms of procedure safety. For example, patients operated on with a ≥ 25 mm Hg pressure had a median of 26 months of follow-up, while those who had operations with a < 25 mm Hg pressure had only a median of 19 months of follow-up (It is important to notice that pressures between 20 and 25 mm Hg can still be considered to be a relatively high pressure (most PRA being performed with a pressure around 20 mm Hg) when compared with normal intraperitoneal laparoscopy pressure (around 16 mm Hg). An insufflation pressure > 25 mm Hg should be considered even more to be very high. Thus we suggest adopting a strategy based on a moderate pressure elevation starting with 20 mm Hg or less (e.g. 18 mm Hg). That strategy may be sufficient to achieve better exposition without exposing the patient to the risks of pressures > 25 mm Hg. Due to its design, our study is not able to determine whether normal laparoscopy pressures (around 16 mm Hg) are sufficient to perform the PRA procedure safely.Finally further limitations to our study include (i) exclusion of patients who did not fulfil the 30-day follow-up and (ii) the restriction of our analysis to patients with benign tumours. These factors may both have led to a degree of selection bias. Further studies are required to specifically investigate the observed effects in other clinical settings .Our study shows that insufflation pressures below 25 mm Hg do not compromise patient safety or operative success in PRA. Moreover, moderate initial pressure (20 mm Hg or less), followed by increased pressures where required, may be sufficient to achieve better exposition and to overcome intraoperative bleeding. Taken together, our results call for the careful re-evaluation of the need for routine high insufflation pressures; a practice based on sparse clinical evidence. Prospective investigations are required to definitely determine whether an optimal insufflation pressure exists which allows both safe completion of the procedure and improved patient outcomes.


Sleep apnea is very common in patients with cardiovascular disease, especially in patients with hypertension. Over the last few decades a number of discoveries have helped support a causal relationship between the two and even resistant hypertension. The role neurogenic mechanisms play has gathered more attention in the recent past due to their immediate bedside utility. Several innovative discoveries in pathogenesis including those exploring the role of baroreflex gain, cardiovascular variability, chemoreceptor reflex activation and the sympathetic nervous system have emerged. In this review, we discuss the epidemiology of sleep apnea and hypertension and the pathogenic mechanisms contributing to neurogenic hypertension. Furthermore, recent management strategies in addition to continuous positive airway pressure (CPAP), such as upper airway stimulation and renal denervation that target these pathogenic mechanisms, are also discussed. Sleep has far reaching implications for overall health and wellbeing. Sleep disruption, particularly obstructive sleep apnea (OSA), has been implicated in adverse outcomes ranging from decreased daytime alertness and quality to life to increased hospitalization . PatientIn adults, an apnea is defined as the absence of inspiratory airflow for ≥10 seconds. Hypopnea on the other hand, is a decrease in airflow, lasting ≥10 seconds, which is associated with an arousal or a drop in arterial oxygen saturation. Sleep disordered breathing (SDB) is characterized by frequent apneas and hypopneas during sleep. Abnormal respiratory events can be central or obstructive and result from an absence or reduction in brainstem neural output to the genioglossus or the thoracic respiratory muscles.OSA should be considered as a neural disease, as the onset of sleep is the event that causes the hypoxemia rather than the effect of lying in the supine position alone.  An obstrSmall airways lead to increased airflow resistance and greater intra-pharyngeal negative pressure during inspiration and in wakefulness. This excites the laryngeal mechanoceptors, which cause increased activity of the pharyngeal dilator muscles, thereby maintaining the airway ,6. SleepChanges in lung volumes can also impact pharyngeal patency, where lung inflation causes a longitudinal strain on the pharyngeal airway. The caudal strain tends to harden the airway and decreases collapsibility. Thus, transitioning from the upright to the supine position during sleep causes a decrease in lung volume which increases the risk of apnea .Snoring and wake-time sleepiness are the most common manifestations of OSA; although they are relatively sensitive, they lack specificity . Other sOSA is the most common sleep-related breathing disorder, estimated to affect approximately 20–30% of males and 10–15% of females, when OSA is characterized as an AHI >5/h of sleep .Both OSA and hypertension are quite prevalent; about 50% of OSA patients are hypertensive. An estimated 30% to 40% of hypertensive patients also have OSA, often undiagnosed . A majorA more recent study by Peppard et al.  providedThe association between OSA and hypertension has been shown across patient groups including the elderly, and those with a history of stroke ,15. In tOSA may not only increase the risk of hypertension, but also the risk of its complications. After adjusting for hypertension as a confounder, patients with OSA were nearly at three times the risk of having a stroke. Additionally, a dose-response relationship was seen here too, where patients with mild OSA were nearly two and a half times more likely to have a stroke, while those with severe OSA were at 3.6 times the risk of having a stroke than individuals without OSA .The groundwork of cardiorespiratory sympathetic physiology was laid by Ludwig et al. in 1871, where they performed concurrent recordings of intrathoracic pressures and arterial BP changes using early kymographs . These eHaselton and Guyenet showed increased medullary firing frequency at inspiration with the phrenic nerve generating the respiratory burst in the thoracic sympathetic chain . HypoxiaMicro-neurographic measurements of intraneural recordings of sympathetic burst frequency correlate with plasma norepinephrine levels and have an advantage of providing continuous moment-by-moment measures of sympathetic activity . These fIn normal subjects, muscle sympathetic nerve activity (MSNA), BP and heart rate are lower while in deep NREM sleep than while awake . This isOSA is accompanied by high levels of sympathetic drive, even during resting normoxic wakefulness, and is independent of obesity, likely due to a heightened chemoreflex drive even during normoxia . In contCardiovascular variability, in large part determined by autonomic neural mechanisms, appears to be an important marker of cardiovascular risk. Kleiger et al.  initiallOSA has been known to be associated with characteristic heart rhythm disturbances . CompareGula et al.  hypothesnd order neurons of the caudal nucleus tractus solitarius (cNTS) [2 and a rise in PaCO2 and this reflexively increased pulmonary ventilation and the activated vagus nerves slowed the heart rate [Prolonged hypoxemia may produce persistent changes in cellular activity, leading to tissue dysfunction and death. To counteract this, the peripheral chemoreflex, mediated by hypoxic activation of the carotid bodies, sends stimulatory inputs to the 2s (cNTS) . The cNTs (cNTS) . Routineart rate .In contrast, when apnea occurs centrally or reflexively, carotid chemoreceptor excitation results in an enhanced bradycardia and even cardiac arrest, but paradoxically does not affect respiration. This is called the diving reflex. The respiratory effect of chemoreflex activation depends on the balance that exists between the hyper-ventilatory effect of the reflex itself and the downstream effects of increased ventilation, such as the activation of lung stretch receptors and the central ventilatory inhibition . In summInitial rodent models exposed to chronic intermittent hypoxia (CIH), showed a continued increase in basal arterial pressures that was prevented by denervation of the carotid body . The CIHAnother rodent model sought to examine the sensory role of the carotid body  Peng et Xie et al.  assessedNarkiewicz et al. showed the effects of chemoreflex deactivation on SNA, heart rate and BP in 14 untreated patients with OSA by administering 100% oxygen for 15 min . They obArterial baroreceptors in the carotid sinus and aortic arch, relaying in the nucleus tractus solitarius, modulate heart rate and peripheral vascular responses to blood pressure fluctuations, whereby baroreflex activation in response to increased BP, causes decreased SNA, thus causing a drop in BP and heart rate ,39.Baroreflex function during sleep is state-dependent, and changes with different sleep–wake phase cycles and their adaptive behaviors . It has Heistad et al. showed in dogs that the inhibition of the baroreflex augments the ventilatory response to stimulation of the peripheral chemoreceptors . In studA clear impairment of baroreflex control in hypertensive patients with OSA was seen most prominently in the NREM phases of sleep ,44. In cThe contribution of genetic polymorphisms in mediating the relationship between hypertension and OSA has been studied by several investigators ,48. In hCPAP therapy results in acute reductions in both sympathetic drive and BP during sleep . In termCPAP in and of itself may have limited utility as an antihypertensive strategy, since CPAP alone may not decrease BP if the hypertension is unrelated to OSA. Furthermore, if OSA-induced hypertension is chronic, it may cause vascular bed remodeling with an increased BP set point. However, considering a long-term reduction of 2–3 mmHg in SBP is associated with a 4%–8% decrease in mortality , the potAdditionally, BP improvement with CPAP therapy is highly variable as severity of OSA, baseline BP and CPAP compliance (a threshold of 4 h or more) determine the reduction of BP levels, and these factors would cause some patients to have better antihypertensive benefits than others .Greater reductions are seen in patients with resistant hypertension, where a 4.7 to 7.2 mmHg reduction was seen in systolic blood pressure (SBP) and a 2.9 to 4.9 mmHg reduction seen in diastolic blood pressure (DBP) ,54. In rCurrent treatment standards place continuous positive airway pressure (CPAP) as the first line of OSA therapy due to the well based evidence of efficacy and safety, and especially the benefits of treatment in sleepy patients. Unfortunately, despite its documented efficacy, adherence remains a problem with CPAP. The APPLES  and HomeThe onset of apneic asphyxia is usually accompanied by a decreased stimulatory drive in the upper airway muscles ,58; patep < 0.001)). Electrode breakage and sensor malfunction prevented use beyond 6 months, proving to be a challenge of this technique and thus limiting applicability. The genioglossus muscle is the largest airway dilator muscle and causes tongue protrusion and stiffening of the anterior pharyngeal wall, with genioglossus stimulation causing improvement of pharyngeal collapsibility, and increased upper airway diameter and maximal inspiratory flow , along wThe next generation devices were investigated in two larger studies ,65. EastThese studies paved the way for the multicenter prospective Stimulation Therapy for Apnea Reduction (STAR) Trial . A totalWalia et al. compared the effects of positive airway pressure and hypoglossal stimulation on BP. . They obIn conclusion, neural stimulation of the hypoglossal nerve can potentially be used for the treatment of OSA, with attenuation of apneic events and sleepiness, but does not have any effects on BP.Increased sympathetic nerve activity, a characteristic of patients with OSA, plays a major role in the development of resistant hypertension . It has p < 0.01). Interestingly, there was also an improvement in sleep apnea severity. Following this, a phase II trial (testing a larger population to assess efficacy and side effects) was conducted in 60 patients with resistant hypertension along with coexisting moderate-to-severe OSA [However, the effect of this procedure in patients with resistant hypertension and OSA was not clear until 2011, when Witkowski et al.  studied vere OSA . At 3 moThus, while repetitive apneic events result in markedly increased SNA, the responses seen following RDN suggest an important role of renal SNA in the development of resistant hypertension in OSA. Furthermore, RDN may not only lower BP, but also may attenuate apnea severity, in resistant hypertensive patients with sleep-disordered breathing. Wolf et al.  hypothesSympathetic neural responses to hypoxemia and hypercapnia result in marked nocturnal increases in adrenergic drive and BP. There is significant carryover of heightened sympathetic activation even during daytime wakefulness, in part due to tonic chemoreflex activation. Chemoreflex, baroreflex, and vasoactive mechanisms may contribute to an increased risk of hypertension in OSA .However, both OSA and hypertension are common and hence may often exist as comorbidities. Not all patients with OSA and hypertension necessarily have hypertension occurring as a result of OSA. Hence, treatment of OSA may not always elicit marked decreases in BP.OSA-related hypertension shows multiple neurogenic mechanisms of pathogenesis and these are potential mechanisms which have been targeted for the treatment of hypertension associated with OSA and treatment resistant hypertension. Neural modulation therapy, such as renal denervation, may have a role in lowering BP in OSA patients with resistant hypertension, in whom there is suggestive evidence that apnea severity may also be attenuated. Other neural modulatory strategies, such as hypoglossal nerve stimulation, are specifically targeted at reducing apnea severity, and may be able to lower BP on the basis of improved oxygenation and sleep quality in selected patients. Future studies should look to further evaluate the above approaches and identify other treatment strategies, including chemoreflex and baroreflex modulation, to attenuate apnea severity and/or neurogenic hypertensive consequences of OSA.


Introduction: We postulate a relationship between a transcutaneous hepatic NIRS measurement and a directly obtained hepatic vein saturation. If true, hepatic NIRS monitoring  might increase the sensitivity for detecting shock since regional oxygen delivery changes in the splanchnic circulation before the kidney or brain. We explored a reliable technique for hepatic NIRS monitoring as a prelude to rigorously testing this hypothesis. This proof-of-concept study aimed to validate hepatic NIRS monitoring by comparing hepatic NIRS measurements to direct hepatic vein samples obtained during cardiac catheterization.Method: IRB-approved prospective pilot study of hepatic NIRS monitoring involving 10 patients without liver disease who were already undergoing elective cardiac catheterization. We placed a NIRS monitor on the skin overlying liver during catheterization. Direct measurement of hepatic vein oxygen saturation during the case compared with simultaneous hepatic NIRS measurement.Results: There was no correlation between the Hepatic NIRS values and the directly measured hepatic vein saturation . However, the Hepatic NIRS values correlated with the cardiac output , the systolic arterial blood pressure , and the diastolic arterial blood pressure .Conclusions: Using the technique described, hepatic NIRS does not correlate well with the hepatic vein saturation. Further optimization of the technique might provide a better measurement. Hepatic NIRS does correlate with cardiac output and thus may still provide a valuable additional piece of hemodynamic information when combined with other non-invasive monitoring. Patients admitted to the pediatric cardiovascular intensive care unit (CVICU) are at high risk of developing shock, a leading cause of cardiac arrest in children. Early recognition of shock is associated with expedited treatment and improved outcomes while delayed recognition leads to end organ dysfunction, including profound neurologic injury, and mortality , 2. Curr2). This technology has demonstrated utility in pediatric critical care, especially in the perioperative period, and many centers in the United States consider dual-site organ centric NIRS monitoring (brain and kidney) an important component of Intensive Care Unit (ICU) care (Transcutaneous Near Infra-Red Spectroscopy (NIRS) technology allows for non-invasive, real-time monitoring of regional tissue oxygenation saturation (rS0CU) care . Dual-siCU) care , becauseCU) care .2 value might signal changes in blood flow to that organ. Thus, the addition of hepatic NIRS monitoring to the existing two-site paradigm could theoretically reveal invaluable new insights into the regional oxygenation and redistribution of blood flow in low cardiac output states, facilitating earlier goal directed interventions and improved patient outcomes.The addition of NIRS monitoring to the hepatic vascular bed would theoretically help capture important changes in oxygen distribution to the splanchnic circulation during the time leading up to and including clinical shock. . In that way, changes in the rS02 by NIRS have provided mixed results, potentially due to multiple factors, including outdated NIRS technology and excessive surface artifact  Previous attempts to measure hepatic rSOartifact –12. The An outline of the overall study design, along with a timeline, is shown in 2-H) measurement, the invasive arterial blood pressure, the heart rate, and the arterial saturation by pulse oximetry. The blood samples were immediately processed by a portable oximeter in the catheterization lab by the trained staff, and the hepatic venous saturations (SvH02) were recorded. Additional recorded procedural variables included: height, weight, body surface area (BSA), cardiac output (Fick method or thermodilution method), cardiac index, Qp:Qs, invasive oximetry saturations  The patient's primary diagnosis as well as past medical and surgical history were also recorded.All typical institutional cardiac catheterization practice was followed including general endotracheal anesthesia. During patient preparation, a study team member placed one Cerebral/Somatic Oximetry Sensor  on the patient's skin overlying the superior angle of the ninth right rib in the midaxillary line. The sensor has one light emitting diode and two detectors (730 nm and 810 nm wavelengths) with inter-optode distances of 3 cm and 4 cm, providing an optical field with a depth of 2 cm beneath the skin. The probe was placed running parallel atop the rib  See . Then pe2-H) with hepatic vein blood saturation values (SvH02) obtained during the catheterization. rS02-H was defined as the average of the two hepatic NIRS measurements and SvH02 was defined as the average of the two invasive hepatic vein saturation measurements. Scatterplots were created among all numeric variables to explore relationships between factors. Simple correlational analysis and descriptive statistics appropriate for the normality and type of data were utilized.Ten patients were enrolled. The specific aim of the study was to validate a technique for transcutaneous hepatic NIRS monitoring as a surrogate for hepatic vein saturation. We compared simultaneous hepatic NIRS values (rS0N = 2), orthotopic heart transplant (N = 4), patent ductus arteriosus (N = 2), double outlet right ventricle (N = 1), and one patient with pulmonary stenosis and partial anomalous pulmonary venous return.A summary of basic patient demographic data as well as correlation analysis is provided in R = −0.035; P = 0.9238). There was also no correlation between the Hepatic NIRS values and the central or mixed venous saturation  . However, the Hepatic NIRS value was strongly correlated with the cardiac output , the systolic arterial blood pressure , and the diastolic arterial blood pressure , indicating that it may reflect systemic perfusion over a discrete range of blood pressure measurements , body surface area , and was borderline statistically significant for relationship to age at intervention .Correlations between hepatic NIRS value and the various factors are also shown in 2-H value and the directly measured SvH02. We also found no correlation between the reported rS02-H value and the central or mixed venous saturation. These findings are important since they demonstrate that there might be significant difficulty in obtaining a reliable non-invasive measure of the regional oxygen saturation of the liver. At the same time, we found unexpectedly that the Hepatic NIRS value was strongly correlated with the cardiac output and systemic blood pressure, indicating that while the measurement may not accurately reflect the saturation of the hepatic vein, it may still contain important hemodynamic information. While we admit the small numbers and design of this pilot study do not allow for a full exploration of these results, in the remaining discussion we offer theoretical reasons for these findings, which can serve as a springboard toward future studies.We found that using a technique placing the NIRS probe directly over and running parallel to the ninth right rib at the mid-axillary line, there is no correlation between the reported rS0The concept of multisite NIRS monitoring to characterize changes in integrative circulatory physiology has been previously described and has been extensively evaluated in the cerebral –18, splaNIRS technology uses a modified Beer- Lambert principle to measure the relative concentrations of oxy and deoxy-hemoglobin species, yielding an assessment of tissue oxygenation by measuring the color of oxygen in the blood circulating through the optical field beneath the probe. Unlike pulse oximetry, which evaluates the pulsatile arterial flow, NIRS devices evaluate the entirety of the optical field, including the non-pulsatile optical component. In most organs, the resulting measurement is venous-weighted and predictable, since the pulsatile component is artery/arteriole and the non-pulsatile component is venule/vein. However, the liver is unique in its microcirculatory anatomy and physiology.The hepatic afferent vascular supply is dual, split between the splanchnic supply from the portal vein and the systemic arterial supply from the hepatic artery (~70:30 vein:artery under physiologic conditions) . HepaticAnother explanation for the lack of correlation between our NIRS measurements and hepatic vein saturations is due to heterogeneity of the venous and arterial supply to different portions of the liver. Using contrast agents injected into the portal venous system, Timm and Vollmar found some areas of liver which seemed to have almost no portal venous input , which cIn contrast to the theoretical explanations offered above, a simpler explanation to our negative primary endpoint might be a product of our specific technique for NIRS probe placement. Our technique was based around the idea that placement of the NIRS probe overlying the rib would be optimal because the bone would provide a “window” of relatively under-vascularized tissue, allowing the NIRS monitor to gather a pure signal from the underlying hepatic tissue. However, flat bones including ribs, are active sites of hematopoiesis. It is possible that the signal from various erythrocyte precursor cells, etc., which are the byproduct of bone marrow activity,  could have an out-sized effect on the reported NIRS signal. Thus, it might be helpful in future studies to position the probe so as to minimize the amount of rib in line with the NIRS signal, placing the probe perpendicular to the rib rather than parallel. Additionally, although we used physical exam findings to place our NIRS probe (as outlined above), we did not use ultrasound or other imaging to identify the exact location of the liver or its depth beneath our probe. We posit that for most non-obese pediatric patients, a depth of 2–3 cm below the skin should provide a window to the liver tissue, but these findings need further study to be confirmed.Although our study was negative for our primary outcome, the correlation with cardiac output (as well as blood pressure) we report suggests possible utility for hepatic NIRS in concert with other oximetry data for non-invasive cardiac output monitoring. Tibby et al. have shown that using only clinical variables (before widespread use of NIRS) including heart rate, blood pressure, central venous pressure, urine output, capillary refill, and serum lactate, even experienced ICU providers could not reliably estimate cardiac output in children . Direct Given the risks and complications associated with invasive monitoring, less invasive methods of estimating cardiac output  are theoThe most obvious limitation of our study was the small number of patients enrolled that limits the confidence is any statistical estimates. Potential inaccuracies inherent to liver physiology and due to our placement of the NIRS monitor have been discussed above and will need to be accounted for in future studies with more patients. Additionally, we did not use ultrasound to measure the depth of liver tissue in relation to our pobe. In future studies, we would consider adding this step to our methods to ensure that the liver tissue is being interrogated by the NIRS monitor. We would also consider using a NIRS instrument with adjustable interoptode distances, which might provide more depth of tissue penetration and a better signal. An additional factor is the heterogeneity of our study population in terms of age, size, and underlying congenital heart disease. We attempted to keep the exclusion criteria limited in the hopes that this technique would be widely applicable. However, in future studies we may attempt to limit our population in order to protect against confounding which is inherent in a heterogeneous study population. Finally, multiple NIRS and hepatic vein saturation measurements throughout the catheterization, as well as cerebral and renal NIRS values for the different time points, would allow for a more robust analysis and the exploration of longitudinal trajectories and trends. These data would help establish a more concrete connection between cardiac output and hepatic NIRS, but go beyond the objectives of this limited pilot study, and acquisition of multiple blood samples in pediatric patients often pose regulatory hurdles for study completion.In a pilot study of a novel technique for transcutaneous NIRS monitoring of the hepatic vascular bed, no correlation was found between the NIRS measurements and a direct sample of hepatic venous blood during a cardiac catheterization. Interestingly, the hepatic NIRS measurement was strongly correlated to some clinical factors, including cardiac output , and systemic blood pressure. Further study is needed to better understand the correlation with these hemodynamic parameters and whether or not NIRS monitoring of the liver can provide relevant data in a clinical setting. Finally, it is possible that iterative refinement to the technique based on our preliminary findings might still produce an accurate measurement of the hepatic vein saturation.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Institutional Review Board The University of California, San Diego. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.RR conceived the project idea and edited the manuscript. PG designed the project workflow, obtained permission from the IRB, directed patient consent, directed data collection, and was primary author of the manuscript. TK directed the statistical analysis and edited the manuscript. KR, HE-S, and JM aided data collection, guided project design, and edited the manuscript. All authors contributed to the article and approved the submitted version.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.