Background and Objectives: Preoperative echocardiography is widely performed in patients undergoing major surgeries to evaluate cardiac functions and detect structural abnormalities. However, studies on the clinical usefulness of preoperative echocardiography in patients undergoing cerebral aneurysm clipping are limited. Therefore, this study aimed to investigate the correlation between preoperative echocardiographic parameters and the incidence of postoperative complications in patients undergoing clipping of unruptured intracranial aneurysms. Materials and Methods: Electronic medical records of patients who underwent clipping of an unruptured intracranial aneurysm from September 2018 to April 2020 were retrospectively reviewed. Data on baseline characteristics, laboratory variables, echocardiographic parameters, postoperative complications, and hospital stays were obtained. Univariable and multivariable logistic regression analyses were performed to identify independent variables related to the occurrence of postoperative complications and prolonged hospital stay (≥8 d). Results: Among 531 patients included in the final analysis, 27 (5.1%) had postoperative complications. In multivariable logistic regression, the total amount of crystalloids infused (1.002 (1.001–1.003), p = 0.001) and E/e’ ratio (1.17 (1.01–1.35), p = 0.031) were significant independent factors associated with the occurrence of a postoperative complication. Additionally, the maximal diameter of a cerebral aneurysm (1.13 (1.02–1.25), p = 0.024), total amount of crystalloids infused (1.001 (1.000–1.002), p = 0.031), E/A ratio (0.22 (0.05–0.95), p = 0.042), and E/e’ ratio (1.16 (1.04–1.31), p = 0.011) were independent factors related to prolonged hospitalization. Conclusions: Echocardiographic parameters related to diastolic function might be associated with postoperative complications in patients undergoing clipping of unruptured intracranial aneurysms. Preoperative echocardiography is widely performed in patients undergoing major surgeries to evaluate cardiac functions and detect structural abnormalities. Echocardiographic parameters related to systolic and diastolic functions are known to be associated with postoperative outcomes, especially in cardiac surgery ,2,3. RegUnruptured intracranial aneurysms have a prevalence rate of 3.2% and pose a potentially serious risk to the patient, as ruptured intracranial aneurysms cause subarachnoid hemorrhage, leading to a high mortality rate ,9,10. SuThe relationship between echocardiographic LV dysfunction findings and prognosis in patients with aneurysmal subarachnoid hemorrhage has been reported. Changes in echocardiographic findings, including regional wall motion abnormalities, are commonly observed in patients with aneurysmal subarachnoid hemorrhage , and theIn this study, we aimed to investigate the correlation between preoperative echocardiographic parameters and postoperative outcomes, including the incidence of postoperative complications and prolonged hospitalization in patients undergoing clipping of unruptured intracranial aneurysms.This study was approved by the institutional review board of Asan Medical Center (No. 2021-0928). The requirement for written informed consent was waived owing to the retrospective nature of the study.Electronic medical records of patients who underwent clipping of unruptured intracranial aneurysm from September 2018 to April 2020 were retrospectively reviewed. Patients aged below 18 years who underwent emergency or combined procedures were excluded. Patients without preoperative echocardiography were also excluded.All data, including baseline characteristics, laboratory variables, echocardiographic parameters, intraoperative variables, and outcome variables, were collected from an electronic medical recording system . Age, sex, body mass index, underlying disease, and location and maximal diameter of intracranial aneurysm were included in baseline characteristics. Intraoperative variables included transfusion, administration of albumin, mannitol infusion, total infused volume of crystalloids, and urine output. Preoperative echocardiographic variables included valvular abnormality; left ventricular (LV) internal diameter; left atrium dimension; LV posterior wall thickness; LV end-diastolic and end-systolic volume; interventricular septal thickness; LV ejection fraction; LV mass; peak E and A wave velocity; E/A ratio; deceleration time; S, E, and A velocity on tissue Doppler; E/e’ ratio; peak systolic tricuspid pressure gradient; and wall motion index.Anesthetic management followed routine anesthesia protocol for intracranial aneurysm clipping of our center. Approximately 25–50 mg of pethidine was administered intravenously after applying non-invasive blood pressure measurement, pulse oximetry, and routine monitors. Then, an arterial catheter was placed for continuous blood pressure monitoring after lidocaine was locally infiltrated. For anesthesia induction, 2 mg/kg of intravenous propofol and 0.8–1 mg/kg of intravenous rocuronium was injected. Remifentanil and propofol were injected via a target-controlled injection pump . To prevent a sudden increase in blood pressure, intubation was performed gently with the administration of 10–30 mg intravenous esmolol as required. After intubation, ventilation was calibrated to an arterial carbon dioxide pressure of 35 ± 2 mmHg, and the patient was ventilated with an air/oxygen mixture . To analyze the appropriate depth of anesthesia, the bispectral index  was used (target index 40 ± 5). When hypotension or bradycardia occurred, a continuous infusion of phenylephrine (0.5–3.0 mg/h) and/or bolus injection of atropine (0.25–0.5 mg) was administered to maintain the systolic blood pressure within 100–150 mmHg and to increase the heart rate over 45 beats per minute.The primary outcome was overall postoperative complications, which included neurological and non-neurological complications. Neurological complications included postoperative motor weakness, altered mentality, dysarthria, dysphagia, hydrocephalus, brain edema, cerebral infarction, and brain death. Non-neurological complications included postoperative cardiac events, surgical site hemorrhage, pneumonia, pulmonary edema, elevated liver enzymes, and other complications of non-neurological causes. The secondary outcome was prolonged hospital stay defined as hospitalization of ≥8 d.p-value were illustrated within the univariable and multivariable analyses. All statistical tests were performed using R 4.1.0.Baseline characteristics, perioperative variables, and preoperative echocardiographic variables are expressed as mean (standard deviation), median (interquartile range), or n (proportion). Univariable and multivariable logistic regression analyses were performed to identify the independent variables associated with the occurrence of postoperative complication and prolonged hospital stay. The stepwise selection approach was used to select variables for multivariable logistic regression. The model with the lowest Akaike information criterion was selected as the final model. The odds ratio, 95% confidence interval, and 2. The location of the aneurysm was most common in the middle cerebral artery at 41.6%, followed by the anterior cerebral artery at 20.5%. The maximal diameter of the aneurysm was 5.0 ± 2.3 mm (p = 0.594). Quantitative variables such as LV internal diameter, LV wall thickness, end-systolic volume, end-diastolic volume, LV ejection fraction, LV mass, peak E wave and A wave velocity, deceleration time, and tissue Doppler parameters also did not show significant differences between the groups with and without postoperative complications (p = 0.008)  were included in the final analysis . Demogra± 2.3 mm . Overallications . Among t= 0.008) .Among the 531 patients, 27 (5.1%) had postoperative complications. Neurologic complications were the most frequent (55.6%), followed by wound problems and respiratory complications . Among tp = 0.001) and E/e’ ratio  were independent variables associated with postoperative complications (p = 0.008) (p = 0.024), total amount of crystalloids infused (1.001 (1.000–1.002), p = 0.031), E/A ratio (0.22 (0.05–0.95), p = 0.042), and E/e’ ratio (1.16 (1.04–1.31), p = 0.011)  . The var= 0.008) . The sec= 0.011) . RBC traIn the present study, diastolic-function-related echocardiographic parameters, such as E/A and E/e’ ratios, showed a relationship with postoperative outcomes. The E/e’ ratio was associated with both postoperative overall complications and prolonged hospitalization. Other than echocardiographic parameters, the total amount of infused crystalloids was an independent factor associated with postoperative overall complications, while the maximum diameter of a cerebral aneurysm and the total infused crystalloids were associated with prolonged hospitalization.Doppler echocardiography is widely used as a modality to evaluate diastolic function . The E/eSeveral studies exist on the association between cardiac diastolic function and neurologic outcomes. In a multicenter study evaluating the association of echocardiographic parameters related to LV diastolic function with ischemic stroke in patients with atrial fibrillation, the E/e’ ratio was significantly greater in those with a stroke history, and E/e’ ratio was also a significant independent predictor of ischemic stroke in multivariable analysis . AlthougThe present study is in line with the aforementioned studies in that it investigated the association between cardiac diastolic dysfunction and neurologic outcome. However, the study differs from previous studies in that study subjects were specifically limited to patients undergoing clipping of intracranial aneurysm via craniotomy. To our knowledge, this is the first study to examine the association between cardiac diastolic function and postoperative outcome in patients undergoing aneurysm clipping. While establishing a clear mechanism for the results of this study is difficult, we believe that endothelial injury, arterial stiffness, and hypercoagulability may explain some of the findings. These explanations are consistent with previous studies on diastolic dysfunction and neurological outcomes ,29,30,31E/A ratio, a ratio of early diastolic peak flow to late diastolic peak flow, has also been used as a marker of diastolic function . E/A ratThere are several limitations in the current study. First, as a retrospective study, unexpected biases may have affected the results and interpretation of the study. As data were obtained by reviewing electronic medical records, variables related to outcome could be omitted from the data acquisition process or the medical record itself. Owing to the limitations of this retrospective study, we are planning a prospective study on this topic in future. Second, the incidence of cardiovascular complications related to the echocardiographic parameters was too low to perform subgroup analysis. Although cardiovascular complications can be a direct indicator of the impact of diastolic dysfunction on postoperative prognosis, our study population had few cardiovascular comorbidities and stable perioperative vital signs, resulting in only one cardiovascular complication. Considering that most of the complications in this study were neurological complications, such as cerebral infarction, there seems to be a need for research on the association between diastolic dysfunction and cerebrovascular status.There is a possibility of an association between preoperative echocardiography parameters, which reflect diastolic function, and postoperative outcomes, including the incidence of postoperative complication and hospital stay, in patients undergoing clipping of unruptured intracranial aneurysms. Therefore, a prospective study to identify the value of preoperative echocardiographic parameters in predicting postoperative outcomes in this population is warranted.


Cox proportional hazard models unveiled that, compared to T1, the risk of a six-point MACE was significantly decreased in T3 (adjusted hazard ratio (HR) 0.376, 95% confidence interval (CI) 0.207 to 0.683). The restricted cubic spline curve analysis visualized an inverted S-shaped association between 24 h UPE level and the risk of a six-point MACE, indicating a significantly increased risk of a six-point MACE in patients with a low 24 h UPE level. In conclusion, low 24 h UPE is associated with adverse cardiovascular outcomes in patients with CKD. Our finding emphasizes that low 24 h UPE should not be a reliable marker for dietary restriction of phosphorus that essentially leads to better outcomes in patients with CKD.The relationship between 24-h urinary phosphorus excretion (24 h UPE) and cardiovascular disease in patients with pre-dialysis chronic kidney disease (CKD) has rarely been studied, despite the fact that the relationship between serum phosphorus level and the risk of a cardiovascular event is well established. A total of 1701 patients with pre-dialysis CKD were finally included for the analyses and were divided into tertiles by 24 h UPE  ± 88.413 (standard deviation)), second tertile , and third tertile . The study outcome was a six-point major adverse cardiac event (MACE). The median follow-up duration was 7.992 years. Kaplan–Meier curve analysis visualized that the cumulative incidences of a six-point MACE ( The kidney is a major organ for the regulation of phosphorus homeostasis ,2,3. TheAs dietary phosphorus restriction is a critical strategy to avoid hyperphosphatemia in patients with CKD ,16,17, 2A recent study in patients with CKD, however, revealed that 24 h UPE is highly variable despite a tightly controlled dietary loading of phosphorus, and that 24 h UPE is not well correlated with dietary loading or intestinal absorption, but is instead inversely associated with net phosphorus retention . Based on = 1701), long-term cohort (median duration of follow-up 7.992 years), the purpose of the current study was to examine the association between 24 h UPE and the risk of CVE in patients with CKD. We here hypothesized that low 24 h UPE may be associated with adverse CV outcomes, a six-point major adverse cardiac event (MACE), in patients with CKD.Therefore, taking advantage of a large-sized  [n = 535) and those without data on follow-up duration (n = 2) (The Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) (NCT01630486 at ne 2019)  involves (n = 2) . The stu2 (g/m2) led to the calculation of the LV mass index (LVMI) [Demographic data includes information on age, sex, comorbidity indexed by Charlson comorbidity index score, the primary cause of CKD, smoking status, and medication history . The participants’ height, weight, and waist-to-hip ratio (WHR) were all measured by skilled staff members. The body mass index (BMI) was calculated as the weight divided by the square of the height. Systolic and diastolic blood pressure (SBP and DBP) were measured with an electronic sphygmomanometer following 5 min of seated relaxation. Venous samples were collected for laboratory tests, such as creatinine (Cr), after an overnight fast. Estimated glomerular filtration rate (eGFR) was computed using the serum Cr level and the Chronic Kidney Disease Epidemiology Collaboration equation . Urine sx (LVMI) .The study participants were divided into tertiles by 24 h UPE (1st tertile (T1), 2nd tertile (T2), and 3rd tertile (T3)) . The pri2 test were used for continuous and categorical variables, respectively, to assess the baseline characteristics by 24 h UPE level. The cumulative incidence of the outcome events was represented using Kaplan–Meier curves, and the data was assessed using the log-rank test. Individuals with any missing data were eliminated from further investigation. In order to evaluate the relationship between the 24 h UPE level and the likelihood of CVE, Cox proportional hazard regression models were employed. Patients who were lost to follow-up were censored based on their last scheduled appointment. The following variables were adjusted using models. Crude hazard ratios (HRs) are represented by Model 1. Age, gender, Charlson comorbidity index, primary CKD cause, smoking status, medication , WHR, and SBP were all adjusted in Model 2. Hemoglobin, albumin, total calcium, inorganic phosphorus, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting glucose, 25(OH)D, high-sensitivity C-reactive protein (hs-CRP), eGFR, and spot urine ACR were also adjusted in Model 3. Additional LVMI and LVEF adjustments were made to Model 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to present the findings of Cox proportional hazard models. Using restricted cubic spline curves, the link between the risk of CVE and the 24 h UPE level (a continuous variable) was assessed. We performed numerous sensitivity analyses in order to validate our conclusions. First, we looked at whether there was a relationship between the 24 h UPE level and the risk of a 3-point MACE, which was defined as a CV death, a non-fatal myocardial infarction, or a non-fatal stroke [p values were less than 0.05. R  and SPSS for Windows version 22.0  were used to conduct the statistical analysis.One-way analysis of variance and the χl stroke , or a 4-p = 0.044), that of diuretic use or medication for no less than three anti-hypertensive drugs was significantly higher in T1. BMI, WHR, and DBP were significantly higher in T3. Hemoglobin, albumin, total calcium, total cholesterol, LDL-C, and 25(OH)D levels were also significantly higher in T3, whereas serum phosphorus level was highest in T1. Spot urine ACR and serum creatinine level were significantly higher in T1. Accordingly, mean eGFR was significantly lower in T1. The incidence of a six-point MACE also significantly differed from the baseline CKD stages (p = 0.048), while E/e’ was highest in T1. Left atrial diameter and the frequency of valve calcification were significantly higher in T1, whereas posterior wall thickness, interventricular wall thickness, LV end-diastolic diameter, and LV end-systolic diameter were significantly higher in T3.The baseline characteristics of the study participants were described according to 24 h UPE levels . The meaD stages . The echD stages . LVMI wap = 0.029) significantly differed from 24 h UPE levels, as the incidence rate of the study outcomes was highest in T1 and lowest in T3. To assess the independent association between 24 h UPE level and the risk of CVE, Cox proportional hazard models were analyzed  is also associated with a lower risk of three-point  or four-point  MACE . After ep for interaction = 0.025), although gender, obesity (BMI < 23 kg/m2 vs. BMI ≥ 23 kg/m2), kidney function (eGFR ≥ 45 mL/min./1.73 m2 vs. eGFR < 45 mL/min./1.73 m2), or albuminuria (spot urine ACR < 300 mg/g vs. spot urine ACR ≥ 300 mg/g) did not significantly modify the association , and serum phosphorus level was not different from 24 h UPE level [2) was substantially lower than that of the previous study. In concordance with our findings, an impaired phosphaturic response to FGF23 with low fractional excretion of phosphorus to FGF23 ratio was associated with severe abdominal aortic calcification among patients with CKD stages 3 to 4 [The association between low 24 h UPE and the risk of CVE has been once previously reported , where hPE level . In conts 3 to 4 . TherefoThis unexpected association could be primarily attributed to the inverse correlation between 24 h UPE and net phosphorus retention in patients with CKD . In a prYet, we still cannot completely exclude the possibility that low 24 h UPE may indicate protein malnutrition that is closely related to adverse CV outcomes in patients with CKD ,29. AlthWe acknowledge some limitations of the present study. First, we cannot present confirmatory data on the causal relation between low 24 h UPE and the risk of CVE due to the observational nature of the study. However, a similar result from the patients with moderate CKD has been previously reported , supportIn conclusion, we report that low 24 h UPE is associated with adverse CV outcomes in patients with CKD. Our findings emphasize that low 24 h UPE should not be a reliable marker for dietary restriction of phosphorus that essentially leads to better outcomes in patients with CKD.


Patients with advanced chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney transplants (KT) are at an elevated risk for COVID-19 infection, hospitalization, and mortality. A comprehensive comparison of morbidity and mortality between these populations with kidney disease and individuals without any kidney disease is lacking.We analysed the 2020 Nationwide Inpatient Sample (NIS) database for non-elective adult COVID-19 hospitalizations, categorizing patients into advanced CKD, ESKD, KT, and kidney disease-free cohorts. Our analysis included a description of the distribution of comorbidities across the entire spectrum of CKD, ESKD, and KT. Additionally, we investigated in-hospital mortality, morbidity, and resource utilization, adjusting for potential confounders through multivariable regression models.The study included 1,018,915 adults hospitalized for COVID-19 in 2020. The incidence of advanced CKD, ESKD, and KT in this cohort was 5.8%, 3.8%, and 0.4%, respectively. Patients with advanced CKD, ESKD, and KT exhibited higher multimorbidity burdens, with 90.3%, 91.0%, and 75.2% of patients in each group having a Charlson comorbidity index (CCI) equal to or greater than 3. The all-cause in-hospital mortality ranged from 9.3% in kidney disease-free patients to 20.6% in advanced CKD, 19.4% in ESKD, and 12.4% in KT patients. After adjusting for potential confounders at both the patient and hospital levels, CKD stages 3–5; ESKD; and KT were found to be associated with increased odds of mortality, with adjusted odds ratios (aOR) of 1.34, 1.80, 2.66, 1.97, and 1.69, respectively.Patients hospitalized for COVID-19 with advanced CKD, ESKD, or KT demonstrated a higher burden of comorbidities and increased mortality rates compared to those without kidney disease. After adjusting for confounders, CKD stages 3–5; ESKD; and KT were identified as independent risk factors for in-hospital mortality, illustrating a dose-response relationship between the odds of mortality and adverse outcomes as CKD progressed from stages 3 to 5. Our study highlights the necessity for enhanced management of comorbidities, targeted interventions, and vigorous vaccination efforts to mitigate the risk of adverse outcomes in the vulnerable populations of patients with CKD, ESKD, and KT. IdentifDespite the abundance of research, there is a paucity of comprehensive national-level data from the United States that compares in-hospital mortality and clinical outcomes of COVID-19 among patients with advanced CKD (stages 3–5), ESKD, and KT, against a control group of individuals without any underlying kidney conditions. Previous investigations often encountered methodological limitations, such as insufficient sample sizes, suboptimal data collection, a lack of rigorous stratification and controls, or an oversight of relevant comorbidities and socioeconomic factors. Although meta-analyses have attempted to overcome these limitations, they have been hampered by the very same methodological challenges, making cross-study comparisons difficult. Utilizing aggregated outcomes from studies without adequate consideration or adjustment for potential confounders can lead to constrained conclusions, a fact that has been well recognized in literature , 15. ThiTo address this knowledge gap, we employed the Nationwide Inpatient Sample (NIS)—the largest inpatient database in the United States, to evaluate the in-hospital mortality and morbidity of patients admitted with COVID-19 in 2020, differentiating between those with and without pre-existing kidney conditions. The primary objective of our investigative initiative is to elucidate the clinical outcomes of individuals with CKD, ESKD, and KT hospitalized due to COVID-19, juxtaposed against a control cohort without any pre-existing kidney disease. To the best of our knowledge, this endeavor represents the first nationwide, population-based comparative analysis that delves into the clinical outcomes of COVID-19 hospitalizations, stratified by kidney disease, in the United States. We posit that the findings from our research will provide healthcare practitioners with an enriched perspective on how CKD/ESKD/KT affects the clinical trajectory and outcomes of COVID-19.2.2.1.This study is a retrospective, observational, population-based analysis leveraging the 2020 NIS database, a part of the Healthcare Cost and Utilization Project (HCUP), supported by the Agency for Healthcare Research and Quality (AHRQ) . The NIShttps://hcup-us.ahrq.gov/db/nation/nis/nisdbdocumentation.jsp.All data for this study are publicly available at 2.2.Approval from an Institutional Review Board was not required for this study due to its retrospective nature and the use of de-identified data. The study was conducted in strict adherence to the data-use agreements of the NIS-HCUP.2.3.We employed the 2020 NIS database to identify all patients hospitalized with a primary diagnosis of COVID-19. We excluded patients under the age of 18 and those admitted to the hospital for elective reasons, as opposed to emergency admissions. Following these exclusions, the remaining patients in the study cohort were stratified based on their pre-existing kidney disease status into five distinct categories: the advanced CKD group ; the ESKD group ; the KT group (patients with a secondary diagnosis indicating a history of kidney transplantation); the kidney disease-free group (consisting of patients without any secondary diagnosis of kidney disease) and others (patients who do not fit into any of the aforementioned categories). Data extraction was performed using the ICD-10-CM diagnostic codes refer to .2.4.The primary outcome of interest in this study was all-cause in-hospital mortality. The secondary outcomes include (1) morbidity, ascertained by the incidence rates of septic shock, acute respiratory failure, acute respiratory distress syndrome (ARDS), mechanical ventilation, and vasopressor requirement; and (2) resource utilization, evaluated by the length of hospital stay (LOS) and total hospitalization charges.To mitigate the impact of confounders, potential confounding variables were extracted and considered. These variables included patient demographics like age, gender, and race; socioeconomic factors such as household income and insurance status (primary payer); prevalent comorbidities such as diabetes, hypertension, obesity, congestive heart failure, coronary artery disease, chronic pulmonary disease, chronic liver disease, non-metastatic solid tumors, and metastatic cancer. Furthermore, variables such as history of alcohol consumption, smoking, drug abuse, and hospital characteristics  were taken into account. The Charlson comorbidity index (CCI) was adopted to measure the cumulative impact of comorbidities. This index offers a validated, efficient, and readily applicable means to estimate the mortality risk associated with coexisting diseases . A compr2.5.Statistical analyses were performed using Stata 17.0 . The NIS employs a multifaceted sampling design incorporating stratification, clustering, and weighting. Consequently, data were processed as survey data and adjusted using the discharge-level weight variable provided by AHRQ. Unless explicitly mentioned, all statistics presented herein reflect these weighted estimates. Categorical variables were presented as percentages, while continuous variables as means with standard deviations. The chi-square test and ANOVA were used for descriptive comparisons.p < 0.2) in the univariable regression analysis. All statistical interpretations were grounded on a significance level defined by a p-value threshold of 0.05.Univariate regression analyses were conducted to ascertain the unadjusted odds ratio for primary and secondary outcomes with respect to potential confounding factors. If data were absent for any of the regression variables, the corresponding patient entry was omitted from the analysis. These confounders were subsequently accounted for in subsequent multivariable regression models. To verify the absence of multicollinearity in our multivariable models, we assessed the variance inflation factor (VIF). It is worth noting that only the Charlson comorbidity index (CCI) presented a VIF greater than five and was therefore excluded from subsequent multivariable analysis. None of the remaining risk factors manifested a VIF above five, thereby confirming the absence of multicollinearity. A refined regression model was formulated, encompassing only those variables that exhibited a potential association , diabetes (59.6%), and hypertension (92.4%), all of which were significantly higher compared to the kidney disease-free group .The ESKD group had a significant proportion of patients who identified as Black, 34.4%, compared to 17.0% in the kidney disease-free group. Additionally, the prevalence of low annual income was markedly higher among the ESKD cohort, with 42.4% earning an annual income below $50,000, compared to 33.5% in the kidney disease-free group, 35.5% in the advanced CKD group, and 35.2% in the KT group. Clinically, the ESKD group had the highest prevalence of comorbid conditions such as congestive heart failure at 44.2%, diabetes at 71.6%, hypertension at 95.2%, and 91% with a CCI ≥3.The KT group was the youngest demographic with an average age of 59.1 ± 0.4 years. This group also had the lowest proportion of female patients (35.5%). From a comorbidity perspective, a significant 75.2% of the KT group had a CCI equal to or exceeding 3, which stands in notable contrast to the 12.8% observed in the kidney disease-free group. Additionally, 80% of patients within the KT group were treated in urban teaching institutions.A comparison of patient and hospital characteristics across all stages of CKD was also conducted. All observed variations were found to be statistically significant, as detailed in 3.2.p < 0.001).Among the 1,018,915 adult patients non-electively admitted for COVID-19, 113,180 patients died in the hospital, yielding an overall in-hospital all-cause mortality rate of 11.1%. The mortality rate stratified by kidney disease is shown in p-value greater than 0.2 in univariable regression. After adjusting for relevant confounders, the advanced CKD, ESKD, and KT groups all demonstrated significantly increased odds of in-hospital mortality compared to the kidney disease-free group. Specifically, the adjusted OR (aOR) of mortality for advanced CKD was 1.52 , for ESKD was 1.97 , and for KT was 1.69  , obesity , diabetes , chronic heart failure , chronic lung disease , chronic liver disease , solid tumor without metastasis  and metastasis . Of note, CKD stage 5 and liver disease had an aOR of more than 2.5 for mortality. Female sex was associated with a decreased risk of mortality .Several independent risk factors associated with increased odds of in-hospital all-cause mortality were identified by the multivariable regression model , CKD stage 4 , CKD stage 5 , and ESKD  exhibited a significant increase in all-cause in-hospital mortality odds when compared to patients without any kidney disease. Importantly, our data revealed a dose-response trend from CKD stage 3 to 5, with CKD 5 having the highest aOR among all variables investigated, including ESKD.3.4.3.4.1.The overall incidence of septic shock among hospitalized adult patients with COVID-19 was 3.4%. The incidence of septic shock in the kidney disease-free group, advanced CKD group, ESKD group, and KT group was 3.0%, 4.7%, 8.0%, and 4.6%, respectively .p-values were greater than 0.2 in the univariate regression. This adjusted logistic regression analysis revealed significantly increased odds for septic shock in advanced CKD, ESKD and KT groups when compared to the kidney disease-free group   .p = 0.004); CKD stage 4, aOR 1.43, ; CKD stage 5, aOR 1.61   .3.4.2.The overall incidence of acute respiratory failure among hospitalized adult patients with COVID-19 was 56.5%. The rate was 56.4% in the kidney disease-free group, 56.1% in the advanced CKD group, 54.8% in the ESKD group, and 46.4% in the KT group .p-values being greater than 0.2 in univariate regression. The adjusted logistic regression analysis revealed significantly decreased odds for acute respiratory failure in the advanced CKD, ESKD and KT groups when compared to the kidney disease-free group  (The factor of chronic liver disease was excluded from subsequent multivariable regression models due to its  for KT) .3.4.3.The overall incidence of ARDS among hospitalized COVID-19 adult patients was 5.3%. In the kidney disease-free group, the incidence rate was 5.1%, while it was 6.3% in the advanced CKD group, 6.3% in the ESKD group, and 6.2% in the KT group .p-values being greater than 0.2 in univariate regression. The adjusted logistic regression analysis demonstrated a 17% increase in the odds of ARDS in the advanced CKD group compared to the kidney disease-free group . No significant difference was found between the ESKD/KT group and the kidney disease-free group . However, there was no statistically significant difference between the KT group and the kidney disease-free group   .p = 0.001) and CKD stage 5  demonstrated a significant increase in the odds of requiring mechanical ventilation, displaying a dose–response trend . However, there was no statistically significant difference in vasopressor requirements observed between the KT group and the kidney disease-free group  (Chronic lung disease was excluded from subsequent multivariable regression models due to its  for KT) .p = 0.002), CKD stage 4  and CKD stage 5  all exhibited a significant increase in the odds of vasopressor requirement, demonstrating a dose–response trend : 0.88, 95% CI: 0.70–1.06, p < 0.001 for advanced CKD; aMD: 2.31, 95% CI: 2.01–2.61, p < 0.001 for ESKD]. However, there were no significant differences in LOS between the KT group and the kidney disease-free group   .3.5.2.p-values being greater than 0.2 in univariable regression. Adjusted linear regression analysis revealed a significant increase in hospitalization charges in the advanced CKD and ESKD group compared to the kidney disease-free group . However, no statistically significant difference was observed between the KT group and the kidney disease-free group   .3.6.We conducted a sensitivity analysis, incorporating confounders that met the following criteria: they have an association with kidney disease, they are identified as risk factors for in-hospital mortality and other adverse outcomes, and they are neither resultant outcomes of kidney disease nor factors within the causal pathway connecting kidney disease to these outcomes. The confounders incorporated into our analysis encompassed age, race, obesity, hypertension, diabetes, coronary artery disease, chronic heart failure, chronic lung disease, and chronic liver disease. The adjusted odds ratio (aOR) derived from the multivariable analysis is detailed in 4.In this study, utilizing the largest inpatient database in the United States, we provide an in-depth overview of the characteristics of patients hospitalized with COVID-19 during its 2020 peak. Encompassing over a million patients, this represents the most exhaustive comparative analysis to date. The study primarily focuses on comparing in-hospital mortality and clinical outcomes among patients with CKD, ESKD, and KT against a control cohort without any underlying kidney conditions. Our study yielded four significant findings. First, comorbidities and multimorbidity were prevalent among patients with CKD, ESKD, and KT, and were associated with increased in-hospital mortality. Furthermore, we described, for the first time to our knowledge, the distribution of comorbidities across the entire spectrum of CKD, ESKD and KT using national U.S. data. Second, the highest in-hospital mortality rate was observed in the advanced CKD group (20.6%), followed by the ESKD group (19.4%) and the KT group (12.4%), all of which were higher than the kidney disease-free group (9.3%). Third, CKD stages 3–5, ESKD, and KT were identified as independent risk factors of mortality, with CKD stage 5 having the highest adjusted odds ratio (aOR) (2.66) for mortality among all variables investigated, surpassing even ESKD. Lastly, a dose-response relationship was observed, wherein the odds of mortality, septic shock, requirement for mechanical ventilation, and vasopressors increased with the increase of CKD stages from 3 to 5.Our study underscores the potential for severe clinical outcomes due to COVID-19, with an overall 11.1% in-hospital all-cause mortality rate among patients admitted for COVID-19 in the US during the pre-vaccine era, 8.6% receiving invasive mechanical ventilation, and 1.8% requiring vasopressors. The mean hospital LOS was 7.5 days, with an average hospital charge of 79,101 US dollars. The mortality rate estimated in our study is slightly lower than the previously reported 13%–25% in published US studies . For exaIn our study, we found that advanced age, male gender, obesity, diabetes, chronic heart failure, chronic lung disease, chronic liver disease, and malignancy were associated with an increased risk of mortality, which aligns with previous reports . The comThe study also highlighted significant disparities influenced by race/ethnicity and socioeconomic status in COVID-19-related hospitalizations and fatalities. For instance, Native Americans had the highest mortality associated with COVID-19 among all ethnic groups, consistent with existing literature , 23, empThe COVID-19 pandemic has disproportionately impacted patients with kidney disease. Earlier studies have identified CKD as an independent risk factor for SARS-COV-2 infection, increased mortality, and adverse COVID-19 outcomes , 8, 26. Our analysis further indicated that patients with ESKD hospitalized due to COVID-19 exhibited a significantly elevated in-hospital all-cause mortality rate of 19.4%. ESKD was pinpointed as an independent risk factor for mortality (aOR 1.97), septic shock (aOR 2.12), mechanical ventilation (aOR 1.29), and the need for vasopressors (aOR 1.96), and correlated with an extended length of stay by an average of two additional days. Although initial data from Wuhan, China, suggested a modest impact of COVID-19 on dialysis patients, with a mortality rate of 4.7% and predominantly mild clinical symptoms without progression to severe pneumonia , subsequOur study included 4,450 hospitalized COVID-19 patients who were KT recipients, with an average age of 59 years. We observed an in-hospital all-cause mortality rate of 12.4%, which is higher than the 9.3% rate observed in the cohort without kidney disease and the 11.1% rate observed in the general population. After adjusting for confounding variables, the mortality odds for KT recipients were 1.69 times higher than for patients without kidney disease, and the odds of developing septic shock were 1.42 times higher. This is consistent with Fisher’s et al.  findingsDespite the strengths of our study, such as its large, nationwide sample size and comprehensive scope, there are several notable limitations. First, our data were extracted from an administrative database, which does not contain detailed clinical information. As a result, important information such as the cause of kidney disease, stages of CKD in the kidney allograft, the age of the transplant, and medication usage were unavailable. Additionally, the identification of clinical conditions and procedures depended on the accuracy of the diagnoses and procedure codes reported by the hospitals, making the database vulnerable to inaccuracies or missing codes. Second, due to the retrospective observational nature of this study, exposures could not be randomized. Although we employed regression analysis to adjust for confounders, the possibility of residual confounding remains. Lastly, while the findings of this study are representative of the clinical outcomes of adult patients hospitalized for COVID-19 in the United States, outcomes may differ in other settings or regions around the world.5.In conclusion, our nationwide study highlights a greater burden of multimorbidity in COVID-19 patients hospitalized with advanced CKD, ESKD, and KT, compared to those without pre-existing kidney disease. We meticulously detailed the distribution of comorbidities across all stages of CKD, ESKD, and KT, thereby providing essential insights necessary for strategizing treatment and preventive services for individuals with kidney disease, during and beyond the pandemic. Moreover, our findings indicate higher in-hospital mortality rates in patients with advanced CKD, ESKD, and KT compared to those without kidney disease. Stages 3 to 5 CKD, ESKD, and KT emerged as independent risk factors of mortality, illustrating a dose-response relationship between increasing CKD stages (from 3 to 5) and the odds of mortality and adverse outcomes. This study emphasizes the necessity for targeted interventions to mitigate the risk of adverse outcomes in the vulnerable population of patients with CKD, ESKD, and KT. It is imperative that further research be conducted to understand the long-term effects of COVID-19 on these populations and to develop strategies to optimize their care and outcomes.https://hcup-us.ahrq.gov/news/announcements/nis2020.jsp.Publicly available datasets were analyzed in this study. This data can be found at: Ethical approval was not required for the studies involving humans because approval from an Institutional Review Board was not required for this study due to its retrospective nature and the use of de-identified data. The study was conducted in strict adherence to the data-use agreements of the NIS-HCUP. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements because approval from an Institutional Review Board was not required for this study for the aforementioned reason. The study was conducted in strict adherence to the data-use agreements of the NIS-HCUP.MH conceived the study, accessed, verified the data, led the data analysis with support from AG, and led the writing of the paper. YW, SL, and AG commented on the paper, oversaw the analysis, and edited the final manuscript. All authors contributed to the article and approved the submitted version.Publication of this article was funded in part by the Temple University Libraries Open Access Publishing Fund. We sincerely appreciate the support.


Takayasu's arteritis is a rare vasculitis affecting the aorta and its branches. Disease progression can result in arterial stenosis and subsequent organ dysfunction. Estimating organ perfusion by measuring the peripheral blood pressure can be challenging because it may be altered by arterial stenosis. We report the case of a 61‐year‐old woman with Takayasu's arteritis with aortic and mitral regurgitation who presented for aortic valve replacement and mitral valvuloplasty. Peripheral arterial pressure was considered a less reliable surrogate for organ perfusion because the patient had diminished blood flow in both the lower and upper extremities. In addition to the bilateral radial arterial pressure, the blood pressure in the ascending aorta was monitored to estimate the patient's organ perfusion pressure during cardiopulmonary bypass. The initial target blood pressure was determined based on the pre‐operative baseline and modified by measurement of the aortic pressure. Cerebral oximetry using near‐infrared spectroscopy and mixed venous saturation was monitored to estimate oxygen supply‐demand balance, which helped evaluate cerebral perfusion and determine the transfusion threshold. The entire procedure was uneventful, and no organ dysfunction was observed postoperatively. Takayasu's arteritis is a rare form of chronic vasculitis involving the aorta and its branches. Disease progression can result in arterial stenosis and subsequent organ dysfunction . Women aThe anaesthetic management of patients with Takayasu's arteritis is challenging because most patients have refractory hypertension and stenosis of the aorta and/or its branches. Consequently, these patients are susceptible to organ ischaemia. Furthermore, the estimation of organ perfusion is difficult because of possible discrepancies between the peripheral blood pressure and actual organ perfusion pressure. Although several studies have described the peri‐operative management of patients with this disease , 3, to tThis report describes the successful management of a patient with Takayasu's arteritis undergoing aortic valve replacement and mitral valvuloplasty under CPB.A 61‐year‐old woman with diabetes mellitus presented with dyspnoea on exertion. Transthoracic echocardiography revealed a preserved left ventricular ejection fraction with severe aortic and moderate mitral regurgitation. The patient was scheduled for aortic valve replacement and mitral valvuloplasty.−1.Preoperatively, the patient was diagnosed with Takayasu's arteritis based on contrast‐enhanced computed tomography. Findings included multiple arterial stenoses in the brachiocephalic, left subclavian and bilateral common iliac arteries Fig. . No othe−1 midazolam 0.06 mg.kg−1 and rocuronium 0.9 mg.kg−1. After tracheal intubation, a right radial arterial line and pulmonary artery catheter (PAC) were inserted. The MAP reading in both radial arteries was nearly identical. We adopted a target MAP of > 50 mmHg to maintain blood pressure within 20% of the pre‐operative non‐invasive value. General anaesthesia was maintained using 1.5% sevoflurane and 0.4 μg.kg−1.min−1 remifentanil. Intra‐operatively, near‐infrared spectroscopy (NIRS) was used to monitor cerebral oximetry. The NIRS values were 70% bilaterally at induction, and we aimed to maintain the saturation within 20% of the baseline value. In addition, the mixed venous saturation (SvO2) was monitored with a target of > 65%.In the operating room, a left radial arterial line was inserted, showing a mean arterial pressure (MAP) of 55 mmHg. General anaesthesia was induced with intravenous injections of fentanyl 5 μg.kg−1.m−2, and the alpha‐stat strategy was used during CPB. The patient was cooled to a core temperature of 30 °C. Aortic valve replacement, mitral valvuloplasty and an ascending aorta‐to‐left axillary artery bypass with a prosthetic vascular graft were performed. After the left axillary artery was revascularised, the MAP in the left radial artery increased to 56 mmHg, while that in the ascending aorta was 65 mmHg. We retargeted the MAP of the left radial artery to > 50 mmHg. We used ephedrine and phenylephrine to manage hypotension during the procedure, in addition to 2250 ml of fluid administration with reference to central venous pressure and stroke volume variation to maintain the targeted MAP. The entire procedure was performed successfully. Three units of allogeneic red blood cells were administered intra‐operatively to maintain the targeted NIRS and SvO2 values and a haemoglobin level of > 80 g.l−1. The intra‐operative data are shown in Table Before starting CPB, we lowered the blood pressure to prevent aortic dissection and inserted a 4 Fr cannula into the ascending aorta to measure the blood pressure in this location directly. Systolic blood pressure and MAP in the ascending aorta were 120 and 63 mmHg, while those in the radial arteries were about 65 and 45 mmHg, respectively Fig. . The MAPThe patient was transferred to the ICU, and blood pressure was targeted to the left radial arterial pressure. Nicardipine was used to maintain a systolic blood pressure of < 100 mmHg to prevent haemorrhage. The target MAP remained unchanged. The patient was liberated from invasive ventilation on postoperative day 1, and their postoperative course was uneventful; no new organ dysfunction was observed during their recovery.Takayasu's arteritis presents with various symptoms due to ischaemia and systemic inflammation, including fever, dizziness, headaches, loss of pulses, pain in the extremities and dyspnoea . GuideliThe initial treatment for patients with Takayasu's arteritis is high‐dose glucocorticoids in combination with other immunosuppressive drugs such as methotrexate or azathioprine. Those patients with coronary artery disease should be considered for percutaneous revascularisation or cardiac surgery. For patients requiring surgical intervention, the type and timing of the procedure should be determined via a multidisciplinary team discussion . In our Anaesthetic management of patients with Takayasu's arteritis is challenging because most patients have refractory hypertension and stenosis of the aorta and/or its branches. Consequently, these patients are susceptible to organ ischaemia. Therefore, the most important management principles are to prevent organ ischaemia and maintain adequate perfusion. However, monitoring is not always straightforward because there may be discrepancies in blood flow between the extremities and visceral organs. The optimal strategy for monitoring should be considered based on the individual patient profile and the type of surgery planned.The appropriate location for blood pressure measurement is affected by the arterial lesions in each case. Takayasu's arteritis is classified into four types based on the location of the arterial lesions . In typeWe measured blood pressure in the bilateral radial arteries because the procedure included revascularisation of the left axillary artery, and we wished to compare the left and right blood pressures. A previous report has recommended measuring blood pressure in both the upper and lower extremities . HoweverThe optimal target blood pressure in patients with impaired peripheral perfusion is controversial. Peripheral arterial pressure may not be a reliable surrogate for organ perfusion if the stenosis is present in the arteries perfusing the upper and lower extremities. Under these circumstances, targeting the pre‐operative blood pressure is reasonable. During cardiac surgery, direct measurement of aortic pressure is feasible, which can help determine the target blood pressure. In our case, the target blood pressure in ICU was modified with reference to the intra‐operative aortic pressure to prevent postoperative haemorrhage.Tissue oxygenation monitoring is helpful in patients at risk for ischaemia. In patients undergoing cardiac surgery, the use of NIRS for monitoring oxygenation is encouraged to decrease the incidence of neurological injuries . Abnorma2 which reflects the whole‐body oxygen supply–demand balance. During CPB, SvO2 can be measured from the venous cannula. A drop in the SvO2 and NIRS values triggered transfusion of red blood cells in our patient. Monitoring SvO2 and NIRS is effective for preventing organ damage during cardiac surgery [Monitoring the oxygen supply–demand balance as an indirect parameter for assessing the adequacy of organ perfusion is reasonable. Although the use of PAC is controversial, particularly in type IV Takayasu's arteritis, PAC placement enables the determination of SvO surgery , 8. Ther−1 and > 1 ml.kg−1.h−1, respectively [Abdominal organ ischaemia is a crucial concern in patients with stenosis of the abdominal vasculature. We monitored serum lactate levels and urine output with targets of < 4 mmol.lectively . The detectively , and sub2 and NIRS can guide optimal management.In summary, we describe the successful anaesthetic management of a patient with Takayasu's arteritis undergoing open heart surgery. Ensuring organ perfusion in patients with stenosis of arteries to all extremities is challenging. Direct measurement of aortic pressure and monitoring of SvO


M) maneuver in isoflurane-anesthetized dogs undergoing acute blood volume manipulations. The study also examined the simultaneous effect of performing the PLRM on dynamic variables such as stroke distance variation (SDV), peak velocity variation (PVV), and stroke volume variation (SVV).This study investigated the performance among four cardiac output (CO) monitoring techniques in comparison with the reference method intermittent pulmonary artery thermodilution (iPATD) and their ability to diagnose fluid responsiveness (FR) during a modified passive leg raise , transesophageal echocardiography (TEECO), arterial pressure waveform analysis (APWACO), and electrical cardiometry (ECCO). Additionally, SDV, PVV, and SVV were recorded. Intermittent pulmonary artery thermodilution (iPATDCO) measurements were also recorded before, during, and after the PLRM maneuver. A successful FR diagnosis made using a specific test indicated that CO increased by more than 15% during the PLRM maneuver. Statistical analysis was performed using one-way analysis of variance for repeated measures with post hoc Tukey test, linear regression, Lin’s concordance correlation coefficient (ρc), and Bland–Altman analysis. Statistical significance was set at p < 0.05.The dogs were anesthetized with propofol and isoflurane and mechanically ventilated under neuromuscular blockade. After instrumentation, they underwent a series of sequential, nonrandomized steps: Step 1: baseline data collection; Step 2: removal of 33 mL kgp < 0.001) during hemorrhage and an increase in CO after blood re-transfusion and colloid infusion (p < 0.001) compared with baseline. During hemorrhage, CO increases with the PLRM maneuver were as follows: 33% for iPATD (p < 0.001), 19% for EC (p = 0.03), 7% for APWA (p = 0.97), 39% for TEE (p < 0.001), and 17% for ED (p = 0.02). Concurrently, decreases in SVV, SDV, and PVV values (p < 0.001) were also observed. The percentage error for TEE, ED, and EC was less than 30% but exceeded 55% for APWA. While TEECO and ECCO slightly underestimated iPATDCO values, EDCO and APWACO significantly overestimated iPATDCO values. TEE and EC exhibited good and acceptable agreement with iPATD. However, CO measurements using all four techniques and iPATD did not differ before, during, and after PLRM at baseline, blood re-transfusion, and colloid infusion.All techniques detected a reduction in CO (M maneuver, while the performance of APWA was unacceptable and not recommended. SVV, SDV, and PVV could be used to monitor CO changes during PLRM and acute blood volume manipulations, suggesting their potential clinical utility.iPATD, EC, TEE, and ED effectively assessed FR in hypovolemic dogs during the PLR Amidst such hemodynamic instability, the cornerstone of treatment lies in fluid therapy, which ameliorates venous return, cardiac preload, cardiac output (CO), and tissue oxygen utilization . Over thHistorically, passive leg raising was employed as an emergency measure during acute circulatory crises or hemorrhagic events in human patients. This simple bedside test shifts a patient from a semi-recumbent to a horizontal trunk position, raising the lower limbs at 30–45° , 16, 17.M) maneuver was developed and demonstrated in anesthetized pigs (CO). While iPATDCO is often regarded as the “gold standard” for veterinary research  or noninvasive  methods that provide continuous, reproducible CO measurements remain unvalidated for assessing PLRM in animals.Until recently, only limited literature has been available on this maneuver in veterinary species. Recognizing inter-species variations in pelvic limb conformation, size, and blood volume distribution, a modified passive leg raise  evaluating the ability of EDCO, TEECO, APWACO, and ECCO to identify more than 15% iPATDCO increase, indicative of FR; and (3) investigating the correlation between EC and ED-derived dynamic variables like SVV, stroke distance variation (SDV), and peak velocity variation (PVV) with iPATDCO measurements during PLRM analysis. The following hypotheses were proposed: (1) strong and acceptable agreement will be observed between EDCO, TEECO, APWACO, ECCO, and iPATDCO; (2) all test methods will detect more than 15% increase in CO signifying FR; and (3) SVV, SDV, and PVV will demonstrate correlation with iPATDCO readings during PLRM.The objectives of the present study were as follows: (1) gaging the agreement between invasive iPATD2.2.1.This prospective, nonrandomized, crossover experimental study involving dogs was reviewed and granted approval by the Institutional Animal Care and Use Committee of Virginia Tech University (protocol number 20-235).2.2.M maneuver in pigs . An effect size greater than 0.8, derived from these animal studies, indicated a substantial difference effect. The dogs were individually housed in kennels under controlled temperature conditions and were acclimatized to the laboratory environment for 2 weeks. Food was withheld for 12 h before the experimental procedures, while access to water was maintained. A physical examination was conducted for all dogs on the day of general anesthesia.Six adult, sexually intact male, healthy Beagles aged 13–16 months and weighing 10.5 ± 0.3 kg (mean ± standard deviation), bred specifically for research, were included in this investigation. A comprehensive physical examination, complete blood count, and serum chemistry panel were conducted on all dogs. The dogs were deemed healthy as no abnormalities were observed in the blood test results or during the cardiopulmonary examination. Following an extensive review of pertinent literature on human studies detecting a positive CO response to the passive leg raising test , 12–15,  in pigs , and an 2.3.https://www.randomizer.org/. On the designated study day, intravenous (IV) catheterization of the right cephalic vein was performed. This was followed by preoxygenation using a facemask to administer oxygen at a flow rate of 4Lmin−1. General anesthesia was induced facemask to administer IV propofol , titrated until orotracheal intubation could be accomplished with an appropriately sized, cuffed endotracheal tube. After securing the airway, the dog was connected to an anesthesia workstation integrated with a ventilator  through a circle anesthetic breathing circuit. Anesthetic maintenance was achieved using isoflurane  in oxygen (1–2 L min−1), targeting an end-tidal concentration of isoflurane between 1.5 and 1.7%. The dogs were placed in a right lateral recumbent position. End-tidal isoflurane concentration and end-tidal carbon dioxide concentration were continuously monitored using a calibrated side-stream infrared gas analyzer linked to a multiparameter monitor . Using the same monitor, Standard lead II electrocardiogram, heart rate (HR), esophageal temperature, and peripheral hemoglobin oxygen saturation were also recorded at 5-min intervals throughout the experiment, as part of routine anesthetic monitoring and record keeping. Body temperature was maintained between 36.7°C and 38.1°C during anesthesia using a forced-air warming blanket and a circulating water-heating system.The determination of the order in which each dog underwent the experiment on a given day was randomized using a tool available at: −1) and connected to a three-way Luer lock stopcock. The transducer was positioned at a height approximating the right atrium location. Neuromuscular paralysis was initiated to prevent patient-ventilator dyssynchrony, with an initial IV dose of 0.4 mg kg−1 rocuronium , followed by a continuous rate infusion of 0.4 mg kg−1 h−1. Supramaximal stimulation of the common peroneal nerve was generated using a peripheral nerve stimulator  to assess the effectiveness of the blockade. Mechanical ventilator settings were adjusted to a volume-controlled mode set at 12 mL kg−1, with an inspiratory-to-expiratory ratio ranging from 1:2 to 1:3, and the respiratory rate was adjusted to maintain end-tidal carbon dioxide concentration between 30 and 40 mmHg. Throughout the experiment, no maintenance crystalloid fluids were administered to prevent potential blood volume changes that could skew hemodynamic data.Arterial catheterization of the dorsal pedal artery was performed to measure invasive systolic, diastolic, and mean arterial blood pressures. The catheter was connected to a disposable pressure transducer through non-compliant short tubing (15.24 cm) filled with heparinized saline  electrocardiographic electrodes with adhesive patches were positioned. Two electrodes were placed on the left aspect of the neck (at the level of the common carotid artery), and the other two electrodes were attached to the left thoracic area (at the level of the T8-T13 vertebrae), as previously described in published studies  and an external communication cable, facilitating efficient data management. The ICON monitor employed the Electrical Velocimetry™  physiological model to assess changes in thoracic electrical bioimpedance during cardiac systole, thereby capturing volumetric changes in the aorta. Detailed information on the physiology and algorithmic calculations used for ECCO derivation can be found in other studies  for continuous hemodynamic data monitoring, including EC studies –29. Thes studies , 29. Addmax and SVmin are the maximum and minimum stroke volume (mL), respectively, over one respiratory cycle.where SVCO (L min−1) and SVV (%) data were recorded as an averaged value over a 1-min interval, as configured in the internal database settings.At each data point, the EC2.5.CO, a 3-mL chilled (2–5°C) bolus of 0.9% sodium chloride solution was injected at the end of the expiration phase for <3 s through the proximal injectate port. The appropriate computation constant was selected on the CO monitor screen based on the catheter model, injectate volume, and temperature, as advised by the manufacturers. The catheter thermistor measured core body temperature as well as the difference in blood temperature downstream, which the CO monitor converted into a dilution curve through a modified Stewart-Hamilton equation. At each data timepoint, a CO reading represented the mean of three consecutive measurements within a 10% variation range. The injections were manually executed consistently by the same individual, with a minimum interval of 90 s between each injection.Subsequently, the dogs were positioned in dorsal recumbency and maintained in this posture throughout the course of the experiment. Areas of approximately 4 × 4 cm over the left and right jugular veins were clipped and prepared with aseptic techniques. A 5 Fr 13-cm double-lumen central venous catheter  was introduced into the left jugular vein to draw a consistent blood volume during acute hemorrhagic shock and to facilitate blood transfusion and colloid solution administration during correction of hypovolemia. Concurrently, a 6 Fr 8.5 cm hemostasis introducer  was positioned in the right jugular vein, through which a 5 Fr 75 cm pulmonary artery Swan Ganz catheter  was inserted. Both the proximal and distal ports of the pulmonary artery catheter were connected to additional disposable pressure transducers. These transducers were calibrated and positioned in a manner analogous to the arterial pressure transducer. The pulmonary artery catheter was cautiously advanced through the right atrium and right ventricle until its distal port was situated within the pulmonary artery. The positioning accuracy was affirmed by monitoring characteristic pressure waveforms and values, using the CO monitor . Measurement of the pulmonary artery wedge aided the assessment of left ventricular filling and left atrial pressure, pertaining to a concurrent independent research study. For the determination of iPATD2.6.−1 IV bolus of lithium chloride (LiDCO Ltd.) was injected through the central venous catheter in the left jugular vein. The concentration of lithium was measured by a lithium ion-sensitive electrode sensor connected to a three-way stopcock on the indwelling arterial catheter  was determined using the following formula  employed the PulseCO algorithm based on pulse power analysis to continuously determine real-time CO values. This algorithm relied on arterial pressure waveforms and lithium dilution for intermittent calibration. To calibrate, a 0.006 mmol kgcatheter , 31. Blo formula , 33:CO  was automatically calculated as the product of stroke volume and heart rate (HR), continuously monitored and recorded by the LiDCOplus monitor. At each data point, the recorded value for PulseCO was an average over a 1-min interval.The PulseCO algorithm integrated a time-based autocorrelation and transformed the arterial waveform into a volume-time waveform, accounting for compliance and aortic volume. The root mean square method, independent of waveform morphology, estimated the effective value  of this volume waveform, calculating the “nominal stroke volume.” This was then scaled to an “actual stroke volume” using a patient-specific calibration derived from the lithium dilution CO measurement, considering the individual’s age, height, and weight –35. The 2.7.π × (LVOT diameter/2)2. To minimize sources of error, given that LVOTArea was not anticipated to vary significantly over the study duration, the LVOTArea was measured only once for each dog  was inserted into the esophagus, reaching a mid-esophageal position. The image plane was digitally rotated forward until a mid-esophageal long-axis view was obtained , 37. Theeach dog . For eac2.8.CO values. Therefore, the LVOTArea measured using TEE was used to calculate EDCO (L min−1) with the following formula, referencing a study conducted in canines , equipped with a 4.02-MHz continuous Doppler ultrasound emitting probe , was utilized to estimate stroke distance (cm), SDV (%), and PVV (%). The probe, measuring 120 cm in length, featured 6 depth markers to aid in guiding the insertion depth and ensuring proper probe placement. Following lubrication with aqueous gel, the probe was introduced into the oral cavity alongside the existing TEE probe and gently advanced into the esophagus. Further insertion continued until the probe tip reached a position approximately aligned with the fifth to sixth thoracic vertebra, coinciding with peak aortic blood flow. Once a characteristic triangular waveform, accompanied by a distinct maximal pitch Doppler “whip crack” sound, was visualized, the probe was stabilized in that position to confirm peak blood flow from the descending thoracic aorta. The working principle of this method, Doppler waveform analysis, and the derived variables have been recently documented in canine studies . The Car canines :During each mechanical breath delivered by the ventilator, SDV and PVV were automatically computed by an internal software program, and the results were continuously displayed on the CardioQ-EDMV+ monitor screen . Before 2.9.−1 of circulating blood volume from the left jugular catheter over a 15-min period (induction of hypovolemia). The removed blood was stored in blood collection bags coated with citrate phosphate dextrose adenine as an anticoagulant. Step 3 encompassed autologous blood transfusion through the left jugular catheter over 15 min using an infusion pump (to restore lost blood volume); Step 4 comprised the administration of a 20 mL kg−1 IV bolus of 6% hydroxyethyl starch  as a colloid solution into the left jugular vein over a 15-min period (induction of hypervolemia). After each step, a 10-min period was provided for hemodynamic stabilization. The purpose of subjecting the dogs to various blood volume phases was to induce significant CO changes during each step, creating a physiological context to demonstrate and simultaneously assess the presence or absence of FR using the various CO techniques.After completing the instrumentation process and confirming the proper functioning of all CO equipment, each dog underwent a sequential nonrandomized study design to induce acute alterations in blood volume. The experiment followed a four-step sequence : Step 1 M), as depicted in M maneuver  was randomized (using https://www.randomizer.org/), iPATDCO measurements were consistently performed after acquiring CO data from the other CO techniques. This sequencing was designed to prevent the fluid volume from multiple 0.9% saline injections for iPATDCO potentially affecting data from the test methods. Moreover, preserving the required sodium concentrations for LiDCOplus CO calibration in determining APWACO values was essential, which could be influenced by the administration of 0.9% saline injections. Calibration of CO by the LiDCOplus monitor for estimating APWACO values was conducted before Step 1, Step 3, and Step 4. The data recorded under each step for studying the effects of the PLRM maneuver  are summarized as follows:To ensure unbiased data collection, each researcher was assigned to collect data from a specific CO monitoring technique and remained unaware of the data recorded by others. One researcher was responsible for altering body positions during the PLRCO and SVV values.ICON electrical cardiometry monitor measured ECCO values.LiDCOplus monitor with the PulseCO algorithm for pulse power analysis- measured APWACO measurements.Transesophageal echocardiography probe measured velocity time integral and LVOTArea to calculate TEECardioQ-EDMV+ esophageal Doppler monitor measured stroke distance, SDV, and PVV values.CO values.Carescape B850 intermittent pulmonary artery thermodilution monitor measured iPATD2.11.2O negative pressure during spontaneous inspiration were taken as indicators of recovery from rocuronium-induced neuromuscular block. The pulmonary artery, jugular, and arterial catheters were removed with careful application of external pressure on the catheter sites to prevent bleeding and hematoma formation. Anesthetic recovery was marked by discontinuing the isoflurane vaporizer. Following extubation, all dogs received 0.3 mg kg−1 IV methadone , and they were transferred to individual kennels. Cardiopulmonary parameters were monitored, and catheter sites were periodically observed over the subsequent 96 h. Pain scores were assessed using the Glasgow composite pain scale short form, along with physical examination and noninvasive blood pressure measurements. Additional administration of 0.25 mg kg−1 IV methadone was considered if needed based on pain scores.Subsequent to the final data collection, rocuronium administration was ceased. A train-of-four ratio ≥0.9, consistent spontaneous ventilation, and generation of more than 3 cmH2.12.Post hoc Tukey adjustment was applied for multiple pairwise comparisons. Student t-tests were also conducted for pairwise comparisons, with significance set at p < 0.05 for all analyses. According to the definition of FR  for each CO measurement method  was assessed using the Shapiro–Wilk and D’Agostino-Pearson tests. All variables were determined to be normally distributed and are presented as mean ± standard deviation. A one-way analysis of variance for repeated measures was employed to compare differences between the sequential steps during acute blood volume manipulation for all variables, with the Greenhouse and Geisser correction applied when sphericity assumptions were not met. on of FR –5, the tCO and CO values for each of the other methods  was expressed as a percentage of the average CO values between iPATDCO and the specific method. This relative bias was represented as a percentage of average CO values, utilizing a formula previously reported  proposed in the literature  were analyzed using linear regression, and concordance was assessed using Lin’s concordance correlation coefficient (ρc), where perfect concordance equated to a value of 1  method (CO) depended on the magnitude of the original measurement, a BA analysis for nonuniform differences was performed, and the bias was regressed linearly against the average bias. The distance from the center indicated the absolute values of the mean change in ([∆COPATD+ ∆COEC]/2), while the angle with the horizontal  indicated disagreement. A good trend was evident when data were situated within 10% of mean CO values. Commercial statistical software  was utilized for all analyses, with BA and polar plots generated using available software The relationships between the reference method iPATDlue of 1 . Agreeme) method , and a p) method , 44. In 3.p = 0.51), time spent during hemorrhage (p = 0.46), time spent during blood transfusion (p = 0.89), and colloid administration (p = 0.66) among the dogs.The anesthetic induction, maintenance, and recovery phases proceeded without adverse events for all dogs. In each case, iPATD instrumentation and placement of the thermodilution catheter were successfully executed without any reported complications. No missing data were noted for iPATD, EC, APWA, TEE, and ED. The experimental procedures were completed successfully across all dogs. The dogs maintained normothermia throughout the anesthetic period (37.2 ± 0.6°C). No discernible differences were noted in total anesthesia time  in hemorrhage Pre-PLRM CO values were detected by iPATD, EC, APWA, TEE, and ED. Following blood transfusion and colloid infusion, Pre-PLRM CO values were notably higher (p < 0.001) than baseline measurements, consistent across all test methods, including iPATD. Throughout baseline, blood transfusion, and colloid infusion, iPATDCO measurements displayed no disparity between the Pre-PLRM, PLRM, and Post-PLRM readings. This trend was mirrored in ECCO, APWACO, TEECO, and EDCO measurements. During blood volume depletion, iPATDCO showed an approximately 33% increase during the PLRM maneuver as compared to Pre-PLRM CO measurements. When evaluating the test methods, EC, APWA, TEE, and ED identified an approximate increase in PLRM CO values of 19% (p = 0.03), 7% (p = 0.97), 39% (p < 0.001), and 17% (p = 0.02), respectively. Thus, alongside iPATD, only EC, TEE, and ED could successfully diagnose FR in response to the maneuver in hypovolemic dogs. Derived dynamic variables from EC (SVV) and ED (SDV and PVV) accurately tracked changes in CO values resulting from acute blood volume manipulation (p < 0.001) compared with baseline. Following volume replacement with blood and colloids, these variables returned to baseline levels. However, no differences were observed between Pre-PLRM, PLRM, and Post-PLRM readings for these variables during Steps 1, 3, and 4. By contrast, during hypovolemia, the maneuver led to a significant decrease in SVV, SDV, and PVV (p < 0.001) compared with Pre-PLRM values. Returning the abdomen and legs to the horizontal position significantly increased these values, moving them closer to Pre-PLRM readings (p < 0.001).Compared with baseline Pre-PLRpulation . CommencM, PLRM, and Post-PLRM timepoints, during baseline, hemorrhage, autologous blood transfusion, and colloid infusion. Thus, 12 pairs of CO comparisons between iPATD and the four test methods were collected for each dog, amounting to 72 pairs per test method across all six dogs. Percentage error, relative bias, LOA, and Lin’s concordance correlation coefficient for all test methods across all time points are presented in CO measurements, TEECO .For each dog, pairs of CO measurements were obtained using iPATD and EC, APWA, TEE, and ED techniques at Pre-PLRs, TEECO  and ECCOEECO . Contrarily, the trending ability of APWACO was poor, with >50% of data points located outside the limits of good agreement, as depicted in the polar plot  and 28% (dogs), respectively. In instances of euvolemia and hypervolemia, marginal variations in CO were observed, indicating fluid nonresponsiveness. Remarkably, the percentage CO increase attributed to PLRM surpassed the conventional 15% benchmark from human studies  and ED (such as SDV and PVV) exhibited close alignment with fluctuations in iPATDCO values stemming from abrupt blood volume shifts and responses to the PLRM maneuver. This correspondence harmonizes with previously reported canine literature  between CO readings influenced by the test and those by fluid administration. The optimal threshold mean was a CO elevation of more than 10 ± 2%, reflective of test performance. Across multiple clinical trials , reported pooled sensitivity and specificity values of 89.4 and 91.4%, respectively, based on the analysis of 351 fluid boluses. The pooled area under the curve stood at 0.95, with the prediction threshold for fluid responsiveness ranging from 8 to 15%. The alterations in CO resulting from the passive leg raise test correlated well with the CO increase facilitated by fluid infusion, effectively distinguishing between fluid responders and nonresponders . Correspl trials –15, primM maneuver.Minimally invasive TEE not only delivers precise, swift, and reliable CO measurements but also assesses derived parameters such as respiratory variations in superior and inferior vena cava diameter, maximal Doppler velocity in the LVOT, left ventricular ejection fraction, LVOT velocity–time integral, and ventricular end-diastolic area ratio. These parameters have demonstrated utility in investigating the effects of the passive leg raise test within human medicine . While TCO values, despite the percentage error remaining within acceptable bounds, this method consistently exhibited an overestimation of iPATDCO measurements and displayed lower data reproducibility. Notably, the precision of measuring descending aortic blood velocity is significantly influenced by the alignment between the Doppler ultrasound beam and blood flow direction, termed the angle of insonation  provides continuous CO measurements grounded in a human nomogram derived from patient age, height, and weight, correlating with the relationship between descending aortic blood velocity and iPATDCO values , iPATDCO measurements and variables such as SVV, SDV, and PVV values reverted to those recorded prior to the maneuver (Pre-PLRM).Cardiac preload hinges upon the pressure gradient between mean systemic filling pressure and the right atrium, alongside vascular resistance. A considerable pressure gradient coupled with lower right atrial pressure corresponds to higher preload. Mean systemic filling pressure propels forward flow toward the right atrium, influenced by global blood volume and vascular compliance , 65. A sM maneuver in pigs (CO increase of ≈33% observed in our study during hypovolemia corroborates: (1) significant recruitment of unstressed blood volume from the pelvic limb and caudal abdomen venous reservoirs; (2) substantial conversion of unstressed blood to stressed blood by PLRM; and (3) preload responsiveness exhibited by both ventricles. The angle of inclination used for the PLRM maneuver in our study was consistent with the established standard in dogs  were aligned with the canine study, which demonstrated key hemodynamic changes within this timeframe. Continuous measurement of cardiovascular variables such as stroke distance, SDV, PVV, SVV, and ECCO was maintained throughout the 5-min period. Based on data evaluation, we believe that the PLRM maneuver induces a stable hemodynamic state lasting at least 5 min, although it remains unclear whether, after this period, the heart gradually adjusts to the new volume status or the effects start to diminish, potentially complicating their capture.The intensity of the hemodynamic response triggered by the passive leg raise test hinges on the extent to which unstressed volume from the lower body’s venous reservoir is redirected toward the cardiac ventricles, manifesting as a significant rise in venous return and CO. In human patients, this test can be executed using two methods: (1) beginning from a 45° semirecumbent position, then lowering the head and upper torso to lie supine while simultaneously elevating the legs at a 45° angle; and 2) initiating from a supine  position and elevating the legs to a 30° to 45° angle . Upon co initiati in pigs  and dogs in pigs  is undis in dogs . In acco in dogs , 17. DatIn the context of fluid administration decision-making, a pivotal question arises: does preload responsiveness invariably correlate with fluid resuscitation, while nonresponsiveness mandates fluid avoidance? Changes in cardiac contractility and afterload not only shift the Frank-Starling curve but also impact cardiac performance for a given preload. As a result, the ventricle does not operate on a single Frank-Starling curve; rather, a family of curves exists, characterized by inotropy and afterload , 5. ClinM maneuver, as indicated by human studies investigating the passive leg raise test  arrhythmias; (2) hemodynamic collapse due to trauma; (3) absolute hypovolemia; (4) sepsis; or (5) admission to intensive care units, enabling repeated FR assessment without the risk of inducing pulmonary edema or cor pulmonale in potential fluid nonresponders.Several factors may influence the response to the PLRise test , 12–15. rtension , 17. WhiM and the responsiveness of the tested CO methods. If hypervolemia preceded hypovolemia, crossover effects would significantly affect hemodynamics and our study data. The minimally invasive or noninvasive CO measurement techniques  were selected based on current literature on CO monitoring in canines. It is acknowledged that while these techniques are less invasive and easy to learn, they may be costly for clinical practices and not universally available. Hence, other CO monitoring methods such as transpulmonary thermodilution, bioreactance, transpulmonary ultrasound dilution, and partial carbon dioxide rebreathing should be evaluated during PLRM for their potential applicability in clinical settings. While integrating EC, ED, and APWA into veterinary species, careful scrutiny is needed regarding the mathematical models’ application based on human data for animals. The study involved healthy canines weighing approximately 10 kg placed in dorsal recumbency. Further clinical exploration is imperative to demonstrate the application of these CO measurement techniques during PLRM in critically ill canine patients, encompassing different sizes, breeds, limb conformations, relative hypovolemia, and septic shock.Our study has several limitations. The small sample size is a notable constraint. The stepwise approach for acute blood volume manipulation was not randomized; its fixed sequence was crucial for detecting FR by PLR5.M response evaluation in anesthetized healthy dogs undergoing acute blood volume manipulation. TEE, EC, and ED effectively diagnosed FR in hypovolemic dogs during this maneuver by detecting CO increases of >15%. Percentage error for TEE, ED, and EC fell within acceptable ranges, whereas it exceeded 55% for APWA. Moreover, TEE, EC, and iPATD exhibited good agreement, suggesting potential clinical applicability. Also, TEECO, ECCO, and EDCO displayed a satisfactory trending pattern across the range of CO values in our study dogs. Lin’s concordance was the highest for TEE and EC, followed by ED, and lowest for APWA. Further studies are essential to validate the constancy of TEE, EC, and ED performance across diverse clinical canine populations when applied during this maneuver.This study represents one of the first exploratory efforts to assess minimally invasive or noninvasive CO measurement techniques potentially substituting the invasive gold standard iPATD during PLRThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The animal study was approved by Virginia Tech University-Institutional Animal Care and Use Committee (protocol number 20-235). The study was conducted in accordance with the local legislation and institutional requirements.VP: conception and study design, funding acquisition, execution and supervision of the study, animal care and management, training for the selected cardiac output techniques, data collection, data interpretation, original manuscript draft preparation, and artwork. NH-G and GM: data collection, review, and editing during manuscript preparation. SS: statistical analysis, data interpretation, review and editing during manuscript preparation, and figures for data presentation. All authors contributed to the article and approved the submitted version.


Resistance is the ratio between MAP and mean blood flow. Resistance is contributed by the arterial vessels beyond the site of the BP measurement towards the periphery. These include small arteries (lumen diameter 100 to 400 microns) that branch into arterioles (<100 microns). Stiffness, in the present context, is the ratio between pressure change and the corresponding relative change in arterial volume . PP, the mean arterial pressure change during the early systole, is a widely accepted correlate of stiffness x[heart rate]) multiplied by resistance. Therefore, a persistent elevation of resistance, e.g., due to increased SNA, requires higher MAP to preserve the blood supply, which occurs in arterial hypertension. A recently reported phenomenological model enables the determination of resistance and stiffness from 24-h ambulatory BP (24hABP) measurements [Blood pressure (BP) is the driving force providing blood flow to the body tissues, via the arterial system, in an attempt to meet the local need for gas and nutrient exchange via the capillaries. These needs vary over a 24-hour period with physiological activities and environmental changes, and are affected by age and other demographic characteristics. The mechanical properties of the arterial system are known determinants of BP. It may be clinically informative to graphically present mean BP of individuals, with domains representing ranges of arterial properties, age and BP control status. For the purpose of the present Comment, systolic BP (SBP) and diastolic BP (DBP) are, respectively, the mean measured values of the maximum and minimum arterial pressure waveforms generated during the heart cycle, in response to the left-ventricular ejection of the stroke volume. The difference between SBP and DBP (SBP-DBP) is the mean pulse pressure (PP) that represents the pulsatile part of the arterial pressure, and the mean arterial pressure (MAP), defined by DBP + PP/3. The two main mechanical properties of the arterial system defined urements ; stiffneurements . The welurements . Figure urements , and incIn this issue Li et al.  presente